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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Snyder-Robinson Syndrome - GeneReviews® - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="GeneReviews® [Internet]">
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<meta name="citation_title" content="Snyder-Robinson Syndrome">
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<meta name="citation_publisher" content="University of Washington, Seattle">
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<meta name="citation_date" content="2020/02/13">
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<meta name="citation_author" content="Charles E Schwartz">
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<meta name="citation_author" content="Angela Peron">
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<meta name="citation_author" content="Mary Jo Kutler">
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<meta name="citation_pmid" content="23805436">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK144284/">
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<meta name="citation_keywords" content="Spermine Synthase Deficiency">
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<meta name="citation_keywords" content="Spermine Synthase Deficiency">
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<meta name="citation_keywords" content="Spermine synthase">
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<meta name="citation_keywords" content="SMS">
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<meta name="citation_keywords" content="Snyder-Robinson Syndrome">
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<meta name="DC.Title" content="Snyder-Robinson Syndrome">
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<meta name="DC.Contributor" content="Charles E Schwartz">
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<meta name="DC.Contributor" content="Angela Peron">
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<meta name="DC.Contributor" content="Mary Jo Kutler">
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<meta name="description" content="Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, speech abnormalities, and seizures. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.">
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<meta name="og:description" content="Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, speech abnormalities, and seizures. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.">
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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="_NBK144284_"><span class="title" itemprop="name">Snyder-Robinson Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonym: Spermine Synthase Deficiency</div><p class="contribs">Schwartz CE, Peron A, Kutler MJ.</p><p class="fm-aai"><a href="#_NBK144284_pubdet_">Publication Details</a></p><p><em>Estimated reading time: 20 minutes</em></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="snyder-robinson.Summary" itemprop="description"><h2 id="_snyder-robinson_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome characterized by asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, speech abnormalities, and seizures. Developmental delay usually presents as failure to meet early developmental milestones and then evolves to moderate to profound intellectual disability (which appears to remain stable over time) and variable motor disability. Asthenic habitus and low muscle mass usually develop during the first year, even in males who are ambulatory. During the first decade, males with SRS develop osteoporosis, resulting in fractures in the absence of trauma.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of SRS is established by identification of a hemizygous loss-of-function <i>SMS</i> pathogenic variant on molecular genetic testing.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Speech, physical, and/or occupational therapy may be helpful. Standard surgical treatment by craniofacial team for those with cleft palate. Calcium supplementation has slightly improved bone mineral density in a few individuals. Standard management of kyphoscoliosis by orthopedics. Seizures have shown varying responses to anti-seizure medications; carbamazepine, phenobarbital, clobazam, levetiracetam, and valproic acid have been used successfully in some individuals.</p><p><i>Surveillance:</i> Monitor developmental progress and educational needs. Clinical examination and DXA scans to evaluate for progression of osteoporosis and investigate for factures if medically indicated. While receiving calcium supplementation, individuals should be evaluated regularly for ectopic calcification by endocrinology. Clinical examinations for kyphoscoliosis at each visit. Monitor those with seizures as clinically indicated.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>SRS is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%: Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers (to date, features of SRS have not been observed in heterozygous females). Affected males are not known to reproduce. Once an SMS pathogenic variant is identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.</p></div></div><div id="snyder-robinson.Diagnosis"><h2 id="_snyder-robinson_Diagnosis_">Diagnosis</h2><p>Formal diagnostic criteria have not been established for Snyder-Robinson syndrome (SRS).</p><div id="snyder-robinson.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Snyder-Robinson syndrome <b>should be</b>
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<b>suspected</b> in males with the following findings [<a class="bibr" href="#snyder-robinson.REF.arena.1996.50" rid="snyder-robinson.REF.arena.1996.50">Arena et al 1996</a>, <a class="bibr" href="#snyder-robinson.REF.cason.2003.937" rid="snyder-robinson.REF.cason.2003.937">Cason et al 2003</a>, <a class="bibr" href="#snyder-robinson.REF.de_alencastro.2008.539" rid="snyder-robinson.REF.de_alencastro.2008.539">de Alencastro et al 2008</a>, <a class="bibr" href="#snyder-robinson.REF.becerrasolano.2009.328" rid="snyder-robinson.REF.becerrasolano.2009.328">Becerra-Solano et al 2009</a>, <a class="bibr" href="#snyder-robinson.REF.schwartz.2011" rid="snyder-robinson.REF.schwartz.2011">Schwartz et al 2011</a>, <a class="bibr" href="#snyder-robinson.REF.peron.2013.2316" rid="snyder-robinson.REF.peron.2013.2316">Peron et al 2013</a>, <a class="bibr" href="#snyder-robinson.REF.zhang.2013.3789" rid="snyder-robinson.REF.zhang.2013.3789">Zhang et al 2013</a>, <a class="bibr" href="#snyder-robinson.REF.albert.2015.27" rid="snyder-robinson.REF.albert.2015.27">Albert et al 2015</a>, <a class="bibr" href="#snyder-robinson.REF.abela.2016.131" rid="snyder-robinson.REF.abela.2016.131">Abela et al 2016</a>]:</p><ul><li class="half_rhythm"><div><b>Intellectual disability</b> (100% [20/20]); classified as moderate to severe generalized psychomotor delay that begins in infancy. IQ ranges from unmeasurable to 60.</div></li><li class="half_rhythm"><div><b>Hypotonia</b> (100% [20/20]); secondary to poor muscular development</div></li><li class="half_rhythm"><div><b>Asthenic body build and diminished body bulk</b> (95% [19/20]). Many individuals also have measurably long fingers and toes.</div></li><li class="half_rhythm"><div><b>Bone abnormalities</b> including osteoporosis (100% [14/14]), fractures and kyphoscoliosis (84%; 16/19 individuals had both fractures and kyphoscoliosis), and joint contractures (15% [3/14])</div></li><li class="half_rhythm"><div><b>Facial dysmorphism</b> including asymmetric face (64% [13/20]) and prominent lower lip (79% [16/20])</div></li><li class="half_rhythm"><div><b>Ambulation abnormalities</b> ranging from unsteady gait to inability to walk (71% [14/19])</div></li><li class="half_rhythm"><div><b>Speech abnormalities</b> including nasal, dysarthric, coarse, or absent speech (100% [19/19])</div></li><li class="half_rhythm"><div><b>Abnormal palate</b> morphology including high, narrow, or cleft palate (83% [15/17])</div></li><li class="half_rhythm"><div><b>Mild short stature</b> (73% [14/19]). Growth rates are normal but the length or height is at least 1 SD below the mean. Height in four of seven (on whom data are available) was less than 2 SD below the mean.</div></li><li class="half_rhythm"><div><b>Seizures</b> (67%). Usually present by early childhood. Severity and frequency vary and success of treatment varies.</div></li><li class="half_rhythm"><div><b>Genital abnormalities</b> (15% [3/20]) including low testicular volume, hypospadias, and undescended testes</div></li><li class="half_rhythm"><div><b>Renal complications</b> (15% [3/20]). Nephrocalcinosis (unrelated to calcium administration) and renal cysts have been reported in three individuals with SRS.</div></li></ul></div><div id="snyder-robinson.Establishing_the_Diagnos"><h3>Establishing the Diagnosis</h3><p><b>Male proband.</b> The diagnosis of Snyder-Robinson syndrome <b>is established</b> in a male proband with <b>EITHER</b> of the following:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Spermine synthase (SMS) enzyme analysis.</b> Decreased or absent SMS enzyme activity in fresh white cells or cultured lymphoblasts</div><div class="half_rhythm">Note: Increased spermidine to spermine ratio in fresh white cells or cultured lymphoblasts is pathognomonic of SRS. (Absolute levels of spermidine or spermine do not differ significantly between affected individuals and controls.)</div></li><li class="half_rhythm"><div class="half_rhythm"><b>Molecular genetic testing.</b> Identification of a hemizygous loss-of-function pathogenic (or likely pathogenic) variant in <i>SMS</i> (see <a href="/books/NBK144284/table/snyder-robinson.T.molecular_genetic_test/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTmoleculargenetictest">Table 1</a>).</div></li></ul><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="#snyder-robinson.REF.richards.2015.405" rid="snyder-robinson.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>Molecular genetic testing approaches can include a combination of <b>gene-targeted testing</b> (single-gene testing, multigene panel) and <b>comprehensive</b>
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<b>genomic testing</b> (exome sequencing, genome sequencing, exome array or high-density microarray) depending on the phenotype.</p><p>Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Snyder-Robinson syndrome is broad, individuals with the distinctive findings described in <a href="#snyder-robinson.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#snyder-robinson.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with intellectual disability are more likely to be diagnosed using genomic testing (see <a href="#snyder-robinson.Option_2">Option 2</a>).</p><div id="snyder-robinson.Option_1"><h4>Option 1</h4><p>When the phenotypic findings suggest the diagnosis of Snyder-Robinson syndrome, molecular genetic testing approaches can include <b>single-gene testing</b> or use of a <b>multigene panel</b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-gene testing.</b> Sequence analysis of <i>SMS</i> detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. If no pathogenic variant is found, performing gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications should be done if possible.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>An intellectual disability multigene panel</b> that includes <i>SMS</i> and other genes of interest (see <a href="#snyder-robinson.Differential_Diagnosis">Differential Diagnosis</a>) may be considered to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.</div><div class="half_rhythm">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>.</div></li></ul></div><div id="snyder-robinson.Option_2"><h4>Option 2</h4><p>When the phenotype is indistinguishable from many other inherited disorders characterized by intellectual disability, <b>comprehensive</b>
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<b>genomic testing</b> (which does not require the clinician to determine which gene[s] are likely involved) is the best option. <b>Exome sequencing</b> is most commonly used; <b>genome sequencing,</b> however<b>,</b> is slowly becoming the preferred approach.</p><p>If exome sequencing is not diagnostic, <b>exome array</b> (when clinically available) or high-density microarray may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.</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="figsnyderrobinsonTmoleculargenetictest"><a href="/books/NBK144284/table/snyder-robinson.T.molecular_genetic_test/?report=objectonly" target="object" title="Table 1. " class="img_link icnblk_img" rid-ob="figobsnyderrobinsonTmoleculargenetictest"><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="snyder-robinson.T.molecular_genetic_test"><a href="/books/NBK144284/table/snyder-robinson.T.molecular_genetic_test/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTmoleculargenetictest">Table 1. </a></h4><p class="float-caption no_bottom_margin">Molecular Genetic Testing Used in Snyder-Robinson Syndrome </p></div></div></div></div></div><div id="snyder-robinson.Clinical_Characteristics"><h2 id="_snyder-robinson_Clinical_Characteristics_">Clinical Characteristics</h2><div id="snyder-robinson.Clinical_Description"><h3>Clinical Description</h3><p>Snyder-Robinson syndrome (SRS) is an X-linked intellectual disability syndrome with a specific clinical phenotype consisting of asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, and speech abnormalities.</p><p>To date, 20 individuals have been identified with a pathogenic variant in <i>SMS</i> [<a class="bibr" href="#snyder-robinson.REF.peron.2013.2316" rid="snyder-robinson.REF.peron.2013.2316">Peron et al 2013</a>, <a class="bibr" href="#snyder-robinson.REF.zhang.2013.3789" rid="snyder-robinson.REF.zhang.2013.3789">Zhang et al 2013</a>, <a class="bibr" href="#snyder-robinson.REF.albert.2015.27" rid="snyder-robinson.REF.albert.2015.27">Albert et al 2015</a>, <a class="bibr" href="#snyder-robinson.REF.abela.2016.131" rid="snyder-robinson.REF.abela.2016.131">Abela et al 2016</a>, <a class="bibr" href="#snyder-robinson.REF.larcher.2020.103777" rid="snyder-robinson.REF.larcher.2020.103777">Larcher et al 2020</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figsnyderrobinsonTfeaturesofsnyderrobi"><a href="/books/NBK144284/table/snyder-robinson.T.features_of_snyderrobi/?report=objectonly" target="object" title="Table 2. " class="img_link icnblk_img" rid-ob="figobsnyderrobinsonTfeaturesofsnyderrobi"><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="snyder-robinson.T.features_of_snyderrobi"><a href="/books/NBK144284/table/snyder-robinson.T.features_of_snyderrobi/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTfeaturesofsnyderrobi">Table 2. </a></h4><p class="float-caption no_bottom_margin">Features of Snyder-Robinson Syndrome </p></div></div><p><b>Onset.</b> Developmental delay and facial dysmorphism manifest within the first year of life.</p><p><b>Developmental delay.</b> Hypotonia is usually present in the neonatal period which can persist into early childhood. Developmental delay usually presents as failure to meet milestones and then evolves to moderate to profound intellectual disability. The majority of males with SRS (22 published, 13 unpublished) do not appear to have progressive cognitive decline; rather, they remain cognitively stable throughout their lifetime. Those who develop speech (10/14) develop it late, some as late as age five years. Most individuals with SRS are able to follow simple commands. For two individuals who had no speech, it is unclear if a contributing factor was the absence of social contact [<a class="bibr" href="#snyder-robinson.REF.de_alencastro.2008.539" rid="snyder-robinson.REF.de_alencastro.2008.539">de Alencastro et al 2008</a>]. Delay in motor development, observed in the majority of individuals with SRS, usually presents with delays in normal movements that occur in early childhood and do not resolve.</p><p><b>Progression.</b> All reported males with SRS have maintained previously acquired skills; however, two recently identified unreported males have had progressive neurologic decline and loss of previously obtained skills. The measured IQ and cognitive functioning were highest in the original family, possibly due to the presence of residual SMS enzyme activity [<a class="bibr" href="#snyder-robinson.REF.snyder.1969.669" rid="snyder-robinson.REF.snyder.1969.669">Snyder & Robinson 1969</a>, <a class="bibr" href="#snyder-robinson.REF.cason.2003.937" rid="snyder-robinson.REF.cason.2003.937">Cason et al 2003</a>].</p><p><b>Asthenic habitus</b> and low muscle mass usually develop during the first year. Although decreased strength is not described in males with SRS, most have progressive loss of muscle mass. Loss of muscle mass occurs even in males who are ambulatory, suggesting that the loss is probably the result of an underlying defect, not lack of use.</p><p><b>Mild short stature</b> (73%). Growth rates are normal but the length or height is at least 1 SD below the mean. However, height on the 13 males for which data was available was variable, ranging from the 95th percentile to 3 SD below the mean.</p><p><b>Craniofacial features</b> include asymmetric face (64% [13/20]), prominent lower lip (79% [16/20]), and high, narrow, or cleft palate (83% [15/17]). Head circumference is often in the upper centiles.</p><p><b>Osteoporosis.</b> During the first decade of life, males with SRS develop osteoporosis. Most experience fractures in the absence of trauma or after minor trauma within the first decade, at which point the osteoporosis is discovered; the long bones are most severely affected. Among males reported, the osteoporosis and fracture activity do not progressively worsen with age but remain at the severity found at the time of diagnosis. Bone density measurements were documented in two individuals [<a class="bibr" href="#snyder-robinson.REF.albert.2015.27" rid="snyder-robinson.REF.albert.2015.27">Albert et al 2015</a>]. The mechanism of decreased bone mineral density is not well understood</p><p><b>Other musculoskeletal features.</b> Kyphoscoliosis (13/16) can appear within the first decade of life. This observation is rather rare in other X-linked conditions. Limb contractures are rare, having only been noted in four males. Abnormal pectus was noted in nine males.</p><p><b>Seizures</b> (67%). Usually present by early childhood. Severity and frequency vary. In some affected individuals, seizures may be drug-resistant [Authors’ personal observation].</p><p><b>Brain MRI findings.</b> In individuals for which brain imaging was done, ventricular dilatation was noted in two of 11 individuals, a thin corpus callosum was noted in three of ten individuals. Abnormal calcification (which has been noted in a few individuals) occurs in the absence of calcium supplementation.</p><p><b>Genital abnormalities</b> reported in 15% of males included low testicular volume, hypospadias, and undescended testes.</p><p><b>Renal complications</b> have occurred in 15% of males including nephrocalcinosis (unrelated to calcium administration) and renal cysts reported in three individuals with SRS.</p><p>Skewed X-chromosome inactivation has been observed in heterozygous females in at least three families with SRS [<a class="bibr" href="#snyder-robinson.REF.cason.2003.937" rid="snyder-robinson.REF.cason.2003.937">Cason et al 2003</a>; <a class="bibr" href="#snyder-robinson.REF.de_alencastro.2008.539" rid="snyder-robinson.REF.de_alencastro.2008.539">de Alencastro et al 2008</a>; Author, personal communication]. It is unclear if skewed X-chromosome inactivation is a protective mechanism. In at least one of the families, presence of the <i>SMS</i> pathogenic variant in a heterozygous female is not associated with skewing of X-chromosome inactivation [<a class="bibr" href="#snyder-robinson.REF.cason.2003.937" rid="snyder-robinson.REF.cason.2003.937">Cason et al 2003</a>].</p></div><div id="snyder-robinson.GenotypePhenotype_Correl"><h3>Genotype-Phenotype Correlations</h3><p>No clear genotype-phenotype correlations have been established for Snyder-Robinson syndrome. Even within a family, the phenotype varies; for example, in one family IQ values ranged from 46 to 77.</p><p>Based on the limited data available, the <a href="/books/NBK144284/table/snyder-robinson.T.notable_sms_pathogenic/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTnotablesmspathogenic">c.166G>A</a> (p.Gly56Ser), <a href="/books/NBK144284/table/snyder-robinson.T.notable_sms_pathogenic/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTnotablesmspathogenic">c.388C>T</a> (p.Arg130Cys), and <a href="/books/NBK144284/table/snyder-robinson.T.notable_sms_pathogenic/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTnotablesmspathogenic">c.443A>G</a> (p.Gln148Arg) pathogenic variants have been associated with more severe manifestations [<a class="bibr" href="#snyder-robinson.REF.de_alencastro.2008.539" rid="snyder-robinson.REF.de_alencastro.2008.539">de Alencastro et al 2008</a>, <a class="bibr" href="#snyder-robinson.REF.albert.2015.27" rid="snyder-robinson.REF.albert.2015.27">Albert et al 2015</a>, <a class="bibr" href="#snyder-robinson.REF.abela.2016.131" rid="snyder-robinson.REF.abela.2016.131">Abela et al 2016</a>].</p><p>A male infant with an <i>SMS</i> truncating variant, the first one observed, died a short time after birth [<a class="bibr" href="#snyder-robinson.REF.larcher.2020.103777" rid="snyder-robinson.REF.larcher.2020.103777">Larcher et al 2020</a>]. The clinical presentation was quite severe, with multiple organ systems involved.</p></div><div id="snyder-robinson.Penetrance"><h3>Penetrance</h3><p>All individuals with SRS have deficient spermine synthase enzyme activity. However, as its prevalence in the general population has not been determined, penetrance of deficient spermine synthase activity as SRS cannot be stated.</p><p>Sequence variants of <i>SMS</i> have been reported for one seemingly unaffected male [<a class="bibr" href="#snyder-robinson.REF.kim.2009.1011" rid="snyder-robinson.REF.kim.2009.1011">Kim et al 2009</a>]. Spermine synthase activity was not measured, and thus the functional consequences of this variant are unclear.</p><p>Additionally, five other nonsynonymous <i>SMS</i> variants were identified in large sequencing cohorts; phenotype, sex, and enzyme function are unavailable for these individuals.</p></div><div id="snyder-robinson.Nomenclature"><h3>Nomenclature</h3><p>When Snyder and Robinson first described this syndrome, they labeled it "recessive sex-linked mental retardation in the absence of other recognizable abnormalities" [<a class="bibr" href="#snyder-robinson.REF.snyder.1969.669" rid="snyder-robinson.REF.snyder.1969.669">Snyder & Robinson 1969</a>]. It is now considered an X-linked intellectual disability syndrome with a specific clinical phenotype consisting of asthenic build, facial dysmorphism with a prominent lower lip, kyphoscoliosis, osteoporosis, seizures, and speech abnormalities (see <a href="#snyder-robinson.Clinical_Description">Clinical Description</a>).</p></div><div id="snyder-robinson.Prevalence"><h3>Prevalence</h3><p>The prevalence of SRS is unknown. Of the twenty individuals evaluated and reported in the current literature, 13 were identified in the Americas: Mexico, Brazil, and the United States, and seven were identified in Western European countries, indicating that the disorder probably exists in most populations.</p></div></div><div id="snyder-robinson.Genetically_Related_Alle"><h2 id="_snyder-robinson_Genetically_Related_Alle_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with germline pathogenic variants in <i>SMS</i>.</p><p><b>Contiguous gene deletions including <i>SMS</i>.</b> Among more than 11,300 individuals studied, 14 deletions and duplications have been reported to span <i>SMS</i>. Of the copy number variations (CNVs) spanning <i>SMS</i>, only one (which was detected in 2 women) caused clinical pathology: dysmorphic features, intellectual disability, and ocular abnormalities including oculomotor apraxia, heterochromia of the iris, and vision problems. Confounding attribution of these features to hemizygosity for <i>SMS</i>: the CNV deleting <i>SMS</i> also deleted 106 other genes including 35 associated with other disorders; moreover, these women had another deletion spanning <i>SHOX</i>, which is associated with <a href="/books/n/gene/lwd/?report=reader">Leri-Weill dyschondrosteosis</a> [<a class="bibr" href="#snyder-robinson.REF.firth.2009.524" rid="snyder-robinson.REF.firth.2009.524">Firth et al 2009</a>].</p></div><div id="snyder-robinson.Differential_Diagnosis"><h2 id="_snyder-robinson_Differential_Diagnosis_">Differential Diagnosis</h2><p><b>X-linked intellectual disability</b>
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<b>syndromes with osteoporosis.</b> The observation that 30% more males than females have intellectual disability (ID) suggests that pathogenic variants of genes on the X chromosome are among the most frequent causes of ID among males [<a class="bibr" href="#snyder-robinson.REF.stevenson.2012" rid="snyder-robinson.REF.stevenson.2012">Stevenson et al 2012</a>]. X-linked intellectual disability (XID) should be considered in males who are simplex cases (i.e., a single occurrence of ID in a family) as well as in males with a family history of intellectual disability consistent with X-linked inheritance. Consideration of XID as a cause of ID in simplex cases is relevant since approximately 33% of pathogenic variants causing the more severe forms of XID arise <i>de novo</i>.</p><p>Distinguishing between various forms of syndromic ID by clinical findings alone is often difficult because of overlapping clinical features, and diagnosis frequently requires identification of the molecular cause. Nonetheless, Snyder-Robinson syndrome (SRS) can be distinguished from many forms of syndromic XID by the combination of hypotonia, facial dysmorphism, asthenic body build, and both osteoporosis and kyphoscoliosis. While kyphoscoliosis is visible, osteoporosis is not, although the presence of fractures is suggestive of it. Because osteoporosis is rare in XID, it can be utilized as a distinguishing feature and should certainly be considered in a male with fractures.</p><p>XID intellectual disability syndromes with overlapping findings of SRS and osteoporosis are summarized in <a href="/books/NBK144284/table/snyder-robinson.T.xlinked_intellectual_d/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTxlinkedintellectuald">Table 3</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figsnyderrobinsonTxlinkedintellectuald"><a href="/books/NBK144284/table/snyder-robinson.T.xlinked_intellectual_d/?report=objectonly" target="object" title="Table 3. " class="img_link icnblk_img" rid-ob="figobsnyderrobinsonTxlinkedintellectuald"><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="snyder-robinson.T.xlinked_intellectual_d"><a href="/books/NBK144284/table/snyder-robinson.T.xlinked_intellectual_d/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTxlinkedintellectuald">Table 3. </a></h4><p class="float-caption no_bottom_margin">X-linked Intellectual Disability Syndromes with Overlapping Findings of Snyder-Robinson Syndrome and Osteoporosis </p></div></div><p><b>Other syndromes with osteoporosis</b> to be considered in the differential diagnosis of SRS include the following:</p><ul><li class="half_rhythm"><div><b>Cerebral palsy (CP).</b> CP is a heterogeneous group of disorders arising from multiple genetic and environmental etiologies. In some individuals the phenotype overlaps that of SRS. Shared features can include seizures, osteoporosis, scoliosis, and developmental delay.</div></li><li class="half_rhythm"><div><a href="/books/n/gene/pws/?report=reader"><b>Prader-Willi syndrome</b></a>
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<b>(PWS).</b> Neonatal hypotonia, developmental delay, osteoporosis, and scoliosis are also features of PWS. Unlike individuals with SRS, those with PWS have metabolic syndrome, obesity, and severe behavior problems. PWS is caused by abnormal parent-specific imprinting within the Prader-Willi critical region (PWCR) on chromosome 15. The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.</div></li><li class="half_rhythm"><div><b>Urban syndrome,</b> described in two teenage males, in one family, is characterized by intellectual disability, osteoporosis, and short stature [<a class="bibr" href="#snyder-robinson.REF.urban.1979.52" rid="snyder-robinson.REF.urban.1979.52">Urban et al 1979</a>]. Unlike SRS, affected males were obese with normal muscle tone. The molecular basis of Urban syndrome is unknown.</div></li></ul></div><div id="snyder-robinson.Management"><h2 id="_snyder-robinson_Management_">Management</h2><div id="snyder-robinson.Evaluations_Following_In"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with Snyder-Robinson syndrome (SRS), the evaluations summarized in <a href="/books/NBK144284/table/snyder-robinson.T.recommended_evaluation/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTrecommendedevaluation">Table 4</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figsnyderrobinsonTrecommendedevaluation"><a href="/books/NBK144284/table/snyder-robinson.T.recommended_evaluation/?report=objectonly" target="object" title="Table 4. " class="img_link icnblk_img" rid-ob="figobsnyderrobinsonTrecommendedevaluation"><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="snyder-robinson.T.recommended_evaluation"><a href="/books/NBK144284/table/snyder-robinson.T.recommended_evaluation/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTrecommendedevaluation">Table 4. </a></h4><p class="float-caption no_bottom_margin">Recommended Evaluations Following Initial Diagnosis in Individuals with Snyder-Robinson Syndrome </p></div></div></div><div id="snyder-robinson.Treatment_of_Manifestati"><h3>Treatment of Manifestations</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figsnyderrobinsonTtreatmentofmanifesta"><a href="/books/NBK144284/table/snyder-robinson.T.treatment_of_manifesta/?report=objectonly" target="object" title="Table 5. " class="img_link icnblk_img" rid-ob="figobsnyderrobinsonTtreatmentofmanifesta"><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="snyder-robinson.T.treatment_of_manifesta"><a href="/books/NBK144284/table/snyder-robinson.T.treatment_of_manifesta/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTtreatmentofmanifesta">Table 5. </a></h4><p class="float-caption no_bottom_margin">Treatment of Manifestations in Individuals with Snyder-Robinson Syndrome </p></div></div></div><div id="snyder-robinson.Surveillance"><h3>Surveillance</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figsnyderrobinsonTrecommendedsurveillan"><a href="/books/NBK144284/table/snyder-robinson.T.recommended_surveillan/?report=objectonly" target="object" title="Table 6. " class="img_link icnblk_img" rid-ob="figobsnyderrobinsonTrecommendedsurveillan"><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="snyder-robinson.T.recommended_surveillan"><a href="/books/NBK144284/table/snyder-robinson.T.recommended_surveillan/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTrecommendedsurveillan">Table 6. </a></h4><p class="float-caption no_bottom_margin">Recommended Surveillance for Individuals with Snyder-Robinson Syndrome </p></div></div></div><div id="snyder-robinson.Evaluation_of_Relatives"><h3>Evaluation of Relatives at Risk</h3><p>See <a href="#snyder-robinson.Related_Genetic_Counseli">Genetic Counseling</a> for issues related to testing of at-risk relatives for genetic counseling purposes.</p></div><div id="snyder-robinson.Therapies_Under_Investig"><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 access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.</p></div></div><div id="snyder-robinson.Genetic_Counseling"><h2 id="_snyder-robinson_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="snyder-robinson.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Snyder-Robinson syndrome (SRS) is inherited in an X-linked manner.</p></div><div id="snyder-robinson.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
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<b>Parents of a male proband</b>
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</p><ul><li class="half_rhythm"><div>The father of an affected male will not have the disorder nor will he be hemizygous for the <i>SMS</i> pathogenic variant; therefore, he does not require further evaluation/testing.</div></li><li class="half_rhythm"><div>In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one affected child and no other affected relatives and if the <i>SMS</i> pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism. There are no data regarding frequency or possibility of germline mosaicism in SRS.</div></li><li class="half_rhythm"><div>If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote (carrier) or the affected male may have a <i>de novo</i>
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<i>SMS</i> pathogenic variant, in which case the mother is not a carrier. Of the 20 published cases reported to date, two individuals were shown to have SRS as the result of a <i>de novo</i> pathogenic variant.</div></li></ul><p><b>Sibs of a male proband.</b> The risk to sibs depends on the genetic status of the mother:</p><ul><li class="half_rhythm"><div>If the mother of the proband has an <i>SMS</i> pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers). In the families reported to date, features of SRS have not been observed in heterozygous females.</div></li><li class="half_rhythm"><div>If the proband represents a simplex case (i.e., a single occurrence in a family) and if the <i>SMS</i> pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is greater than that of the general population because of the possibility of maternal germline mosaicism.</div></li></ul><p><b>Offspring of a male proband.</b> Affected males are not known to reproduce.</p><p><b>Other family members.</b> The proband's maternal aunts may be at risk of being heterozygotes (carriers) for the pathogenic variant and the aunts' offspring, depending on their sex, may be at risk of being carriers for the pathogenic variant or of being affected.</p><p>Note: Molecular genetic testing may be able to identify the family member in whom a <i>de novo</i> pathogenic variant arose, information that could help determine genetic risk status of the extended family.</p></div><div id="snyder-robinson.Heterozygote_Carrier_Det"><h3>Heterozygote (Carrier) Detection</h3><p>Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the pathogenic variant in the family.</p><p>Note: Females are heterozygotes for this X-linked disorder; hypothetically, they could develop clinical findings related to the disorder secondary to partial loss of SMS function or skewing of X-chromosome inactivation. To date, no identified heterozygotes have had signs or symptoms attributable to their <i>SMS</i> pathogenic variant.</p></div><div id="snyder-robinson.Related_Genetic_Counseli"><h3>Related Genetic Counseling Issues</h3><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, clarification of carrier status, 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 carriers or are at risk of being carriers.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).</p></div><div id="snyder-robinson.Prenatal_Testing_and_Pre"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>SMS</i> pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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="snyder-robinson.Resources"><h2 id="_snyder-robinson_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>Snyder-Robinson Foundation</b>
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</div><div>McLean VA </div><div><b>Phone:</b> 703-533-9844</div><div><b>Email:</b> info@snyder-robinson.org</div><div>
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<a href="https://snyder-robinson.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.snyder-robinson.org</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="http://www.nlm.nih.gov/medlineplus/ency/article/001523.htm" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Intellectual Disability</a>
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</div></li><li class="half_rhythm"><div>
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<b>National Library of Medicine Genetics Home Reference</b>
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</div><div>
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<a href="https://ghr.nlm.nih.gov/condition/snyder-robinson-syndrome" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Snyder-Robinson syndrome</a>
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</div></li><li class="half_rhythm"><div>
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<b>EuroMRX Consortium Registry</b>
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</div><div>Radboud University Nijmegen Medical Centre, Department of Human Genetics</div><div>PO Box 9101</div><div>Nijmegen 6500 HB</div><div>Netherlands</div><div><b>Phone:</b> +31 24 3614017</div><div><b>Fax:</b> +31 24 3668752</div><div><b>Email:</b> a.debrouwer@antrg.umcn.nl</div><div>
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<a href="http://www.euromrx.com" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">www.euromrx.com</a>
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</div></li><li class="half_rhythm"><div>
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<b>Human Disease Genes Website Series - Registry</b>
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</div><div>
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<i>This website was created to share and collect information about clinic, management and research projects to gather more knowledge and provide better treatment of patients with mutations in the SMS gene.</i>
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</div><div>
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<a href="https://humandiseasegenes.nl/sms/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SMS</a>
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</div></li></ul>
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</div><div id="snyder-robinson.Molecular_Genetics"><h2 id="_snyder-robinson_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="figsnyderrobinsonmolgenTA"><a href="/books/NBK144284/table/snyder-robinson.molgen.TA/?report=objectonly" target="object" title="Table A." class="img_link icnblk_img" rid-ob="figobsnyderrobinsonmolgenTA"><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="snyder-robinson.molgen.TA"><a href="/books/NBK144284/table/snyder-robinson.molgen.TA/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonmolgenTA">Table A.</a></h4><p class="float-caption no_bottom_margin">Snyder-Robinson Syndrome: Genes and Databases </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figsnyderrobinsonmolgenTB"><a href="/books/NBK144284/table/snyder-robinson.molgen.TB/?report=objectonly" target="object" title="Table B." class="img_link icnblk_img" rid-ob="figobsnyderrobinsonmolgenTB"><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="snyder-robinson.molgen.TB"><a href="/books/NBK144284/table/snyder-robinson.molgen.TB/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonmolgenTB">Table B.</a></h4><p class="float-caption no_bottom_margin">OMIM Entries for Snyder-Robinson Syndrome (View All in OMIM) </p></div></div><div id="snyder-robinson.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p>Polyamines are small organic molecules containing at least two amino groups, which play a wide range of regulatory functions in the cell thereby ensuring normal cell growth, differentiation, and survival [<a class="bibr" href="#snyder-robinson.REF.murraystewart.2018" rid="snyder-robinson.REF.murraystewart.2018">Murray-Stewart et al 2018</a>]. <i>SMS</i> encodes spermine synthase (SMS), which catalyzes the production of spermine, a polyamine, from spermidine and decarboxylated S-adenosylmethionine (dcSAM). Pathogenic variants in <i>SMS</i> lead to an almost total loss of enzymatic activity which in turn leads to a lack of spermine and an increase in spermidine. Therefore, Snyder-Robinson syndrome is a polyamine deficiency syndrome [<a class="bibr" href="#snyder-robinson.REF.cason.2003.937" rid="snyder-robinson.REF.cason.2003.937">Cason et al 2003</a>].</p><p><b>Mechanism of disease causation.</b> Loss of function</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figsnyderrobinsonTnotablesmspathogenic"><a href="/books/NBK144284/table/snyder-robinson.T.notable_sms_pathogenic/?report=objectonly" target="object" title="Table 7. " class="img_link icnblk_img" rid-ob="figobsnyderrobinsonTnotablesmspathogenic"><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="snyder-robinson.T.notable_sms_pathogenic"><a href="/books/NBK144284/table/snyder-robinson.T.notable_sms_pathogenic/?report=objectonly" target="object" rid-ob="figobsnyderrobinsonTnotablesmspathogenic">Table 7. </a></h4><p class="float-caption no_bottom_margin">Notable <i>SMS</i> Pathogenic Variants </p></div></div></div></div><div id="snyder-robinson.Chapter_Notes"><h2 id="_snyder-robinson_Chapter_Notes_">Chapter Notes</h2><div id="snyder-robinson.Author_History"><h3>Author History</h3><p>Jessica Albert, PhD; National Human Genome Research Institute (2013-2020)<br />Cornelius F Boerkoel, MD, PhD; National Human Genome Research Institute (2013-2020)<br />Mary Jo Kutler, MD (2020-present)<br />Angela Peron, MD (2020-present)<br />Roger E Stevenson, MD; Greenwood Genetic Center (2013-2020)<br />Charles E Schwartz, PhD (2013-present)</p></div><div id="snyder-robinson.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>13 February 2020 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>27 June 2013 (me) Review posted live</div></li><li class="half_rhythm"><div>28 January 2013 (ja) Original submission</div></li></ul></div></div><div id="snyder-robinson.References"><h2 id="_snyder-robinson_References_">References</h2><div id="snyder-robinson.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.abela.2016.131">Abela L, Simmons L, Steindl K, Schmitt B, Mastrangelo M, Joset P, Papuc M, Sticht H, Baumer A, Crowther LM, Mathis D, Rauch A, Plecko B. N. (8)-acetylspermidine as a potential plasma biomarker for Snyder-Robinson syndrome identified by clinical metabolomics. <span><span class="ref-journal">J Inherit Metab Dis. </span>2016;<span class="ref-vol">39</span>:131–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26174906" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26174906</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.albert.2015.27">Albert JS, Bhattacharyya N, Wolfe LA, Bone WP, Maduro V, Accardi J, Adams DR, Schwartz CE, Norris J, Wood T, Gafni RI, Collins MT, Tosi LL, Markello TC, Gahl WA, Boerkoel CF. Impaired osteoblast and osteoclast function characterize the osteoporosis of Snyder - Robinson syndrome. <span><span class="ref-journal">Orphanet J Rare Dis. </span>2015;<span class="ref-vol">10</span>:27.</span> [<a href="/pmc/articles/PMC4428506/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4428506</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25888122" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25888122</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.arena.1996.50">Arena JF, Schwartz C, Ouzts L, Stevenson R, Miller M, Garza J, Nance M, Lubs H. X-linked mental retardation with thin habitus, osteoporosis, and kyphoscoliosis: linkage to Xp21.3-p22.12. <span><span class="ref-journal">Am J Med Genet. </span>1996;<span class="ref-vol">64</span>:50–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8826448" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8826448</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.becerrasolano.2009.328">Becerra-Solano LE, Butler J, Castaneda-Cisneros G, McCloskey DE, Wang X, Pegg AE, Schwartz CE, Sánchez-Corona J, García-Ortiz JE. A missense mutation, p.V132G, in the X-linked spermine synthase gene (SMS) causes Snyder-Robinson syndrome. <span><span class="ref-journal">Am J Med Genet A. </span>2009;<span class="ref-vol">149A</span>:328–35.</span> [<a href="/pmc/articles/PMC2653108/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2653108</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19206178" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19206178</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.cason.2003.937">Cason AL, Ikeguchi Y, Skinner C, Wood TC, Holden KR, Lubs HA, Martinez F, Simensen RJ, Stevenson RE, Pegg AE, Schwartz CE. X-linked spermine synthase gene (SMS) defect: the first polyamine deficiency syndrome. <span><span class="ref-journal">Eur J Hum Genet. </span>2003;<span class="ref-vol">11</span>:937–44.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14508504" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14508504</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.de_alencastro.2008.539">de Alencastro G, McCloskey DE, Kliemann SE, Maranduba CM, Pegg AE, Wang X, Bertola DR, Schwartz CE, Passos-Bueno MR, Sertié AL. New SMS mutation leads to a striking reduction in spermine synthase protein function and a severe form of Snyder-Robinson X-linked recessive mental retardation syndrome. <span><span class="ref-journal">J Med Genet. </span>2008;<span class="ref-vol">45</span>:539–43.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18550699" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18550699</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.firth.2009.524">Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Van Vooren S, Moreau Y, Pettett RM, Carter NP. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. <span><span class="ref-journal">Am J Hum Genet. </span>2009;<span class="ref-vol">84</span>:524–33.</span> [<a href="/pmc/articles/PMC2667985/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2667985</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19344873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19344873</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.kim.2009.1011">Kim JI, Ju YS, Park H, Kim S, Lee S, Yi JH, Mudge J, Miller NA, Hong D, Bell CJ, Kim HS, Chung IS, Lee WC, Lee JS, Seo SH, Yun JY, Woo HN, Lee H, Suh D, Lee S, Kim HJ, Yavartanoo M, Kwak M, Zheng Y, Lee MK, Park H, Kim JY, Gokcumen O, Mills RE, Zaranek AW, Thakuria J, Wu X, Kim RW, Huntley JJ, Luo S, Schroth GP, Wu TD, Kim H, Yang KS, Park WY, Kim H, Church GM, Lee C, Kingsmore SF, Seo JS. A highly annotated whole-genome sequence of a Korean individual. <span><span class="ref-journal">Nature. </span>2009;<span class="ref-vol">460</span>:1011–5.</span> [<a href="/pmc/articles/PMC2860965/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2860965</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19587683" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19587683</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.klitten.2011.1">Klitten LL, Moller RS, Ravn K, Hjalgrim H, Tommerup N. Duplication of MAOA, MAOB, and NDP in a patient with mental retardation and epilepsy. <span><span class="ref-journal">Eur J Hum Genet. </span>2011;<span class="ref-vol">19</span>:1–2.</span> [<a href="/pmc/articles/PMC3039513/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3039513</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20808325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20808325</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.larcher.2020.103777">Larcher L, Norris JW, Lejeune E, Buratti J, Mignot C, Garel C, Keren B, Schwartz CE, Whalen S. The complete loss of function of the SMS gene results in a severe form of Snyder-Robinson syndrome. <span><span class="ref-journal">Eur J Med Genet. </span>2020;<span class="ref-vol">63</span>:103777. </span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31580924" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 31580924</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.lemke.2012.1387">Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, Hansen J, Courage C, Gallati S, Bürki S, Strozzi S, Simonetti BG, Grunt S, Steinlin M, Alber M, Wolff M, Klopstock T, Prott EC, Lorenz R, Spaich C, Rona S, Lakshminarasimhan M, Kröll J, Dorn T, Krämer G, Synofzik M, Becker F, Weber YG, Lerche H, Böhm D, Biskup S. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. <span><span class="ref-journal">Epilepsia. </span>2012;<span class="ref-vol">53</span>:1387–98.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22612257" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22612257</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.mills.2006.1182">Mills RE, Luttig CT, Larkins CE, Beauchamp A, Tsui C, Pittard WS, Devine SE. An initial map of insertion and deletion (INDEL) variation in the human genome. <span><span class="ref-journal">Genome Res. </span>2006;<span class="ref-vol">16</span>:1182–90.</span> [<a href="/pmc/articles/PMC1557762/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1557762</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16902084" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16902084</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.murraystewart.2018">Murray-Stewart T, Dunworth M, Foley JR, Schwartz CE, Casero RA Jr. Polyamine homeostasis in Snyder-Robinson syndrome. <span><span class="ref-journal">Med Sci (Basel). </span>2018;<span class="ref-vol">6</span>(4)</span> [<a href="/pmc/articles/PMC6318755/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6318755</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/30544565" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 30544565</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.peron.2013.2316">Peron A, Spaccini L, Norris J, Bova SM, Selicorni A, Weber G, Wood T, Schwartz CE, Mastrangelo M. Snyder-Robinson syndrome: a novel nonsense mutation in spermine synthase and expansion of the phenotype. <span><span class="ref-journal">Am J Med Genet A. </span>2013;<span class="ref-vol">161A</span>:2316–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23897707" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23897707</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.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="snyder-robinson.REF.schwartz.2011">Schwartz CE, Wang X, Stevenson RE, Pegg AE. Spermine synthase deficiency resulting in X-linked intellectual disability (Snyder–Robinson syndrome). In: Pegg AE, Casero RA Jr, eds. <em>Polyamines: Methods and Protocols.</em> Methods in Molecular Biology, vol 720. New York, NY: Springer Science + Business Media; 2011:437-45. [<a href="https://pubmed.ncbi.nlm.nih.gov/21318891" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21318891</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.snyder.1969.669">Snyder RD, Robinson A. Recessive sex-linked mental retardation in the absence of other recognizable abnormalities. Report of a family. <span><span class="ref-journal">Clin Pediatr (Phila). </span>1969;<span class="ref-vol">8</span>:669–74.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/5823961" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5823961</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.stevenson.2012">Stevenson RE, Schwartz CE, Rogers RC. <em>Atlas of X-Linked Intellectual Disability Syndromes</em>. 2 ed. New York, NY: Oxford University Press; 2012.</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.urban.1979.52">Urban MD, Rogers JG, Meyer WJ 3rd. Familial syndrome of mental retardation, short stature, contractures of the hands, and genital anomalies. <span><span class="ref-journal">J Pediatr. </span>1979;<span class="ref-vol">94</span>:52–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/758422" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 758422</span></a>]</div></p></li><li class="half_rhythm"><p><div class="bk_ref" id="snyder-robinson.REF.zhang.2013.3789">Zhang Z, Norris J, Kalscheuer V, Wood T, Wang L, Schwartz C, Alexov E, Van Esch H. A Y328C missense mutation in spermine synthase causes a mild form of Snyder-Robinson syndrome. <span><span class="ref-journal">Hum Mol Genet. </span>2013;<span class="ref-vol">22</span>:3789–97.</span> [<a href="/pmc/articles/PMC3749864/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3749864</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23696453" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23696453</span></a>]</div></p></li></ul></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK144284_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><div class="contrib half_rhythm"><span itemprop="author">Charles E Schwartz</span>, PhD<div class="affiliation small">Senior Research Scientist, Emeritus<br />Greenwood Genetic Center<br />Greenwood, South Carolina<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="moc.liamg@422ztrawhcs.selrahc" class="oemail">moc.liamg@422ztrawhcs.selrahc</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Angela Peron</span>, MD<div class="affiliation small">Child Neuropsychiatry Unit - Epilepsy Center (Medical Genetics)<br />San Paolo Hospital<br />Department of Health Sciences<br />Università degli Studi di Milano<br />Milan, Italy</div><div class="affiliation small">Department of Pediatrics<br />Division of Medical Genetics<br />University of Utah School of Medicine<br />Salt Lake City, Utah<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ti.iminu@norep.alegna" class="oemail">ti.iminu@norep.alegna</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Mary Jo Kutler</span>, DO<div class="affiliation small">Medical Advisor, The Snyder-Robinson Foundation<br />McLean, Virginia</div><div class="affiliation small">Clinical Assistant Professor, Pediatrics<br />Midwestern University<br />Arizona College of Osteopathic Medicine<br />Glendale, Arizona<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.nosnibor-redyns@reltuk.ojyram" class="oemail">gro.nosnibor-redyns@reltuk.ojyram</a></div></div></div><h3>Publication History</h3><p class="small">Initial Posting: <span itemprop="datePublished">June 27, 2013</span>; Last Update: <span itemprop="dateModified">February 13, 2020</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>Schwartz CE, Peron A, Kutler MJ. Snyder-Robinson Syndrome. 2013 Jun 27 [Updated 2020 Feb 13]. 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/sms/?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/sotos/?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="figobsnyderrobinsonTmoleculargenetictest"><div id="snyder-robinson.T.molecular_genetic_test" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Snyder-Robinson Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.T.molecular_genetic_test/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.T.molecular_genetic_test_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_snyder-robinson.T.molecular_genetic_test_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_snyder-robinson.T.molecular_genetic_test_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_snyder-robinson.T.molecular_genetic_test_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_snyder-robinson.T.molecular_genetic_test_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SMS</i>
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</td><td headers="hd_h_snyder-robinson.T.molecular_genetic_test_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_snyder-robinson.T.molecular_genetic_test_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">37/37 <sup>4</sup></td></tr><tr><td headers="hd_h_snyder-robinson.T.molecular_genetic_test_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted deletion/duplication analysis <sup>5</sup></td><td headers="hd_h_snyder-robinson.T.molecular_genetic_test_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No pathogenic deletion/duplication has been reported in an affected male. <sup>6</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="snyder-robinson.TF.1.1"><p class="no_margin">See <a href="/books/NBK144284/?report=reader#snyder-robinson.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="snyder-robinson.TF.1.2"><p class="no_margin">See <a href="#snyder-robinson.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this gene.</p></div></dd></dl><dl class="bkr_refwrap"><dt>3. </dt><dd><div id="snyder-robinson.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="snyder-robinson.TF.1.4"><p class="no_margin"><a class="bibr" href="#snyder-robinson.REF.peron.2013.2316" rid="snyder-robinson.REF.peron.2013.2316">Peron et al [2013]</a>; <a class="bibr" href="#snyder-robinson.REF.zhang.2013.3789" rid="snyder-robinson.REF.zhang.2013.3789">Zhang et al [2013]</a>; <a class="bibr" href="#snyder-robinson.REF.albert.2015.27" rid="snyder-robinson.REF.albert.2015.27">Albert et al [2015]</a>; <a class="bibr" href="#snyder-robinson.REF.abela.2016.131" rid="snyder-robinson.REF.abela.2016.131">Abela et al [2016]</a>; <a class="bibr" href="#snyder-robinson.REF.larcher.2020.103777" rid="snyder-robinson.REF.larcher.2020.103777">Larcher et al [2020]</a>; Schwartz et al, unpublished data.</p></div></dd></dl><dl class="bkr_refwrap"><dt>5. </dt><dd><div id="snyder-robinson.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="snyder-robinson.TF.1.6"><p class="no_margin">Among more than 11,300 individuals studied, 14 deletions and duplications have been reported to span <i>SMS</i> (see <a href="#snyder-robinson.Genetically_Related_Alle">Genetically Related Disorders</a>). Two other variants of unknown significance are reported in the database of genomic variants: an intronic deletion observed in 36 unaffected male and female controls [<a class="bibr" href="#snyder-robinson.REF.mills.2006.1182" rid="snyder-robinson.REF.mills.2006.1182">Mills et al 2006</a>] and an exon 7 deletion observed in an unaffected Korean male [<a class="bibr" href="#snyder-robinson.REF.kim.2009.1011" rid="snyder-robinson.REF.kim.2009.1011">Kim et al 2009</a>].</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobsnyderrobinsonTfeaturesofsnyderrobi"><div id="snyder-robinson.T.features_of_snyderrobi" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Features of Snyder-Robinson Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.T.features_of_snyderrobi/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.T.features_of_snyderrobi_lrgtbl__"><table><thead><tr><th id="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Persons w/Feature</th><th id="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Intellectual</b>
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<br />
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<b>disability</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22/22</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderate to severe</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Hypotonia</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">22/22</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Usually presents at birth & is persistent</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Speech</b>
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<br />
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<b>abnormalities</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19/21</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Nasal, dysarthric, coarse, or absent</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ambulation</b>
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<br />
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<b>abnormalities</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15/19</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ranges from unsteady gait to inability to walk</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Asthenic</b>
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<br />
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<b>body build</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">19/20</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low muscle mass persistent</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_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>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14/19</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1-2 SD below mean</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Craniofacial</b>
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<br />
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<b>features</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">18/20</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl asymmetric face, prominent lower lip, & high, narrow, or cleft palate</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Early-onset</b>
|
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<br />
|
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<b>osteoporosis</b>
|
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">16/16</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Fractures</td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Seizures</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">15/22</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Long hands</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14/15</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
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<b>Long great toes</b>
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</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10/14</td><td headers="hd_h_snyder-robinson.T.features_of_snyderrobi_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobsnyderrobinsonTxlinkedintellectuald"><div id="snyder-robinson.T.xlinked_intellectual_d" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>X-linked Intellectual Disability Syndromes with Overlapping Findings of Snyder-Robinson Syndrome and Osteoporosis</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.T.xlinked_intellectual_d/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.T.xlinked_intellectual_d_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_2" style="text-align:left;vertical-align:middle;">DiffDx Disorder</th><th id="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:center;vertical-align:middle;">Clinical Features of DiffDx Disorder</th></tr><tr><th headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3" id="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/SRS</th><th headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3" id="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from SRS</th></tr></thead><tbody><tr><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GK</i>
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</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Glycerol kinase deficiency (OMIM <a href="https://omim.org/entry/307030" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">307030</a>)</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>DD</div></li><li class="half_rhythm"><div>Growth restriction</div></li><li class="half_rhythm"><div>Muscle weakness</div></li><li class="half_rhythm"><div>Osteoporosis</div></li></ul>
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</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adrenal insufficiency</td></tr><tr><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>GRIA3</i>
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</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><i>GRIA3</i>-related ID (OMIM <a href="https://omim.org/entry/300699" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">300699</a>)</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>ID</div></li><li class="half_rhythm"><div>Asthenic habitus</div></li><li class="half_rhythm"><div>Seizures</div></li></ul>
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</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Aggressive behavior</td></tr><tr><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>MAOA</i>
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<br />
|
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<i>MAOB</i>
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<br />
|
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<i>NDP</i>
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</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Xp11.3 duplication <sup>1</sup></td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Moderate-to-severe ID</div></li><li class="half_rhythm"><div>Osteoporosis</div></li><li class="half_rhythm"><div>Scoliosis</div></li><li class="half_rhythm"><div>Seizures</div></li><li class="half_rhythm"><div>Speech abnormalities</div></li></ul>
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</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Excessively friendly demeanor</div></li><li class="half_rhythm"><div>Normal facial features</div></li><li class="half_rhythm"><div>Normal stature</div></li></ul>
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</td></tr><tr><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SLC16A2</i>
|
|
</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MCT8 deficiency (See <a href="/books/n/gene/thctd/?report=reader">Allan-Herndon-Dudley Syndrome</a>.)</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>ID</div></li><li class="half_rhythm"><div>Hypotonia</div></li><li class="half_rhythm"><div>↓ muscle mass</div></li><li class="half_rhythm"><div>Unsteady gait / ataxia</div></li></ul>
|
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</td><td headers="hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_1_3 hd_h_snyder-robinson.T.xlinked_intellectual_d_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Different facial features</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">DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; SRS = Snyder-Robinson syndrome</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="snyder-robinson.TF.3.1"><p class="no_margin">
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<a class="bibr" href="#snyder-robinson.REF.klitten.2011.1" rid="snyder-robinson.REF.klitten.2011.1">Klitten et al [2011]</a>
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</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobsnyderrobinsonTrecommendedevaluation"><div id="snyder-robinson.T.recommended_evaluation" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Snyder-Robinson Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.T.recommended_evaluation/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.T.recommended_evaluation_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Development</b>
|
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</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Developmental assessment</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>To incl motor, adaptive, cognitive, & speech/language eval</div></li><li class="half_rhythm"><div>Eval for early intervention / special education</div></li></ul>
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</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Constitutional</b>
|
|
</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Weight, length/height, & head circumference</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for evidence of short stature, macrocephaly.</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Cleft palate</b>
|
|
</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical eval incl feeding assessment</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
|
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<b>Musculoskeletal</b>
|
|
</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bone density assessment by DXA scan</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To determine degree of osteoporosis & need for calcium supplements or bisphosphonates <sup>1</sup></td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Clinical eval for kyphoscoliosis</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consider radiographic scoliosis survey based on clinical suspicion & referral for orthopedic surgery as appropriate.</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Neurologic</b>
|
|
</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neurologic eval</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Assessment for hypotonia</div></li><li class="half_rhythm"><div>To incl brain MRI to assess abnormal calcification &/or brain abnormalities</div></li><li class="half_rhythm"><div>Consider EEG if seizures are a concern.</div></li></ul>
|
|
</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_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_snyder-robinson.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Renal ultrasound</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To assess for renal abnormalities (rare)</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_1" scope="row" rowspan="1" 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_snyder-robinson.T.recommended_evaluation_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Consultation w/clinical geneticist &/or genetic counselor</td><td headers="hd_h_snyder-robinson.T.recommended_evaluation_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To incl genetic counseling</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">DXA = dual-energy x-ray absorptiometry</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="snyder-robinson.TF.4.1"><p class="no_margin">Bisphosphonates have been used for osteoporosis in general; their efficacy in Snyder-Robinson syndrome has not been demonstrated, and initial evidence of efficacy is controversial.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobsnyderrobinsonTtreatmentofmanifesta"><div id="snyder-robinson.T.treatment_of_manifesta" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Snyder-Robinson Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.T.treatment_of_manifesta/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.T.treatment_of_manifesta_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/<br />Concern</th><th id="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>DD/ID</b>
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</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Speech therapy, PT, &/or OT</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Some persons have performed appropriately in special education programs, learned to follow commands, & held simple jobs [<a class="bibr" href="#snyder-robinson.REF.arena.1996.50" rid="snyder-robinson.REF.arena.1996.50">Arena et al 1996</a>]; others showed no improvement of psychomotor skills w/special education [<a class="bibr" href="#snyder-robinson.REF.becerrasolano.2009.328" rid="snyder-robinson.REF.becerrasolano.2009.328">Becerra-Solano et al 2009</a>].</td></tr><tr><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Cleft palate</b>
|
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</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard surgical treatment per craniofacial team</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Osteoporosis</b>
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</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Calcium supplementation</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Calcium supplementation has slightly improved bone mineral density in a few persons [<a class="bibr" href="#snyder-robinson.REF.becerrasolano.2009.328" rid="snyder-robinson.REF.becerrasolano.2009.328">Becerra-Solano et al 2009</a>]. Calcium supplementation should be started once ↓ bone mineral density is noted.</div></li><li class="half_rhythm"><div>The use of bisphosphonates is controversial & no studies currently demonstrate their effectiveness [<a class="bibr" href="#snyder-robinson.REF.albert.2015.27" rid="snyder-robinson.REF.albert.2015.27">Albert et al 2015</a>].</div></li></ul>
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</td></tr><tr><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Kyphoscoliosis</b>
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</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard mgmt per orthopedist</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Epilepsy</b>
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</td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standardized treatment w/ASM by experienced neurologist <sup>1</sup></td><td headers="hd_h_snyder-robinson.T.treatment_of_manifesta_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Carbamazepine, phenobarbital, clobazam, levetiracetam & valproic acid have successfully controlled seizures in some persons.</div></li><li class="half_rhythm"><div>Avoid medications known to affect bone (e.g., some ASMs) as they can potentially worsen osteoporosis & ↑ risk of spontaneous fractures.</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">ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; OT = occupational therapy; PT = physical therapy</p></div></dd></dl><dl class="bkr_refwrap"><dt>1. </dt><dd><div id="snyder-robinson.TF.5.1"><p class="no_margin">Education of parents regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see <a href="https://www.epilepsy.com/tools-resources/forms-resources#Epilepsy-Foundation-Toolbox" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Epilepsy Foundation Toolbox</a>.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobsnyderrobinsonTrecommendedsurveillan"><div id="snyder-robinson.T.recommended_surveillan" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with Snyder-Robinson Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.T.recommended_surveillan/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.T.recommended_surveillan_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>DD/ID</b>
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</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor developmental progress & educational needs</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">At each visit</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Osteoporosis</b>
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</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Clinical exam & DXA scans to monitor progression of osteoporosis</div></li><li class="half_rhythm"><div>Radiographs to investigate for factures</div></li></ul>
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</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">When medically indicated</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Ectopic calcification</b>
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</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Referral to endocrinologist to manage calcium supplementation due to risk of ectopic calcification</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<b>Kyphoscoliosis</b>
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</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Monitor for scoliosis.</div></li><li class="half_rhythm"><div>Orthopedic eval as indicated</div></li></ul>
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</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor clinically at each visit.</td></tr><tr><td headers="hd_h_snyder-robinson.T.recommended_surveillan_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_snyder-robinson.T.recommended_surveillan_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Monitor those w/seizures as clinically indicated.</td><td headers="hd_h_snyder-robinson.T.recommended_surveillan_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">When medically indicated</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">DD/ID = developmental delay / intellectual disability; DXA = dual-energy x-ray absorptiometry</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobsnyderrobinsonmolgenTA"><div id="snyder-robinson.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Snyder-Robinson Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_snyder-robinson.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_snyder-robinson.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_snyder-robinson.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_snyder-robinson.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_snyder-robinson.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_snyder-robinson.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_snyder-robinson.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/6611" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>SMS</i>
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</a>
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</td><td headers="hd_b_snyder-robinson.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=6611" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Xp22<wbr style="display:inline-block"></wbr>​.11</a>
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</td><td headers="hd_b_snyder-robinson.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/P52788" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Spermine synthase</a>
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</td><td headers="hd_b_snyder-robinson.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://www.LOVD.nl/SMS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SMS @ LOVD</a>
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</td><td headers="hd_b_snyder-robinson.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=SMS" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SMS</a>
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</td><td headers="hd_b_snyder-robinson.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=SMS[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">SMS</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="snyder-robinson.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="figobsnyderrobinsonmolgenTB"><div id="snyder-robinson.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Snyder-Robinson Syndrome (<a href="/omim/300105,309583" 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/NBK144284/table/snyder-robinson.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.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/300105" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">300105</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SPERMINE SYNTHASE; SMS</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
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<a href="/omim/309583" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">309583</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">INTELLECTUAL DEVELOPMENTAL DISORDER, X-LINKED, SYNDROMIC, SNYDER-ROBINSON TYPE; MRXSSR</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobsnyderrobinsonTnotablesmspathogenic"><div id="snyder-robinson.T.notable_sms_pathogenic" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Notable <i>SMS</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK144284/table/snyder-robinson.T.notable_sms_pathogenic/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__snyder-robinson.T.notable_sms_pathogenic_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change</th><th id="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_1" rowspan="5" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_004595.4" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NM_004595<wbr style="display:inline-block"></wbr>​.4</a>
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<br />
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<a href="https://www.ncbi.nlm.nih.gov/protein/NP_004586.2" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">NP_004586<wbr style="display:inline-block"></wbr>​.2</a>
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</td><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.166G>A</td><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gly56Ser</td><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_4" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">Assoc w/severe manifestations [<a class="bibr" href="#snyder-robinson.REF.de_alencastro.2008.539" rid="snyder-robinson.REF.de_alencastro.2008.539">de Alencastro et al 2008</a>, <a class="bibr" href="#snyder-robinson.REF.lemke.2012.1387" rid="snyder-robinson.REF.lemke.2012.1387">Lemke et al 2012</a>, <a class="bibr" href="#snyder-robinson.REF.albert.2015.27" rid="snyder-robinson.REF.albert.2015.27">Albert et al 2015</a>, <a class="bibr" href="#snyder-robinson.REF.abela.2016.131" rid="snyder-robinson.REF.abela.2016.131">Abela et al 2016</a>, <a class="bibr" href="#snyder-robinson.REF.larcher.2020.103777" rid="snyder-robinson.REF.larcher.2020.103777">Larcher et al 2020</a>]</td></tr><tr><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.174T>A</td><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Phe58Leu</td></tr><tr><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.388C>T</td><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg130Cys</td></tr><tr><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.443A>G</td><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Gln148Arg</td></tr><tr><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.908_911del</td><td headers="hd_h_snyder-robinson.T.notable_sms_pathogenic_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Met303LysfsTer3</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></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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