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Hand-foot-genital syndrome

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Description

Hand-foot-genital syndrome is a rare condition that affects the development of the hands and feet, the urinary tract, and the reproductive system. People with this condition have abnormally short thumbs and first (big) toes, small fifth fingers that curve inward (clinodactyly), short feet, and fusion or delayed hardening of bones in the wrists and ankles. The other bones in the arms and legs are normal.

Abnormalities of the genitals and urinary tract can vary among affected individuals. Many people with hand-foot-genital syndrome have defects in the ureters, which are tubes that carry urine from each kidney to the bladder, or in the urethra, which carries urine from the bladder to the outside of the body. Recurrent urinary tract infections and an inability to control the flow of urine (urinary incontinence) have been reported. About half of males with this disorder have the urethra opening on the underside of the penis (hypospadias).

People with hand-foot-genital syndrome are usually able to have children (fertile). In some affected females, problems in the early development of the uterus can later increase the risk of pregnancy loss, premature labor, and stillbirth.

Frequency

Hand-foot-genital syndrome is very rare; only a few families with the condition have been reported worldwide.

Causes

Mutations in the HOXA13 gene cause hand-foot-genital syndrome. The HOXA13 gene provides instructions for producing a protein that plays an important role in development before birth. Specifically, this protein appears to be critical for the formation and development of the limbs (particularly the hands and feet), urinary tract, and reproductive system. Mutations in the HOXA13 gene cause the characteristic features of hand-foot-genital syndrome by disrupting the early development of these structures. Some mutations in the HOXA13 gene result in the production of a nonfunctional version of the HOXA13 protein. Other mutations alter the protein's structure and interfere with its normal function within cells. Mutations that result in an altered but functional HOXA13 protein may cause more severe signs and symptoms than mutations that lead to a nonfunctional HOXA13 protein.

Inheritance

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

Other Names for This Condition

  • Hand-foot-uterus syndrome
  • HFG syndrome
  • HFGS
  • HFU syndrome

Additional Information & Resources

Genetic and Rare Diseases Information Center

Catalog of Genes and Diseases from OMIM

Scientific Articles on PubMed

References

  • 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 Jul;67(1):197-202. Epub 2000 Jun 5. Citation on PubMed or Free article on PubMed Central
  • Goodman FR, Scambler PJ. Human HOX gene mutations. Clin Genet. 2001 Jan;59(1):1-11. Review. Citation on PubMed
  • Goodman FR. Limb malformations and the human HOX genes. Am J Med Genet. 2002 Oct 15;112(3):256-65. Review. Citation on PubMed
  • 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 Nov 15;13(22):2841-51. Epub 2004 Sep 22. Citation on PubMed
  • Innis JW. Hand-Foot-Genital Syndrome. 2006 Jul 11 [updated 2019 Aug 8]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1423/ Citation on PubMed
  • Mortlock DP, Innis JW. Mutation of HOXA13 in hand-foot-genital syndrome. Nat Genet. 1997 Feb;15(2):179-80. Citation on PubMed
  • Utsch B, McCabe CD, Galbraith K, Gonzalez R, Born M, Dötsch J, Ludwig M, Reutter H, Innis JW. Molecular characterization of HOXA13 polyalanine expansion proteins in hand-foot-genital syndrome. Am J Med Genet A. 2007 Dec 15;143A(24):3161-8. Citation on PubMed
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