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Hand-Foot-Genital Syndrome

Synonyms: HFGS, HFG Syndrome
, MD, PhD
Professor, Human Genetics, Pediatrics
Director, Division of Pediatric Genetics
University of Michigan
Director, Michigan Medical Genetics Laboratories
Ann Arbor, Michigan

Initial Posting: ; Last Update: May 3, 2012.

Summary

Disease characteristics. Hand-foot-genital syndrome (HFGS) is characterized by limb malformations and urogenital defects. Mild 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 abnormalities include: abnormalities of the ureters and urethra and various degrees of incomplete Müllerian fusion in females; hypospadias of variable severity with or without chordee in males. Vesicoureteral reflux, recurrent urinary tract infections, and chronic pyelonephritis are common; fertility is normal.

Diagnosis/testing. Diagnosis is based on physical examination including radiographs of the hands and feet and imaging studies of the kidneys, bladder, and female reproductive tract. HOXA13 is the only gene in which mutations are known to cause HFGS. Approximately 60% of mutations are polyalanine expansions.

Management. Treatment of manifestations: Hand or foot surgery is not usually necessary. Ureteric reimplantation and surgical correction of bladder outlet abnormalities is 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.

Prevention of secondary complications: 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 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

Surveillance: Follow-up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection.

Genetic counseling. Hand-foot-genital syndrome is inherited in an autosomal dominant manner. The proportion of cases caused by de novo mutations is unknown because of the small number of individuals described. If a parent of the proband is affected, the risk to the sibs is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. Each child of an individual with HFGS has a 50% chance of inheriting the mutation. If the disease-causing mutation has been identified in the family, prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.

Diagnosis

Clinical Diagnosis

Hand-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 Malformations

Bilateral 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 Defects

Females 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.

Testing

Cytogenetic 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 Testing

Gene. 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

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 testing

Table 1. Summary of Molecular Genetic Testing Used in Hand-Foot-Genital Syndrome

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
HOXA13Sequence analysis Polyalanine expansion ~50%-60%
Sequence variants 2~35%

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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.

Clinical Description

Natural History

Hand-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:

  • Strabismus
  • Ventriculoseptal 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 Correlations

Although 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].

Penetrance

Skeletal defects are 100% penetrant.

Penetrance for urogenital malformations is greater than 50% overall and may be greater for affected females.

Anticipation

Anticipation is not observed. Polyalanine expansions are stable for many generations.

Prevalence

HFGS is extremely rare.

Differential Diagnosis

Thumb hypoplasia, often in addition to other anomalies, should prompt the consideration of the following disorders:

Incomplete Müllerian fusion and/or longitudinal vaginal septum should prompt the consideration of the following disorders:

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To 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 function
  • Urologic 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 consultation

Treatment of Manifestations

Urologic 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 Complications

The 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 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

Surveillance

Follow-up with a urologist in the presence of vesicoureteral reflux and/or documented urinary tract infection is warranted.

Evaluation of Relatives at Risk

Physical 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 Management

In 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 Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, 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. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Hand-foot-genital syndrome (HFGS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with HFGS have an affected parent.
  • A proband with HFGS may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown because of the small number of individuals described.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include history and physical examination followed by radiographic examination of hands and feet, and possibly referral for urologic and/or gynecologic examination. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although some individuals diagnosed with HFGS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or death of the parent before appropriate evaluation. (2) Although it has not yet been reported it is possible that a parent is the individual in whom the mutation first occurred; s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected or unaffected [Innis, unpublished].

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low, but may be greater than that of the general population if germline mosaicism exists.

Offspring of a proband. Each child of an individual with HFGS has a 50% chance of inheriting the mutation.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal HOXA13 DNA mutation analysis has not been reported. However, if the disease-causing mutation has been identified in an affected family member, prenatal testing for at-risk pregnancies is possible through laboratories offering either prenatal testing for the gene of interest or custom testing.

Fetal ultrasound examination. Prenatal ultrasound has not been reported in HFGS.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory.

Resources

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 here.

No specific resources for Hand-Foot-Genital Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
HOXA137p15​.2Homeobox protein Hox-A13HOXA13 homepage - Mendelian genesHOXA13

Data 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)

140000HAND-FOOT-GENITAL SYNDROME; HFG
142959HOMEOBOX A13; HOXA13

Normal 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 GeneReview

Class of Variant AlleleDNA Nucleotide Change 1Protein Amino Acid Change
(Alias 2)
Reference Sequences
Normalc.112GCN[14]p.Ala38[14]NM_000522​.4
NP_000513​.2
c.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.Ser136X
c.586C>Tp.Gln196X
c.1093C>Tp.Gln365X
c.1107G>Ap.Trp369X
c.1114A>Cp.Asn372His
(N51H)

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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 conventions

Normal 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].

References

Literature Cited

  1. Becker K, Brock D, Ludwig M, Bidlingmaier F, Albers N, Lentze MJ, Utsch B (2002) Dominantly inherited hand-foot-genital syndrome: malformations of hands and feet associated with Müllerian duct fusion anomalies. In German. Monatsschr Kinderh. 151:57-60.
  2. 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. J Med Genet. 2002;39:852–6. [PMC free article: PMC1735011] [PubMed: 12414828]
  3. 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. Am J Hum Genet. 1999;65:249–51. [PMC free article: PMC1378097] [PubMed: 10364539]
  4. 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. Am J Med Genet. 1992;44:482–4. [PubMed: 1442892]
  5. 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. J Med Genet. 2003;40:e49. [PMC free article: PMC1735421] [PubMed: 12676922]
  6. 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. Am J Hum Genet. 2000;67:197–202. [PMC free article: PMC1287077] [PubMed: 10839976]
  7. Guttmacher AE. Autosomal dominant preaxial deficiency, postaxial polydactyly, and hypospadias. Am J Med Genet. 1993;46:219–22. [PubMed: 8484413]
  8. Halal F. A new syndrome of severe upper limb hypoplasia and Mullerian duct anomalies. Am J Med Genet. 1986;24:119–26. [PubMed: 3706400]
  9. Hennekam RC. Acral-genital anomalies combined with ear anomalies. Am J Med Genet. 1989;34:454–5. [PubMed: 2596533]
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  11. 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. Hum Mol Genet. 2004;13:2841–51. [PubMed: 15385446]
  12. 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. Fertil Steril. 2010;94:1235–8. [PMC free article: PMC2889242] [PubMed: 19591980]
  13. 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. Am J Med Genet A. 2011;155A:642–7. [PubMed: 21344639]
  14. 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. Hum Mol Genet. 2003;12:2967–79. [PubMed: 14519685]
  15. Michels VV, Caskey CT. Mullerian aplasia with hypoplastic thumbs: Two case reports. Int J Gynaecol Obstet. 1978;17:6–10. [PubMed: 39840]
  16. Mortlock DP, Innis JW. Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet. 1997;15:179–80. [PubMed: 9020844]
  17. Mortlock DP, Sateesh P, Innis JW. Evolution of N-terminal sequences of the vertebrate HOXA13 protein. Mamm Genome. 2000;11:151–8. [PubMed: 10656931]
  18. Pinsky L. A community of human malformation syndromes involving the Mullerian ducts, distal extremities, urinary tract, and ears. Teratology. 1974;9:65–79. [PubMed: 4855855]
  19. Post LC, Margulies EH, Kuo A, Innis JW. Severe limb defects in Hypodactyly mice result from the expression of a novel, mutant HOXA13 protein. Dev Biol. 2000;217:290–300. [PubMed: 10625554]
  20. Simpson JL. Genetics of the female reproductive ducts. Am J Med Genet. 1999;89:224–39. [PubMed: 10727998]
  21. Stern AM, Gall JC, Perry BL, Stimson CW, Weitkamp LR, Poznanski AK. The hand-food-uterus syndrome: a new hereditary disorder characterized by hand and foot dysplasia, dermatoglyphic abnormalities, and partial duplication of the female genital tract. J Pediatr. 1970;77:109–16. [PubMed: 5450271]
  22. 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? Hum Genet. 2002;110:488–94. [PubMed: 12073020]
  23. Utsch B, Kaya A, Ozburun A, Lentze MJ, Albers N, Ludwig M. Exclusion of WTAP and HOXA13 as candidate genes for isolated hypospadias. Scand J Urol Nephrol. 2003;37:498–501. [PubMed: 14675924]
  24. Utsch B, McCabe CD, Galbraith K, Gonzalez R, Born M. Molecular characterization of HOXA13 polyalanine expansion proteins in Hand-Foot-Genital Syndrome. Am J Med Genet. 2007;143A:3161–3168. [PubMed: 17935235]
  25. 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. Fertil Steril. 1983;40:80–5. [PubMed: 6862042]

Suggested Reading

  1. Innis JW. HOXA13: Hand-foot-genital and Guttmacher syndromes. In: Epstein CJ, Erickson RP, Wynshaw-Boris A, eds. Inborn Errors of Development. 2 ed. San Francisco, CA: Oxford University Press. 2008:670-80.

Chapter Notes

Author Notes

Author’s Web site

Revision History

  • 3 May 2012 (me) Comprehensive update posted live
  • 2 February 2010 (me) Comprehensive update posted live
  • 11 July 2006 (me) Review posted to live Web site
  • 16 February (jwi) Original submission
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