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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>KBG Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_title" content="KBG Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2018/03/22">
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<meta name="citation_author" content="Dayna Morel Swols">
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<meta name="citation_author" content="Mustafa Tekin">
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<meta name="citation_keywords" content="Ankyrin repeat domain-containing protein 11">
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<meta name="citation_keywords" content="ANKRD11">
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<meta name="citation_keywords" content="KBG Syndrome">
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<meta name="DC.Title" content="KBG Syndrome">
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<meta name="DC.Contributor" content="Dayna Morel Swols">
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<meta name="DC.Contributor" content="Mustafa Tekin">
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<meta name="description" content="KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family.">
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<meta name="og:description" content="KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family.">
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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="_NBK487886_"><span class="title" itemprop="name">KBG Syndrome</span></h1><p class="contribs">Morel Swols D, Tekin M.</p><p class="fm-aai"><a href="#_NBK487886_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 25 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="kbgs.Summary" itemprop="description"><h2 id="_kbgs_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors), characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip), short stature, developmental delay / intellectual disability, and behavioral issues. Affected individuals may have feeding difficulties (particularly in infancy), skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis), hearing loss (conductive, mixed, and sensorineural), seizure disorder, and brain malformations. There is significant variability in the clinical findings, even between affected members of the same family.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of KBG syndrome is confirmed in a proband by detection of either a heterozygous pathogenic variant in <i>ANKRD11</i> or deletion of 16q24.3 that includes <i>ANKRD11</i>.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Surgical corrections and/or speech therapy for palatal anomalies; nasogastric tube feeding in infants; pharmacologic treatment for gastroesophageal reflux disease; pressure-equalizing tubes and/or tonsillectomy/adenoidectomy for chronic otitis media; consideration of amplification for hearing loss; consideration of growth hormone therapy for short stature and medication to arrest puberty for premature pubertal development; standard treatment of seizure disorder, undescended testis in males, congenital heart defects, strabismus / refractive errors, and developmental disabilities.</p><p><i>Surveillance:</i> Routine monitoring of hearing, vision, growth, pubertal status (in prepubertal individuals), and cognitive development.</p><p><i>Agents/circumstances to avoid:</i> Ototoxic drugs should be avoided because of the risk for hearing loss.</p><p><i>Pregnancy management:</i> Pregnancy management should be tailored to the specific features in the affected woman. For example, involvement of a cardiologist and maternal fetal medicine physician for a pregnant woman with a history of a congenital heart defect; control of seizures during pregnancy for those with a seizure disorder.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Recurrence risk for sibs of a proband with KBG syndrome depends on the genetic alteration:</p><ul><li class="half_rhythm"><div>Deletion of 16q24.3 (~75% of reported pathogenic variants are <i>de novo</i> and the remainder are inherited in an autosomal dominant manner.)</div></li><li class="half_rhythm"><div><i>ANKRD11</i> sequence variants (~66% of reported pathogenic variants are <i>de novo</i> and the remainder are inherited in an autosomal dominant manner.)</div></li></ul><p>Prenatal testing and preimplantation genetic testing are possible if the causative genetic alteration has been identified in an affected family member.</p></div></div><div id="kbgs.Diagnosis"><h2 id="_kbgs_Diagnosis_">Diagnosis</h2><p>While no consensus clinical diagnostic criteria for KBG syndrome have been published, several authors have suggested diagnostic criteria [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>, <a class="bibr" href="#kbgs.REF.skjei.2007.292" rid="kbgs.REF.skjei.2007.292">Skjei et al 2007</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</p><div id="kbgs.Suggestive_Findings"><h3>Suggestive Findings</h3><p>KBG syndrome <b>should be suspected</b> in a proband with developmental delay / cognitive impairment or significant behavioral issues who has [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>, <a class="bibr" href="#kbgs.REF.skjei.2007.292" rid="kbgs.REF.skjei.2007.292">Skjei et al 2007</a>, <a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]:</p><ul><li class="half_rhythm"><div>At least two of the findings highlighted by an asterisk (*); OR</div></li><li class="half_rhythm"><div>One finding highlighted by an asterisk and at least two additional findings.</div></li></ul><p>
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<b>Craniofacial features</b>
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</p><ul><li class="half_rhythm"><div><b>*</b> Macrodontia (mesiodistal width of permanent central incisors ≥10 mm in males, ≥9.7 mm in females) (see <a class="figpopup" href="/books/NBK487886/figure/kbgs.F1/?report=objectonly" target="object" rid-figpopup="figkbgsF1" rid-ob="figobkbgsF1">Figure1</a>), especially of the upper central incisors</div></li><li class="half_rhythm"><div><b>*</b> Characteristic facial appearance (See <a class="figpopup" href="/books/NBK487886/figure/kbgs.F2/?report=objectonly" target="object" rid-figpopup="figkbgsF2" rid-ob="figobkbgsF2">Figure 2</a>.)</div></li><li class="half_rhythm"><div>Conductive hearing loss and/or chronic/recurrent otitis media</div></li><li class="half_rhythm"><div>Palatal abnormalities</div></li><li class="half_rhythm"><div>Hair anomalies (e.g., low hairline, coarse hair)</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col fig" id="figkbgsF1" co-legend-rid="figlgndkbgsF1"><a href="/books/NBK487886/figure/kbgs.F1/?report=objectonly" target="object" title="Figure 1. " class="img_link icnblk_img figpopup" rid-figpopup="figkbgsF1" rid-ob="figobkbgsF1"><img class="small-thumb" src="/books/NBK487886/bin/kbgs-Image001.gif" src-large="/books/NBK487886/bin/kbgs-Image001.jpg" alt="Figure 1. " /></a><div class="icnblk_cntnt" id="figlgndkbgsF1"><h4 id="kbgs.F1"><a href="/books/NBK487886/figure/kbgs.F1/?report=objectonly" target="object" rid-ob="figobkbgsF1">Figure 1. </a></h4><p class="float-caption no_bottom_margin">Macrodontia of permanent upper central incisors, dental pits, and prominent mamelons </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figkbgsF2" co-legend-rid="figlgndkbgsF2"><a href="/books/NBK487886/figure/kbgs.F2/?report=objectonly" target="object" title="Figure 2. " class="img_link icnblk_img figpopup" rid-figpopup="figkbgsF2" rid-ob="figobkbgsF2"><img class="small-thumb" src="/books/NBK487886/bin/kbgs-Image002.gif" src-large="/books/NBK487886/bin/kbgs-Image002.jpg" alt="Figure 2. " /></a><div class="icnblk_cntnt" id="figlgndkbgsF2"><h4 id="kbgs.F2"><a href="/books/NBK487886/figure/kbgs.F2/?report=objectonly" target="object" rid-ob="figobkbgsF2">Figure 2. </a></h4><p class="float-caption no_bottom_margin">Triangular face, synophrys, prominent nasal bridge, anteverted nares, long philtrum, and thin vermilion of the upper lip in two affected males </p></div></div><p>
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<b>Skeletal features</b>
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</p><ul><li class="half_rhythm"><div>Costovertebral anomalies</div></li><li class="half_rhythm"><div>* Postnatal short stature (length and/or height <10th centile)</div></li><li class="half_rhythm"><div>Delayed bone age (>2SD below mean)</div></li><li class="half_rhythm"><div>Brachydactyly</div></li><li class="half_rhythm"><div>Large anterior fontanelle with delayed closure</div></li><li class="half_rhythm"><div>Scoliosis</div></li></ul><p>
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<b>Neurologic features</b>
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</p><ul><li class="half_rhythm"><div>Learning difficulties of variable severity</div></li><li class="half_rhythm"><div>EEG abnormalities with or without seizures</div></li></ul><p>
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<b>Family history</b>
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</p><ul><li class="half_rhythm"><div>* A first-degree relative with KBG syndrome</div></li><li class="half_rhythm"><div>Note: Absence of a family history of KBG syndrome does not preclude the diagnosis.</div></li></ul><p>
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<b>Other</b>
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</p><ul><li class="half_rhythm"><div>Feeding difficulties</div></li><li class="half_rhythm"><div>Cryptorchidism in males</div></li></ul></div><div id="kbgs.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of KBG syndrome <b>is established</b> in a proband by detection of either a heterozygous pathogenic (or likely pathogenic) variant in <i>ANKRD11</i> or deletion of 16q24.3 that includes <i>ANKRD11</i> (see <a href="/books/NBK487886/table/kbgs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobkbgsTmoleculargenetictestingusedin">Table 1</a>). However, some individuals with clinical findings highly suggestive of KBG syndrome do not have a detectable pathogenic <i>ANKRD11</i> variant or 16q24.3 deletion [<a class="bibr" href="#kbgs.REF.sirmaci.2011.289" rid="kbgs.REF.sirmaci.2011.289">Sirmaci et al 2011</a>].</p><p>Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [<a class="bibr" href="#kbgs.REF.richards.2015.405" rid="kbgs.REF.richards.2015.405">Richards et al 2015</a>]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.</p><p>Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive features described in <a href="#kbgs.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#kbgs.Option_1">Option 1</a>), whereas those in whom a specific diagnosis has been elusive are more likely to be diagnosed using genomic testing (see <a href="#kbgs.Option_2">Option 2</a>).</p><div id="kbgs.Option_1"><h4>Option 1</h4><p>When the phenotypic findings suggest the diagnosis of KBG syndrome, genetic testing approaches can include EITHER:</p><ul><li class="half_rhythm"><div><b>Single-gene testing</b> or use of a <b>multigene panel</b>; OR</div></li><li class="half_rhythm"><div><b>Chromosomal microarray analysis</b>.</div></li></ul><p><b>Single-gene testing.</b> Sequence analysis of <i>ANKRD11</i> is performed first. If no pathogenic variant is found, gene-targeted deletion/duplication analysis could be considered (see <a href="/books/NBK487886/table/kbgs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobkbgsTmoleculargenetictestingusedin">Table 1</a> for information on deletion/duplication analysis).</p><p><b>A multigene intellectual disability</b>
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<b>panel</b> that includes <i>ANKRD11</i> and other genes of interest (see <a href="#kbgs.Differential_Diagnosis">Differential Diagnosis</a>) may also be considered. 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>; thus, clinicians need to determine which multigene panel 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. (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. For this condition, a multigene panel that also includes deletion/duplication analysis is recommended (see <a href="/books/NBK487886/table/kbgs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobkbgsTmoleculargenetictestingusedin">Table 1</a>).</p><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><p><b>Chromosomal microarray analysis (CMA)</b> using oligonucleotide arrays or single nucleotide polymorphism (SNP) arrays in current clinical use target the 16q24.3 region.</p></div><div id="kbgs.Option_2"><h4>Option 2</h4><p>When the diagnosis of KBG syndrome has not been considered, <b>comprehensive</b>
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<b>genomic testing</b> (when clinically available) including exome sequencing and genome sequencing is likely to be the diagnostic modality selected.</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="figkbgsTmoleculargenetictestingusedin"><a href="/books/NBK487886/table/kbgs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobkbgsTmoleculargenetictestingusedin"><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="kbgs.T.molecular_genetic_testing_used_in"><a href="/books/NBK487886/table/kbgs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobkbgsTmoleculargenetictestingusedin">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in KBG Syndrome </p></div></div></div></div></div><div id="kbgs.Clinical_Characteristics"><h2 id="_kbgs_Clinical_Characteristics_">Clinical Characteristics</h2><div id="kbgs.Clinical_Description"><h3>Clinical Description</h3><p>KBG syndrome was first described in 1975. The name KBG is derived from the initials of the first three families in which the condition was characterized [<a class="bibr" href="#kbgs.REF.herrmann.1975.7" rid="kbgs.REF.herrmann.1975.7">Herrmann et al 1975</a>]. More than 100 affected individuals have been reported in the literature – the majority of whom are simplex (meaning the first individual in the family to be affected by the condition); although familial cases have been described. There is variable expressivity among and within families. More males than females with KBG syndrome have been reported. In some families a mildly affected mother is diagnosed only after a typically affected son is recognized [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>].</p><p>Macrodontia of the permanent upper incisors is a main finding, making diagnosis prior to the eruption of these teeth more difficult. It is likely this syndrome is underdiagnosed, since many of the features are nonspecific [<a class="bibr" href="#kbgs.REF.sirmaci.2011.289" rid="kbgs.REF.sirmaci.2011.289">Sirmaci et al 2011</a>].</p><div id="kbgs.Dental"><h4>Dental</h4><p>Macrodontia of permanent upper central incisors is reported in 85%-95% of affected individuals [<a class="bibr" href="#kbgs.REF.skjei.2007.292" rid="kbgs.REF.skjei.2007.292">Skjei et al 2007</a>, <a class="bibr" href="#kbgs.REF.ockeloen.2015.1176" rid="kbgs.REF.ockeloen.2015.1176">Ockeloen et al 2015</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. In addition to macrodontia (see <a href="#kbgs.Suggestive_Findings">Suggestive Findings</a>), cleft teeth, shovel-shaped incisors, enamel hypoplasia, hypo/oligodontia, dental pits, talon cusps, dental crowding, large dental pulps, and supernumerary mamelons can be seen [<a class="bibr" href="#kbgs.REF.kumar.2009.e72" rid="kbgs.REF.kumar.2009.e72">Kumar et al 2009</a>, <a class="bibr" href="#kbgs.REF.ockeloen.2015.1176" rid="kbgs.REF.ockeloen.2015.1176">Ockeloen et al 2015</a>].</p></div><div id="kbgs.Craniofacial"><h4>Craniofacial</h4><p>Craniofacial findings have been reported in 62%-80% of affected individuals. The characteristic facial appearance (see <a class="figpopup" href="/books/NBK487886/figure/kbgs.F1/?report=objectonly" target="object" rid-figpopup="figkbgsF1" rid-ob="figobkbgsF1">Figure 1</a>) includes a triangular face, brachycephaly, synophrys with full eyebrows, and widely spaced eyes. A prominent nasal bridge, bulbous nose, anteverted nares, broad or bushy eyebrows, prominent ears, long philtrum, and thin vermilion of the upper lip are also common [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>, <a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. Less commonly, cleft of the soft palate or submucous cleft, bifid uvula, and velopharyngeal insufficiency have been reported [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>, <a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. The craniofacial findings may not always be apparent, so lack of these features does not preclude the diagnosis.</p></div><div id="kbgs.Feeding"><h4>Feeding</h4><p>Feeding issues, especially during infancy, are reported in 20% of affected individuals and include vomiting, constipation, and gastroesophageal reflux disease [<a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</p></div><div id="kbgs.Growth"><h4>Growth</h4><p>Short stature (below the 3rd centile) has been observed in 40%-77% of affected individuals [<a class="bibr" href="#kbgs.REF.reynaert.2015.361" rid="kbgs.REF.reynaert.2015.361">Reynaert et al 2015</a>, <a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>]. Birth weight, length, and head circumference are usually normal. Delayed bone age is an additional finding [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>]. Endocrinologic evaluations for short stature typically are normal. Preliminary evidence suggests that growth hormone therapy may increase the height potential of affected individuals [<a class="bibr" href="#kbgs.REF.reynaert.2015.361" rid="kbgs.REF.reynaert.2015.361">Reynaert et al 2015</a>].</p></div><div id="kbgs.Skeletal"><h4>Skeletal</h4><p>Variable skeletal anomalies have been reported in 75% of affected individuals [<a class="bibr" href="#kbgs.REF.skjei.2007.292" rid="kbgs.REF.skjei.2007.292">Skjei et al 2007</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. The most frequent findings are costovertebral anomalies, such as cervical ribs, abnormal vertebral shape, end plate abnormalities, posterior fusion defects, or spina bifida occulta [<a class="bibr" href="#kbgs.REF.skjei.2007.292" rid="kbgs.REF.skjei.2007.292">Skjei et al 2007</a>]. A large anterior fontanelle with delayed closure can also be seen [<a class="bibr" href="#kbgs.REF.ockeloen.2015.1176" rid="kbgs.REF.ockeloen.2015.1176">Ockeloen et al 2015</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. Other abnormalities include a short and webbed neck, abnormal ribs, brachydactyly, clinodactyly, syndactyly of toes 2-3, kyphosis, scoliosis, hip dysplasia or Perthes disease, sternum abnormalities, and wormian bones in the skull [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>]. Clavicular pseudoarthrosis and osteopenia have also been reported [<a class="bibr" href="#kbgs.REF.murray.2017.1866" rid="kbgs.REF.murray.2017.1866">Murray et al 2017</a>].</p></div><div id="kbgs.Neurologic"><h4>Neurologic</h4><p><b>Intellectual abilities – childhood.</b> Cognitive skills can be quite variable among affected individuals. More than 90% will have some degree of developmental delay, especially in speech [<a class="bibr" href="#kbgs.REF.locastro.2013.17" rid="kbgs.REF.locastro.2013.17">Lo-Castro et al 2013</a>, <a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>]. The voice character may be hoarse. No developmental regression has been reported. Average age for walking is 21 months [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. Average age for first words is 36 months [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>]. Some affected children attend mainstream classes with minimal additional aid while others require special education [<a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</p><p><b>Intellectual abilities – adulthood.</b> Intelligence ranges from moderate intellectual disability to normal intelligence, with most individuals having mild intellectual disability [<a class="bibr" href="#kbgs.REF.locastro.2013.17" rid="kbgs.REF.locastro.2013.17">Lo-Castro et al 2013</a>, <a class="bibr" href="#kbgs.REF.van_dongen.2017.248" rid="kbgs.REF.van_dongen.2017.248">van Dongen et al 2017</a>]. It is not uncommon for verbal IQ to surpass performance IQ. Completing a regular high school without support appears to be rare; however, some reported adults have completed trade school. More than half of affected adults had jobs and were self-sufficient. Some were able to live completely independently, while others required some assistance with tasks at home, such as finances. Some affected women have had children and raised them with help from a spouse or other family members [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</p><p><b>Seizures.</b> EEG abnormalities, with or without seizures, have been reported in about 50% of affected individuals [<a class="bibr" href="#kbgs.REF.skjei.2007.292" rid="kbgs.REF.skjei.2007.292">Skjei et al 2007</a>]. Age of onset can range from infancy to the teenage years [<a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. The type of epilepsy is variable. Although tonic-clonic seizures are most common, no one specific type of epilepsy has been associated with the syndrome. Treatment with anti-seizure medication has proven effective in the majority of affected individuals. Many have remission of symptoms after adolescence [<a class="bibr" href="#kbgs.REF.locastro.2013.17" rid="kbgs.REF.locastro.2013.17">Lo-Castro et al 2013</a>]. A few affected individuals have reportedly had severe seizures at a young age (described as infantile spasms / epileptic encephalopathy), in some cases drug resistant [C Ockeloen, personal communication; <a class="bibr" href="#kbgs.REF.samanta.2015.779" rid="kbgs.REF.samanta.2015.779">Samanta & Willis 2015</a>].</p><p><b>Brain malformations.</b> Various brain abnormalities have been reported, including cerebellar vermis hypoplasia [<a class="bibr" href="#kbgs.REF.zollino.1994.302" rid="kbgs.REF.zollino.1994.302">Zollino et al 1994</a>], enlarged cysterna magna, chiari I malformation, periventricular nodular heterotopia, pineal cyst, dysgenesis of the corpus callosum, colpocephaly, posterior fossa arachnoid cyst, and optic nerve hypoplasia [<a class="bibr" href="#kbgs.REF.oegema.2010.164" rid="kbgs.REF.oegema.2010.164">Oegema et al 2010</a>, <a class="bibr" href="#kbgs.REF.willemsen.2010.429" rid="kbgs.REF.willemsen.2010.429">Willemsen et al 2010</a>, <a class="bibr" href="#kbgs.REF.ockeloen.2015.1176" rid="kbgs.REF.ockeloen.2015.1176">Ockeloen et al 2015</a>]. Meningomyelocele has also been reported [<a class="bibr" href="#kbgs.REF.maegawa.2004.150" rid="kbgs.REF.maegawa.2004.150">Maegawa et al 2004</a>, <a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>]. The frequency of brain malformations is not known because brain MRI has not been performed in large cohorts of affected individuals. In a cohort of 13 affected children, two had mild periventricular leukomalacia with normal ventricles and an isolated dilated left ventricle, and the other two showed moderate enlargement of the cisterna magna with normal ventricles [<a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. In another cohort five out of six affected individuals who had neuroimaging had significant brain changes including widespread calcification, agenesis of corpus callosum, and small optic nerves [<a class="bibr" href="#kbgs.REF.murray.2017.1866" rid="kbgs.REF.murray.2017.1866">Murray et al 2017</a>].</p><p><b>Behavior.</b> Behavioral issues are reported in at least half of affected persons with KBG syndrome. Milder issues include poor concentration and restless movement. More severe issues include obsessions and deteriorating behavior when routines are changed. Anxiety and shyness are common, as are reports of difficulty in understanding social situations.</p><ul><li class="half_rhythm"><div>Attention deficit hyperactivity disorder is diagnosed in 10%-15% of affected individuals [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</div></li><li class="half_rhythm"><div>While behavior issues are common among affected individuals, reports regarding the extent of association between autism spectrum disorder (ASD) and KBG syndrome are conflicting:</div><ul><li class="half_rhythm"><div>Previous studies reported an association between ASD and the 16q24.3 deletion [<a class="bibr" href="#kbgs.REF.willemsen.2010.429" rid="kbgs.REF.willemsen.2010.429">Willemsen et al 2010</a>, <a class="bibr" href="#kbgs.REF.handrigan.2013.163" rid="kbgs.REF.handrigan.2013.163">Handrigan et al 2013</a>].</div></li><li class="half_rhythm"><div>ASD has not been commonly seen in affected individuals with intragenic <i>ANKRD11</i> pathogenic variants: <a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al [2016]</a> reported one affected individual with ASD in a cohort of 35 affected people; in a study by <a class="bibr" href="#kbgs.REF.murray.2017.1866" rid="kbgs.REF.murray.2017.1866">Murray et al [2017]</a> one of 18 affected individuals met DSM-V criteria for ASD; <a class="bibr" href="#kbgs.REF.ockeloen.2015.1176" rid="kbgs.REF.ockeloen.2015.1176">Ockeloen et al [2015]</a> reported ASD in eight of 20 affected individuals (40%); <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al [2016]</a> reported eight children with ASD out of 32 (25%) who had intragenic <i>ANKRD11</i> pathogenic variants. Ascertainment bias may have played a role in this discrepancy.</div></li></ul></li></ul></div><div id="kbgs.Hearing"><h4>Hearing</h4><p>Hearing issues are seen in 25%-31% of affected individuals. Recurrent otitis media has been shown to cause hearing loss in some individuals with KBG syndrome. All types of hearing loss (conductive, mixed, and sensorineural) have been reported in association with the condition, with conductive loss being the most common.</p></div><div id="kbgs.Less_Common_Findings"><h4>Less Common Findings</h4><p>Undescended testicles have been reported in 25%-35% of males [<a class="bibr" href="#kbgs.REF.brancati.2004.144" rid="kbgs.REF.brancati.2004.144">Brancati et al 2004</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</p><p>Cardiac defects, including ASD and VSD, have been reported [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>] in 10%-26% of affected individuals.</p><p>Various ocular findings, including strabismus, congenital bilateral cataract, high myopia, and megalocornea [<a class="bibr" href="#kbgs.REF.brancati.2006" rid="kbgs.REF.brancati.2006">Brancati et al 2006</a>], have also been reported.</p><p>Advanced puberty, sometimes requiring treatment, has been reported in some individuals.</p><p>Skin and hair abnormalities, such as hyperpigmentation, ichthyosis, hypertrichosis, abnormal hair whorls, and dystrophic nails, have been reported [<a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</p></div><div id="kbgs.Prenatal"><h4>Prenatal</h4><p>There is one report of prenatal diagnosis of KBG syndrome [<a class="bibr" href="#kbgs.REF.hodgetts_morton.2017.189" rid="kbgs.REF.hodgetts_morton.2017.189">Hodgetts Morton et al 2017</a>]. A 1.86-Mb microdeletion encompassing <i>ANKRD11</i> and 25 other genes was identified in a male fetus showing multiple external congenital anomalies including a triangular-shaped face, mildly low-set ears, and a right retained testis. Internal congenital anomalies included incomplete lobation of the left lung, lobulated spleen, cervical ribs, irregularity of vertebral body C1-4, and calcification of the liver associated with the portal tracts.</p></div></div><div id="kbgs.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>The vast majority of pathogenic variants are loss-of-function variants. No specific genotype/phenotype correlations have been reported, with the exception of those who have a larger 16q24.3 deletion.</p><p><b>16q24.3 deletions.</b> Individuals with a 16q24.3 deletion have the findings of KBG syndrome listed previously in addition to intellectual disability and autism spectrum disorder (although the increased frequency of autism spectrum diagnoses in this cohort may be a result of ascertainment bias) [<a class="bibr" href="#kbgs.REF.willemsen.2010.429" rid="kbgs.REF.willemsen.2010.429">Willemsen et al 2010</a>, <a class="bibr" href="#kbgs.REF.sacharow.2012.547" rid="kbgs.REF.sacharow.2012.547">Sacharow et al 2012</a>, <a class="bibr" href="#kbgs.REF.khalifa.2013.835" rid="kbgs.REF.khalifa.2013.835">Khalifa et al 2013</a>, <a class="bibr" href="#kbgs.REF.miyatake.2013.1073" rid="kbgs.REF.miyatake.2013.1073">Miyatake et al 2013</a>].</p><ul><li class="half_rhythm"><div>Deletions in the 16q24.3 region are not recurrent; each affected individual or family appears to have a novel deletion. It is likely that other genes deleted in this region have an effect on the phenotype [<a class="bibr" href="#kbgs.REF.sacharow.2012.547" rid="kbgs.REF.sacharow.2012.547">Sacharow et al 2012</a>, <a class="bibr" href="#kbgs.REF.lim.2014.390" rid="kbgs.REF.lim.2014.390">Lim et al 2014</a>].</div></li><li class="half_rhythm"><div>Individuals with a 16q24.3 deletion that includes <i>ANKRD11</i> and surrounding genes have a more severe phenotype, with brain anomalies detected in 28%, congenital heart defects in 33%, severe astigmatism in 28%, and thrombocytopenia in 22% [<a class="bibr" href="#kbgs.REF.novara.2017.694" rid="kbgs.REF.novara.2017.694">Novara et al 2017</a>].</div></li></ul></div><div id="kbgs.Prevalence"><h3>Prevalence</h3><p>KBG syndrome was initially thought to be quite rare; however, it is likely underdiagnosed because of mild and nonspecific features in some affected individuals especially before eruption of the permanent dentition [<a class="bibr" href="#kbgs.REF.sirmaci.2011.289" rid="kbgs.REF.sirmaci.2011.289">Sirmaci et al 2011</a>]. To date, more than 100 individuals have been reported in the literature.</p></div></div><div id="kbgs.Genetically_Related_Allelic_Disorde"><h2 id="_kbgs_Genetically_Related_Allelic_Disorde_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants in <i>ANKRD11</i>.</p><p>Individuals with larger deletions of the 16q24.3 region that include <i>ANKRD11</i> have findings of KBG syndrome in addition to other features (see <a href="#kbgs.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a>). This disorder is occasionally referred to as "16q24.3 microdeletion syndrome" [<a class="bibr" href="#kbgs.REF.novara.2017.694" rid="kbgs.REF.novara.2017.694">Novara et al 2017</a>], although deletions of this region are non-recurrent.</p></div><div id="kbgs.Differential_Diagnosis"><h2 id="_kbgs_Differential_Diagnosis_">Differential Diagnosis</h2><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkbgsTdisorderstoconsiderinthediff"><a href="/books/NBK487886/table/kbgs.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobkbgsTdisorderstoconsiderinthediff"><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="kbgs.T.disorders_to_consider_in_the_diff"><a href="/books/NBK487886/table/kbgs.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object" rid-ob="figobkbgsTdisorderstoconsiderinthediff">Table 2. </a></h4><p class="float-caption no_bottom_margin">Disorders to Consider in the Differential Diagnosis of KBG Syndrome </p></div></div></div><div id="kbgs.Management"><h2 id="_kbgs_Management_">Management</h2><div id="kbgs.Evaluations_Following_Initial_Diagn"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with KBG syndrome, the evaluations summarized in <a href="/books/NBK487886/table/kbgs.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobkbgsTrecommendedevaluationsfollowing">Table 3</a> (if they have not already been completed) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkbgsTrecommendedevaluationsfollowing"><a href="/books/NBK487886/table/kbgs.T.recommended_evaluations_following/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobkbgsTrecommendedevaluationsfollowing"><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="kbgs.T.recommended_evaluations_following"><a href="/books/NBK487886/table/kbgs.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobkbgsTrecommendedevaluationsfollowing">Table 3. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis of KBG Syndrome </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkbgsTevaluationstoconsiderfollowing"><a href="/books/NBK487886/table/kbgs.T.evaluations_to_consider_following/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobkbgsTevaluationstoconsiderfollowing"><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="kbgs.T.evaluations_to_consider_following"><a href="/books/NBK487886/table/kbgs.T.evaluations_to_consider_following/?report=objectonly" target="object" rid-ob="figobkbgsTevaluationstoconsiderfollowing">Table 4. </a></h4><p class="float-caption no_bottom_margin">Evaluations To Consider Following Initial Diagnosis of KBG Syndrome </p></div></div></div><div id="kbgs.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkbgsTtreatmentofmanifestationsinin"><a href="/books/NBK487886/table/kbgs.T.treatment_of_manifestations_in_in/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobkbgsTtreatmentofmanifestationsinin"><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="kbgs.T.treatment_of_manifestations_in_in"><a href="/books/NBK487886/table/kbgs.T.treatment_of_manifestations_in_in/?report=objectonly" target="object" rid-ob="figobkbgsTtreatmentofmanifestationsinin">Table 5. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with KBG Syndrome </p></div></div><div id="kbgs.Developmental_Delay__Intellectual_D"><h4>Developmental Delay / Intellectual Disability Management Issues</h4><p>The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.</p><p><b>Ages 0-3 years.</b> Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy. In the US, early intervention is a federally funded program available in all states.</p><p><b>Ages 3-5 years.</b> In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed.</p><p>
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<b>Ages 5-21 years</b>
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</p><ul><li class="half_rhythm"><div>In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.</div></li><li class="half_rhythm"><div>Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.</div></li></ul><p><b>All ages.</b> Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.</p><p>Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.</p><p>In the US:</p><ul><li class="half_rhythm"><div>Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.</div></li><li class="half_rhythm"><div>Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.</div></li></ul></div><div id="kbgs.Motor_Dysfunction"><h4>Motor Dysfunction</h4><p>
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<b>Gross motor dysfunction</b>
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</p><ul><li class="half_rhythm"><div>Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).</div></li><li class="half_rhythm"><div>Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).</div></li></ul><p><b>Fine motor dysfunction.</b> Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function (e.g., feeding, grooming, dressing, writing).</p><p><b>Oral motor dysfunction.</b> Assuming that the individual is safe to eat by mouth, feeding therapy – typically from an occupational or speech therapist – is recommended for affected individuals who have difficulty feeding as a result of poor oral motor control.</p><p><b>Communication issues.</b> Consider evaluation for alternative means of communication (e.g., <a href="https://www.asha.org/NJC/AAC/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">augmentative and alternative communication</a> [AAC]) for individuals who have expressive language difficulties.</p></div><div id="kbgs.SocialBehavioral_Concerns"><h4>Social/Behavioral Concerns</h4><p>Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.</p><p>Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications when necessary.</p></div></div><div id="kbgs.Surveillance"><h3>Surveillance</h3><p>Routine monitoring for the following should be considered:</p><ul><li class="half_rhythm"><div>Hearing, to assess for hearing loss</div></li><li class="half_rhythm"><div>Vision, if ophthalmologic issues are present</div></li><li class="half_rhythm"><div>Growth and pubertal status, to assess for short stature, growth velocity, and advanced or premature puberty [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]</div></li><li class="half_rhythm"><div>Regular developmental assessments to evaluate cognition and learning</div></li></ul></div><div id="kbgs.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Because of the risk of hearing loss, ototoxic drugs should be avoided.</p></div><div id="kbgs.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#kbgs.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="kbgs.Pregnancy_Management"><h3>Pregnancy Management</h3><p>There are no universal pregnancy issues in women with KBG syndrome. Pregnancy management should be tailored to the specific features present in the affected woman. For those who have congenital heart defects, management by a cardiologist and maternal fetal medicine physician during pregnancy should be considered. For those who have a seizure disorder that requires medical therapy, management by a neurologist during pregnancy should be considered.</p><p>In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [<a class="bibr" href="#kbgs.REF.sarma.2016.467" rid="kbgs.REF.sarma.2016.467">Sarma et al 2016</a>].</p><p>See <a href="https://www.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="kbgs.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><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 information on clinical studies for a wide range of diseases and conditions.</p></div></div><div id="kbgs.Genetic_Counseling"><h2 id="_kbgs_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="kbgs.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>KBG syndrome, caused by a non-recurrent deletion of 16q24.3 that includes <i>ANKRD11</i> or by a pathogenic variant within <i>ANKRD11</i>, is inherited in an autosomal dominant manner.</p></div><div id="kbgs.Risk_to_Family_Members"><h3>Risk to Family Members</h3><div id="kbgs.NonRecurrent_Deletion_of_16q24_3_In"><h4>Non-Recurrent Deletion of 16q24.3 Including <i>ANKRD11</i></h4><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>25% of probands with KBG syndrome caused by deletion of 16q24.3 have a parent who is mildly affected and/or harbors the deletion in a mosaic fashion.</div></li><li class="half_rhythm"><div>75% of probands with KBG syndrome caused by deletion 16q24.3 have a <i>de novo</i> deletion.</div></li><li class="half_rhythm"><div>Evaluation of the parents by genomic testing that will detect the deletion identified in the proband is recommended.</div></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to the sibs of a proband depends on the genetic status of the proband's parents.</div></li><li class="half_rhythm"><div>If the 16q24.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is low (<1%) but greater than that of the general population because of the possibility of parental germline mosaicism [<a class="bibr" href="#kbgs.REF.khalifa.2013.835" rid="kbgs.REF.khalifa.2013.835">Khalifa et al 2013</a>].</div></li><li class="half_rhythm"><div>If one of the parents has the deletion identified in the proband, the risk to each sib of inheriting the deletion is 50%. However, it is not possible to reliably predict clinical severity in sibs who inherit the deletion.</div></li></ul><p><b>Offspring of a proband.</b> Each child of an individual with deletion 16q24.3 has a 50% chance of inheriting the 16q24.3 deletion; however, it is not possible to reliably predict clinical severity in offspring who inherit the deletion.</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 16q24.3 deletion, the parent's family members may be at risk.</p></div><div id="kbgs.Pathogenic_Variant_Within_ANKRD11"><h4>Pathogenic Variant Within <i>ANKRD11</i></h4><p>
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<b>Parents of a proband</b>
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</p><ul><li class="half_rhythm"><div>Approximately 34% of individuals with KBG syndrome caused by a pathogenic variant within <i>ANKRD11</i> have an affected parent<i>.</i></div></li><li class="half_rhythm"><div>Approximately 66% of individuals with KBG syndrome caused by a pathogenic variant within <i>ANKRD11</i> have a <i>de novo</i> variant.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a proband with an apparent <i>ANKRD11</i> pathogenic variant to determine if the variant was inherited or is <i>de novo</i> in the proband.</div></li><li class="half_rhythm"><div>If the <i>ANKRD11</i> pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a <i>de novo</i>
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<i>ANKRD11</i> pathogenic variant in the proband or, theoretically, germline mosaicism in a parent.</div><ul><li class="half_rhythm"><div>If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [<a class="bibr" href="#kbgs.REF.crippa.2015.20" rid="kbgs.REF.crippa.2015.20">Crippa et al 2015</a>].</div></li><li class="half_rhythm"><div>No cases of mosaicism for the <i>ANKRD11</i> pathogenic variant limited to only the germline have been reported.</div></li></ul></li></ul><p>
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<b>Sibs of a proband</b>
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</p><ul><li class="half_rhythm"><div>The risk to the sibs of a proband depends on the genetic status of the proband's parents:</div><ul><li class="half_rhythm"><div>If a parent of the proband has the <i>ANKRD11</i> pathogenic variant, the risk to sibs of inheriting the variant is 50%. Intrafamilial clinical variability has been reported.</div></li><li class="half_rhythm"><div>If the <i>ANKRD11</i> pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism.</div></li></ul></li><li class="half_rhythm"><div>If the parents have not been tested for the <i>ANKRD11</i> pathogenic variant but are clinically unaffected, sibs are still at increased risk for KBG syndrome because of the possibility of parental somatic mosaicism leading to a very mild phenotype [<a class="bibr" href="#kbgs.REF.crippa.2015.20" rid="kbgs.REF.crippa.2015.20">Crippa et al 2015</a>] or the theoretic possibility of parental germline mosaicism.</div></li></ul><p><b>Offspring of a proband</b> have a 50% chance of inheriting the <i>ANKRD11</i> sequence variant; however, it is not possible to reliably predict clinical severity in offspring who inherit the 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 <i>ANKRD11</i> pathogenic variant, the parent's family members may be at risk.</p></div></div><div id="kbgs.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p><b>Considerations in families with an apparent <i>de novo</i> pathogenic variant.</b> When neither parent of a proband with an autosomal dominant condition has the genetic alteration identified in the proband or clinical evidence of the disorder, the genetic alteration is likely <i>de novo;</i> however, gonadal mosaicism cannot be excluded. Further non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.</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 of having a child with KBG syndrome.</div></li></ul></div><div id="kbgs.Prenatal_Testing_and_Preimplantatio"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once an intragenic <i>ANKRD11</i> pathogenic variant or deletion of 16q24.3 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="kbgs.Resources"><h2 id="_kbgs_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>KBG Foundation</b>
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</div><div>8539 South Redwood Road</div><div>West Jordan UT 84088</div><div><b>Phone:</b> 801-566-5949</div><div><b>Fax:</b> 801-566-5949</div><div><b>Email:</b> contact@KBGFoundation.com</div><div>
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<a href="http://www.kbgfoundation.com/home.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.kbgfoundation.com</a>
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</div></li><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/kbg-syndrome/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">KBG syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>Children's Craniofacial Association</b>
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</div><div><b>Phone:</b> 800-535-3643</div><div><b>Email:</b> contactCCA@ccakids.com</div><div>
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<a href="https://ccakids.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ccakids.org</a>
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</div></li><li class="half_rhythm"><div>
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<b>World Craniofacial Foundation</b>
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</div><div>7777 Forest Lane</div><div>Suite C-616</div><div>Dallas TX 75230</div><div><b>Phone:</b> 800-533-3315</div><div><b>Fax:</b> 972-566-3850</div><div><b>Email:</b> info@worldcf.org</div><div>
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<a href="https://worldcf.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.worldcf.org</a>
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</div></li></ul>
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</div><div id="kbgs.Molecular_Genetics"><h2 id="_kbgs_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="figkbgsmolgenTA"><a href="/books/NBK487886/table/kbgs.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobkbgsmolgenTA"><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="kbgs.molgen.TA"><a href="/books/NBK487886/table/kbgs.molgen.TA/?report=objectonly" target="object" rid-ob="figobkbgsmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">KBG Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkbgsmolgenTB"><a href="/books/NBK487886/table/kbgs.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobkbgsmolgenTB"><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="kbgs.molgen.TB"><a href="/books/NBK487886/table/kbgs.molgen.TB/?report=objectonly" target="object" rid-ob="figobkbgsmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for KBG Syndrome (View All in OMIM) </p></div></div><div id="kbgs.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><b>Gene structure.</b> The <i>ANKRD11</i> transcript <a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_013275.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_013275.5</a> has 13 exons, of which exons 1 and 2 are noncoding.</p><p><b>Pathogenic variants.</b> The great majority of pathogenic variants are frameshift and nonsense. Most are clustered within exon 9, although this is likely because this exon represents more than 80% of the coding region; missense variants should be interpreted with caution, as many have been reported among the general population [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>]. The vast majority of reported pathogenic variants are private to individual families. The pathogenic c.1903_1907delAAACA variant has been reported in multiple affected individuals from different backgrounds [<a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]. Pathogenic deletion can involve all of <i>ANKRD11</i> or only a portion of the gene [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>]. One intragenic multiexon duplication has been reported [<a class="bibr" href="#kbgs.REF.crippa.2015.20" rid="kbgs.REF.crippa.2015.20">Crippa et al 2015</a>].</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figkbgsTankrd11pathogenicvariantsdiscu"><a href="/books/NBK487886/table/kbgs.T.ankrd11_pathogenic_variants_discu/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobkbgsTankrd11pathogenicvariantsdiscu"><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="kbgs.T.ankrd11_pathogenic_variants_discu"><a href="/books/NBK487886/table/kbgs.T.ankrd11_pathogenic_variants_discu/?report=objectonly" target="object" rid-ob="figobkbgsTankrd11pathogenicvariantsdiscu">Table 6. </a></h4><p class="float-caption no_bottom_margin"><i>ANKRD11</i> Pathogenic Variants Discussed in This <i>GeneReview</i> </p></div></div><p><b>Normal gene product.</b>
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<i>ANKRD11</i> encodes the ankryn repeat domain-containing protein 11 (ANKRD11). The protein typically regulates transcription by binding chromatin modifying enzymes, such as histone deacetylases. This is important for nervous system development and function. The gene contains two transcriptional repression domains at the N and C terminals. There is also an activation domain that can stimulate transcription. ANKRD11 is known to interact with TP53 and there is an indirect association with CDKN1A, both of which are proteins known to be important in cell cycle progression. It is proposed that ANKRD11 functions as a transcriptional co-regulator for histone acetylation, thereby affecting the developing nervous system [<a class="bibr" href="#kbgs.REF.gallagher.2015.31" rid="kbgs.REF.gallagher.2015.31">Gallagher et al 2015</a>, <a class="bibr" href="#kbgs.REF.walz.2015.181" rid="kbgs.REF.walz.2015.181">Walz et al 2015</a>, <a class="bibr" href="#kbgs.REF.sirmaci.2011.289" rid="kbgs.REF.sirmaci.2011.289">Sirmaci et al 2011</a>]. Recent findings suggest that ANKRD11 plays a role in epigenetic modification of genes involved in neuron differentiation during brain development [<a class="bibr" href="#kbgs.REF.ka.2018.138" rid="kbgs.REF.ka.2018.138">Ka & Kim 2018</a>].</p><p><b>Abnormal gene product.</b> The mechanism of pathogenicity for ANKRD11 has not yet been fully elucidated; however, there are two proposed mechanisms. It is possible that ANKRD11 is involved in synaptogenesis. Another likely possibility is that the protein is involved in early nervous system development, and abnormal localization causes a damaged template for the circuitry of the nervous system to be built, thereby causing abnormal cognitive function [<a class="bibr" href="#kbgs.REF.sirmaci.2011.289" rid="kbgs.REF.sirmaci.2011.289">Sirmaci et al 2011</a>, <a class="bibr" href="#kbgs.REF.walz.2015.181" rid="kbgs.REF.walz.2015.181">Walz et al 2015</a>, <a class="bibr" href="#kbgs.REF.gallagher.2015.31" rid="kbgs.REF.gallagher.2015.31">Gallagher et al 2015</a>]. It appears that haploinsufficiency results in the KBG syndrome phenotype [<a class="bibr" href="#kbgs.REF.sirmaci.2011.289" rid="kbgs.REF.sirmaci.2011.289">Sirmaci et al 2011</a>]; however, since the vast majority of detected pathogenic variants affect the ANKRD11 C terminal region, and the N terminal region contains a dimerization motif, a dominant-negative effect of the pathogenic allele has not been excluded [<a class="bibr" href="#kbgs.REF.walz.2015.181" rid="kbgs.REF.walz.2015.181">Walz et al 2015</a>].</p></div></div><div id="kbgs.Chapter_Notes"><h2 id="_kbgs_Chapter_Notes_">Chapter Notes</h2><div id="kbgs.Acknowledgments"><h3>Acknowledgments</h3><p>We are grateful to Rena Pressman for her critical reading.</p></div><div id="kbgs.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>22 March 2018 (ma) Review posted live</div></li><li class="half_rhythm"><div>21 June 2017 (mt) Original submission</div></li></ul></div></div><div id="kbgs.References"><h2 id="_kbgs_References_">References</h2><div id="kbgs.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.brancati.2004.144">Brancati F, D'Avanzo MG, Digilio MC, Sarkozy A, Biondi M, De Brasi D, Mingarelli R, Dallapiccola B. KBG syndrome in a cohort of Italian patients. <span><span class="ref-journal">Am J Med Genet A. </span>2004;2004;<span class="ref-vol">131</span>:144–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15523620" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15523620</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.brancati.2006">Brancati F, Sarkozy A, Dallapiccola B (2006). KBG syndrome. Orphanet J Rare Dis. 12;1:50. [<a href="/pmc/articles/PMC1764006/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1764006</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17163996" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17163996</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.crippa.2015.20">Crippa M, Rusconi D, Castronovo C, Bestetti I, Russo S, Cereda A, Selicorni A, Larizza L, Finelli P. Familial intragenic duplication of ANKRD11 underlying three patients of KBG syndrome. <span><span class="ref-journal">Mol Cytogenet. </span>2015;<span class="ref-vol">8</span>:20.</span> [<a href="/pmc/articles/PMC4383199/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4383199</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25838844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25838844</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.gallagher.2015.31">Gallagher D, Voronova A, Zander MA, Cancino GI, Bramall A, Krause MP, Abad C, Tekin M, Neilsen PM, Callen DF, Scherer SW, Keller GM, Kaplan DR, Walz K, Miller FD. <em>Ankrd11</em> is a chromatin regulator involved in autism that is essential for neural development. <span><span class="ref-journal">Dev Cell. </span>2015;<span class="ref-vol">32</span>:31–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25556659" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25556659</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.goldenberg.2016.2847">Goldenberg A, Riccardi F, Tessier A, Pfundt R, Busa T, Cacciagli P, Capri Y, Coutton C, Delahaye-Duriez A, Frebourg T, et al. Clinical and molecular findings in 39 patients with KBG syndrome caused by deletion or mutation of ANKRD11. <span><span class="ref-journal">Am J Med Genet A. </span>2016;<span class="ref-vol">170</span>:2847–59.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27605097" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27605097</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.handrigan.2013.163">Handrigan GR, Chitayat D, Lionel AC, Pinsk M, Vaags AK, Marshall CR, Dyack S, Escobar LF, Fernandez BA, Stegman JC, Rosenfeld JA, Shaffer LG, Goodenberger M, Hodge JC, Cain JE, Babul-Hirji R, Stavropoulos DJ, Yiu V, Scherer SW, Rosenblum ND. Deletions in 16q24.2 are associated with autism spectrum disorder, intellectual disability and congenital renal malformation. <span><span class="ref-journal">J Med Genet. </span>2013;<span class="ref-vol">50</span>:163–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23335808" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23335808</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.herrmann.1975.7">Herrmann J, Pallister PD, Tiddy W, Opitz JM. The KBG syndrome-a syndrome of short stature, characteristic facies, mental retardation, macrodontia and skeletal anomalies. <span><span class="ref-journal">Birth Defects Orig Artic Ser. </span>1975;<span class="ref-vol">11</span>:7–18.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1218237" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1218237</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.hodgetts_morton.2017.189">Hodgetts Morton V, Quinlan-Jones E, Butts N, Williams D, Hamilton S, Marton T, Morris K. The first antenatal diagnosis of KBG syndrome: a microdeletion at chromosome 16q24.2q24.3 containing multiple genes including ANKRD11 associated with the disorder. <span><span class="ref-journal">Clin Case Rep. </span>2017;<span class="ref-vol">6</span>:189–91.</span> [<a href="/pmc/articles/PMC5771919/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5771919</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29375862" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29375862</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.ka.2018.138">Ka M, Kim W-Y. ANKRD11 associated with intellectual disability and autism regulates dendrite differentiation via the BDNF/TrkB signaling pathway. <span><span class="ref-journal">Neurobiol Dis. </span>2018;<span class="ref-vol">111</span>:138–52.</span> [<a href="/pmc/articles/PMC5803300/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5803300</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29274743" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29274743</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.khalifa.2013.835">Khalifa M, Stein J, Grau L, Nelson V, Meck J, Aradhya S, Duby J. Partial deletion of ANKRD11results in the KBG phenotype distinct from the 16q24.3 microdeletion syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2013;2013;<span class="ref-vol">161A</span>:835–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23494856" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23494856</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.kumar.2009.e72">Kumar H, Prabhu N, Cameron A. KBG syndrome: review of the literature and findings of 5 affected patients. <span><span class="ref-journal">Oral Surg Oral Med Oral Pathol Oral Radiol Endod. </span>2009;<span class="ref-vol">108</span>:e72–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19716495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19716495</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.lim.2014.390">Lim JH, Seo EJ, Kim YM, Cho HJ, Lee JO, Cheon CK, Yoo HW. A de novo microdeletion of ANKRD11 gene in a Korean patient with KBG syndrome. <span><span class="ref-journal">Ann Lab Med. </span>2014;2014;<span class="ref-vol">34</span>:390–4.</span> [<a href="/pmc/articles/PMC4151010/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4151010</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25187894" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25187894</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.locastro.2013.17">Lo-Castro A, Brancati F, Digilio MC, Garaci FG, Bollero P, Alfieri P, Curatolo P. Neurobehavioral phenotype observed in KBG syndrome caused by ANKRD11 mutations. <span><span class="ref-journal">Am J Med Genet B Neuropsychiatr Genet. </span>2013;<span class="ref-vol">162B</span>:17–23.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23184435" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23184435</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.low.2016.2835">Low K, Ashraf T, Canham N, Clayton-Smith J, Deshpande C, Donaldson A, Fisher R, Flinter F, Foulds N, Fryer A, et al. Clinical and genetic aspects of KBG syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2016;<span class="ref-vol">170</span>:2835–46.</span> [<a href="/pmc/articles/PMC5435101/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5435101</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/27667800" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27667800</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.maegawa.2004.150">Maegawa GH, Leite JC, Félix TM, da Silveira HL, da Silveira HE. Clinical variability in KBG syndrome: report of three unrelated families. <span><span class="ref-journal">Am J Med Genet A. </span>2004;2004;<span class="ref-vol">131</span>:150–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15384099" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15384099</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.miyatake.2013.1073">Miyatake S, Murakami A, Okamoto N, Sakamoto M, Miyake N, Saitsu H, Matsumoto N. A de novo deletion at 16q24.3 involving ANKRD11 in a Japanese patient with KBG syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2013;<span class="ref-vol">161A</span>:1073–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23463723" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23463723</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.murray.2017.1866">Murray N, Burgess B, Hay R, Colley A, Rajagopalan S, McGaughran J, Patel C, Enriquez A, Goodwin L, Stark Z, Tan T, Wilson M, Roscioli T, Tekin M, Goel H. KBG syndrome: an Australian experience. <span><span class="ref-journal">Am J Med Genet A. </span>2017;<span class="ref-vol">173</span>:1866–77.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/28449295" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28449295</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.novara.2017.694">Novara F, Rinaldi B, Sisodiya SM, Coppola A, Giglio S, Stanzial F, Benedicenti F, Donaldson A, Andrieux J, Stapleton R, Weber A, Reho P, van Ravenswaaij-Arts C, Kerstjens-Frederikse WS, Vermeesch JR, Devriendt K, Bacino CA, Delahaye A, Maas SM, Iolascon A, Zuffardi O. Haploinsufficiency for ANKRD11-flanking genes makes the difference between KBG and 16q24.3 microdeletion syndromes: 12 new cases. <span><span class="ref-journal">Eur J Hum Genet. </span>2017;<span class="ref-vol">25</span>:694–701.</span> [<a href="/pmc/articles/PMC5533198/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5533198</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28422132" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 28422132</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.ockeloen.2015.1176">Ockeloen CW, Willemsen MH, de Munnik S, van Bon BW, de Leeuw N, Verrips A, Kant SG, Jones EA, Brunner HG, van Loon RL, et al. Further delineation of the KBG syndrome caused by ANKDR11 aberrations. <span><span class="ref-journal">Eur J Hum Genet. </span>2015;<span class="ref-vol">23</span>:1176–85.</span> [<a href="/pmc/articles/PMC4538199/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4538199</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25424714" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25424714</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.oegema.2010.164">Oegema R, Schot R, de Wit MC, Lequin MH, Oostenbrink R, de Coo IF, Mancini GM. KBG syndrome associated with periventricular nodular heterotopia. <span><span class="ref-journal">Clin Dysmorphol. </span>2010;2010;<span class="ref-vol">19</span>:164–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20354438" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20354438</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.reynaert.2015.361">Reynaert N, Ockeloen CW, Sävendahl L, Beckers D, Devriendt K, Kleefstra T, Carels CE, Grigelioniene G, Nordgren A, Francois I, de Zegher F, Casteels K. Short stature in KBG syndrome: first responses to growth hormone treatment. <span><span class="ref-journal">Horm Res Paediatr. </span>2015;<span class="ref-vol">83</span>:361–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25833229" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25833229</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.richards.2015.405">Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. <span><span class="ref-journal">Genet Med. </span>2015;<span class="ref-vol">17</span>:405–24.</span> [<a href="/pmc/articles/PMC4544753/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4544753</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25741868" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25741868</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.sacharow.2012.547">Sacharow S, Li D, Fan YS, Tekin M. Familial 16q24.3 microdeletion involving ANKRD11 causes a KBG-like syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2012;<span class="ref-vol">158A</span>:547–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22307766" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22307766</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.samanta.2015.779">Samanta D, Willis E. Electroencephalographic findings in KBG syndrome: a child with novel mutation in ANKRD11 gene. <span><span class="ref-journal">Acta Neurol Belg. </span>2015;<span class="ref-vol">115</span>:779–82.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25543316" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25543316</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.sarma.2016.467">Sarma AK, Khandker N, Kurczewski L, Brophy GM. Medical management of epileptic seizures: challenges and solutions. <span><span class="ref-journal">Neuropsychiatr Dis Treat. </span>2016;<span class="ref-vol">12</span>:467–85.</span> [<a href="/pmc/articles/PMC4771397/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4771397</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/26966367" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26966367</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.sirmaci.2011.289">Sirmaci A, Spiliopoulos M, Brancati F, Powell E, Duman D, Abrams A, Bademci G, Agolini E, Guo S, Konuk B, Kavaz A, Blanton S, Digilio MC, Dallapiccola B, Young J, Zuchner S, Tekin M. Mutations in ANKRD11 cause KBG syndrome, characterized by intellectual disability, skeletal malformations, and macrodontia. <span><span class="ref-journal">Am J Hum Genet. </span>2011;2011;<span class="ref-vol">89</span>:289–94.</span> [<a href="/pmc/articles/PMC3155157/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3155157</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21782149" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21782149</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.skjei.2007.292">Skjei KL, Martin M, Slavotinek A. KBG syndrome: report of twins, neurological characteristics, and delineation of diagnostic criteria. <span><span class="ref-journal">Am J Med Genet A. </span>2007;<span class="ref-vol">143A</span>:292–300.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17230487" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17230487</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.van_dongen.2017.248">van Dongen LCM, Wingbermühle E, Oomens W, Bos-Roubus AG, Ockeloen CW, Kleefstra T, Egger JIM. Intellectual profiles in KBG-syndrome: a Wechsler based case-control study. <span><span class="ref-journal">Front Behav Neurosci. </span>2017;<span class="ref-vol">11</span>:248.</span> [<a href="/pmc/articles/PMC5742227/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC5742227</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29311865" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 29311865</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.walz.2015.181">Walz K, Cohen D, Neilsen PM, Foster J 2nd, Brancati F, Demir K, Fisher R, Moffat M, Verbeek NE, Bjørgo K, Lo Castro A, Curatolo P, Novelli G, Abad C, Lei C, Zhang L, Diaz-Horta O, Young JI, Callen DF, Tekin M. Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome. <span><span class="ref-journal">Hum Genet. </span>2015;<span class="ref-vol">134</span>:181–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/25413698" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25413698</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.willemsen.2010.429">Willemsen MH, Fernandez BA, Bacino CA, Gerkes E, de Brouwer AP, Pfundt R, Sikkema-Raddatz B, Scherer SW, Marshall CR, Potocki L, van Bokhoven H, Kleefstra T. Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome. <span><span class="ref-journal">Eur J Hum Genet. </span>2010;<span class="ref-vol">18</span>:429–35.</span> [<a href="/pmc/articles/PMC2987261/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2987261</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19920853" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19920853</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="kbgs.REF.zollino.1994.302">Zollino M, Battaglia A, D'Avanzo MG, Della Bruna MM, Marini R, Scarano G, Cappa M, Neri G. Six additional cases of the KBG syndrome: clinical reports and outline of the diagnostic criteria. <span><span class="ref-journal">Am J Med Genet. </span>1994;<span class="ref-vol">52</span>:302–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7810561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7810561</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK487886_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Dayna Morel Swols</span>, MS, CGC<div class="affiliation small">Division of Clinical and Translational Genetics<br />Dr John T Macdonald Foundation Department of Human Genetics<br />John P Hussman Institute for Human Genomics<br />Miller School of Medicine<br />University of Miami<br />Miami, Florida<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.imaim.dem@leromd" class="oemail">ude.imaim.dem@leromd</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Mustafa Tekin</span>, MD<div class="affiliation small">Division of Clinical and Translational Genetics<br />Dr John T Macdonald Foundation Department of Human Genetics<br />John P Hussman Institute for Human Genomics<br />Miller School of Medicine<br />University of Miami<br />Miami, Florida<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.imaim.dem@niketm" class="oemail">ude.imaim.dem@niketm</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">March 22, 2018</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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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>Morel Swols D, Tekin M. KBG Syndrome. 2018 Mar 22. 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/kat6b-dis/?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/kcnk9-is/?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="figobkbgsTmoleculargenetictestingusedin"><div id="kbgs.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 KBG Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK487886/table/kbgs.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>ANKRD11</i>
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</td><td headers="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>3</sup></td><td headers="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">69% <sup>4</sup></td></tr><tr><td headers="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5, 6</sup></td><td headers="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14% <sup>4</sup></td></tr><tr><td headers="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">CMA <sup>7</sup></td><td headers="hd_h_kbgs.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">17% <sup>4</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="kbgs.TF.1.1"><p class="no_margin">See <a href="/books/NBK487886/?report=reader#kbgs.molgen.TA">Table A. Genes and Databases</a> for chromosome locus and protein.</p></div></dd></dl><dl class="bkr_refwrap"><dt>2. </dt><dd><div id="kbgs.TF.1.2"><p class="no_margin">See <a href="#kbgs.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="kbgs.TF.1.3"><p class="no_margin">Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; 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>4. </dt><dd><div id="kbgs.TF.1.4"><p class="no_margin">The percentage represents the proportion of affected individuals who were detected to have a causative <i>ANKRD11</i> variant using each method [<a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>, <a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>]. The proportion of individuals who have suggestive clinical findings of KBG syndrome but do not have a detectable <i>ANKRD11</i> variant has not been clearly established.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="kbgs.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.</p></div></dd></dl><dl class="bkr_refwrap"><dt>6. </dt><dd><div id="kbgs.TF.1.6"><p class="no_margin">Gene-targeted deletion/duplication testing will detect single-exon up to whole-gene deletions; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods. Note that one intragenic duplication variant that included <i>ANKRD11</i> exons 3-9 was reported [<a class="bibr" href="#kbgs.REF.crippa.2015.20" rid="kbgs.REF.crippa.2015.20">Crippa et al 2015</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>7. </dt><dd><div id="kbgs.TF.1.7"><p class="no_margin">Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 16q24.3 region. Note: The 16q24.3 deletion may not have been detectable by older oligonucleotide or bacterial artificial chromosome (BAC) platforms.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkbgsTdisorderstoconsiderinthediff"><div id="kbgs.T.disorders_to_consider_in_the_diff" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of KBG Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK487886/table/kbgs.T.disorders_to_consider_in_the_diff/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.T.disorders_to_consider_in_the_diff_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_1" style="text-align:left;vertical-align:middle;">DiffDx Disorder</th><th id="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_2" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of the DiffDx Disorder</th></tr><tr><th headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4" id="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/KBG syndrome</th><th headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4" id="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from KBG syndrome</th></tr></thead><tbody><tr><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/cdls/?report=reader">Cornelia de Lange syndrome</a>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>NIPBL</i>
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<br />
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<i>SMC1A</i>
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<br />
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<i>HDAC8</i>
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<br />
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<i>SMC3</i>
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<br />
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<i>RAD21</i>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD<br />XL</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Facial features</div></li><li class="half_rhythm"><div>DD</div></li><li class="half_rhythm"><div>Growth restriction</div></li><li class="half_rhythm"><div>Hearing loss</div></li><li class="half_rhythm"><div>Cryptorchidism</div></li></ul>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Typically:
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<ul><li class="half_rhythm"><div>Head circumference small</div></li><li class="half_rhythm"><div>ID more severe</div></li></ul></td></tr><tr><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/rss/?report=reader">Silver-Russell syndrome</a>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 1.</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See footnote 1.</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Facial features</div></li><li class="half_rhythm"><div>DD</div></li><li class="half_rhythm"><div>Growth restriction</div></li><li class="half_rhythm"><div>Cryptorchidism</div></li></ul>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>IUGR</div></li><li class="half_rhythm"><div>Limb/facial asymmetry</div></li></ul>
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</td></tr><tr><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aarskog-Scott syndrome<br />(OMIM <a href="https://omim.org/entry/305400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">305400</a>)</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGD1</i>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">XL</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Short stature</div></li><li class="half_rhythm"><div>Distinctive facial features</div></li><li class="half_rhythm"><div>Macrodontia</div></li><li class="half_rhythm"><div>Brachydactyly</div></li><li class="half_rhythm"><div>Vertebral anomalies</div></li><li class="half_rhythm"><div>Cryptorchidism</div></li></ul>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Cognitive ability normal in most</div></li><li class="half_rhythm"><div>Shawl scrotum in males</div></li></ul>
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</td></tr><tr><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/cohen/?report=reader">Cohen syndrome</a>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>VPS13B</i>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Prominent central incisors</div></li><li class="half_rhythm"><div>DD</div></li></ul>
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</td><td headers="hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_1_4 hd_h_kbgs.T.disorders_to_consider_in_the_diff_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<ul><li class="half_rhythm"><div>Microcephaly</div></li><li class="half_rhythm"><div>Obesity</div></li><li class="half_rhythm"><div>Myopia</div></li><li class="half_rhythm"><div>Choreoretinal dystrophy</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">AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="kbgs.TF.2.1"><p class="no_margin">Silver-Russell syndrome has multiple etiologies including: epigenetic changes that modify expression of genes in the imprinted region of chromosome 11p15.5, maternal UPD7, and (infrequently) autosomal dominant or autosomal recessive inheritance.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkbgsTrecommendedevaluationsfollowing"><div id="kbgs.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis of KBG Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK487886/table/kbgs.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.T.recommended_evaluations_following_lrgtbl__"><table><thead><tr><th id="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">System/Concern</th><th id="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Evaluation</th><th id="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Oropharynx</b>
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|
</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dental eval for anomalies incl macrodontia, oligodontia, enamel hypoplasia [<a class="bibr" href="#kbgs.REF.kumar.2009.e72" rid="kbgs.REF.kumar.2009.e72">Kumar et al 2009</a>]</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assessment for cleft palate, bifid uvula, velopharyngeal insufficiency</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer to cleft/craniofacial team if palatal anomalies are present or suspected.</td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
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</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">EEG if seizures are suspected</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider head MRI to evaluate for brain malformations if seizures are present.</td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Genitourinary</b>
|
|
</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assessment for undescended testes in males</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer to urologist as needed.</td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Hearing</b>
|
|
</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Audiologic eval</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Cardiovascular</b>
|
|
</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Echocardiogram to assess for congenital heart disease</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer to cardiologist as needed.</td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Eyes</b>
|
|
</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ophthalmologic eval</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Miscellaneous/</b>
|
|
<br />
|
|
<b>Other</b>
|
|
</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider psychiatric eval for severe behavioral issues.</td></tr><tr><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_kbgs.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobkbgsTevaluationstoconsiderfollowing"><div id="kbgs.T.evaluations_to_consider_following" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Evaluations To Consider Following Initial Diagnosis of KBG Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK487886/table/kbgs.T.evaluations_to_consider_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.T.evaluations_to_consider_following_lrgtbl__"><table><thead><tr><th id="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">System/Concern</th><th id="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Evaluation</th><th id="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Gastrointestinal</b>
|
|
</td><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feeding & nutrition eval [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>]</td><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider nasogastric or gastrostomy tube placement if clinically indicated.</td></tr><tr><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Musculoskeletal</b>
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|
</td><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Skeletal survey to assess for costovertebral anomalies, scoliosis, kyphosis</td><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider referral to orthopedist if indicated.</td></tr><tr><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Endocrine</b>
|
|
</td><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for short stature.</td><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider bone age assessment.</td></tr><tr><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Assess for advanced or premature puberty.</td><td headers="hd_h_kbgs.T.evaluations_to_consider_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer to endocrinologist as needed.</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobkbgsTtreatmentofmanifestationsinin"><div id="kbgs.T.treatment_of_manifestations_in_in" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with KBG Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK487886/table/kbgs.T.treatment_of_manifestations_in_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.T.treatment_of_manifestations_in_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Manifestation/Concern</th><th id="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Treatment</th><th id="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Palatal anomalies</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Surgical correction &/or speech therapy may be required.</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Feeding issues</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nasogastric tube during infancy or medication for GERD may be required.</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Refer to nutritionist or dietician as needed [<a class="bibr" href="#kbgs.REF.goldenberg.2016.2847" rid="kbgs.REF.goldenberg.2016.2847">Goldenberg et al 2016</a>, <a class="bibr" href="#kbgs.REF.low.2016.2835" rid="kbgs.REF.low.2016.2835">Low et al 2016</a>].</td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Seizures</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment per neurologist based on type of seizure present [<a class="bibr" href="#kbgs.REF.locastro.2013.17" rid="kbgs.REF.locastro.2013.17">Lo-Castro et al 2013</a>]</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Undescended testes</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per urologist</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Chronic otitis media</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to otolaryngologist for consideration of pressure-equalizing tubes &/or tonsillectomy/adenoidectomy</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Hearing loss</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider amplification.</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See <a href="/books/n/gene/deafness-overview/?report=reader">Hereditary Hearing Loss and Deafness Overview</a>.</td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Cardiovascular anomalies</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per cardiologist</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
|
<b>Vision issues / strabismus</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard treatment per ophthalmologist</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Short stature</b>
|
|
</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider growth hormone therapy.</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Premature puberty</b>
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</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider medication to arrest puberty, as per endocrinologist.</td><td headers="hd_h_kbgs.T.treatment_of_manifestations_in_in_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">GERD = gastroesophageal reflux disease</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobkbgsmolgenTA"><div id="kbgs.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>KBG Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK487886/table/kbgs.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_kbgs.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_kbgs.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_kbgs.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_kbgs.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_kbgs.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_kbgs.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_kbgs.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/29123" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>ANKRD11</i>
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</a>
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</td><td headers="hd_b_kbgs.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=29123" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">16q24<wbr style="display:inline-block"></wbr>​.3</a>
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</td><td headers="hd_b_kbgs.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/Q6UB99" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Ankyrin repeat domain-containing protein 11</a>
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</td><td headers="hd_b_kbgs.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://lovd.nl/ANKRD11" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ANKRD11 @ LOVD</a>
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<br />
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<a href="http://www.iranome.ir/gene/ENSG00000167522" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Iran Variation Database - ANKRD11</a>
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</td><td headers="hd_b_kbgs.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=ANKRD11" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ANKRD11</a>
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</td><td headers="hd_b_kbgs.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=ANKRD11[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ANKRD11</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="kbgs.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="figobkbgsmolgenTB"><div id="kbgs.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for KBG Syndrome (<a href="/omim/148050,611192" 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/NBK487886/table/kbgs.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.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/148050" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">148050</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">KBG SYNDROME; KBGS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/611192" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">611192</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 11; ANKRD11</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobkbgsTankrd11pathogenicvariantsdiscu"><div id="kbgs.T.ankrd11_pathogenic_variants_discu" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p><i>ANKRD11</i> Pathogenic Variants Discussed in This <i>GeneReview</i></p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK487886/table/kbgs.T.ankrd11_pathogenic_variants_discu/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__kbgs.T.ankrd11_pathogenic_variants_discu_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_kbgs.T.ankrd11_pathogenic_variants_discu_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_kbgs.T.ankrd11_pathogenic_variants_discu_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_kbgs.T.ankrd11_pathogenic_variants_discu_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th></tr></thead><tbody><tr><td headers="hd_h_kbgs.T.ankrd11_pathogenic_variants_discu_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1903_1907delAAACA</td><td headers="hd_h_kbgs.T.ankrd11_pathogenic_variants_discu_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Lys635GlnfsTer26</td><td headers="hd_h_kbgs.T.ankrd11_pathogenic_variants_discu_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_013275.5" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_013275<wbr style="display:inline-block"></wbr>​.5</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_037407.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_037407<wbr style="display:inline-block"></wbr>​.4</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><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/?report=reader">Quick Reference</a> for an explanation of nomenclature.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobkbgsF1"><div id="kbgs.F1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK487886/bin/kbgs-Image001.jpg" alt="Figure 1. " /></div><h3><span class="label">Figure 1. </span></h3><div class="caption"><p>Macrodontia of permanent upper central incisors, dental pits, and prominent mamelons</p></div></div></article><article data-type="fig" id="figobkbgsF2"><div id="kbgs.F2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK487886/bin/kbgs-Image002.jpg" alt="Figure 2. " /></div><h3><span class="label">Figure 2. </span></h3><div class="caption"><p>Triangular face, synophrys, prominent nasal bridge, anteverted nares, long philtrum, and thin vermilion of the upper lip in two affected males</p></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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