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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Hand-Foot-Genital Syndrome" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2019/08/08" /><meta name="citation_author" content="Jeffrey W Innis" /><meta name="citation_pmid" content="20301596" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1423/" /><meta name="citation_keywords" content="HFGS" /><meta name="citation_keywords" content="HFG Syndrome" /><meta name="citation_keywords" content="HFGS" /><meta name="citation_keywords" content="HFG Syndrome" /><meta name="citation_keywords" content="Homeobox protein Hox-A13" /><meta name="citation_keywords" content="HOXA13" /><meta name="citation_keywords" content="Hand-Foot-Genital Syndrome" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Hand-Foot-Genital Syndrome" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="Jeffrey W Innis" /><meta name="DC.Date" content="2019/08/08" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1423/" /><meta name="description" content="Hand-foot-genital syndrome (HFGS) is characterized by limb malformations and urogenital defects. Mild-to-severe bilateral shortening of the thumbs and great toes, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal, is the most common limb malformation and results in impaired dexterity or apposition of the thumbs. Urogenital malformations include abnormalities of the ureters and urethra and various degrees of incomplete müllerian fusion in females, and hypospadias of variable severity with or without chordee in males. Vesicoureteral reflux, recurrent urinary tract infections, and chronic pyelonephritis may occur; fertility is normal." /><meta name="og:title" content="Hand-Foot-Genital Syndrome" /><meta name="og:type" content="book" /><meta name="og:description" content="Hand-foot-genital syndrome (HFGS) is characterized by limb malformations and urogenital defects. Mild-to-severe bilateral shortening of the thumbs and great toes, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal, is the most common limb malformation and results in impaired dexterity or apposition of the thumbs. Urogenital malformations include abnormalities of the ureters and urethra and various degrees of incomplete müllerian fusion in females, and hypospadias of variable severity with or without chordee in males. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1423_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1423_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/hyal2-def/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/gene/haplo-a20/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1423_"><span class="title" itemprop="name">Hand-Foot-Genital Syndrome</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: HFGS, HFG Syndrome</div><p class="contrib-group"><span itemprop="author">Jeffrey W Innis</span>, MD, PhD.</p><a data-jig="ncbitoggler" href="#__NBK1423_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1423_ai__"><div class="contrib half_rhythm"><span itemprop="author">Jeffrey W Innis</span>, MD, PhD<div class="affiliation small">Professor, Human Genetics, Pediatrics and Internal Medicine
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Director, Division of Pediatric Genetics, Metabolism and Genomic Medicine
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||
University of Michigan
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||
Director, Michigan Medical Genetics Laboratories
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Ann Arbor, Michigan<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.hcimu@sinni" class="oemail">ude.hcimu@sinni</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">July 11, 2006</span>; Last Update: <span itemprop="dateModified">August 8, 2019</span>.</p><p><em>Estimated reading time: 19 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="hfg.Summary" itemprop="description"><h2 id="_hfg_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Hand-foot-genital syndrome (HFGS) is characterized by limb malformations and urogenital defects. Mild-to-severe bilateral shortening of the thumbs and great toes, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal, is the most common limb malformation and results in impaired dexterity or apposition of the thumbs. Urogenital malformations include abnormalities of the ureters and urethra and various degrees of incomplete müllerian fusion in females, and hypospadias of variable severity with or without chordee in males. Vesicoureteral reflux, recurrent urinary tract infections, and chronic pyelonephritis may occur; fertility is normal.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>Diagnosis is based on physical examination including radiographs of the hands and feet and imaging studies of the kidneys, bladder, and female reproductive tract. Identification of a <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> can establish the diagnosis if clinical and radiographic features are inconclusive. Approximately 50%-60% of pathogenic variants are polyalanine expansions.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> Hand or foot surgery is not usually necessary. Ureteric reimplantation and surgical correction of bladder outlet abnormalities are often necessary. Surgical removal of a longitudinal vaginal septum is rarely indicated. Surgery for removal of a uterine septum or reunification of a bicornuate uterus is exceptional in the absence of recurrent mid-trimester pregnancy loss. Hymenectomy may be necessary for tight constriction ring.</p><p><i>Prevention of secondary complications:</i> Prophylactic antibiotics or surgery as needed to prevent urinary tract infections or other complications of ureteral reflux or ureteropelvic junction obstruction; gynecologic examination prior to menstruation for small hymenal opening; pre-pregnancy evaluation of the vaginal and uterine anatomy because of the increased risk for premature labor and fetal loss associated with structural abnormalities of the uterus.</p><p><i>Surveillance:</i> Follow up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>Hand-foot-genital syndrome is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner. The proportion of cases caused by a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> is unknown because of the small number of individuals described. If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to the sibs is 50%. If the proband has a known <i>HOXA13</i> pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a>. Each child of an individual with HFGS has a 50% chance of inheriting the pathogenic variant. Prenatal testing for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible if the pathogenic variant in the family is known.</p></div></div><div id="hfg.Diagnosis"><h2 id="_hfg_Diagnosis_">Diagnosis</h2><div id="hfg.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Hand-foot-genital syndrome <b>should be suspected</b> in individuals with the following clinical and radiographic features.</p><div id="hfg.Limb_Malformations"><h4>Limb Malformations</h4><p><b>Bilateral thumb and great-toe hypoplasia</b> are the hallmark malformations, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal. Shortening is often mild to moderate but on occasion may be more severe and may cause shortening of the distal phalanx of other digits (see <a class="bk_pop" href="#hfg.REF.mortlock.1997.179">Mortlock & Innis [1997]</a>, <a class="bk_pop" href="#hfg.REF.goodman.2000.197">Goodman et al [2000]</a> (family 5), and <a class="bk_pop" href="#hfg.REF.imagawa.2014.2398">Imagawa et al [2014]</a>). Additional findings that may be present:</p><ul><li class="half_rhythm"><div>Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger</div></li><li class="half_rhythm"><div>Hypoplastic thenar eminences</div></li><li class="half_rhythm"><div>Hallus valgus of the distal phalanx of the great toe is common; hallux varus can be observed associated with significant metatarsal shortening.</div></li><li class="half_rhythm"><div>Small great toenail</div></li><li class="half_rhythm"><div>Sandal gap (i.e., increased gap between 1st and 2nd toes)</div></li></ul><p>
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<b>Other</b>
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</p><ul><li class="half_rhythm"><div>Fifth-finger clinodactyly, secondary to a shortened middle phalanx</div></li><li class="half_rhythm"><div>Short feet</div></li><li class="half_rhythm"><div>Altered dermatoglyphics of the hands; when present, primarily involving distal placement of the axial triradius, lack of thenar or hypothenar patterning, low arches on the thumbs, thin ulnar loops (deficiency of radial loops and whorls), and a greatly reduced ridge count on the fingers</div></li></ul><p>
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<b>Radiographic findings</b>
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</p><ul><li class="half_rhythm"><div>Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes; rare hypoplasia of the distal phalanges of other digits</div></li><li class="half_rhythm"><div>Pointed distal phalanges of the thumb</div></li><li class="half_rhythm"><div>Lack of normal tufting of the distal phalanges of the great toes</div></li><li class="half_rhythm"><div>Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals</div></li><li class="half_rhythm"><div>Short calcaneus</div></li><li class="half_rhythm"><div>Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes</div></li><li class="half_rhythm"><div>Delayed carpal or tarsal maturation</div></li><li class="half_rhythm"><div>Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits</div></li></ul></div><div id="hfg.Urogenital_Defects"><h4>Urogenital Defects</h4><p><b>Females</b> may have the following:</p><ul><li class="half_rhythm"><div>Vesicoureteral reflux secondary to ureteric incompetence</div></li><li class="half_rhythm"><div>Ectopic ureteral orifices</div></li><li class="half_rhythm"><div>Trigonal hypoplasia</div></li><li class="half_rhythm"><div>Hypospadiac urethra</div></li><li class="half_rhythm"><div>Subsymphyseal epispadias</div></li><li class="half_rhythm"><div>Patulous urethra</div></li><li class="half_rhythm"><div>Urinary incontinence</div></li><li class="half_rhythm"><div>Small hymenal opening</div></li><li class="half_rhythm"><div>Various degrees of incomplete müllerian fusion with or without two cervices or a longitudinal vaginal septum</div></li></ul><p><b>Males</b> may have the following:</p><ul><li class="half_rhythm"><div>Vesicoureteral reflux</div></li><li class="half_rhythm"><div>Hypospadias of variable severity with or without chordee</div></li></ul></div></div><div id="hfg.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of hand-foot-genital syndrome <b>is established</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with characteristic fully penetrant limb malformations described in <a href="#hfg.Suggestive_Findings">Suggestive Findings</a> with or without incompletely penetrant urogenital defects.</p><p>The diagnosis of hand-foot-genital syndrome <b>can be confirmed</b> in a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> who has <b>one of the following</b> on <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> (see <a href="/books/NBK1423/table/hfg.T.molecular_genetic_testing_used_in/?report=objectonly" target="object" rid-ob="figobhfgTmoleculargenetictestingusedin">Table 1</a>):</p><ul><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> polyalanine expansion involving <i>HOXA13</i> (~50%-60% of affected individuals) [<a class="bk_pop" href="#hfg.REF.quinonez.2014.4">Quinonez & Innis 2014</a>]</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> sequence variant involving <i>HOXA13</i> (35% of affected individuals) [<a class="bk_pop" href="#hfg.REF.quinonez.2014.4">Quinonez & Innis 2014</a>]</div></li></ul><p><b>Allele sizes.</b> HOXA13 protein has three extended polyalanine tracts encoded in the first <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, referred to as Tracts I, II, and III. Approximately 50%-60% of individuals with HFGS have a polyalanine expansion of one of the tracts. No affected individual has been described with expansions in more than one tract.</p><ul><li class="half_rhythm"><div>
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<b>Normal alleles</b>
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</div><ul><li class="half_rhythm"><div><b>Tract I.</b> p.Ala38[14] residues</div></li><li class="half_rhythm"><div><b>Tract II.</b> p.Ala73[12] residues</div></li><li class="half_rhythm"><div><b>Tract III.</b> p.Ala116[8], p.Ala116[12], or p.Ala116[18] residues</div></li></ul></li><li class="half_rhythm"><div><b>Reduced-<a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> alleles.</b> Not reported</div></li><li class="half_rhythm"><div>
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<b>Full-<a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> alleles</b>
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</div><ul><li class="half_rhythm"><div><b>Tract I.</b> An <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> with eight additional alanine residues (termed "+8" alleles) was reported in association with HFGS [<a class="bk_pop" href="#hfg.REF.innis.2004.2841">Innis et al 2004</a>].</div></li><li class="half_rhythm"><div><b>Tract II.</b> An <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> with six additional alanine residues (termed "+6" alleles) was reported in association with HFGS [<a class="bk_pop" href="#hfg.REF.fris_n.2003.e49">Frisén et al 2003</a>].</div></li><li class="half_rhythm"><div><b>Tract III.</b> Polyalanine expansions of at least six additional polyalanine residues (termed "+6" alleles) to as many as 14 additional polyalanine residues (termed "+14" alleles) [<a class="bk_pop" href="#hfg.REF.innis.2004.2841">Innis et al 2004</a>, <a class="bk_pop" href="#hfg.REF.utsch.2007.3161">Utsch et al 2007</a>] may cause HFGS.</div></li></ul></li><li class="half_rhythm"><div>
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<b>Alleles of questionable significance – Tract III</b>
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</div><ul><li class="half_rhythm"><div>The significance of a shortened <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> of eight polyalanine residues observed in one family is not clear given the occurrence of another disorder in the same family that complicates interpretation of the skeletal <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#hfg.REF.innis.2004.2841">Innis et al 2004</a>]. A shortened allele of eight polyalanine residues was also reported in an unaffected woman [<a class="bk_pop" href="#hfg.REF.owens.2013.1019">Owens et al 2013</a>].</div></li><li class="half_rhythm"><div>It is unknown whether a shortened <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> of 12 polyalanine residues observed in expressed sequence tag databases [<a class="bk_pop" href="#hfg.REF.lavoie.2003.2967">Lavoie et al 2003</a>] is associated with phenotypic variation.</div></li></ul></li></ul><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of hand-foot-genital syndrome is broad, individuals with the distinctive findings described in <a href="#hfg.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <a href="#hfg.Option_1">Option 1</a>), whereas those with a phenotype indistinguishable from many other inherited disorders with limb anomalies and/or urogenital anomalies are more likely to be diagnosed using genomic testing (see <a href="#hfg.Option_2">Option 2</a>).</p><div id="hfg.Option_1"><h4>Option 1</h4><p>When the phenotypic and laboratory findings suggest the diagnosis of hand-foot-genital syndrome, <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Targeted testing for the expanded polyalanine repeat in <i>HOXA13</i> is performed first.</div><div class="half_rhythm">Sequence analysis of <i>HOXA13</i> can be performed next if no polyalanine repeat expansion is found on targeted testing.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>HOXA13</i> and other genes of interest (see <a href="#hfg.Differential_Diagnosis">Differential Diagnosis</a>) may be considered. To date, <a class="def" href="/books/n/gene/glossary/def-item/next-generation-sequencing/">next-generation sequencing</a> strategies cannot identify expanded repeats and therefore cannot confirm the diagnosis in the majority of individuals with HFGS. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> 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 <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, 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/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul></div><div id="hfg.Option_2"><h4>Option 2</h4><p>When the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> is indistinguishable from many other inherited disorders characterized by limb anomalies, <b>comprehensive</b>
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<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) can be considered. To date, <a class="def" href="/books/n/gene/glossary/def-item/next-generation-sequencing/">next-generation sequencing</a> strategies cannot identify expanded repeats and therefore cannot confirm the diagnosis in the majority of individuals with HFGS. <b>Exome sequencing</b> is most commonly used; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><div id="hfg.T.molecular_genetic_testing_used_in" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in Hand-Foot-Genital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1423/table/hfg.T.molecular_genetic_testing_used_in/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hfg.T.molecular_genetic_testing_used_in_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene <sup>1</sup></th><th id="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Probands with a Pathogenic Variant <sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>HOXA13</i>
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</td><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Targeted testing for polyalanine repeat expansion <sup>3</sup></td><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~50%-60% <sup>4</sup></td></tr><tr><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis <sup>5</sup></td><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~35% <sup>4</sup></td></tr><tr><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> <sup>6</sup></td><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown, none reported <sup>7</sup></td></tr><tr><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Unknown <sup>8</sup></td><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NA</td><td headers="hd_h_hfg.T.molecular_genetic_testing_used_in_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="hfg.TF.1.1"><p class="no_margin">See <a href="/books/NBK1423/#hfg.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="hfg.TF.1.2"><p class="no_margin">See <a href="#hfg.Molecular_Genetics">Molecular Genetics</a> for information on allelic variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="hfg.TF.1.3"><p class="no_margin"><a class="def" href="/books/n/gene/glossary/def-item/pcr/">PCR</a>-based methods to identify <i>HOXA13</i> expansion (resulting in increased polyalanine residues)</p></div></dd><dt>4. </dt><dd><div id="hfg.TF.1.4"><p class="no_margin">
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<a class="bk_pop" href="#hfg.REF.quinonez.2014.4">Quinonez & Innis [2014]</a>
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</p></div></dd><dt>5. </dt><dd><div id="hfg.TF.1.5"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>6. </dt><dd><div id="hfg.TF.1.6"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>7. </dt><dd><div id="hfg.TF.1.7"><p class="no_margin">Other than <a class="def" href="/books/n/gene/glossary/def-item/in-frame/">in-frame</a> contractions of polyalanine repeats, intragenic deletions causing HFGS that involve only part or all of <i>HOXA13</i> have not been reported. Large deletions including <i>HOXA13</i> and other surrounding genes have been reported [<a class="bk_pop" href="#hfg.REF.devriendt.1999.249">Devriendt et al 1999</a>, <a class="bk_pop" href="#hfg.REF.dun_.2004.459">Dunø et al 2004</a>, <a class="bk_pop" href="#hfg.REF.jun.2011.642">Jun et al 2011</a>, <a class="bk_pop" href="#hfg.REF.pezzani.2015.31">Pezzani et al 2015</a>, <a class="bk_pop" href="#hfg.REF.tas.2017.221">Tas et al 2017</a>]; however, these events result in additional clinical features (see <a href="#hfg.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>).</p></div></dd><dt>8. </dt><dd><div id="hfg.TF.1.8"><p class="no_margin">A few individuals with the clinical features of HFGS do not have <i>HOXA13</i> pathogenic variants [<a class="bk_pop" href="#hfg.REF.goodman.2000.197">Goodman et al 2000</a>; Innis et al, unpublished].</p></div></dd></dl></div></div></div></div></div></div><div id="hfg.Clinical_Characteristics"><h2 id="_hfg_Clinical_Characteristics_">Clinical Characteristics</h2><div id="hfg.Clinical_Description"><h3>Clinical Description</h3><p>Hand-foot-genital syndrome (HFGS) has been reported in several families and individuals [<a class="bk_pop" href="#hfg.REF.mortlock.1997.179">Mortlock & Innis 1997</a>, <a class="bk_pop" href="#hfg.REF.devriendt.1999.249">Devriendt et al 1999</a>, <a class="bk_pop" href="#hfg.REF.goodman.2000.197">Goodman et al 2000</a>, <a class="bk_pop" href="#hfg.REF.debeer.2002.852">Debeer et al 2002</a>, <a class="bk_pop" href="#hfg.REF.innis.2002.573">Innis et al 2002</a>, <a class="bk_pop" href="#hfg.REF.utsch.2002.488">Utsch et al 2002</a>, <a class="bk_pop" href="#hfg.REF.fris_n.2003.e49">Frisén et al 2003</a>, <a class="bk_pop" href="#hfg.REF.innis.2004.2841">Innis et al 2004</a>, <a class="bk_pop" href="#hfg.REF.owens.2013.1019">Owens et al 2013</a>]. Although some minor variation in the severity of limb defects may be observed, the defects are usually similar bilaterally. The radius/ulna, humerus, tibia/fibula, and femur are normal. With the exception of thenar hypoplasia, abnormalities of muscle have not been reported. There is <a class="def" href="/books/n/gene/glossary/def-item/intrafamilial-variability/">intrafamilial variability</a>.</p><p>HFGS may first be suspected in infants or children during evaluation for urogenital problems including hypospadias, ureteral reflux, urethral misplacement, recurrent urinary tract infections, or chronic pyelonephritis, or for small thumbs with impaired dexterity or apposition. Renal insufficiency leading to renal transplantation has been reported in one female.</p><p>Of all affected males, only one has had a documented history of urinary tract infection (UTI); two brothers had hypospadias (Grades II and III); one had bilateral vesicoureteral reflux with UTI, and the other had ureteropelvic junction (UPJ) obstruction. This family was first reported by <a class="bk_pop" href="#hfg.REF.verp.1983.80">Verp et al [1983]</a> (family 1) and later by <a class="bk_pop" href="#hfg.REF.donnenfeld.1992.482">Donnenfeld et al [1992]</a>. Retrograde ejaculation was reported in one affected male [<a class="bk_pop" href="#hfg.REF.debeer.2002.852">Debeer et al 2002</a>].</p><p>Affected males are not at increased risk for cryptorchidism and are fertile. No anomalies of the prostate or seminal vesicles have been described; however, directed examinations in males with HFGS to evaluate for such abnormalities have not been reported.</p><p>Menarche is usually normal. Females with varying degrees of incomplete müllerian fusion are at increased risk for premature labor, premature birth, second-trimester fetal loss, or stillbirth.</p><p>Other, possibly unrelated abnormalities are found rarely in individuals or families with HFGS:</p><ul><li class="half_rhythm"><div>Strabismus</div></li><li class="half_rhythm"><div>Ventriculoseptal defect (propositus of <a class="bk_pop" href="#hfg.REF.stern.1970.109">Stern et al [1970]</a>)</div></li><li class="half_rhythm"><div>Inguinal hernia, epididymal cyst, short stature, cervical ribs, supernumerary nipple, lower limit of functioning, onychodysplasia</div></li><li class="half_rhythm"><div>Sacral dimple</div></li><li class="half_rhythm"><div>Psychomotor retardation, microcephaly, and hypertelorism (in 1 of 4 affected members of a single family in which HFGS occurs)</div></li><li class="half_rhythm"><div>Difficulty with balance when standing (in 1 adult)</div></li></ul><p>The following are normal:</p><ul><li class="half_rhythm"><div>Developmental milestones</div></li><li class="half_rhythm"><div>External ears and hearing</div></li></ul></div><div id="hfg.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>Although the number of affected individuals in whom pathogenic variants in <i>HOXA13</i> have been identified is small, some <a class="def" href="/books/n/gene/glossary/def-item/genotype-phenotype-correlations/">genotype-phenotype correlations</a> are emerging.</p><p>The limb malformations in individuals with the <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variants in either <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> 1 or 2 or a polyalanine expansion in exon 1 are similar to those described in individuals with a <a class="def" href="/books/n/gene/glossary/def-item/cytogenetic/">cytogenetic</a> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of the <i>HOXA</i> cluster and adjacent <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> DNA [<a class="bk_pop" href="#hfg.REF.devriendt.1999.249">Devriendt et al 1999</a>, <a class="bk_pop" href="#hfg.REF.tas.2017.221">Tas et al 2017</a>], suggesting that these typical features result from HOXA13 <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a>. Minor differences may be attributable to effects of other genetic loci or stochastic variables.</p><p>Generally speaking, <i>HOXA13</i> homeodomain pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants appear to produce more severe features or unusual digital malformations; the variant p.Asn372His was associated with a severe skeletal <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> [<a class="bk_pop" href="#hfg.REF.goodman.2000.197">Goodman et al 2000</a>].</p><p>The variables that determine whether an individual <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> develops genitourinary problems are not clear. Hypospadias does not always occur in males with <i>HOXA13</i> pathogenic variants. When it does, it is most often glandular, although variability in severity occurs even in males with the same pathogenic variant. Females may be likely to have more severe genitourinary tract problems than males [<a class="bk_pop" href="#hfg.REF.innis.2004.2841">Innis et al 2004</a>]. The small number of families described limits further conclusions, although females with polyalanine expansions may have a greater frequency of urinary tract problems [<a class="bk_pop" href="#hfg.REF.innis.2004.2841">Innis et al 2004</a>].</p></div><div id="hfg.Penetrance"><h3>Penetrance</h3><p>Skeletal defects are 100% penetrant.</p><p>Penetrance for urogenital malformations is greater than 50% overall and may be greater for affected females.</p></div><div id="hfg.Anticipation"><h3>Anticipation</h3><p>Anticipation is not observed. Polyalanine expansions are stable for many generations.</p></div><div id="hfg.Prevalence"><h3>Prevalence</h3><p>HFGS is extremely rare.</p></div></div><div id="hfg.Genetically_Related_Allelic_Disorder"><h2 id="_hfg_Genetically_Related_Allelic_Disorder_">Genetically Related (Allelic) Disorders</h2><p>Guttmacher syndrome (OMIM <a href="https://omim.org/entry/176305" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">176305</a>) refers to one family reported by <a class="bk_pop" href="#hfg.REF.guttmacher.1993.219">Guttmacher [1993]</a> in which features of HFGS were observed (e.g., preaxial deficiency, clinobrachydactyly, hypospadias) along with more unusual phenotypic features of upper-limb postaxial polydactyly and uniphalangeal second toes. <a class="bk_pop" href="#hfg.REF.innis.2002.573">Innis et al [2002]</a> identified a pathogenic <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variant in the <i>HOXA13</i> homeodomain p.Gln371Leu (the so-called "homeodomain Q50L variant") in association, in <a class="def" href="/books/n/gene/glossary/def-item/cis/"><i>cis</i></a> configuration, with a dinucleotide <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> in the <a class="def" href="/books/n/gene/glossary/def-item/promoter-region/">promoter region</a> in this family.</p><p>An individual with a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
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<i>HOXA13</i> variant, p.Val375Phe, had features of HFGS including bilateral vesicoureteral junction obstruction with ectopic ureters and brachydactyly; however, small thumbs with atypical bilateral preaxial polydactyly was observed [<a class="bk_pop" href="#hfg.REF.wallis.2016.717">Wallis et al 2016</a>]. This individual also had a 0.5-Mb <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a> of 2p16.3 including the 5' exons of <i>NRXN1</i>.</p><p><b>Chromosome <a class="def" href="/books/n/gene/glossary/def-item/deletion/">deletion</a>.</b> A microdeletion involving the <i>HOXA</i> cluster on <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 7p14-p15 was reported in an individual with features of HFGS and additional findings of velopharyngeal insufficiency, shortened soft palate, gastroesophageal reflux, and persistent patent ductus Botalli [<a class="bk_pop" href="#hfg.REF.devriendt.1999.249">Devriendt et al 1999</a>]. Deletions involving <i>HOXA13</i> and additional genes with variable endpoints have been subsequently reported [<a class="bk_pop" href="#hfg.REF.dun_.2004.459">Dunø et al 2004</a>, <a class="bk_pop" href="#hfg.REF.jun.2011.642">Jun et al 2011</a>, <a class="bk_pop" href="#hfg.REF.pezzani.2015.31">Pezzani et al 2015</a>, <a class="bk_pop" href="#hfg.REF.tas.2017.221">Tas et al 2017</a>].</p></div><div id="hfg.Differential_Diagnosis"><h2 id="_hfg_Differential_Diagnosis_">Differential Diagnosis</h2><div id="hfg.T.disorders_to_consider_in_the_diffe" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Disorders to Consider in the Differential Diagnosis of Hand-Foot-Genital Syndrome (HFGS)</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1423/table/hfg.T.disorders_to_consider_in_the_diffe/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hfg.T.disorders_to_consider_in_the_diffe_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Features Overlapping w/HFGS</th><th id="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Differential Diagnosis<br />Disorder</th><th id="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene(s) /<br />Genetic Mechanism</th><th id="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Clinical Features of Differential Diagnosis Disorder Distinguishing It from HFGS</th></tr></thead><tbody><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_1" rowspan="7" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">Thumb hypoplasia, often in addition to other anomalies</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/fa/">Fanconi anemia</a>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">21 genes</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR<br />AD<br />XL</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Bone marrow failure</div></li><li class="half_rhythm"><div>↑ risk of malignancy</div></li></ul>
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</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/rts/">Rothmund-Thomson syndrome</a>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>RECQL4</i>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Rash, poikiloderma</div></li><li class="half_rhythm"><div>Cataracts</div></li><li class="half_rhythm"><div>↑ risk of malignancy</div></li></ul>
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</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/hos/">Holt-Oram syndrome</a>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>TBX5</i>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cardiac malformation</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Lacrimo-auriculo-dento-digital syndrome (OMIM <a href="https://omim.org/entry/149730" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">149730</a>)</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FGFR3</i>
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<br />
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<i>FGF10</i>
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<br />
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<i>FGFR2</i>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Characteristic facial features</div></li><li class="half_rhythm"><div>Dental anomalies</div></li></ul>
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</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Nager syndrome (OMIM <a href="https://omim.org/entry/154400" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">154400</a>)</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SF3B4</i>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Characteristic facial features w/ear anomalies</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/tbs/">Townes-Brocks syndrome</a>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SALL1</i>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Imperforate or stenotic anus</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" rowspan="2" colspan="1" scope="row" style="text-align:left;vertical-align:middle;"><a href="/books/n/gene/drrs/"><i>SALL4</i>-related disorders</a> (incl Duane-radial ray syndrome & acro-renal-ocular syndrome)</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>SALL4</i>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Radial ray malformation</div></li><li class="half_rhythm"><div>Duane anomaly</div></li></ul>
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</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_1" rowspan="5" colspan="1" style="text-align:left;vertical-align:middle;">Incomplete müllerian fusion &/or longitudinal vaginal septum</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/bbs/">Bardet-Biedl syndrome</a>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">≥19 genes</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Obesity</div></li><li class="half_rhythm"><div>Rod-cone dystrophy</div></li></ul>
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</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">
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<a href="/books/n/gene/bws/">Beckwith-Wiedemann syndrome</a>
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</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">11p15 <a class="def" href="/books/n/gene/glossary/def-item/epigenetic/">epigenetic</a> & <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> alterations <sup>1</sup></td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">See<br />footnote<br />1.</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Somatic overgrowth</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Fraser syndrome (OMIM <a href="https://omim.org/phenotypicSeries/PS219000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS219000</a>)</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<i>FRAS1</i>
|
||
<br />
|
||
<i>FREM2</i>
|
||
<br />
|
||
<i>GRIP1</i>
|
||
</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ocular involvement</div></li><li class="half_rhythm"><div>Ear anomalies</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Meckel syndrome (OMIM <a href="https://omim.org/phenotypicSeries/PS249000" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">PS249000</a>)</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~13 genes</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_hfg.T.disorders_to_consider_in_the_diffe_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Renal cystic dysplasia</div></li><li class="half_rhythm"><div>Biliary abnormalities & liver fibrosis</div></li><li class="half_rhythm"><div>Encephalocele</div></li></ul>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a>; XL = <a class="def" href="/books/n/gene/glossary/def-item/x-linked/">X-linked</a></p></div></dd><dt>1. </dt><dd><div id="hfg.TF.2.1"><p class="no_margin">Beckwith-Wiedemann syndrome is associated with abnormal regulation of <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> transcription in two <a class="def" href="/books/n/gene/glossary/def-item/imprinted/">imprinted</a> domains on <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> 11p15.5. Most individuals with BWS are reported to have normal chromosome studies or karyotypes. Approximately 85% of individuals with BWS have no family history of BWS; approximately 15% have a family history consistent with parent-of-origin <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> transmission.</p></div></dd></dl></div></div></div><p><b>Other disorders</b> with incomplete müllerian fusion and/or longitudinal vaginal septum:</p><ul><li class="half_rhythm"><div><a href="/books/n/gene/fryns/"><b>Fryns syndrome</b></a><b>,</b> an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a> disorder of unknown genetic cause, can be distinguished from HFGS by ear anomalies and diaphragmatic defects.</div></li><li class="half_rhythm"><div><b>Halal syndrome.</b> One family was reported with upper-limb hypoplasia and müllerian duct anomalies. Inheritance appeared to be <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; the genetic cause is unknown [<a class="bk_pop" href="#hfg.REF.halal.1986.119">Halal 1986</a>].</div></li></ul><p>Note: <i>HOXA13</i> pathogenic variants have yet to be identified in individuals with <a class="def" href="/books/n/gene/glossary/def-item/isolated/">isolated</a> hypospadias (i.e., without skeletal malformations) [<a class="bk_pop" href="#hfg.REF.utsch.2003.498">Utsch et al 2003</a>] or isolated forms of incomplete müllerian fusion or uterovaginal septa [<a class="bk_pop" href="#hfg.REF.jorgensen.2010.1235">Jorgensen et al 2010</a>; Innis, unpublished].</p></div><div id="hfg.Management"><h2 id="_hfg_Management_">Management</h2><div id="hfg.Evaluations_Following_Initial_Diagno"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with hand-foot-genital syndrome (HFGS), the evaluations summarized in <a href="/books/NBK1423/table/hfg.T.recommended_evaluations_following/?report=objectonly" target="object" rid-ob="figobhfgTrecommendedevaluationsfollowing">Table 3</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="hfg.T.recommended_evaluations_following" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with Hand-Foot-Genital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1423/table/hfg.T.recommended_evaluations_following/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hfg.T.recommended_evaluations_following_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_hfg.T.recommended_evaluations_following_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_hfg.T.recommended_evaluations_following_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_hfg.T.recommended_evaluations_following_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_hfg.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Musculoskeletal</b>
|
||
</td><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Physical exam & radiographs of hands & feet</td><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To evaluate for abnormalities that may affect function</td></tr><tr><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Renal</b>
|
||
</td><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Urologic assessment of bladder, ureter function, urethral competence & position</td><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Incl renal ultrasound & VCUG for UPJ obstruction</td></tr><tr><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gynecologic</b>
|
||
</td><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Gynecologic exam prior to menstruation or pregnancy.</div></li><li class="half_rhythm"><div>Eval may incl ultrasound, hysterosalpingogram, hysteroscopy, sonohysterogram, MRI, or other imaging studies.</div></li></ul>
|
||
</td><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>For evidence of incomplete müllerian fusion, longitudinal vaginal septum, or extremely small hymenal opening</div></li><li class="half_rhythm"><div>Such studies could be accomplished at the same time as urologic imaging.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_hfg.T.recommended_evaluations_following_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Other</b>
|
||
</td><td headers="hd_h_hfg.T.recommended_evaluations_following_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_hfg.T.recommended_evaluations_following_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">UPJ = ureteropelvic junction; VCUG = voiding cystourethrogram</p></div></dd></dl></div></div></div></div><div id="hfg.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="hfg.T.treatment_of_manifestations_in_ind" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with Hand-Foot-Genital Syndrome</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1423/table/hfg.T.treatment_of_manifestations_in_ind/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hfg.T.treatment_of_manifestations_in_ind_lrgtbl__"><table><thead><tr><th id="hd_h_hfg.T.treatment_of_manifestations_in_ind_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_hfg.T.treatment_of_manifestations_in_ind_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_hfg.T.treatment_of_manifestations_in_ind_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_hfg.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Bladder outlet abnormalities</b>
|
||
</td><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Urologic referral</td><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For surgical correction & ureteric implantation</td></tr><tr><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Gynecologic anomalies</b>
|
||
</td><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gynecologic referral</td><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Surgical removal of longitudinal vaginal septum is rarely indicated, even in <a class="def" href="/books/n/gene/glossary/def-item/anticipation/">anticipation</a> of labor.</div></li><li class="half_rhythm"><div>Surgery for removal of a uterine septum or reunification of a bicornuate uterus is likewise exceptional in the absence of recurrent mid-trimester pregnancy losses.</div></li><li class="half_rhythm"><div>Hymenectomy may be necessary for tight constriction ring.</div></li></ul>
|
||
</td></tr><tr><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
|
||
<b>Hallux varus & tarsal fusion</b>
|
||
</td><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthopedic referral</td><td headers="hd_h_hfg.T.treatment_of_manifestations_in_ind_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Extremity surgery is usually unnecessary.</td></tr></tbody></table></div></div></div><div id="hfg.Prevention_of_Secondary_Complication"><h3>Prevention of Secondary Complications</h3><p>The following are appropriate:</p><ul><li class="half_rhythm"><div>Prophylactic antibiotics or surgery as needed to prevent urinary tract infections or other complications of ureteral reflux or UPJ obstruction</div></li><li class="half_rhythm"><div>Gynecologic examination prior to menstruation for small hymenal opening</div></li><li class="half_rhythm"><div>Pre-pregnancy evaluation of the vaginal and uterine anatomy because of the increased risk for premature labor and fetal loss associated with structural abnormalities of the uterus</div></li></ul></div><div id="hfg.Surveillance"><h3>Surveillance</h3><p>Follow up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection is warranted.</p></div><div id="hfg.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those at risk for genitourinary and reproductive tract complications.</p><p>Evaluations can include:</p><ul><li class="half_rhythm"><div>Molecular genetic testing if the <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family is known;</div></li><li class="half_rhythm"><div>Physical examination, radiographic examination of hands and feet, and consideration of referral for urologic and/or gynecologic examination if the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in the family is not known.</div></li></ul><p>See <a href="#hfg.Related_Genetic_Counseling_Issues">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="hfg.Pregnancy_Management"><h3>Pregnancy Management</h3><p>In women with HFGS, pregnancy loss is possible secondary to uterine malformation. Consultation with an obstetrician before pregnancy is recommended and should include evaluation for and discussion of potential pregnancy complications. Affected fetuses are generally healthy, but could be at risk for premature birth secondary to maternal uterine malformation if the mother is also affected.</p></div><div id="hfg.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Search <a href="https://clinicaltrials.gov" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">EU Clinical Trials Register</a> in Europe for 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="hfg.Genetic_Counseling"><h2 id="_hfg_Genetic_Counseling_">Genetic Counseling</h2><p>
|
||
<i>Genetic counseling is the process of providing individuals and families with
|
||
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
|
||
make informed medical and personal decisions. The following section deals with genetic
|
||
risk assessment and the use of family history and genetic testing to clarify genetic
|
||
status for family members; it is not meant to address all personal, cultural, or
|
||
ethical issues that may arise or to substitute for consultation with a genetics
|
||
professional</i>. —ED.</p><div id="hfg.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Hand-foot-genital syndrome (HFGS) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> manner.</p></div><div id="hfg.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
|
||
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
|
||
</p><ul><li class="half_rhythm"><div>Some individuals diagnosed with HFGS have an affected parent.</div></li><li class="half_rhythm"><div>A <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with HFGS may have the disorder as the result of a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a>
|
||
<i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. The proportion of cases caused by <i>de novo</i> variants is unknown because of the small number of individuals described.</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>. If a <i>HOXA13</i> pathogenic variant has not been identified in the proband, recommendations may also include history and physical examination followed by radiographic examination of hands and feet, and possibly referral for urologic and/or gynecologic examination.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that cannot be detected in the leukocyte DNA of either parent, possible explanations include a <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> pathogenic variant in the proband or <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> in a parent. Somatic and germline mosaicism for a polyalanine expansion was reported in an unaffected parent who transmitted the polyalanine expansion to his affected offspring [<a class="bk_pop" href="#hfg.REF.owens.2013.1019">Owens et al 2013</a>].</div></li><li class="half_rhythm"><div>The family history of some individuals diagnosed with HFGS may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation or death of the parent before appropriate evaluation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.</div></li><li class="half_rhythm"><div>Note: If the parent is the individual in whom the <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> first occurred, the parent may have <a class="def" href="/books/n/gene/glossary/def-item/somatic-mosaicism/">somatic mosaicism</a> for the pathogenic variant and may be mildly/minimally affected or unaffected [<a class="bk_pop" href="#hfg.REF.owens.2013.1019">Owens et al 2013</a>].</div></li></ul><p><b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:</p><ul><li class="half_rhythm"><div>If a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is affected and/or is known to have the <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> identified in the proband, the risk to the sibs is 50%.</div></li><li class="half_rhythm"><div>If the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has a known <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> that cannot be detected in the leukocyte DNA of either parent, the <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> to sibs is slightly greater than that of the general population because of the possibility of parental <a class="def" href="/books/n/gene/glossary/def-item/germline-mosaicism/">germline mosaicism</a> [<a class="bk_pop" href="#hfg.REF.owens.2013.1019">Owens et al 2013</a>].</div></li></ul><p><b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</b> Each child of an individual with HFGS has a 50% chance of inheriting the <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>.</p><p><b>Other family members.</b> The risk to other family members depends on the genetic status of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents: if a parent has the <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, the parent's family members may be at risk.</p></div><div id="hfg.Related_Genetic_Counseling_Issues"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#hfg.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Considerations in families with an apparent <a class="def" href="/books/n/gene/glossary/def-item/de-novo/"><i>de novo</i></a> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a></b>. When neither parent of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> with an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely <i>de novo</i>. However, non-medical explanations including <a class="def" href="/books/n/gene/glossary/def-item/alternate-paternity/">alternate paternity</a> or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.</p><p>
|
||
<b>Family planning</b>
|
||
</p><ul><li class="half_rhythm"><div>The optimal time for determination of genetic risk and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</div></li><li class="half_rhythm"><div>It is appropriate to offer <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.</div></li></ul><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).</p></div><div id="hfg.Prenatal_Testing_and_Preimplantation"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>HOXA13</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> has been identified in an affected family member, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a> for a pregnancy at increased risk and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible.</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. 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="hfg.Resources"><h2 id="_hfg_Resources_">Resources</h2><p>
|
||
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
|
||
support organizations and/or registries for the benefit of individuals with this disorder
|
||
and their families. GeneReviews is not responsible for the information provided by other
|
||
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
|
||
<ul><li class="half_rhythm"><div>
|
||
<b>National Library of Medicine Genetics Home Reference</b>
|
||
</div><div>
|
||
<a href="https://ghr.nlm.nih.gov/condition/hand-foot-genital-syndrome" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Hand-foot-genital syndrome</a>
|
||
</div></li></ul>
|
||
</div><div id="hfg.Molecular_Genetics"><h2 id="_hfg_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 id="hfg.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Hand-Foot-Genital Syndrome: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1423/table/hfg.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hfg.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_hfg.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_hfg.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_hfg.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_hfg.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_hfg.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_hfg.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_hfg.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="/gene/3209" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=gene">
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<i>HOXA13</i>
|
||
</a>
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</td><td headers="hd_b_hfg.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=3209" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">7p15<wbr style="display:inline-block"></wbr>.2</a>
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</td><td headers="hd_b_hfg.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/P31271" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Homeobox protein Hox-A13</a>
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</td><td headers="hd_b_hfg.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
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<a href="http://databases.lovd.nl/shared/genes/HOXA13" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HOXA13 database</a>
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||
</td><td headers="hd_b_hfg.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=HOXA13" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HOXA13</a>
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||
</td><td headers="hd_b_hfg.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
|
||
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=HOXA13[gene]" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">HOXA13</a>
|
||
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="hfg.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> 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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||
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
|
||
<a href="http://www.omim.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">OMIM</a>;
|
||
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">UniProt</a>.
|
||
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
|
||
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="hfg.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Hand-Foot-Genital Syndrome (<a href="/omim/140000,142959" 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/NBK1423/table/hfg.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__hfg.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/140000" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">140000</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HAND-FOOT-GENITAL SYNDROME; HFG</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
|
||
<a href="/omim/142959" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=omim">142959</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HOMEOBOX A13; HOXA13</td></tr></tbody></table></div></div><div id="hfg.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><b>Introduction.</b>
|
||
<a class="bk_pop" href="#hfg.REF.quinonez.2014.4">Quinonez & Innis [2014]</a> and <a class="bk_pop" href="#hfg.REF.innis.2016">Innis [2016]</a> reviewed historical and evolutionary information about <i>HOX</i> genes, their roles as highly conserved, DNA-binding transcription factors in morphogenetic processes, and the consequences of pathogenic variants in ten of the 39 human <i>HOX</i> genes. There are many other well-written reviews detailing the basic science mechanisms underlying <i>HOX</i> <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> regulation and the ways in which HOX proteins exert their effects in patterning and growth, much of which has been learned through animal models.</p><p>There are four <i>HOX</i> <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> clusters, which map to four different human chromosomes. These clusters, labeled <i>HOXA</i>, <i>HOXB</i>, <i>HOXC</i>, and <i>HOXD</i>, are located on chromosomes 7p14, 17q21, 12q13, and 2q31, respectively. Each cluster has between nine and 11 genes, and members in similar positions among clusters, called paralogs, have an identical or nearly identical 60-amino acid "homeodomain" DNA-binding <a class="def" href="/books/n/gene/glossary/def-item/domain/">domain</a>. <i>HOX</i> genes are expressed along the body axis in restricted anterior-posterior domains that map relative to their position in the cluster. For example, <i>HOXA1</i> is expressed more anteriorly, and <i>HOXA13</i> is expressed in distal/posterior structures including the hands/feet and distal axial structures of the reproductive and gastrointestinal systems. Their expression domains coincide with areas of malformation in the presence of pathogenic variants. Pathogenic variants lead to alteration in <i>HOX</i>-regulated genes and changes in structural identity or size. Molecular pathogenesis is detailed in <a class="bk_pop" href="#hfg.REF.innis.2016">Innis [2016]</a>.</p><p><b>Mechanism of disease causation.</b> For both <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a> variants and pathogenic polyalanine tract expansions of <i>HOXA13</i>, <a class="def" href="/books/n/gene/glossary/def-item/haploinsufficiency/">haploinsufficiency</a> is likely to be the basis for malformations. This is supported by <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> deletions involving the entire <i>HOXA</i> <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> cluster associated with HFGS features and mouse models. However, <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a> variants in the homeodomain may involve altered DNA site specificity and may result in a more severe or slightly unusual <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> as in Guttmacher syndrome [<a class="bk_pop" href="#hfg.REF.innis.2002.573">Innis et al 2002</a>] or as described for another homeodomain variant [<a class="bk_pop" href="#hfg.REF.wallis.2016.717">Wallis et al 2016</a>]. See <a href="#hfg.Genetically_Related_Allelic_Disorder">Genetically Related Disorders</a>.</p><p><b><i>HOXA13</i>-specific laboratory considerations.</b> HFGS caused by expansion of <i>HOXA13</i> polyalanine repeat tracts, which are highly GC-rich, will not be routinely detected by <a class="def" href="/books/n/gene/glossary/def-item/next-generation-sequencing/">next-generation sequencing</a> analysis: assays specifically designed to detect a repeat expansion are required [<a class="bk_pop" href="#hfg.REF.mortlock.2000.151">Mortlock et al 2000</a>, <a class="bk_pop" href="#hfg.REF.innis.2004.2841">Innis et al 2004</a>, <a class="bk_pop" href="#hfg.REF.owens.2013.1019">Owens et al 2013</a>].</p></div></div><div id="hfg.References"><h2 id="_hfg_References_">References</h2><div id="hfg.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.debeer.2002.852">Debeer P, Bacchelli C, Scambler PJ, De Smet L, Fryns JP, Goodman FR. Severe digital abnormalities in a patient heterozygous for both a novel missense mutation in HOXD13 and a polyalanine tract expansion in HOXA13. <span><span class="ref-journal">J Med Genet. </span>2002;<span class="ref-vol">39</span>:852–6.</span> [<a href="/pmc/articles/PMC1735011/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1735011</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12414828" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12414828</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.devriendt.1999.249">Devriendt K, Jaeken J, Matthijs G, Van Esch H, Debeer P, Gewillig M, Fryns JP. Haploinsufficiency of the HOXA gene cluster, in a patient with hand-foot-genital syndrome, velopharyngeal insufficiency, and persistent patent ductus Botalli. <span><span class="ref-journal">Am J Hum Genet. </span>1999;<span class="ref-vol">65</span>:249–51.</span> [<a href="/pmc/articles/PMC1378097/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1378097</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10364539" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10364539</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.donnenfeld.1992.482">Donnenfeld AE, Schrager DS, Corson SL. Update on a family with hand-foot-genital syndrome: hypospadias and urinary tract abnormalities in two boys from the fourth generation. <span><span class="ref-journal">Am J Med Genet. </span>1992;<span class="ref-vol">44</span>:482–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1442892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1442892</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.dun_.2004.459">Dunø M, Hove H, Kirchhoff M, Devriendt K, Schwartz M. Mapping genomic deletions down to the base: a quantitative copy number scanning approach used to characterize and clone the breakpoints of a recurrent 7p14.2p15.l3 deletion. <span><span class="ref-journal">Hum Genet. </span>2004;<span class="ref-vol">115</span>:459–67.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15378350" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15378350</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.fris_n.2003.e49">Frisén L, Lagerstedt K, Tapper-Persson M, Kockum I, Nordenskjöld A. A novel duplication in the HOXA13 gene in a family with atypical hand-foot-genital syndrome. <span><span class="ref-journal">J Med Genet. </span>2003;<span class="ref-vol">40</span>:e49. </span> [<a href="/pmc/articles/PMC1735421/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1735421</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12676922" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12676922</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.goodman.2000.197">Goodman FR, Bacchelli C, Brady AF, Brueton LA, Fryns JP, Mortlock DP, Innis JW, Holmes LB, Donnenfeld AE, Feingold M, Beemer FA, Hennekam RC, Scambler PJ. Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. <span><span class="ref-journal">Am J Hum Genet. </span>2000;<span class="ref-vol">67</span>:197–202.</span> [<a href="/pmc/articles/PMC1287077/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1287077</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/10839976" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10839976</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.guttmacher.1993.219">Guttmacher AE. Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias. <span><span class="ref-journal">Am J Med Genet. </span>1993;<span class="ref-vol">46</span>:219–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8484413" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8484413</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.halal.1986.119">Halal F. A new syndrome of severe upper limb hypoplasia and Mullerian duct anomalies. <span><span class="ref-journal">Am J Med Genet. </span>1986;<span class="ref-vol">24</span>:119–26.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3706400" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3706400</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.imagawa.2014.2398">Imagawa E, Kayserili H, Nishimura G, Nakashima M, Tsurusaki Y, Saitsu H, Ikegawa S, Matsumoto N, Miyake N. Severe manifestations of hand-foot-genital syndrome associated with a novel <em>HOXA13</em> mutation. <span><span class="ref-journal">Am J Med Genet. </span>2014;<span class="ref-vol">164A</span>:2398–402.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24934387" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24934387</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.innis.2016">Innis JW. <em>HOXA13</em>: hand-foot-genital and Guttmacher syndromes. In: Epstein C, Wynshaw-Boris T, Erickson R, eds. <em>Inborn Errors of Development</em>. 3 ed. San Francisco: Oxford University Press; 2016.</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.innis.2002.573">Innis JW, Goodman FR, Bacchelli C, Williams TM, Mortlock DP, Sateesh P, Scambler PJ, McKinnon W, Guttmacher AE. A HOXA13 allele with a missense mutation in the homeobox and a dinucleotide deletion in the promoter underlies Guttmacher syndrome. <span><span class="ref-journal">Hum Mutat. </span>2002;<span class="ref-vol">19</span>:573–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11968094" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11968094</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.innis.2004.2841">Innis JW, Mortlock D, Chen Z, Ludwig M, Williams ME, Williams TM, Doyle CD, Shao Z, Glynn M, Mikulic D, Lehmann K, Mundlos S, Utsch B. Polyalanine expansion in HOXA13: three new affected families and the molecular consequences in a mouse model. <span><span class="ref-journal">Hum Mol Genet. </span>2004;<span class="ref-vol">13</span>:2841–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15385446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15385446</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.jorgensen.2010.1235">Jorgensen EM, Ruman JI, Doherty L, Taylor HS. A novel mutation of HOXA13 in a family with hand-foot-genital syndrome and the role of polyalanine expansions in the spectrum of Müllerian fusion anomalies. <span><span class="ref-journal">Fertil Steril. </span>2010;<span class="ref-vol">94</span>:1235–8.</span> [<a href="/pmc/articles/PMC2889242/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2889242</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19591980" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19591980</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.jun.2011.642">Jun KR, Seo EJ, Lee JO, Yoo HW, Park IS, Yoon HK. Molecular cytogenetic and clinical characterization of a patient with a 5.6-Mb deletion in 7p15 including HOXA cluster. <span><span class="ref-journal">Am J Med Genet A. </span>2011;<span class="ref-vol">155A</span>:642–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21344639" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21344639</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.lavoie.2003.2967">Lavoie H, Debeane F, Trinh QD, Turcotte JF, Corbeil-Girard LP, Dicaire MJ, Saint-Denis A, Page M, Rouleau GA, Brais B. Polymorphism, shared functions and convergent evolution of genes with sequences coding for polyalanine domains. <span><span class="ref-journal">Hum Mol Genet. </span>2003;<span class="ref-vol">12</span>:2967–79.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14519685" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14519685</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.mortlock.1997.179">Mortlock DP, Innis JW. Mutation of HOXA13 in hand-foot-genital syndrome. <span><span class="ref-journal">Nat Genet. </span>1997;<span class="ref-vol">15</span>:179–80.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9020844" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9020844</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.mortlock.2000.151">Mortlock DP, Sateesh P, Innis JW. Evolution of N-terminal sequences of the vertebrate HOXA13 protein. <span><span class="ref-journal">Mamm Genome. </span>2000;<span class="ref-vol">11</span>:151–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10656931" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10656931</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.owens.2013.1019">Owens KM, Quinonez SC, Thomas PE, Keegan CE, Lefebvre N, Roulston D, Larsen CA, Stadler HS, Innis JW. Analysis of de novo <em>HOXA13</em> polyalanine expansions supports replication slippage without repair in their generation. <span><span class="ref-journal">Am J Med Genet. </span>2013;<span class="ref-vol">161A</span>:1019–27.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23532960" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23532960</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.pezzani.2015.31">Pezzani L, Milani D, Manzoni F, Baccarin M, Silipiqni R, Guerneri S, Esposito S. HOXA genes cluster: clinical implications of the smallest deletion. <span><span class="ref-journal">Ital J Pediatr. </span>2015;<span class="ref-vol">41</span>:31.</span> [<a href="/pmc/articles/PMC4395968/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4395968</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25881986" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 25881986</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.quinonez.2014.4">Quinonez SC, Innis JW. Human HOX gene disorders. <span><span class="ref-journal">Mol Genet Metab. </span>2014;<span class="ref-vol">111</span>:4–15.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/24239177" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24239177</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.stern.1970.109">Stern AM, Gall JC Jr, Perry BL, Stimson CW, Weitkamp LR, Poznanski AK. The hand-foot-uterus syndrome: a new hereditary disorder characterized by hand and foot dysplasia, dermatoglyphic abnormalities, and partial duplication of the female genital tract. <span><span class="ref-journal">J Pediatr. </span>1970;<span class="ref-vol">77</span>:109–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/5450271" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 5450271</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.tas.2017.221">Tas E, Sebastian J, Madan-Khetarpal S, Sweet P, Yatsenko AN, Pollock N, Rajkovic A, Schneck FX, Yatsenko SA, Witchel SF. Familial deletion of the <em>HOXA</em> gene cluster associated with hand-foot-genital syndrome and phenotypic variability. <span><span class="ref-journal">Am J Med Genet. </span>2017;<span class="ref-vol">173</span>:221–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/27649277" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 27649277</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.utsch.2002.488">Utsch B, Becker K, Brock D, Lentze MJ, Bidlingmaier F, Ludwig M. A novel stable polyalanine [poly(A)] expansion in the HOXA13 gene associated with hand-foot-genital syndrome: proper function of poly(A)-harbouring transcription factors depends on a critical repeat length? <span><span class="ref-journal">Hum Genet. </span>2002;<span class="ref-vol">110</span>:488–94.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12073020" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12073020</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.utsch.2003.498">Utsch B, Kaya A, Ozburun A, Lentze MJ, Albers N, Ludwig M. Exclusion of WTAP and HOXA13 as candidate genes for isolated hypospadias. <span><span class="ref-journal">Scand J Urol Nephrol. </span>2003;<span class="ref-vol">37</span>:498–501.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14675924" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14675924</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.utsch.2007.3161">Utsch B, McCabe CD, Galbraith K, Gonzalez R, Born M, Dötsch J, Ludwig M, Heiko Reutter H, Innis JW. Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome. <span><span class="ref-journal">Am J Med Genet. </span>2007;<span class="ref-vol">143A</span>:3161–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17935235" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17935235</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.verp.1983.80">Verp MS, Simpson JL, Elias S, Carson SA, Sarto GE, Feingold M. Heritable aspects of uterine anomalies. I. Three familial aggregates with Mullerian fusion anomalies. <span><span class="ref-journal">Fertil Steril. </span>1983;<span class="ref-vol">40</span>:80–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6862042" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6862042</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="hfg.REF.wallis.2016.717">Wallis M, Tsurusaki Y, Burgess T, Borzi P, Matsumoto N, Miyake N, True D, Patel C. Dual genetic diagnoses: atypical hand-foot-genital syndrome and developmental delay due to de novo mutations in <em>HOXA13</em> and <em>NRXN1</em>. <span><span class="ref-journal">Am J Med Genet. </span>2016;<span class="ref-vol">170</span>:717–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/26590955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 26590955</span></a>]</div></li></ul></div></div><div id="hfg.Chapter_Notes"><h2 id="_hfg_Chapter_Notes_">Chapter Notes</h2><div id="hfg.Author_Notes"><h3>Author Notes</h3><p>
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<a href="https://medicine.umich.edu/dept/human-genetics/jeffrey-innis-md-phd" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">Author's website</a>
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</p></div><div id="hfg.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>8 August 2019 (sw) Comprehensive update posted live</div></li><li class="half_rhythm"><div>3 May 2012 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>2 February 2010 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>11 July 2006 (me) Review posted live</div></li><li class="half_rhythm"><div>16 February (jwi) Original submission</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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