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Hand-foot-genital syndrome(HFGS)

MedGen UID:
331103
Concept ID:
C1841679
Disease or Syndrome
Synonyms: Hand foot uterus syndrome; HFG syndrome; HFGS; HFU syndrome
SNOMED CT: Hand-foot-genital syndrome (702425002); Hand-foot-uterus syndrome (702425002)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): HOXA13 (7p15.2)
 
Monarch Initiative: MONDO:0007698
OMIM®: 140000
Orphanet: ORPHA2438

Disease characteristics

Excerpted from the GeneReview: Hand-Foot-Genital Syndrome
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. [from GeneReviews]
Authors:
Jeffrey W Innis   view full author information

Additional descriptions

From OMIM
Hand-foot-genital syndrome (HFGS) is an autosomal dominant condition characterized by distal limb and distal genitourinary tract malformations. The most striking limb abnormality is first-digit hypoplasia, comprising short, proximally placed thumbs with hypoplastic thenar eminences and short, medially deviated halluces. There is also ulnar deviation of the second fingers, clinodactyly/brachydactyly of the fifth fingers, brachydactyly of the second to fifth toes, and delayed ossification, fusion, and shortening of the carpals and tarsals. These abnormalities appear to be fully penetrant, bilateral, and symmetrical, with little variation in severity. In contrast, genitourinary tract abnormalities are incompletely penetrant and variably severe, and include hypospadias in males, Mullerian duct fusion defects in females, vesicoureteric reflux, and pelviureteric junction obstruction (summary by Goodman et al., 2000).  http://www.omim.org/entry/140000
From MedlinePlus Genetics
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), and short feet. The bones in the wrists and ankles may be fused in people with this condition, or hardening of these bones may be delayed. 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.  https://medlineplus.gov/genetics/condition/hand-foot-genital-syndrome

Clinical features

From HPO
Vesicoureteral reflux
MedGen UID:
21852
Concept ID:
C0042580
Disease or Syndrome
Vesicoureteral reflux (VUR) is characterized by the reflux of urine from the bladder into the ureters and sometimes into the kidneys. It is a risk factor for urinary tract infections. Primary VUR results from a developmental defect of the ureterovesical junction (UVJ). In combination with intrarenal reflux, the resulting inflammatory reaction may result in renal injury or scarring, also called reflux nephropathy (RN). Extensive renal scarring impairs renal function and may predispose patients to hypertension, proteinuria, and renal insufficiency (summary by Lu et al., 2007). Genetic Heterogeneity of Vesicoureteral Reflux A locus designated VUR1 maps to chromosome 1p13. VUR2 (610878) is caused by mutation in the ROBO2 gene (602431) on chromosome 3p12; VUR3 (613674) is caused by mutation in the SOX17 gene (610928) on chromosome 8q11; VUR4 (614317) maps to chromosome 5; VUR5 (614318) maps to chromosome 13; VUR6 (614319) maps to chromosome 18; VUR7 (615390) maps to chromosome 12; and VUR8 (615963) is caused by mutation in the TNXB gene (600985) on chromosome 6p21. A possible X-linked form has been reported (VURX; 314550).
Chordee
MedGen UID:
66363
Concept ID:
C0221182
Congenital Abnormality
Ventral, lateral, or ventrolateral bowing of the shaft and glans penis of more than 30 degrees.
Uterus didelphys
MedGen UID:
82740
Concept ID:
C0266393
Congenital Abnormality
A malformation of the uterus in which the uterus is present as a paired organ as a result of the failure of fusion of the mullerian ducts during embryogenesis.
Bifid scrotum
MedGen UID:
90968
Concept ID:
C0341787
Congenital Abnormality
Midline indentation or cleft of the scrotum.
Ureteropelvic junction obstruction
MedGen UID:
105482
Concept ID:
C0521619
Anatomical Abnormality
Blockage of urine flow from the renal pelvis to the proximal ureter.
Hypospadias
MedGen UID:
163083
Concept ID:
C0848558
Congenital Abnormality
Abnormal position of urethral meatus on the ventral penile shaft (underside) characterized by displacement of the urethral meatus from the tip of the glans penis to the ventral surface of the penis, scrotum, or perineum.
Renal insufficiency
MedGen UID:
332529
Concept ID:
C1565489
Disease or Syndrome
A reduction in the level of performance of the kidneys in areas of function comprising the concentration of urine, removal of wastes, the maintenance of electrolyte balance, homeostasis of blood pressure, and calcium metabolism.
Longitudinal vaginal septum
MedGen UID:
331104
Concept ID:
C1841680
Finding
The presence of a longitudinal vaginal septum, thereby creating a vaginal duplication.
Micropenis
MedGen UID:
1633603
Concept ID:
C4551492
Congenital Abnormality
Abnormally small penis. At birth, the normal penis is about 3 cm (stretched length from pubic tubercle to tip of penis) with micropenis less than 2.0-2.5 cm.
Brachydactyly
MedGen UID:
67454
Concept ID:
C0221357
Congenital Abnormality
Digits that appear disproportionately short compared to the hand/foot. The word brachydactyly is used here to describe a series distinct patterns of shortened digits (brachydactyly types A-E). This is the sense used here.
Hallux varus
MedGen UID:
107471
Concept ID:
C0546297
Anatomical Abnormality
Medial deviation of the great toe owing to a deformity of the great toe joint causing the hallux to deviate medially.
Delayed ossification of carpal bones
MedGen UID:
374771
Concept ID:
C1841684
Finding
Ossification of carpal bones occurs later than age-adjusted norms.
Short first metatarsal
MedGen UID:
330663
Concept ID:
C1841688
Finding
Short first metatarsal bone.
Short 5th finger
MedGen UID:
334269
Concept ID:
C1842878
Congenital Abnormality
Hypoplasia (congenital reduction in size) of the fifth finger, also known as the little finger.
Ulnar deviation of the 2nd finger
MedGen UID:
336806
Concept ID:
C1844891
Finding
Displacement of the 2nd (index) finger towards the ulnar side.
Small thenar eminence
MedGen UID:
335432
Concept ID:
C1846474
Finding
Underdevelopment of the thenar eminence with reduced palmar soft tissue mass surrounding the base of the thumb.
Short 1st metacarpal
MedGen UID:
376561
Concept ID:
C1849311
Finding
A developmental defect characterized by reduced length of the first metacarpal (long bone) of the hand.
Clinodactyly of the 5th finger
MedGen UID:
340456
Concept ID:
C1850049
Congenital Abnormality
Clinodactyly refers to a bending or curvature of the fifth finger in the radial direction (i.e., towards the 4th finger).
Shortening of all middle phalanges of the fingers
MedGen UID:
347331
Concept ID:
C1856912
Finding
Short, hypoplastic middle phalanx of finger, affecting all fingers.
Proximal placement of thumb
MedGen UID:
356033
Concept ID:
C1865572
Finding
Proximal mislocalization of the thumb.
Short hallux
MedGen UID:
400890
Concept ID:
C1865992
Finding
Underdevelopment (hypoplasia) of the big toe.
Short 2nd toe
MedGen UID:
867399
Concept ID:
C4021769
Anatomical Abnormality
Underdevelopment (hypoplasia) of the second toe.
Pseudoepiphyses
MedGen UID:
333889
Concept ID:
C1841685
Finding
Delayed tarsal ossification
MedGen UID:
339625
Concept ID:
C1846853
Finding
Delayed maturation and calcification of any of the tarsal bones, seven bones of the foot comprising the calcaneus, talus, cuboid, navicular, and the cuneiform bones.
Pyelonephritis
MedGen UID:
19590
Concept ID:
C0034186
Disease or Syndrome
An inflammation of the kidney involving the parenchyma of kidney, the renal pelvis and the kidney calices.
Small nail
MedGen UID:
537942
Concept ID:
C0263523
Finding
A nail that is diminished in length and width, i.e., underdeveloped nail.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHand-foot-genital syndrome
Follow this link to review classifications for Hand-foot-genital syndrome in Orphanet.

Professional guidelines

PubMed

Valentini AL, Giuliani M, Gui B, Laino ME, Zecchi V, Rodolfino E, Ninivaggi V, Manzoni C, Bonomo L
Am J Perinatol 2016 Apr;33(5):425-32. Epub 2015 Oct 21 doi: 10.1055/s-0035-1565996. PMID: 26489064

Recent clinical studies

Etiology

Owens KM, Quinonez SC, Thomas PE, Keegan CE, Lefebvre N, Roulston D, Larsen CA, Stadler HS, Innis JW
Am J Med Genet A 2013 May;161A(5):1019-27. Epub 2013 Mar 26 doi: 10.1002/ajmg.a.35843. PMID: 23532960
Utsch B, McCabe CD, Galbraith K, Gonzalez R, Born M, Dötsch J, Ludwig M, Reutter H, Innis JW
Am J Med Genet A 2007 Dec 15;143A(24):3161-8. doi: 10.1002/ajmg.a.31967. PMID: 17935235

Diagnosis

Geng W, Li F, Zhang R, Cao L, Du X, Gu W, Xu M
Eur J Med Genet 2023 Mar;66(3):104711. Epub 2023 Jan 24 doi: 10.1016/j.ejmg.2023.104711. PMID: 36702441
Piazza MJ, Urbanetz AA
JBRA Assist Reprod 2018 Jun 1;22(2):157-159. doi: 10.5935/1518-0557.20180025. PMID: 29638102Free PMC Article
Cao L, Chen C, Leng Y, Yan L, Wang S, Zhang X, Luo Y
J Genet 2017 Sep;96(4):647-652. doi: 10.1007/s12041-017-0810-y. PMID: 28947713
Imagawa E, Kayserili H, Nishimura G, Nakashima M, Tsurusaki Y, Saitsu H, Ikegawa S, Matsumoto N, Miyake N
Am J Med Genet A 2014 Sep;164A(9):2398-402. Epub 2014 Jun 16 doi: 10.1002/ajmg.a.36648. PMID: 24934387
Simpson JL
Am J Med Genet 1999 Dec 29;89(4):224-39. doi: 10.1002/(sici)1096-8628(19991229)89:4<224::aid-ajmg7>3.0.co;2-c. PMID: 10727998

Prognosis

Cao L, Chen C, Leng Y, Yan L, Wang S, Zhang X, Luo Y
J Genet 2017 Sep;96(4):647-652. doi: 10.1007/s12041-017-0810-y. PMID: 28947713
Wallis M, Tsurusaki Y, Burgess T, Borzi P, Matsumoto N, Miyake N, True D, Patel C
Am J Med Genet A 2016 Mar;170(3):717-24. Epub 2015 Nov 21 doi: 10.1002/ajmg.a.37478. PMID: 26590955
Quinonez SC, Innis JW
Mol Genet Metab 2014 Jan;111(1):4-15. Epub 2013 Oct 29 doi: 10.1016/j.ymgme.2013.10.012. PMID: 24239177
Grier DG, Thompson A, Kwasniewska A, McGonigle GJ, Halliday HL, Lappin TR
J Pathol 2005 Jan;205(2):154-71. doi: 10.1002/path.1710. PMID: 15643670
Goodman FR
Am J Med Genet 2002 Oct 15;112(3):256-65. doi: 10.1002/ajmg.10776. PMID: 12357469

Clinical prediction guides

Imagawa E, Kayserili H, Nishimura G, Nakashima M, Tsurusaki Y, Saitsu H, Ikegawa S, Matsumoto N, Miyake N
Am J Med Genet A 2014 Sep;164A(9):2398-402. Epub 2014 Jun 16 doi: 10.1002/ajmg.a.36648. PMID: 24934387
Quinonez SC, Innis JW
Mol Genet Metab 2014 Jan;111(1):4-15. Epub 2013 Oct 29 doi: 10.1016/j.ymgme.2013.10.012. PMID: 24239177
Grier DG, Thompson A, Kwasniewska A, McGonigle GJ, Halliday HL, Lappin TR
J Pathol 2005 Jan;205(2):154-71. doi: 10.1002/path.1710. PMID: 15643670
Goodman FR
Am J Med Genet 2002 Oct 15;112(3):256-65. doi: 10.1002/ajmg.10776. PMID: 12357469
Simpson JL
Am J Med Genet 1999 Dec 29;89(4):224-39. doi: 10.1002/(sici)1096-8628(19991229)89:4<224::aid-ajmg7>3.0.co;2-c. PMID: 10727998

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