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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Activated PI3K Delta Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="Activated PI3K Delta Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2025/01/30">
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<meta name="citation_author" content="Keith Sacco">
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<meta name="citation_author" content="Gulbu Uzel">
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<meta name="citation_keywords" content="Activated Phosphoinositide 3-Kinase Delta (PI3Kδ) Syndrome">
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<meta name="citation_keywords" content="APDS">
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<meta name="citation_keywords" content="p110δ-Activating Mutation Causing Senescent T Cells, Lymphadenopathy, and Immunodeficiency Disease">
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<meta name="citation_keywords" content="PASLI Disease">
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<meta name="citation_keywords" content="PI3K Disease">
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<meta name="citation_keywords" content="PASLI Disease">
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<meta name="citation_keywords" content="Activated Phosphoinositide 3-Kinase Delta (PI3Kd) Syndrome">
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<meta name="citation_keywords" content="APDS">
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<meta name="citation_keywords" content="p110d-Activating Mutation Causing Senescent T Cells, Lymphadenopathy, and Immunodeficiency Disease">
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<meta name="citation_keywords" content="PI3K Disease">
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<meta name="citation_keywords" content="Activated PI3K Delta Syndrome Type 1 (APDS1)">
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<meta name="citation_keywords" content="Activated PI3K Delta Syndrome Type 2 (APDS2)">
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<meta name="citation_keywords" content="Phosphatidylinositol 3-kinase regulatory subunit alpha">
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<meta name="citation_keywords" content="Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform">
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<meta name="citation_keywords" content="PIK3CD">
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<meta name="citation_keywords" content="PIK3R1">
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<meta name="citation_keywords" content="Activated PI3K Delta Syndrome">
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<meta name="DC.Title" content="Activated PI3K Delta Syndrome">
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<meta name="DC.Publisher" content="University of Washington, Seattle">
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<meta name="DC.Contributor" content="Keith Sacco">
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<meta name="DC.Contributor" content="Gulbu Uzel">
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<meta name="DC.Date" content="2025/01/30">
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<meta name="description" content="Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported.">
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<meta name="og:description" content="Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported.">
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class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK611655_"><span class="title" itemprop="name">Activated PI3K Delta Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: Activated Phosphoinositide 3-Kinase Delta (PI3Kδ) Syndrome; APDS; p110δ-Activating Mutation Causing Senescent T Cells, Lymphadenopathy, and Immunodeficiency Disease; PASLI Disease; PI3K Disease</div><p class="contribs">Sacco K, Uzel G.</p><p class="fm-aai"><a href="#_NBK611655_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 36 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="apds.Summary" itemprop="description"><h2 id="_apds_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported.</p><p>APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in <i>PIK3CD</i>, and APDS type 2 (APDS2) is caused by a heterozygous loss-of-function pathogenic variant in <i>PIK3R1</i>. The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The clinical diagnosis of APDS can be established in a proband based on suggestive clinical findings, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in <i>PIK3CD</i> (for APDS1) or <i>PIK3R1</i> (for APDS2) identified by molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Targeted therapies:</i> Leniolisib, a selective PI3K delta (PI3Kδ) inhibitor, has shown promise in clinical trials by directly targeting the overactive PI3Kδ signaling pathway, a hallmark of the condition, and is therefore recommended as a first-line treatment of significant lymphoproliferative disease, including lymphadenopathy and splenomegaly. Sirolimus, an inhibitor of the mammalian target of rapamycin (mTOR), is recommended for individuals with lymphoproliferative disease or organomegaly when leniolisib is unavailable; it is also used off-label due to its immunosuppressive and antiproliferative properties. Allogenic hematopoietic stem cell transplant (HSCT) is reserved for individuals with severe or treatment-refractory APDS, including progressive organ damage, recurrent refractory infections, or severe immune dysregulation unresponsive to pharmacologic therapy.</p><p><i>Supportive care:</i> Regular intravenous or subcutaneous immunoglobulin replacement therapy to prevent recurrent bacterial infections and improve immune function; long-term prophylactic antibiotics can be considered to reduce the frequency of bacterial infections; individuals with recurrent herpes simplex or herpes zoster virus can receive prophylactic acyclovir or valganciclovir. Leniolisib or sirolimus targeted therapies for lymphoproliferation. Glucocorticoids for acute management of autoimmune complications; other immunosuppressive agents for chronic management of autoimmune manifestations. Bronchodilators and inhaled steroids for chronic lung disease; pulmonary hygiene and preventative pulmonary care to decrease risk of respiratory infections. Nutritional support and dietary modifications for gastrointestinal manifestations; anti-inflammatory medications including high-dose glucocorticoids for treatment of inflammatory bowel disease (which may also improve gut function and enhance absorption of targeted therapies); consider assisted enteral/parenteral nutrition for severe cases. Developmental interventions and educational support to address developmental delays and cognitive impairments. Offer counseling to address psychosocial impacts.</p><p><i>Surveillance:</i> Annually assess infection risk (blood/sputum cultures for EBV, CMV, and HSV), immune function (immunoglobulin levels, CD4+, CD8+, B-cell subsets, response to vaccines), lymphoproliferative status (CBC, B-cell counts), autoimmunity (ANA screen, TSH, TPO), respiratory function (including pulmonary function tests), and gastrointestinal status (liver function tests); CT or MRI of the chest every three to five years; colonoscopy symptomatically as needed; liver ultrasound at baseline and every two to three years; psychiatric assessments as needed.</p><p><i>Evaluation of relatives at risk:</i> Molecular genetic testing for the APDS pathogenic variant identified in the proband is recommended for all at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Detailed clinical and laboratory evaluations to assess for possible clinical features related to APDS is recommended for family members found to have an APDS pathogenic variant.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>APDS is an autosomal dominant disorder. Approximately 80% of individuals diagnosed with APDS have an affected parent and 20% of individuals have the disorder as the result of a <i>de novo PIK3CD</i> gain-of-function variant (for APDS1) or <i>de novo PIK3R1</i> loss-of-function variant (for APDS2). Once the <i>PIK3CD</i> or <i>PIK3R1</i> pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.</p></div></div><div id="apds.GeneReviews_Scope"><h2 id="_apds_GeneReviews_Scope_"><i>GeneReviews</i> Scope</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTc"><a href="/books/NBK611655/table/apds.Tc/?report=objectonly" target="object" title="Table" class="img_link icnblk_img" rid-ob="figobapdsTc"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.Tc"><a href="/books/NBK611655/table/apds.Tc/?report=objectonly" target="object" rid-ob="figobapdsTc">Table</a></h4><p class="float-caption no_bottom_margin">Activated PI3K delta syndrome type 1 (APDS1) Activated PI3K delta syndrome type 2 (APDS2)</p></div></div></div><div id="apds.Diagnosis"><h2 id="_apds_Diagnosis_">Diagnosis</h2><p>No consensus clinical diagnostic criteria for activated PI3K delta syndrome (APDS) have been published.</p><div id="apds.Suggestive_Findings"><h3>Suggestive Findings</h3><p>APDS types 1 (APDS1) and 2 (APDS2) are characterized by a spectrum of clinical manifestations primarily involving the immune system, leading to increased susceptibility to infections, autoimmunity, and lymphoproliferation. APDS <b>should be considered</b> in probands with the following suggestive findings:</p><p>
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<b>Clinical findings</b>
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</p><ul><li class="half_rhythm"><div><b>Recurrent infections.</b> Individuals with APDS commonly experience recurrent sinopulmonary infections from early childhood. These infections include:</div><ul><li class="half_rhythm"><div>Otitis media (frequent middle ear infections that may lead to conductive hearing loss);</div></li><li class="half_rhythm"><div>Sinusitis (persistent sinus infections that are often difficult to treat);</div></li><li class="half_rhythm"><div>Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis).</div></li></ul></li><li class="half_rhythm"><div><b>Lymphoproliferation</b> is a hallmark of APDS and can present as:</div><ul><li class="half_rhythm"><div class="half_rhythm">Lymphadenopathy (often generalized and can be persistent);</div></li><li class="half_rhythm"><div class="half_rhythm">Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism);</div></li><li class="half_rhythm"><div class="half_rhythm">Nodular lymphoid hyperplasia.</div><div class="half_rhythm">Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract.</div></li></ul></li><li class="half_rhythm"><div><b>Autoimmune manifestations</b> vary widely and can include:</div><ul><li class="half_rhythm"><div>Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia);</div></li><li class="half_rhythm"><div>Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and <a href="https://www.google.com/search?sca_esv=1683a6a8d055e688&sxsrf=ADLYWILaeHxArFRX_EO_dQ7zygq7xRXCiQ:1730921892181&q=intussusception&spell=1&sa=X&ved=2ahUKEwj1wZHEusiJAxVCITQIHY6ZDgIQkeECKAB6BAgMEAE" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">intussusception</a>). Symptoms of chronic diarrhea and abdominal pain are common.</div></li></ul></li><li class="half_rhythm"><div><b>Growth delay.</b> Some individuals may experience growth delay, which can be secondary to chronic infections and autoimmune manifestations.</div></li></ul><p><b>Note:</b> The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2. Growth delay and short stature are notable features of APDS2, while gastrointestinal complications, such as chronic diarrhea and enteropathy, are also more frequently reported in APDS2 compared to APDS1. APDS2 is also associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1. Both types share B-cell abnormalities, but APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels, with increased IgM levels being common to both [<a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al 2016</a>, <a class="bibr" href="#apds.REF.oh.2021.4095" rid="apds.REF.oh.2021.4095">Oh et al 2021</a>, <a class="bibr" href="#apds.REF.maccari.2023.984" rid="apds.REF.maccari.2023.984">Maccari et al 2023</a>].</p><p><b>Laboratory findings.</b> The diagnosis of APDS types 1 and 2 can be supported by a range of laboratory findings that reflect the underlying immune dysfunction. Findings include abnormalities in immunoglobulin levels, lymphocyte populations, and specific cellular responses. It is critical to interpret these laboratory results in the context of the clinical presentation.</p><ul><li class="half_rhythm"><div>
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<b>Immunoglobulin levels</b>
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</div><ul><li class="half_rhythm"><div>Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation.</div></li><li class="half_rhythm"><div>There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections.</div></li><li class="half_rhythm"><div>Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines).</div></li></ul></li><li class="half_rhythm"><div>
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<b>Lymphocyte populations</b>
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</div><ul><li class="half_rhythm"><div>Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation.</div></li><li class="half_rhythm"><div>Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [<a class="bibr" href="#apds.REF.li.2024.102" rid="apds.REF.li.2024.102">Li et al 2024</a>].</div></li></ul></li><li class="half_rhythm"><div>
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<b>Functional assays</b>
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</div><ul><li class="half_rhythm"><div>T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished.</div></li><li class="half_rhythm"><div>A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia.</div></li></ul></li><li class="half_rhythm"><div><b>Tissue biopsy findings.</b> Critical pathologic findings in biologic specimens include nodular lymphoid hyperplasia in airway mucosal and gastrointestinal tract biopsies.</div></li></ul><p>
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<b>Imaging findings</b>
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</p><ul><li class="half_rhythm"><div>Lymphadenopathy and hepatosplenomegaly are common findings on ultrasound and computerized tomography (CT) with evidence of increased fluorodeoxyglucose uptake on positron emission tomography (PET) scans.</div></li><li class="half_rhythm"><div>Bronchiectasis and mosaic attenuation can be identified on CT chest imaging.</div></li></ul><p><b>Family history</b> is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.</p></div><div id="apds.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The <a href="#apds.Clinical_Diagnosis">clinical diagnosis</a> of APDS <b>can be established</b> in a proband based on suggestive clinical findings, or the <a href="#apds.Molecular_Diagnosis">molecular diagnosis</a>
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<b>can be established</b> in a proband with suggestive findings and a heterozygous pathogenic variant in <i>PIK3CD</i> (for APDS1) or <i>PIK3R1</i> (for APDS2) identified by molecular genetic testing (see <a href="/books/NBK611655/table/apds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobapdsTmoleculargenetictestingusedin">Table 1</a>).</p><div id="apds.Clinical_Diagnosis"><h4>Clinical Diagnosis</h4><p>The clinical diagnosis of APDS primarily relies on a constellation of suggestive findings, including clinical manifestations, laboratory findings, and imaging results. While no consensus clinical diagnostic criteria have been universally accepted at this time, the following features are strongly indicative of APDS when combined:</p><ul><li class="half_rhythm"><div>Recurrent sinopulmonary infections from early childhood</div></li><li class="half_rhythm"><div>Evidence of lymphoproliferation, such as lymphadenopathy and hepatosplenomegaly, or nodular lymphoid hyperplasia in the absence of an alternative explanation</div></li><li class="half_rhythm"><div>Autoimmune manifestations, particularly autoimmune cytopenias and inflammatory bowel disease-like symptoms</div></li><li class="half_rhythm"><div>Laboratory findings indicative of immune dysregulation, including elevated IgM levels with decreased IgG and IgA, and poor vaccine responses following T-cell-dependent immunizations (e.g. tetanus toxoid) and T-cell-independent immunizations (e.g., <i>Salmonella</i> and pneumococcal polysaccharide vaccines)</div></li></ul></div><div id="apds.Molecular_Diagnosis"><h4>Molecular Diagnosis</h4><p>The molecular diagnosis of APDS <b>is established</b> in a proband with <a href="#apds.Suggestive_Findings">suggestive findings</a> and <b>one of the following</b> identified by molecular genetic testing (see <a href="/books/NBK611655/table/apds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobapdsTmoleculargenetictestingusedin">Table 1</a>):</p><ul><li class="half_rhythm"><div>A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving <i>PIK3CD</i> (for APDS1; ~75% of affected individuals) [<a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al 2020</a>]</div></li><li class="half_rhythm"><div>A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving <i>PIK3R1</i> (for APDS2; ~25% of affected individuals) [<a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al 2020</a>]</div></li></ul><p>Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [<a class="bibr" href="#apds.REF.richards.2015.405" rid="apds.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this <i>GeneReview</i> is understood to include likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in <i>PIK3CD</i> or <i>PIK3R1</i> does not establish or rule out the diagnosis.</p><p>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see <a href="#apds.Option_1">Option 1</a>), whereas comprehensive genomic testing does not (see <a href="#apds.Option_2">Option 2</a>).</p><div id="apds.Option_1"><h5>
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<b>Option 1</b>
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</h5><p>When the phenotypic and laboratory findings suggest the diagnosis of APDS, molecular genetic testing approaches can include use of <b>single gene testing</b> or a <b>multigene panel</b>.</p><ul><li class="half_rhythm"><div><b>Single-gene testing.</b> Sequence analysis of <i>PIK3CD</i> and <i>PIK3R1</i> is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications, although no deletions or duplications of these genes have been detected in APDS to date.</div></li><li class="half_rhythm"><div><b>An immunodeficiency, inborn errors of immunity or cytopenia multigene panel</b> that includes some or all of the genes listed in <a href="/books/NBK611655/table/apds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobapdsTmoleculargenetictestingusedin">Table 1</a> and other genes of interest (see <a href="#apds.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div></li></ul><p>For an introduction to multigene panels click <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/?report=reader#app5.Multigene_Panels_FAQs">here</a>.</p></div><div id="apds.Option_2"><h5>
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<b>Option 2</b>
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</h5><p>When the diagnosis of APDS has not been considered because an individual has atypical phenotypic features, <b>comprehensive</b>
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<b>genomic testing</b> does not require the clinician to determine which gene is likely involved. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing</b> is also possible. To date, the majority of <i>PIK3CD</i> and <i>PIK3R1</i> pathogenic variants reported (e.g., missense, nonsense) are within the coding region and are likely to be identified on exome sequencing.</p><p>For an introduction to comprehensive genomic testing click <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/?report=reader#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTmoleculargenetictestingusedin"><a href="/books/NBK611655/table/apds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobapdsTmoleculargenetictestingusedin"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.molecular_genetic_testing_used_in"><a href="/books/NBK611655/table/apds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobapdsTmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Activated PI3K Delta Syndrome </p></div></div></div></div></div></div><div id="apds.Clinical_Characteristics"><h2 id="_apds_Clinical_Characteristics_">Clinical Characteristics</h2><div id="apds.Clinical_Description"><h3>Clinical Description</h3><p>Activated PI3K delta syndrome (APDS) is a rare inborn error of immunity characterized primarily by frequent infections, lymphoproliferation, and autoimmune manifestations. To date, at least 250 individuals have been identified with a pathogenic variant in <i>PIK3CD</i> (for APDS1) or <i>PIK3R1</i> (for APDS2) [<a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al 2016</a>, <a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al 2017</a>, <a class="bibr" href="#apds.REF.carpier.2018.2005" rid="apds.REF.carpier.2018.2005">Carpier & Lucas 2018</a>, <a class="bibr" href="#apds.REF.maccari.2018.543" rid="apds.REF.maccari.2018.543">Maccari et al 2018</a>, <a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al 2020</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><p>It is important to note that the severity and presence of these clinical findings can vary widely among affected individuals. Some may present with mild symptoms, while others experience severe manifestations that significantly impact quality of life. The variability within the spectrum of APDS highlights the importance of individualized care and management strategies.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTactivatedpi3kdeltasyndromefre"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_fre/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobapdsTactivatedpi3kdeltasyndromefre"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.activated_pi3k_delta_syndrome_fre"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_fre/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndromefre">Table 2. </a></h4><p class="float-caption no_bottom_margin">Activated PI3K Delta Syndrome: Frequency of Select Features </p></div></div><p><b>Sinopulmonary infections.</b> Recurrent sinopulmonary infections are nearly universal in individuals with APDS. These infections often begin in childhood and are a hallmark of the disease. Common infections include pneumonia, otitis media, and sinusitis. These infections are typically caused by both respiratory viruses and bacterial pathogens, reflecting the underlying B-cell dysfunction. Prophylactic antibiotics and immunoglobulin replacement therapy are commonly used to reduce the frequency and severity of infections.</p><p><b>Bronchiectasis.</b> Bronchiectasis is a significant complication in individuals with APDS, primarily resulting from recurrent and chronic respiratory infections. The clinical features of bronchiectasis are multifaceted and can substantially impact individuals' quality of life and clinical outcomes.</p><p>A hallmark of bronchiectasis in APDS is a chronic productive cough associated with increased frequency of respiratory infections, including pneumonia and bronchitis. These recurrent infections contribute to the progressive destruction and dilation of bronchial walls, perpetuating the cycle of infection and inflammation. Individuals often develop symptoms of obstructive lung disease, including dyspnea, wheezing, and hemoptysis.</p><p>High-resolution computed tomography (HRCT) is the imaging modality of choice for diagnosing and evaluating the extent of bronchiectasis. Typical findings on HRCT include bronchial dilatation, lack of tapering of the bronchi, and bronchial wall thickening. Chronic bronchiectasis can lead to several severe complications, including respiratory failure, group 3 pulmonary hypertension leading to cor pulmonale (right-sided heart failure secondary to lung disease).</p><p><b>Lymphoproliferation.</b> Lymphoproliferation in the context of APDS is a hallmark clinical feature characterized by the abnormal proliferation of lymphoid tissue. This may manifest as the following:</p><ul><li class="half_rhythm"><div><b>Lymphadenopathy.</b> Enlarged lymph nodes are common, often presenting as generalized lymphadenopathy. This can be extensive and may involve multiple lymph node regions.</div></li><li class="half_rhythm"><div><b>Splenomegaly.</b> Enlargement of the spleen is frequently observed, contributing to abdominal discomfort and potential hypersplenism.</div></li><li class="half_rhythm"><div><b>Tonsillar and adenoidal hypertrophy.</b> Enlargement of the tonsils and adenoids can lead to obstructive symptoms, including sleep apnea and difficulty breathing.</div></li><li class="half_rhythm"><div><b>Mucosal nodular lymphoid hyperplasia.</b> This can occur in the respiratory and gastrointestinal tracts, potentially causing airway obstruction and gastrointestinal symptoms.</div></li><li class="half_rhythm"><div><b>Hepatomegaly.</b> Liver enlargement is also noted in some affected individuals, which may be associated with portal hypertension and other complications.</div></li><li class="half_rhythm"><div><b>Malignancy risk.</b> There is an increased risk of developing B-cell lymphomas and other malignancies, which necessitates vigilant monitoring.</div></li></ul><p><b>Growth deficiency.</b> Poor growth is observed in approximately half of individuals with APDS [<a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al 2020</a>]. It is often multifactorial, resulting from chronic infections, gastrointestinal issues, and possibly metabolic demands due to lymphoproliferation and immune dysregulation. Growth delay is especially common in APDS2 [<a class="bibr" href="#apds.REF.maccari.2023.984" rid="apds.REF.maccari.2023.984">Maccari et al 2023</a>].</p><p><b>Herpes group virus infection.</b> Herpes virus infections are a significant complication in APDS, affecting up to 49% of individuals [<a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al 2017</a>]. These infections include Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella zoster (VZV), and cytomegalovirus (CMV). Chronic active viral infections are common and can lead to further complications such as lymphoproliferation and increased risk of malignancies.</p><p><b>Enteropathy.</b> Enteropathy is a significant complication of APDS, reported in up to half of affected individuals and characterized by chronic diarrhea, abdominal pain, and histologic findings such as Crohn-like colitis and nodular lymphoid hyperplasia [<a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al 2016</a>, <a class="bibr" href="#apds.REF.maccari.2018.543" rid="apds.REF.maccari.2018.543">Maccari et al 2018</a>, <a class="bibr" href="#apds.REF.qiu.2022.837" rid="apds.REF.qiu.2022.837">Qiu et al 2022</a>, <a class="bibr" href="#apds.REF.vanselow.2023a.1279652" rid="apds.REF.vanselow.2023a.1279652">Vanselow et al 2023a</a>, <a class="bibr" href="#apds.REF.rao.2024a.3092" rid="apds.REF.rao.2024a.3092">Rao et al 2024a</a>]. Enteropathy is more common in APDS2 compared to APDS1 [<a class="bibr" href="#apds.REF.maccari.2023.984" rid="apds.REF.maccari.2023.984">Maccari et al 2023</a>]. The gastrointestinal involvement contributes to malnutrition and growth deficiency.</p><p><b>Lymphoma.</b> Lymphoma is a significant concern in APDS, with an incidence of approximately 12.8% in APDS1 and up to 28% in APDS2 [<a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al 2016</a>]. The most common lymphoma type in APDS is diffuse large B-cell lymphoma. However, there is increased risk of both Hodgkin and non-Hodgkin lymphomas, which is attributed to chronic immune activation and lymphoproliferation. This necessitates vigilant monitoring and early intervention.</p><p><b>Autoimmune cytopenias.</b> Autoimmune cytopenias, such as autoimmune hemolytic anemia and immune thrombocytopenia, are common in APDS, occurring in about 19%-30% of affected individuals [<a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al 2020</a>]. These cytopenias often present later in the disease course and can be challenging to manage, requiring immunosuppressive therapies or targeted treatment with leniolisib (see <a href="#apds.Targeted_Therapies">Targeted Therapies</a>) [<a class="bibr" href="#apds.REF.schworer.2021.281" rid="apds.REF.schworer.2021.281">Schworer et al 2021</a>].</p><p><b>Autoimmune and autoinflammatory disease.</b> Autoimmune and autoinflammatory manifestations are prevalent in many affected individuals [<a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al 2017</a>]. These can include autoimmune endocrinopathy, enteropathy, arthritis, and vasculitis. At times, individuals may have already received B-cell depleting therapies (e.g., rituximab) prior to their diagnosis of APDS. This may delay the diagnosis of APDS because the hypogammaglobulinemia can be attributed to B-cell depletion caused by rituximab and the characteristic B-cell immunophenotype of APDS cannot be characterized (low naïve B cells and increased transitional B cells).</p><p>Following molecular genetic testing, the pAKT/pS6 functional assay (see <a href="#apds.Suggestive_Findings">Suggestive Findings</a>) can help characterize the immunophenotype following use of immunomodulation. To date, the pAKT/pS6 assay is available on a research basis with plans for Clinical Laboratory Improvement Amendments (CLIA) validation.</p><p><b>Neurodevelopmental delays.</b> Neurodevelopmental delays occur in approximately 19% of individuals with APDS1 and 31% with APDS2 [<a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al 2017</a>]. These can manifest as mild cognitive impairment, speech and language delays, and motor developmental delays. The exact mechanisms remain under investigation, but this underscores the need for early developmental assessments and interventions.</p><p><b>Dental manifestations.</b> APDS2 is associated with delayed tooth eruption, due to its overlap with SHORT syndrome (see <a href="#apds.Genetically_Related_Allelic_Disorde">Genetically Related Disorders</a>). This feature is not typically seen in APDS1.</p></div><div id="apds.Phenotype_Correlations_by_Gene"><h3>Phenotype Correlations by Gene</h3><p>APDS1 is caused by a heterozygous pathogenic gain-of-function variant in <i>PIK3CD</i>, and APDS2 is caused by a heterozygous loss-of-function pathogenic variant in <i>PIK3R1</i>. The key clinical differences between APDS1 and APDS2 include short stature, frequency of gastrointestinal infections, and characteristic dental findings, which are more prominent in APDS2 [<a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al 2016</a>, <a class="bibr" href="#apds.REF.oh.2021.4095" rid="apds.REF.oh.2021.4095">Oh et al 2021</a>, <a class="bibr" href="#apds.REF.maccari.2023.984" rid="apds.REF.maccari.2023.984">Maccari et al 2023</a>].</p><ul><li class="half_rhythm"><div>Growth delay and short stature are notable features of APDS2 and are more common in APDS2 than in APDS1.</div></li><li class="half_rhythm"><div>Gastrointestinal complications, such as chronic diarrhea and enteropathy, are more frequently reported in APDS2 compared to APDS1.</div></li><li class="half_rhythm"><div>APDS2 is associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1.</div></li><li class="half_rhythm"><div>APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels.</div></li></ul></div><div id="apds.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>No clinically relevant genotype-phenotype correlations have been identified to date.</p></div><div id="apds.Penetrance"><h3>Penetrance</h3><p>Penetrance in APDS is believed to approach 100%. However, there is considerable clinical variability, with presentations ranging from nearly asymptomatic with mild laboratory findings to severe manifestations of the disease [<a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al 2020</a>].</p></div><div id="apds.Prevalence"><h3>Prevalence</h3><p>The estimated prevalence of APDS is around one in one million [<a class="bibr" href="#apds.REF.vanselow.2023a.1279652" rid="apds.REF.vanselow.2023a.1279652">Vanselow et al 2023a</a>, <a class="bibr" href="#apds.REF.lougaris.2024.103" rid="apds.REF.lougaris.2024.103">Lougaris et al 2024</a>].</p></div></div><div id="apds.Genetically_Related_Allelic_Disorde"><h2 id="_apds_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>Other phenotypes associated with germline pathogenic variants in <i>PIK3CD</i> and <i>PIK3R1</i> are summarized in <a href="/books/NBK611655/table/apds.T.allelic_disorders_associated_with/?report=objectonly" target="object" rid-ob="figobapdsTallelicdisordersassociatedwith">Table 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTallelicdisordersassociatedwith"><a href="/books/NBK611655/table/apds.T.allelic_disorders_associated_with/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobapdsTallelicdisordersassociatedwith"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.allelic_disorders_associated_with"><a href="/books/NBK611655/table/apds.T.allelic_disorders_associated_with/?report=objectonly" target="object" rid-ob="figobapdsTallelicdisordersassociatedwith">Table 3. </a></h4><p class="float-caption no_bottom_margin">Allelic Disorders Associated with Germline <i>PIK3CD</i> and <i>PIK3R1</i> Pathogenic Variants </p></div></div><p>Mosaic postzygotic pathogenic variants in <i>PIK3CD</i> have been identified in individuals with lymphatic malformations [<a class="bibr" href="#apds.REF.wang.2021.208" rid="apds.REF.wang.2021.208">Wang et al 2021</a>].</p><p><b>Sporadic tumors</b> (including breast cancer, endometrial cancer, and glioblastoma) occurring as single tumors in the absence of any other findings of APDS frequently contain a somatic pathogenic variant in <i>PIK3R1</i> that is not present in the germline. In these circumstances predisposition to these tumors is not heritable [<a class="bibr" href="#apds.REF.tharin.2023.4467" rid="apds.REF.tharin.2023.4467">Tharin et al 2023</a>].</p></div><div id="apds.Differential_Diagnosis"><h2 id="_apds_Differential_Diagnosis_">Differential Diagnosis</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTgenesofinterestinthedifferen"><a href="/books/NBK611655/table/apds.T.genes_of_interest_in_the_differen/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobapdsTgenesofinterestinthedifferen"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.genes_of_interest_in_the_differen"><a href="/books/NBK611655/table/apds.T.genes_of_interest_in_the_differen/?report=objectonly" target="object" rid-ob="figobapdsTgenesofinterestinthedifferen">Table 4. </a></h4><p class="float-caption no_bottom_margin">Genes of Interest in the Differential Diagnosis of Activated PI3K Delta Syndrome </p></div></div></div><div id="apds.Management"><h2 id="_apds_Management_">Management</h2><p>No clinical practice guidelines for activated PI3K delta syndrome (APDS) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.</p><div id="apds.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with APDS, the evaluations summarized in <a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndromerec">Table 5</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTactivatedpi3kdeltasyndromerec"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobapdsTactivatedpi3kdeltasyndromerec"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.activated_pi3k_delta_syndrome_rec"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndromerec">Table 5. </a></h4><p class="float-caption no_bottom_margin">Activated PI3K Delta Syndrome: Recommended Evaluations Following Initial Diagnosis </p></div></div></div><div id="apds.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="apds.Targeted_Therapies"><h4>Targeted Therapies</h4><p>
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<i>In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure</i>. —ED</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTactivatedpi3kdeltasyndrometar"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_tar/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobapdsTactivatedpi3kdeltasyndrometar"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.activated_pi3k_delta_syndrome_tar"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_tar/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndrometar">Table 6. </a></h4><p class="float-caption no_bottom_margin">Activated PI3K Delta Syndrome: Targeted Treatment </p></div></div><p><b>Role of HSCT in APDS.</b> Hematopoietic stem cell transplantation (HSCT) is emerging as a curative approach for individuals with APDS, particularly those with severe or refractory disease [<a class="bibr" href="#apds.REF.okano.2019.266" rid="apds.REF.okano.2019.266">Okano et al 2019</a>, <a class="bibr" href="#apds.REF.dimitrova.2022.410" rid="apds.REF.dimitrova.2022.410">Dimitrova et al 2022</a>, <a class="bibr" href="#apds.REF.vanselow.2023b.1208567" rid="apds.REF.vanselow.2023b.1208567">Vanselow et al 2023b</a>]. It is generally reserved for individuals with severe manifestations such as recurrent, refractory infections, severe lymphoproliferation, or life-threatening complications like cytopenias or enteropathy unresponsive to conventional treatments. Additionally, HSCT can be considered in individuals whose immune dysregulation does not respond to therapies like sirolimus or leniolisib, or for those with progressive organ damage such as bronchiectasis or liver fibrosis caused by chronic immune dysregulation. However, the risk-vs-benefit ratio of HSCT has to be weighed in regard to both the extent of underlying comorbidities (which may preclude HSCT) and donor-related factors (degree of HLA matching).</p><p>Studies on HSCT outcomes in APDS provide helpful insights on the role of this treatment modality. In a cohort of 23 individuals, nine underwent HSCT with varying conditioning regimens, achieving an overall survival rate of 86.1% over 30 years despite challenges such as graft failure, viral reactivation, and treatment-related mortality [<a class="bibr" href="#apds.REF.okano.2019.266" rid="apds.REF.okano.2019.266">Okano et al 2019</a>]. Survivors showed significant improvements in immune function and clinical manifestations [<a class="bibr" href="#apds.REF.vanselow.2023b.1208567" rid="apds.REF.vanselow.2023b.1208567">Vanselow et al 2023b</a>], highlighting HSCT as a curative strategy, particularly for refractory immune dysregulation and severe lymphoproliferation, noting long-term improvements in immune function despite early complications like graft-vs-host disease. In another cohort, the two-year cumulative incidence of graft failure following first HSCT was 17% overall but 42% if mTOR inhibitors were used in the first year post-HCT, compared to 9% without mTOR inhibitors [<a class="bibr" href="#apds.REF.dimitrova.2022.410" rid="apds.REF.dimitrova.2022.410">Dimitrova et al 2022</a>].</p><p>Successful HSCT requires careful pre-transplant optimization, including stabilizing individuals with mTOR inhibitors or PI3Kδ inhibitors as bridging therapies. Conditioning regimens such as fludarabine and treosulfan are critical to balance effective engraftment with minimizing toxicity. HLA-matched donors are ideal, but haploidentical or mismatched donors have also been used with heightened risks. Post-transplant complications, including viral reactivation, graft failure, and transplant-related mortality, remain significant challenges, necessitating early identification and prompt intervention.</p></div><div id="apds.Supportive_Care"><h4>Supportive Care</h4><p>Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see <a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_tre/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndrometre">Table 7</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTactivatedpi3kdeltasyndrometre"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_tre/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobapdsTactivatedpi3kdeltasyndrometre"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.activated_pi3k_delta_syndrome_tre"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_tre/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndrometre">Table 7. </a></h4><p class="float-caption no_bottom_margin">Activated PI3K Delta Syndrome: Treatment of Manifestations </p></div></div><p><b>Role of glucocorticoids in APDS.</b> Glucocorticoids are a cornerstone in the management of gastrointestinal inflammation in APDS. By controlling inflammation, they can improve gut function and potentially enhance the absorption of other medications, such as leniolisib and sirolimus, whose bioavailability may be compromised in the presence of chronic inflammation. In the authors' experience, there have been cases of persistent diarrhea in individuals with APDS despite underwhelming endoscopic findings of inflammation or nodular lymphoid hyperplasia. In these cases, the authors have used off-label high-dose glucocorticoids, typically 1-2 mg/kg/day of methyl prednisolone but up to 5 mg/kg single pulse doses (initiating an intravenous dose, then switching to oral as appropriate) and weaning thereafter. Understandably, the use of glucocorticoids must be carefully balanced due to their potential adverse effects.</p></div></div><div id="apds.Surveillance"><h3>Surveillance</h3><p>To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in <a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec_1/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndromerec1">Table 8</a> are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsTactivatedpi3kdeltasyndromerec1"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec_1/?report=objectonly" target="object" title="Table 8. " class="img_link icnblk_img" rid-ob="figobapdsTactivatedpi3kdeltasyndromerec1"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.T.activated_pi3k_delta_syndrome_rec_1"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec_1/?report=objectonly" target="object" rid-ob="figobapdsTactivatedpi3kdeltasyndromerec1">Table 8. </a></h4><p class="float-caption no_bottom_margin">Activated PI3K Delta Syndrome: Recommended Surveillance </p></div></div></div><div id="apds.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>Molecular genetic testing for the APDS pathogenic variant identified in the proband is recommended for all at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Detailed clinical and laboratory evaluation to assess for possible clinical features related to APDS is recommended for family members who have an APDS pathogenic variant.</p><p>See <a href="#apds.Related_Genetic_Counseling_Issues"><u>Genetic Counseling</u></a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="apds.Pregnancy_Management"><h3>Pregnancy Management</h3><p>The use of sirolimus in pregnancy is not recommended due to limited safety data and potential risks to the developing fetus. Animal studies have shown sirolimus to be harmful to the developing fetus. Therefore, contraception is recommended for females of reproductive age. The same applies for leniolisib, given that animal studies have shown that it interferes with organogenesis. Both leniolisib and sirolimus should therefore be discontinued in individuals planning for pregnancy.</p><p>See <a href="https://mothertobaby.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">MotherToBaby</a> for further information on medication use during pregnancy.</p></div><div id="apds.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>There are currently two clinical trials evaluating the safety and efficacy of leniolisib in individuals age one to six years (<a href="https://clinicaltrials.gov/study/NCT05693129" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT05693129</a>) and four to 11 years old (<a href="https://clinicaltrials.gov/study/NCT05438407" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NCT05438407</a>).</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="apds.Genetic_Counseling"><h2 id="_apds_Genetic_Counseling_">Genetic Counseling</h2><p>
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<i>Genetic counseling is the process of providing individuals and families with
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information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
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make informed medical and personal decisions. The following section deals with genetic
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risk assessment and the use of family history and genetic testing to clarify genetic
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status for family members; it is not meant to address all personal, cultural, or
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ethical issues that may arise or to substitute for consultation with a genetics
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professional</i>. —ED.</p><div id="apds.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Activated PI3K delta syndrome (APDS) is inherited in an autosomal dominant manner. APDS1 is caused by a heterozygous <i>PIK3CD</i> gain-of-function variant, and APDS2 is caused by a heterozygous <i>PIK3R1</i> loss-of-function variant.</p></div><div id="apds.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Approximately 80% of individuals diagnosed with APDS have an affected parent [<a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al 2016</a>].</div></li><li class="half_rhythm"><div>Approximately 20% of individuals diagnosed with APDS have the disorder as the result of a <i>de novo PIK3CD</i> gain-of-function variant (for APDS1) or a <i>de novo PIK3R1</i> loss-of-function variant (for APDS2) [<a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al 2016</a>].</div></li><li class="half_rhythm"><div>If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical evaluation for features of APDS. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, <i>de novo</i> occurrence of an APDS-related gene cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the pathogenic variant identified in the proband).</div></li><li class="half_rhythm"><div>If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:</div><ul><li class="half_rhythm"><div>The proband has a <i>de novo</i> pathogenic variant.</div></li><li class="half_rhythm"><div>The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only.</div></li></ul></li></ul><p><b>Sibs of a proband.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the proband is affected and/or is known to have the <i>PIK3CD</i> or <i>PIK3R1</i> pathogenic variant identified in the proband, the risk to the sibs is 50%.</div></li><li class="half_rhythm"><div>Although penetrance of APDS is high among sibs who inherit a <i>PIK3CD</i> or <i>PIK3R1</i> pathogenic variant, significant intrafamilial clinical variability may be observed; heterozygous sibs may be almost clinically asymptomatic with mild laboratory findings or have severe disease manifestations [<a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al 2017</a>, <a class="bibr" href="#apds.REF.maccari.2023.984" rid="apds.REF.maccari.2023.984">Maccari et al 2023</a>, <a class="bibr" href="#apds.REF.yang.2023.e32816" rid="apds.REF.yang.2023.e32816">Yang et al 2023</a>].</div></li><li class="half_rhythm"><div>If the proband has a known <i>PIK3CD</i> or <i>PIK3R1</i> pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism [<a class="bibr" href="#apds.REF.rahbari.2016.126" rid="apds.REF.rahbari.2016.126">Rahbari et al 2016</a>].</div></li><li class="half_rhythm"><div>If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with APDS has a 50% chance of inheriting a <i>PIK3CD</i> or <i>PIK3R1</i> pathogenic variant.</p><p><b>Other family members.</b> The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, the parent's family members may be at risk.</p></div><div id="apds.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#apds.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p>
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<b>Family planning</b>
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</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bibr" href="#apds.REF.huang.2022.389" rid="apds.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="apds.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the APDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="apds.Resources"><h2 id="_apds_Resources_">Resources</h2><p>
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<i>GeneReviews staff has selected the following disease-specific and/or umbrella
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support organizations and/or registries for the benefit of individuals with this disorder
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and their families. GeneReviews is not responsible for the information provided by other
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organizations. For information on selection criteria, click <a href="/books/n/gene/app4/?report=reader">here</a>.</i></p>
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<ul><li class="half_rhythm"><div>
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<b>MedlinePlus</b>
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</div><div>
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<a href="https://medlineplus.gov/genetics/condition/activated-pi3k-delta-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Activated PI3K-delta syndrome</a>
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</div></li></ul>
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</div><div id="apds.Molecular_Genetics"><h2 id="_apds_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —</i>ED.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsmolgenTA"><a href="/books/NBK611655/table/apds.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobapdsmolgenTA"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.molgen.TA"><a href="/books/NBK611655/table/apds.molgen.TA/?report=objectonly" target="object" rid-ob="figobapdsmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Activated PI3K Delta Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figapdsmolgenTB"><a href="/books/NBK611655/table/apds.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobapdsmolgenTB"><img class="small-thumb" src="/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif" alt="Table Icon" /></a><div class="icnblk_cntnt"><h4 id="apds.molgen.TB"><a href="/books/NBK611655/table/apds.molgen.TB/?report=objectonly" target="object" rid-ob="figobapdsmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Activated PI3K Delta Syndrome (View All in OMIM) </p></div></div><div id="apds.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>PIK3CD</i> encodes phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (also called phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit delta), the p110δ subunit of PI3K. <i>PIK3R1</i> encodes phosphatidylinositol 3-kinase regulatory subunit alpha (also called phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha), the regulatory p85α unit of PI3K. Pathogenic variants identified in activated PI3K delta syndrome (APDS) typically lead to a gain of function of <i>PIK3CD</i> or loss of function of <i>PIK3R1</i> with subsequent increased expression of p110δ or decreased expression of p85α. This leads to hyperactivation of the PI3K-AKT-mTOR signaling pathway. This hyperactivation alters normal lymphocyte development and function, leading to the immunodeficiency observed in APDS. Specifically, it causes an increase in transitional B cells and a reduction in naïve B and T cells. This dysregulation contributes to both the immunodeficiency and the autoimmune manifestations seen in affected individuals.</p><p>
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<b>Mechanism of disease causation</b>
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</p><ul><li class="half_rhythm"><div><i>PIK3CD</i> (associated with APDS1). Gain-of-function pathogenic variants that enhance the enzymatic activity of the p110δ protein, a catalytic subunit of PI3K</div></li><li class="half_rhythm"><div><i>PIK3R1</i> (associated with APDS2). Loss-of-function pathogenic variants affecting the regulatory subunit p85α of PI3K, altering PI3K signaling pathways</div></li></ul></div></div><div id="apds.Chapter_Notes"><h2 id="_apds_Chapter_Notes_">Chapter Notes</h2><div id="apds.Author_Notes"><h3>Author Notes</h3><p><b>Gulbu Uzel, MD</b> (<a href="mailto:dev@null" data-email="vog.hin.diain@lezug" class="oemail">vog.hin.diain@lezug</a>), is actively involved in clinical research regarding individuals with activated PI3K delta syndrome (APDS). Dr Uzel would be happy to communicate with persons who have any questions regarding diagnosis of APDS or other considerations.</p><p><b>Keith Sacco, MD</b> (<a href="mailto:dev@null" data-email="ten.shn@occas.htiek" class="oemail">ten.shn@occas.htiek</a>), is also interested in hearing from clinicians treating families affected by immune dysregulation in whom no causative variant has been identified through molecular genetic testing of the genes known to be involved in this group of disorders.</p><p>Contact Dr Uzel to inquire about review of <i>PIK3R1</i> or <i>PIK3CD</i> variants of uncertain significance.</p></div><div id="apds.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>30 January 2025 (gm) Review posted live</div></li><li class="half_rhythm"><div>15 July 2024 (ks) Original submission</div></li></ul></div></div><div id="apds.References"><h2 id="_apds_References_">References</h2><div id="apds.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="apds.REF.baynes.2000.321">Baynes
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[<a href="/pmc/articles/PMC7497289/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7497289</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/32596782" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 32596782</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="apds.REF.tangye.2022.1473">Tangye
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SG, Al-Herz
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W, Bousfiha
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Z, Richard
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C, Derangère
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V, Ilie
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[<a href="/pmc/articles/PMC10024711/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10024711</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36934165" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36934165</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="apds.REF.vanselow.2023a.1279652">Vanselow
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S, Hanitsch
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L, Hauck
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F, Korholz
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J, Maccari
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ME, Meinhardt
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A, Sogkas
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B. Future directions in the diagnosis and treatment of APDS and IEI: a survey of German IEI centers.
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[<a href="/pmc/articles/PMC10588788/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10588788</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37868971" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37868971</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="apds.REF.vanselow.2023b.1208567">Vanselow
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S, Wahn
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V, Schuetz
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Activated PI3Kdelta syndrome - reviewing challenges in diagnosis and treatment.
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Front Immunol.
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[<a href="/pmc/articles/PMC10432830/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC10432830</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/37600808" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 37600808</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="apds.REF.wang.2018.854">Wang
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Y, Wang
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W, Liu
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L, Hou
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J, Ying
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W, Hui
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X, Zhou
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Q, Liu
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D, Yao
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H, Sun
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J, Wang
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X.
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Report of a Chinese cohort with activated phosphoinositide 3-kinase delta syndrome.
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J Clin Immunol.
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2018;38:854-63.
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[<a href="https://pubmed.ncbi.nlm.nih.gov/30499059" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30499059</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="apds.REF.wang.2021.208">Wang
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S, Wang
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W, Zhang
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X, Gui
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J, Zhang
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J, Guo
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Y, Liu
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Y, Han
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L, Liu
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Q, Li
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Y, Sun
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N, Liu
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Z, Du
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J, Tai
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J, Ni
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X.
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A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation.
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Orphanet J Rare Dis.
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2021;16:208.
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[<a href="/pmc/articles/PMC8106842/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC8106842</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/33964933" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 33964933</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="apds.REF.yang.2023.e32816">Yang
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X, Xi
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R, Bai
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J, Pan
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Y. Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome: case report and literature review.
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Medicine (Baltimore). 2023;102:e32816.
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[<a href="/pmc/articles/PMC9902017/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC9902017</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/36749229" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 36749229</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK611655_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Keith Sacco</span>, MD<div class="affiliation small">The Royal London Hospital<br />Barts Health NHS Trust<br />London, UK<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ten.shn@occas.htiek" class="oemail">ten.shn@occas.htiek</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Gulbu Uzel</span>, MD<div class="affiliation small">National Institute of Allergy and Infectious Diseases<br />National Institutes of Health<br />Bethesda, Maryland<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="vog.hin.diain@lezug" class="oemail">vog.hin.diain@lezug</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">January 30, 2025</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 1993-2025, University of Washington, Seattle. GeneReviews is
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a registered trademark of the University of Washington, Seattle. All rights
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reserved.<p class="small">GeneReviews® chapters are owned by the University of Washington. Permission is
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Washington) are included with each copy; (ii) a link to the original material is provided
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whenever the material is published elsewhere on the Web; and (iii) reproducers,
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distributors, and/or translators comply with the <a href="https://www.ncbi.nlm.nih.gov/books/n/gene/GRcopyright_permiss/" ref="pagearea=meta&targetsite=external&targetcat=link&targettype=uri">GeneReviews® Copyright Notice and Usage
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contact: <a href="mailto:dev@null" data-email="ude.wu@tssamda" class="oemail">ude.wu@tssamda</a>.</p></div></div><h3>Publisher</h3><p><a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>, Seattle (WA)</p><h3>NLM Citation</h3><p>Sacco K, Uzel G. Activated PI3K Delta Syndrome. 2025 Jan 30. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/gene/npab/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/gene/aip/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="table-wrap" id="figobapdsTc"><div id="apds.Tc" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.Tc/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.Tc_lrgtbl__"><table><thead><tr><th id="hd_h_apds.Tc_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Activated PI3K Delta Syndrome: Included Phenotypes</th></tr></thead><tbody><tr><td headers="hd_h_apds.Tc_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Activated PI3K delta syndrome type 1 (APDS1)</div></li><li class="half_rhythm"><div>Activated PI3K delta syndrome type 2 (APDS2)</div></li></ul>
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</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobapdsTmoleculargenetictestingusedin"><div id="apds.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Activated PI3K Delta Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene <sup>1, 2</sup></th><th id="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_2" style="text-align:left;vertical-align:middle;">Proportion of APDS Attributed to Pathogenic Variants in Gene</th><th id="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants <sup>3</sup> Identified by Method</th></tr><tr><th headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>4</sup></th><th headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_3" id="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></th></tr></thead><tbody><tr><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PIK3CD</i>
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</td><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">75%</td><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_apds.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>6</sup></td><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_apds.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported to date <sup>6,</sup> <sup>7</sup></td></tr><tr><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PIK3R1</i>
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</td><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25%</td><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_apds.T.molecular_genetic_testing_used_in_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">100% <sup>6</sup></td><td headers="hd_h_apds.T.molecular_genetic_testing_used_in_1_1_1_3 hd_h_apds.T.molecular_genetic_testing_used_in_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">None reported to date <sup>6,</sup> <sup>7</sup></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="apds.TF.1.1"><p class="no_margin">Genes are listed in alphabetic order.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="apds.TF.1.2"><p class="no_margin">See <a href="/books/NBK611655/?report=reader#apds.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="apds.TF.1.3"><p class="no_margin">See <a href="#apds.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in these genes.</p></div></dd></dl><dl class="bkr_refwrap"><dt>4. </dt><dd><div id="apds.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click <a href="/books/n/gene/app2/?report=reader">here</a>.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="apds.TF.1.5"><p class="no_margin">Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="apds.TF.1.6"><p class="no_margin"><a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al [2020]</a> and data derived from the subscription-based professional view of Human Gene Mutation Database [<a class="bibr" href="#apds.REF.stenson.2020.1197" rid="apds.REF.stenson.2020.1197">Stenson et al 2020</a>]</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="apds.TF.1.7"><p class="no_margin">To date, no large intragenic deletions/duplications have been reported in individuals with APDS.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsTactivatedpi3kdeltasyndromefre"><div id="apds.T.activated_pi3k_delta_syndrome_fre" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Activated PI3K Delta Syndrome: Frequency of Select Features</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_fre/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.activated_pi3k_delta_syndrome_fre_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sinopulmonary infections</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">96%-100%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Severe &/or recurrent</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bronchiectasis</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18%-60%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lymphoproliferation</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">71%-89%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl splenomegaly, hepatomegaly, & lymphadenopathy</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Growth delays</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">45%-62%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Herpes virus infections</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">36%-49%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Persistent, severe, &/or recurrent</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Enteropathy</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">25%-51%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lymphoid aggregates may be seen on histology.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lymphoma</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%-28%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Particularly early onset</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autoimmune cytopenias</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19%-30%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">May be refractory to conventional therapy</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autoimmune & autoinflammatory disease</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17%-42%</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurodevelopmental delay</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19%-31%</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_fre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl autism spectrum disorder</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">Based on <a class="bibr" href="#apds.REF.lucas.2014.88" rid="apds.REF.lucas.2014.88">Lucas et al [2014]</a>, <a class="bibr" href="#apds.REF.elkaim.2016.210" rid="apds.REF.elkaim.2016.210">Elkaim et al [2016]</a>, <a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al [2017]</a>, <a class="bibr" href="#apds.REF.carpier.2018.2005" rid="apds.REF.carpier.2018.2005">Carpier & Lucas [2018]</a>, <a class="bibr" href="#apds.REF.maccari.2018.543" rid="apds.REF.maccari.2018.543">Maccari et al [2018]</a>, <a class="bibr" href="#apds.REF.jamee.2020.323" rid="apds.REF.jamee.2020.323">Jamee et al [2020]</a>, <a class="bibr" href="#apds.REF.oh.2021.4095" rid="apds.REF.oh.2021.4095">Oh et al [2021]</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsTallelicdisordersassociatedwith"><div id="apds.T.allelic_disorders_associated_with" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Allelic Disorders Associated with Germline <i>PIK3CD</i> and <i>PIK3R1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.allelic_disorders_associated_with/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.allelic_disorders_associated_with_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.allelic_disorders_associated_with_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene</th><th id="hd_h_apds.T.allelic_disorders_associated_with_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Disorder</th></tr></thead><tbody><tr><td headers="hd_h_apds.T.allelic_disorders_associated_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PIK3CD</i>
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</td><td headers="hd_h_apds.T.allelic_disorders_associated_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>p110δ deficiency.</b> Biallelic <i>PIK3CD</i> pathogenic variants have been reported in persons w/recurrent respiratory infections, chronic lymphoproliferation, & herpes virus group infections. The immunophenotype commonly incl ↑ IgM, ↓ IgG, & ↓ B cells w/↑ plasmablasts & transitional B cells; however, this can be variable (OMIM <a href="https://omim.org/entry/615214" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615214</a>). <sup>1</sup></td></tr><tr><td headers="hd_h_apds.T.allelic_disorders_associated_with_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>PIK3R1</i>
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</td><td headers="hd_h_apds.T.allelic_disorders_associated_with_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><a href="/books/n/gene/short/?report=reader"><b>SHORT syndrome</b></a> (short stature, <i>h</i>yperextensibility, <i>o</i>cular depression, <i>R</i>ieger anomaly, and <i>t</i>eething delay). Caused by heterozygous <i>PIK3R1</i> pathogenic variants, the most consistently observed features are mild growth delays, mild-to-moderate short stature, partial lipodystrophy, & characteristic facial gestalt. Insulin resistance may be evident in mid-childhood or adolescence, although diabetes mellitus typically does not develop until early adulthood. Pathogenic variants are thought to cause SHORT syndrome via haploinsufficiency; however, few studies have investigated the underlying mechanism.</div></li><li class="half_rhythm"><div><b>p85 deficiency.</b> Homozygous pathogenic variants resulting in a premature stop codon in exon 6 & absence of the p85α isoform (but not the other isoforms, i.e., p55α, p50α) have been reported in 1 person w/agammaglobulinemia (OMIM <a href="https://omim.org/entry/615214" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615214</a>). <sup>1</sup></div></li><li class="half_rhythm"><div>A heterozygous pathogenic variant resulting in an amino acid substitution in the N-terminal SH2 domain of <i>PIK3R1</i> was reported in 1 person w/acanthosis nigricans & severe insulin resistance. <sup>2</sup></div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="apds.TF.3.1"><p class="no_margin">
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<a class="bibr" href="#apds.REF.tangye.2022.1473" rid="apds.REF.tangye.2022.1473">Tangye et al [2022]</a>
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</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="apds.TF.3.2"><p class="no_margin">
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<a class="bibr" href="#apds.REF.baynes.2000.321" rid="apds.REF.baynes.2000.321">Baynes et al [2000]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsTgenesofinterestinthedifferen"><div id="apds.T.genes_of_interest_in_the_differen" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Genes of Interest in the Differential Diagnosis of Activated PI3K Delta Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.genes_of_interest_in_the_differen/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.genes_of_interest_in_the_differen_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Features of Disorder</th></tr><tr><th headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4" id="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/APDS</th><th headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4" id="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from APDS</th></tr></thead><tbody><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>AICDA</i>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyper IgM syndrome 2 (HIGM2) (OMIM <a href="https://omim.org/entry/605258" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">605258</a>)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infections, hypogammaglobulinemia, ↑ IgM, lymphoid hyperplasia</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intact pAKT/pS6 phosphorylation</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CD19</i>
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<br />
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<i>CD81</i>
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<br />
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<i>CR2</i>
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<br />
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<i>ICOS</i>
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<br />
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<i>IKZF1</i>
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<br />
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<i>IL21</i>
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<br />
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<i>IRF2BP2</i>
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<br />
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<i>MS4A1</i>
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<br />
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<i>NFKB1</i>
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<br />
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<i>NFKB2</i>
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<br />
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<i>SEC61A1</i>
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<br />
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<i>TNFRSF13B</i>
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<br />
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<i>TNFRSF13C</i>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Common variable immunodeficiency (CVID) (OMIM <a href="https://omim.org/phenotypicSeries/PS607594" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS607594</a>)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infections, hypogammaglobulinemia, autoimmunity, lymphoproliferation</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">B-cell phenotype typically w/o significant ↑ in transitional B cells</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CD40</i>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyper IgM syndrome 3 (HIGM3) (OMIM <a href="https://omim.org/entry/606843" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606843</a>)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_1" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infections, hypogammaglobulinemia, ↑ IgM, lymphoid hyperplasia</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Intact pAKT/pS6 phosphorylation</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CD40LG</i>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/xlhi/?report=reader">X-linked hyper IgM syndrome</a> (HIGM1)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SH2D1A</i>
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<br />
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<i>XIAP</i>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/x-lpd/?report=reader">X-linked lymphoproliferative disease</a>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Immune dysregulation</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">More severe EBV infections</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>UNG</i>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hyper IgM syndrome 5 (HIGM5) (OMIM <a href="https://omim.org/entry/608106" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">608106</a>)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infections</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intact pAKT/pS6 phosphorylation</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>CTLA4</i>
|
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CTLA4 haploinsufficiency (OMIM <a href="https://omim.org/entry/616100" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">616100</a>)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_1" rowspan="3" colspan="1" style="text-align:left;vertical-align:middle;">Recurrent infections, autoimmunity, lymphoproliferation</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Low CTLA-4 expression</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<i>LRBA</i>
|
|
</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LRBA deficiency (OMIM <a href="https://omim.org/entry/606453" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">606453</a>)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td></tr><tr><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<i>STAT3</i>
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</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Autoimmune disease, multisystem, infantile-onset, 1 (OMIM <a href="https://omim.org/entry/615952" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">615952</a>)</td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD <sup>1</sup></td><td headers="hd_h_apds.T.genes_of_interest_in_the_differen_1_1_1_4 hd_h_apds.T.genes_of_interest_in_the_differen_1_1_2_2" colspan="1" rowspan="1" style="text-align:left;vertical-align:middle;">↑ T helper 17 cells & phosphorylated STAT3</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">AD = autosomal dominant; APDS = activated PI3K delta syndrome; AR = autosomal recessive; CTLA-4 = cytotoxic T-lymphocyte protein 4; EBV = Epstein-Barr virus; MOI = mode of inheritance; STAT3 = signal transducer and activator of transcription 3; XL = X-linked</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="apds.TF.4.1"><p class="no_margin">Caused by <i>STAT3</i> gain-of-function pathogenic variants</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsTactivatedpi3kdeltasyndromerec"><div id="apds.T.activated_pi3k_delta_syndrome_rec" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Activated PI3K Delta Syndrome: Recommended Evaluations Following Initial Diagnosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.activated_pi3k_delta_syndrome_rec_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>General</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comprehensive physical exam</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for presence of lymphadenopathy, splenomegaly, & hepatomegaly</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Infection history</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Detailed review of infection history</div></li><li class="half_rhythm"><div>EBV, CMV, HSV PCR in blood & relevant serologic testing</div></li><li class="half_rhythm"><div>JCV PCR if patient received rituximab <sup>1</sup></div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To identify patterns indicative of immunodeficiency</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Immunodeficiency</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>CBC w/differential</div></li><li class="half_rhythm"><div>Immunoglobulin levels (IgG, IgA, IgM, & IgE)</div></li><li class="half_rhythm"><div>Lymphocyte subset analysis incl naïve/memory T cells & B-cell subsets</div></li><li class="half_rhythm"><div>Vaccine-specific antibody titers</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate immune function & identify immunodeficiency</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lymphoproliferation</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Imaging studies (e.g., ultrasound, CT, MRI)</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To detect organomegaly & lymphadenopathy</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>B-cell clonality studies by V-beta spectratyping</div></li><li class="half_rhythm"><div>LDH, EBV/CMV PCR</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for ↑ susceptibility to lymphoproliferative disorders</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Pulmonary</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Spirometry</div></li><li class="half_rhythm"><div>Consider chest CT</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To detect underlying respiratory issues</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastrointestinal</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Endoscopy or imaging studies</div></li><li class="half_rhythm"><div>Liver function tests</div></li><li class="half_rhythm"><div>Liver ultrasound with Doppler</div></li><li class="half_rhythm"><div>Fibroscan<sup>®</sup></div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for gastrointestinal manifestations incl enteropathy & hepatosplenomegaly</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Autoimmune</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Thyroid function tests</div></li><li class="half_rhythm"><div>TPO antibodies</div></li><li class="half_rhythm"><div>ESR, CRP, ANA testing</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cognitive/</b>
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<br />
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<b>Developmental</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cognitive & developmental evals</div></li><li class="half_rhythm"><div>Consider formal psychiatric eval.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To identify any delays or impairment assoc w/APDS</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals <sup>2</sup></td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of APDS to facilitate medical & personal decision making</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Family support</b>
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<br />
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<b>& resources</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By clinicians, wider care team, & family support organizations</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment of family & social structure to determine need for:
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<ul><li class="half_rhythm"><div>Community or <a href="#apds.Resources">online resources</a> such as <a href="https://www.p2pusa.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Parent to Parent</a></div></li><li class="half_rhythm"><div>Social work involvement for parental support</div></li><li class="half_rhythm"><div>Home nursing referral</div></li></ul>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ANA = antinuclear antibody; APDS = activated PI3K delta syndrome; CBC = complete blood count; CMV = cytomegalovirus; CRP = C-reactive protein; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; HSV = herpes simplex virus; JCV = human polyomavirus 2; LDH = lactate dehydrogenase; MOI = mode of inheritance; PCR = polymerase chain reaction; TPO = thyroid peroxidase</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="apds.TF.5.1"><p class="no_margin">Rituximab, a monoclonal antibody, has been reported to be effective as an immunosuppressive therapy in individuals with APDS; however, it can cause persistent, often permanent, B-cell depletion [<a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al 2017</a>]. Lymphocyte counts can be compromised by prior use of rituximab, because the hypogammaglobulinemia can be attributed to B-cell depletion caused by rituximab, and the characteristic B-cell immunophenotype of APDS cannot be characterized. Caution is advised in using rituximab for individuals with APDS.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="apds.TF.5.2"><p class="no_margin">Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsTactivatedpi3kdeltasyndrometar"><div id="apds.T.activated_pi3k_delta_syndrome_tar" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Activated PI3K Delta Syndrome: Targeted Treatment</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_tar/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.activated_pi3k_delta_syndrome_tar_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment Class</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dosage</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Indication</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Mechanism</th></tr></thead><tbody><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>PI3Kδ inhibitor</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Leniolisib <sup>1, 2</sup></td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>70 mg every 12 hrs, w/ or w/o food</div></li><li class="half_rhythm"><div>For women of reproductive age, pregnancy status should be verified prior to treatment.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Recommended as first-line treatment of significant lymphoproliferative disease, incl lymphadenopathy & splenomegaly</div></li><li class="half_rhythm"><div>FDA approved in persons w/APDS age ≥12 yrs weighing ≥45 kg</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Directly targets the overactive PI3Kδ signaling pathway</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>mTOR inhibitor</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sirolimus <sup>2, 3</sup></td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Dosed to a target trough blood level of 10-15 ng/mL</div></li><li class="half_rhythm"><div>Dose may need to be titrated depending on kidney function or ↓ in persons w/cytopenias.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Recommended for persons w/lymphoproliferative disease or organomegaly when leniolisib is unavailable</div></li><li class="half_rhythm"><div>Is also used off-label due to its immunosuppressive & antiproliferative properties</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Inhibits mTOR, which is downstream of PI3Kδ & overactive in APDS</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Replacement therapy</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Allogeneic hematopoietic stem cell transplant (HSCT)</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Conditioning regimens should be individualized; often incl fludarabine & treosulfan</div></li><li class="half_rhythm"><div>Pre- & post-HSCT optimization w/mTOR or PI3Kδ inhibitors is recommended.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reserved for severe or treatment-refractory APDS, incl progressive organ damage, recurrent refractory infections, or severe immune dysregulation unresponsive to pharmacologic therapy.</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tar_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reconstitutes immune system by replacing affected person's dysfunctional hematopoietic cells w/healthy donor cells, offering potential definitive treatment</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">APDS = activated PI3K delta syndrome; mTOR = mammalian target of rapamycin; PI3Kδ = PI3K delta</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="apds.TF.6.1"><p class="no_margin">In a randomized, placebo-controlled Phase III clinical trial evaluating leniolisib for APDS, results included a significant reduction in the size of the index lymph node, an increase in the percentage of naïve B cells in peripheral blood, decreased spleen volume, and improved immune cell subsets. The treatment was well tolerated [<a class="bibr" href="#apds.REF.rao.2023.971" rid="apds.REF.rao.2023.971">Rao et al 2023</a>]. In an open-label extension study, efficacy outcomes included reduced infection rates, decreased immunoglobulin replacement in some patients, decreased lymphadenopathy and splenomegaly, improved cytopenias, and normalization of lymphocyte subsets, showing durable results over five years [<a class="bibr" href="#apds.REF.rao.2024b.265" rid="apds.REF.rao.2024b.265">Rao et al 2024b</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="apds.TF.6.2"><p class="no_margin">While leniolisib and sirolimus are used as immunomodulators in APDS, their absorption may be impaired by gastrointestinal inflammation, warranting the need to bridge with glucocorticoids as discussed below. Further, while some PI3Kδ inhibitors have shown efficacy in treating APDS, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematologic malignancies [<a class="bibr" href="#apds.REF.cant.2024.69" rid="apds.REF.cant.2024.69">Cant et al 2024</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="apds.TF.6.3"><p class="no_margin">Sirolimus has demonstrated effectiveness in treating APDS by inhibiting the hyperactivated PI3K/AKT/mTOR signaling pathway [<a class="bibr" href="#apds.REF.wang.2018.854" rid="apds.REF.wang.2018.854">Wang et al 2018</a>], which is central to disease pathogenesis. In one study, sirolimus reduced lymphoproliferation and improved gastrointestinal nodular mucosal lymphoid hyperplasia [<a class="bibr" href="#apds.REF.kang.2020.542" rid="apds.REF.kang.2020.542">Kang et al 2020</a>]. Data from the European Society for Immunodeficiencies (ESID) APDS registry supported sirolimus's effectiveness in managing lymphoproliferation, although its impact on cytopenias was less substantial [<a class="bibr" href="#apds.REF.maccari.2018.543" rid="apds.REF.maccari.2018.543">Maccari et al 2018</a>]. However, sirolimus has shown variable effectiveness in controlling gastrointestinal inflammation [<a class="bibr" href="#apds.REF.maccari.2018.543" rid="apds.REF.maccari.2018.543">Maccari et al 2018</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsTactivatedpi3kdeltasyndrometre"><div id="apds.T.activated_pi3k_delta_syndrome_tre" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Activated PI3K Delta Syndrome: Treatment of Manifestations</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_tre/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.activated_pi3k_delta_syndrome_tre_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Immunodeficiency</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><b>Immunoglobulin replacement therapy.</b> Regular IV or SC immunoglobulin replacement therapy to prevent recurrent bacterial infections & improve immune function</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Starting dose is typically 0.5g/kg every 4 weeks for IV dosing or equivalent for SC dosing</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Prophylactic antibiotics.</b> Consider long-term prophylactic antibiotics to reduce frequency of bacterial infections.</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl prophylactic azithromycin, particularly in persons w/recurrent bacterial respiratory infections & bronchiectasis</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Prophylactic antivirals.</b> Persons w/recurrent herpes simplex or herpes zoster should receive prophylactic acyclovir or valganciclovir.</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adjuvant recombinant zoster vaccine series is also recommended.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lymphoproliferation</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>PET/CT scan</div></li><li class="half_rhythm"><div>Consider lymph node biopsy.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For early detection & mgmt of lymphadenopathy & organomegaly</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Leniolisib or sirolimus</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="#apds.Targeted_Therapies">Targeted Therapies</a>.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Rituximab</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 1.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Autoimmune disorders</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Glucocorticoids.</b> For acute mgmt of autoimmune complications such as autoimmune cytopenias</div></li><li class="half_rhythm"><div><b>Immunosuppressive agents.</b> Other immunosuppressive agents (e.g., azathioprine, mycophenolate mofetil) can be used for chronic mgmt of autoimmune manifestations following leniolisib treatment.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dosing per hematology guidelines for the specific disorders</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory issues</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Bronchodilators & inhaled steroids.</b> Used for persons w/asthma-like symptoms or chronic lung disease</div></li><li class="half_rhythm"><div><b>Pulmonary hygiene.</b> Implement regular pulmonary hygiene practices incl chest PT to manage & prevent respiratory infections.</div></li><li class="half_rhythm"><div><b>Preventative pulmonary care.</b> Incl vaccinations (e.g., influenza, pneumococcal vaccine) to ↓ risk of respiratory infections</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manage chronic respiratory infections & improve lung function.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastrointestinal manifestations</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Nutritional support & dietary modifications</b> for persons w/gastrointestinal manifestations such as enteropathy</div></li><li class="half_rhythm"><div><b>Anti-inflammatory medications,</b> incl high-dose IV glucocorticoids (see <b>Role of glucocorticoids in APDS</b> following this table), e.g., 1-2 mg/kg/day of methyl prednisolone, for the treatment of inflammatory bowel disease symptoms</div></li><li class="half_rhythm"><div><b>Consideration of assisted enteral/parenteral nutrition for severe cases</b></div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Address enteropathy & hepatosplenomegaly; consider liver function monitoring & appropriate imaging.</div></li><li class="half_rhythm"><div>Close monitoring of gastrointestinal symptoms, nutritional status, & inflammatory markers is essential. Endoscopic & imaging evals are recommended to assess disease progression & treatment response. The need for assisted enteral/parenteral nutrition should be reassessed w/dietician.</div></li><li class="half_rhythm"><div>Extra doses of IV or SC immunoglobulins may be required in acute gastrointestinal disease due to enteric immunoglobulin losses. This must be weighed judiciously by treating clinician.</div></li></ul>
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</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Growth/Nutrition</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nutritional support & growth monitoring incl mgmt w/endocrinologist as needed</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ensure adequate growth & development; consider dietary supplements if necessary.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurodevelopmental and cognitive support</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Developmental interventions.</b> Early intervention programs, incl PT, OT, & speech therapy to address developmental delays</div></li><li class="half_rhythm"><div><b>Educational support.</b> Tailored educational plans & support services to address cognitive impairments & learning disabilities</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Support cognitive & developmental delays through tailored educational & therapeutic programs.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Psychosocial support</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Counseling and psychotherapy.</b> Offer counseling & psychotherapy to affected persons & their families to address psychosocial impacts of living w/APDS.</div></li><li class="half_rhythm"><div><b>Support groups.</b> Encourage participation in support groups for affected persons & their families to provide emotional & practical support.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genetic counseling</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div><b>Genetic consultation.</b> Provide genetic counseling to discuss the mode of inheritance, implications of diagnosis, & family planning options.</div></li><li class="half_rhythm"><div><b>Family screening.</b> Recommend genetic testing and screening for family members to identify other potentially affected persons.</div></li></ul>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_tre_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">CT = computed tomography; IV = intravenous; PET = positron emission tomography; OT = occupational therapy; PT = physical therapy; SC = subcutaneous</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="apds.TF.7.1"><p class="no_margin">Rituximab, a monoclonal antibody, has been reported to be effective in treating lymphoma and autoimmune disease in individuals with APDS; however, it can cause persistent, often permanent, B-cell depletion [<a class="bibr" href="#apds.REF.coulter.2017.597" rid="apds.REF.coulter.2017.597">Coulter et al 2017</a>]. Lymphocyte counts can be compromised by prior use of rituximab, because the hypogammaglobulinemia can be attributed to B-cell depletion caused by rituximab, and the characteristic B-cell immunophenotype of APDS cannot be characterized. Caution is advised in using rituximab for individuals with APDS.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsTactivatedpi3kdeltasyndromerec1"><div id="apds.T.activated_pi3k_delta_syndrome_rec_1" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Activated PI3K Delta Syndrome: Recommended Surveillance</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.T.activated_pi3k_delta_syndrome_rec_1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.T.activated_pi3k_delta_syndrome_rec_1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Infections</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Blood/sputum cultures</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed for symptoms</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">EBV/CMV/HSV PCR</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Every 12 mos</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Immune</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>IgG, IgA, IgM</div></li><li class="half_rhythm"><div>CD4+, CD8+, B cell subsets</div></li></ul>
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</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Vaccine responses</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At baseline</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Lymphoproliferative disorders</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CBC, B-cell counts, LDH</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 months</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CT or MRI of chest</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 3-5 years</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Abdominal US</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider every 6-12 mos or more frequently in persons w/active lymphoproliferation or gastrointestinal &/or hepatic manifestations.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Autoimmune disorders</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ANA testing, TSH, TPO</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Annually</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Respiratory issues</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Regular pulmonary function tests incl spirometry</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 12 mos (to monitor lung health & intervene early if issues are detected)</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Chest CT</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider every 5 yrs.</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastrointestinal manifestations</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Colonoscopy</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Symptomatically as needed to identify & manage gastrointestinal involvement</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Liver ultrasound studies</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At baseline & every 6-12 mos</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Liver enzymes</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 mos</td></tr><tr><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cognitive/</b>
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<br />
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<b>Developmental</b>
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</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Psychiatric assessment</td><td headers="hd_h_apds.T.activated_pi3k_delta_syndrome_rec_1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As needed</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin">ANA = antinuclear antibody; CMV = cytomegalovirus; EVB = Epstein-Barr virus; HSV= herpes simplex virus; LDH = lactate dehydrogenase; PCR = polymerase chain reaction; TSH = thyroid-stimulating hormone; TPO = thyroid peroxidase</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsmolgenTA"><div id="apds.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Activated PI3K Delta Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_apds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_apds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_apds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_apds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_apds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_apds.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_apds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/5293" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>PIK3CD</i>
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</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=5293" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">1p36<wbr style="display:inline-block"></wbr>​.22</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/O00329" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;"></td><td headers="hd_b_apds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PIK3CD" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PIK3CD</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PIK3CD[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PIK3CD</a>
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</td></tr><tr><td headers="hd_b_apds.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/5295" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>PIK3R1</i>
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</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&acc=5295" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">5q13<wbr style="display:inline-block"></wbr>​.1</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.uniprot.org/uniprot/P27986" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Phosphatidylinositol 3-kinase regulatory subunit alpha</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://structure.bmc.lu.se/idbase/PIK3R1base/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PIK3R1base: Database for pathogenic mutations in the p85-alpha SH2 domain</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=PIK3R1" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PIK3R1</a>
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</td><td headers="hd_b_apds.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=PIK3R1[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PIK3R1</a>
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</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="apds.TFA.1"><p class="no_margin">Data are compiled from the following standard references: gene from
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<a href="http://www.genenames.org/index.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HGNC</a>;
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chromosome locus from
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<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
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protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
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For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
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<a href="/books/n/gene/app1/?report=reader">here</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobapdsmolgenTB"><div id="apds.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Activated PI3K Delta Syndrome (<a href="/omim/171833,602839,615513,616005" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK611655/table/apds.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__apds.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/171833" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">171833</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 1; PIK3R1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/602839" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">602839</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, DELTA; PIK3CD</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/615513" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">615513</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT; IMD14A</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/616005" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">616005</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION; IMD36</td></tr></tbody></table></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script><script type="text/javascript">if (typeof (jQuery) != 'undefined') { (function ($) { $(function () { var min = Math.ceil(1); var max = Math.floor(100000); var randomNum = Math.floor(Math.random() * (max - min)) + min; var surveyUrl = "/projects/Gene/portal/surveys/seqdbui-survey.js?rando=" + randomNum.toString(); $.getScript(surveyUrl, function () { try { ncbi.seqDbUISurvey.init(); } catch (err) { console.info(err); } }).fail(function (jqxhr, settings, exception) { console.info('Cannot load survey script', jqxhr); });; }); })(jQuery); };</script></div></div>
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