DiagnosisClinical DiagnosisHand-foot-genital syndrome (HFGS) is characterized by fully penetrant limb malformations and incompletely penetrant urogenital defects caused by mutations in HOXA13 [Mortlock & Innis 1997].Limb MalformationsBilateral thumb and great-toe hypoplasia are the hallmark malformations, caused primarily by shortening of the distal phalanx and/or the first metacarpal or metatarsal. Shortening is often mild but on occasion may be more severe; see Mortlock & Innis [1997] and Goodman et al [2000] (family 5). Additional findings that may be present: Limited metacarpophalangeal flexion of the thumb or limited ability to oppose the thumb and fifth finger Hypoplastic thenar eminences Medial deviation of the great toe (hallux varus), a useful diagnostic sign when present Small great toenail Other Fifth-finger clinodactyly, secondary to a shortened middle phalanx Short feet 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 Radiographic findings Hypoplasia of the distal phalanx and first metacarpal of the thumbs and great toes Pointed distal phalanges of the thumb Lack of normal tufting of the distal phalanges of the great toes Fusions of the cuneiform to other tarsal bones or trapezium-scaphoid fusion of the carpals Short calcaneus Occasional bony fusions of the middle and distal phalanges of the second, third, fourth, or fifth toes Delayed carpal or tarsal maturation Metacarpophalangeal profile reflecting shortening of the first metacarpal, the first and second phalanges, and the second phalanx of the second and fifth digits Urogenital DefectsFemales may have the following: Vesicoureteral reflux secondary to ureteric incompetence Ectopic ureteral orifices Trigonal hypoplasia Hypospadiac urethra Subsymphyseal epispadias Patulous urethra Urinary incontinence Small hymenal opening Various degrees of incomplete Müllerian fusion with or without two cervices or a longitudinal vaginal septum Males may have hypospadias of variable severity with or without chordee. While hypospadias is often glandular, two males with grade II and III hypospadias and one with grade IV hypospadias have been reported. Therefore, physical examination and radiographic demonstration of characteristic hand and foot anomalies and possibly urogenital defects lead to suspicion of the diagnosis. A family history of similar features with autosomal dominant inheritance is supportive of the diagnosis but may not be present. Demonstration of a HOXA13 mutation is confirmatory. TestingCytogenetic testing. A microdeletion involving the HOXA cluster on chromosome 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 [Devriendt et al 1999]. Molecular Genetic TestingGene. HOXA13 is the only gene in which mutations are known to cause HFGS. Only 14 mutations have been reported to date; approximately 40% are point mutations and 60% are polyalanine expansions. Evidence for locus heterogeneity. A few individuals with the clinical features of HFGS do not have HOXA13 mutations [Goodman et al 2000; Innis et al, unpublished]. Allele sizes. HOXA13 protein has three extended polyalanine tracts encoded in the first exon, referred to as Tracts I, II, and III. Approximately 50% 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. Normal alleles Tract I. p.Ala38[14] residues Tract II. p.Ala73[12] residues Tract III. p.Ala116[12] or p.Ala116[18] residues Reduced penetrance alleles. Not reported Full penetrance alleles Tract I. An allele with eight additional alanine residues, (termed "+8" alleles) was reported in association with HFGS [Innis et al 2004]. Tract II. An allele with six additional alanine residues (termed "+6" alleles) was reported in association with HFGS [Frisén et al 2003]. Tract III. Polyalanine expansions of at least six additional polyalanine residues (termed "+6" alleles) to as many as 14 additional polyalanine residues (termed "+14" alleles) [Innis et al 2004, Utsch et al 2007] may cause HFGS. Alleles of questionable significance — Tract III The significance of a shortened allele 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 phenotype [Innis et al 2004]. Whether or not a shortened allele of 12 polyalanine residues observed in expressed sequence tag databases [Lavoie et al 2003] is associated with phenotypic variation is unknown. Clinical testingTable 1. Summary of Molecular Genetic Testing Used in Hand-Foot-Genital SyndromeView in own windowGene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityHOXA13Sequence analysis Polyalanine expansion ~50%-60% Clinical Sequence variants 2~35% 1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Sequence analysis of HOXA13 in a small number of affected individuals detected nonsense or missense mutations or in-frame polyalanine expansions in the coding region in approximately 35% of affected individuals [Author, unpublished observations].Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a proband PCR to identify gene expansion (resulting in increased polyalanine residues) is usually performed, followed by sequence analysis of HOXA13.In individuals with multiple anomalies in whom features of HFGS may also be present, chromosomal microarray analysis should be considered, with particular attention to the HOXA cluster at chromosomal region7p14-p15. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersGuttmacher syndrome refers to one family reported by Guttmacher [1993] in which features of HFGS were observed (i.e., preaxial deficiency, clinodactyly, hypospadias) along with more unusual phenotypic features of upper-limb postaxial polydactyly and uniphalangeal second toes. Innis et al [2002] identified a missense mutation in the HOXA13 homeodomain p.Gln371Leu (the so-called homeodomain Q50L mutation) in association, in cis configuration, with a dinucleotide deletion in the promoter region in this family. Chromosomal deletion. Chromosome 7p deletions involving the HOXA cluster may result in an HFGS-like syndrome with other anomalies [Devriendt et al 1999].}

Natural HistoryHand-foot-genital syndrome (HFGS) has been reported in several families or individuals [Devriendt et al 1999, Goodman et al 2000, Becker et al 2002, Debeer et al 2002, Innis et al 2002, Utsch et al 2002, Frisén et al 2003, Innis et al 2004]. 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. HFGS may first be suspected in infants or children during evaluation for urogenital problems including hypospadias, ureteral reflux, urethral misplacement, recurrent urinary tract infections, chronic pyelonephritis, or small thumbs with impaired dexterity or apposition. Renal insufficiency leading to renal transplantation has been reported in one female. 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. The family was first reported by Verp et al [1983] (family 1) and later by Donnenfeld et al [1992]. Retrograde ejaculation was reported in one affected male [Debeer et al 2002].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. 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. Other, possibly unrelated abnormalities are found rarely in individuals or families with HFGS:StrabismusVentriculoseptal defect (propositus of Stern et al [1970]) Inguinal hernia, epididymal cyst, short stature, cervical ribs, supernumerary nipple, lower limit of functioning, onychodysplasia Sacral dimple Psychomotor retardation, microcephaly, and hypertelorism in one of four affected members of a single family in which HFGS occurs One adult with difficulty with balance when standing The following are normal:Developmental milestones External ears and hearing

Genotype-Phenotype CorrelationsAlthough the number of affected individuals in whom mutations in HOXA13 have been identified is small, some genotype-phenotype correlations are emerging.The limb malformations in individuals with the heterozygous nonsense mutations in either exon 1 or 2 or a polyalanine expansion in exon 1 are similar to those described in the individual with the cytogenetic deletion of the HOXA cluster [Devriendt et al 1999], suggesting that these typical features result from HOXA13 haploinsufficiency. Minor differences may be attributable to effects of other genetic loci or stochastic variables.Generally speaking, HOXA13 homeodomain missense mutations appear to produce more severe features or unusual digital malformations; the mutation p.Asn372His was associated with a severe skeletal phenotype [Goodman et al 2000]. The variables that determine whether an individual heterozygous for a HOXA13 mutation develops genitourinary problems are not clear. Hypospadias does not always occur in males with HOXA13 mutations. When it does, it is most often glandular, although variability in severity occurs even in males with the same mutation. Females may be likely to have more severe genitourinary tract problems than males [Innis et al 2004]. The small number of families described limits further conclusions, although females with polyalanine expansions may have a greater frequency of urinary tract problems [Innis et al 2004].

Differential DiagnosisThumb hypoplasia, often in addition to other anomalies, should prompt the consideration of the following disorders:Fanconi anemia syndrome Rothmund-Thomson syndrome Holt-Oram syndrome SALL4-related disorders (which includes Duane-radial ray syndrome and acro-renal-ocular syndrome) Nager syndrome Townes-Brocks syndrome Lacrimo-auriculo-dento-digital (LADD) syndrome Incomplete Müllerian fusion and/or longitudinal vaginal septum should prompt the consideration of the following disorders:Acro-renal-mandibular syndrome (see SALL4-Related Disorders)Bardet-Biedl syndrome Beckwith-Wiedemann syndrome Fraser syndrome Fryns syndrome Halal syndrome Meckel syndrome Others [Simpson 1999] Guttmacher syndrome, an allelic disorder, shares some features with HFGS and differs from it in others, including postaxial polydactyly of the hands along with preaxial deficiency, clinobrachydactyly, and hypospadias. The following individual case reports closely resemble HFGS, but molecular analysis has not been performed or failed to demonstrate a HOXA13 mutation.Pinsky [1974] reviewed syndromes with similar features involving distal limb elements and urogenital defects including camptobrachydactyly, hydrometrocolpospolydactyly, and cryptophthalmos. The family studied by Hennekam [1989] had moderately shortened halluces, incomplete Müllerian fusion, and small, thickened, dysplastic helices (not typical for HFGS), but no hand anomalies or the typical HFGS metacarpophalangeal profile. No HOXA13 mutation was identified [Goodman et al 2000]. A report by Halal [1986] described a unique family with Müllerian duct anomalies and upper-limb hypoplasia of varying severity. Michels & Caskey [1978] described two individuals with Müllerian aplasia and hypoplastic thumbs. HOXA13 mutations have yet to be identified in individuals with isolated hypospadias (i.e., without skeletal malformations) [Utsch et al 2003] or isolated forms of incomplete Müllerian fusion or uterovaginal septa [Jorgensen et al 2010; Innis, unpublished] Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with hand-foot-genital syndrome (HFGS), the following evaluations are recommended:Physical examination and radiographs of the hands and feet to evaluate for characteristic abnormalities (e.g., small thumbs, fifth-finger clinodactyly) that may affect hand functionUrologic assessment of bladder/ureter function and urethral competence or position, including renal ultrasound examination and voiding cystourethrogram; examination for UPJ obstruction Gynecologic examination prior to menstruation or pregnancy for evidence of incomplete Müllerian fusion, longitudinal vaginal septum, or extremely small hymenal opening. Evaluation may include ultrasound, hysterosalpingogram, hysteroscopy, sonohysterogram, MRI, or other imaging studies. Such studies could be accomplished at the same time as urologic imaging. Medical genetics consultationTreatment of ManifestationsUrologic referral is indicated. Appropriate treatment includes surgical correction of bladder outlet abnormalities and ureteric implantation. Gynecologic referral is indicated. Surgical removal of longitudinal vaginal septum is rarely indicated, even in anticipation of labor. 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. Hymenectomy may be necessary for tight constriction ring. Usually, extremity surgery is not necessary, although repair of hallux varus and tarsal fusion [Verp et al 1983] have been reported.Prevention of Secondary ComplicationsThe following are appropriate:Prophylactic antibiotics or surgery as needed to prevent urinary tract infections or other complications of ureteral reflux or UPJ obstruction Gynecologic examination prior to menstruation for small hymenal openingPre-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 SurveillanceFollow-up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection is warranted.Evaluation of Relatives at RiskPhysical examination of relatives and HOXA13 sequence analysis will help identify those at risk of genitourinary and reproductive tract complications.See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Pregnancy ManagementIn women with HFGS, premature 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. Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Hand-Foot-Genital Syndrome: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDHOXA137p15​.2Homeobox protein Hox-A13HOXA13 homepage - Mendelian genesHOXA13Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Hand-Foot-Genital Syndrome (View All in OMIM) View in own window 140000HAND-FOOT-UTERUS SYNDROME 142959HOMEOBOX A13; HOXA13Normal allelic variants. HOXA13 has two exons. Normal allelic variants with nucleotides encoding extended polyalanine tracts of 14, 12, and 18 residues are in the first exon and are conserved in mammals [Mortlock et al 2000]. These encoded segments are referred to as Tracts I, II, and III. Pathologic allelic variants. Only 16 mutations have been reported to date; approximately 40% are point mutations and 60% are polyalanine expansions. No affected individual has been described with expansions in more than one tract. See Table 2.Table 2. HOXA13 Allelic Variants Discussed in This GeneReviewView in own windowClass of Variant AlleleDNA Nucleotide Change ^{1Protein Amino Acid Change
(Alias 2) Reference SequencesNormalc.112GCN[14]p.Ala38[14]NM_000522​.4
NP_000513​.2c.217GCN[12]p.Ala73[12]c.346GCN[12]p.Ala116[12]c.346GCN[18]p.Ala116[18]Pathologicc.112GCN[22]
(termed +8 alleles)p.Ala38[22]c.217GCN[18]
(termed +6 alleles)p.Ala73[18]c.346GCN(18_32)
(alleles of +6 to +14)p.Ala116(18_32)c.407C>Ap.Ser136Xc.586C>Tp.Gln196Xc.1093C>Tp.Gln365Xc.1107G>Ap.Trp369Xc.1114A>Cp.Asn372His
(N51H) See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).1. The trinucleotide repeat GCN, where N is either A, C, G, or T (which all code for alanine), is designated with the exact number of repeats in brackets (e.g., c.112GCH[14] designates an allele with exactly 14 GCN repeats). However, a designation of c.346GCN(18_32), for example, means that the GCN sequence can be found repeated 18 to 32 times in the population.2. Variant designation that does not conform to current naming conventionsNormal gene product. HOXA13 is a homeobox transcription factor [Innis et al 2002]. Abnormal gene product. HOXA13 proteins with disease-related polyalanine expansions are unstable [Innis et al 2004]. For both nonsense mutations and polyalanine tract mutations, haploinsufficiency is likely to be the basis for malformations. This is supported by chromosomal deletions involving the entire HOXA gene cluster associated with HFGS features [Devriendt et al 1999; Jun et al 2011] and mouse models [Innis et al 2004]. However, missense mutations of the homeodomain may involve altered DNA site specificity and may result in a more severe or slightly unusual phenotype as in Guttmacher syndrome.Also, at least in the mouse, frame-shifting mutations may lead to the production of novel, stable protein products with the potential for gain of function [Post et al 2000].}