Hand-Foot-Genital Syndrome

A number sign (#) is used with this entry because of evidence that hand-foot-genital syndrome (HFG) is caused by heterozygous mutation in the HOXA13 gene (142959) on chromosome 7p15.

Clinical Features

The clinical features include small feet with unusually short great toes and abnormal thumbs. Females with the disorder have duplication of the genital tract, including longitudinal vaginal septum (Stern et al., 1970). The radiographic changes were reviewed by Poznanski et al. (1970), who suggested that there is a typical metacarpophalangeal profile pattern. The changes included short first metacarpal and metatarsal, short fifth fingers with clinodactyly, trapezium-scaphoid fusion in the wrist, and cuneiform-navicular fusion in the foot.

Poznanski et al. (1975) described another kindred with this disorder. The pattern of radiologic changes in the hands and feet were sufficiently characteristic to suggest the diagnosis when the proband, a girl less than 4 years old, was admitted for evaluation of urinary incontinence and recurrent urinary tract infection. This was the prototype for one of the 'phenotypic communities of human malformation syndromes' discussed by Pinsky (1974).

Elias et al. (1978) investigated a third family in which 5 females in 3 generations were affected. The proband was a 17-year-old girl with strabismus, hypoplastic thenar eminences, malformed thumbs, bilateral fifth finger clinodactyly, short halluces, uterus bicornis bicollis, longitudinal vaginal septum and bilateral ureterovesical reflux.

Halal (1988) described a family in which affected females had urologic abnormalities. At least 3 affected males had penile hypospadias with chordee. A fourth, who had not been married, had a surgical operation on the genitalia at age 45, but the type of surgery was not known. Hypoplastic thenar eminences, 'stubby' thumbs, 5th finger clinodactyly, and short great toes were commented on. One affected female in this family had hypospadiac urethra and ectopic accessory ureteral orifice, with recurrent urinary tract infections leading to chronic pyelonephritis, renal insufficiency, and kidney transplantation. Verp (1989) corroborated the significance of urologic abnormalities as part of this syndrome in females.

Hennekam (1989) pointed out 2 other reports of this syndrome and reported a kindred with autosomal dominant inheritance. Complete duplication of the genital tract including a longitudinal vaginal septum was expressed in 3 females. The diagnosis of HFG syndrome was not completely certain because there were no hand anomalies or typical metacarpophalangeal profile pattern. An additional feature was the presence of external ear anomalies; 6 members of the family had small ears with thickened, dysplastic helices.

Verp et al. (1983) reported a family in which 5 affected individuals in 3 generations, all female, had hand and foot anomalies consisting of short thumbs with hypoplastic distal phalanges, brachyclinodactyly V, bilateral hypoplasia and medial deviation of the distal halluces, and clinodactyly of the fifth toes. In 2 of the 5 women who were thoroughly evaluated, incomplete mullerian fusion defects were found. The proposita had presented with recurrent urinary tract infections due to bilateral vesicoureteral reflux at age 2 years. Donnenfeld et al. (1992) reported on the same family, studied when the proposita presented at 19 years of age in premature labor at 22 weeks of gestation due to her uterine anomaly. They documented the genitourinary abnormalities in her 2 affected sisters, not previously examined, and documented hypospadias and urinary tract anomalies in 2 males from the fourth generation. One of the boys had bilateral vesicoureteral reflux and the other had bilateral ureteropelvic junction obstruction. Hypospadias is a manifestation of the disorder in males (Giedion and Prader, 1976).

Cleveland and Holmes (1990) emphasized the importance of hallux varus in the diagnosis.

Inheritance

Hennekam (1989) reported a kindred with autosomal dominant inheritance of HFG.

Fryns et al. (1993) documented male-to-male transmission. An affected father begot 3 affected sons. A grade IV hypospadias, which was the most severe genital anomaly, was present in the youngest, moderately mentally retarded microcephalic male sib.

Molecular Genetics

On the basis of update and linkage analysis of the family reported by Stern et al. (1970), Mortlock (1996) and his colleagues demonstrated mutation in the HOXA13 gene (142959) as the cause of the hand-foot-uterus syndrome. Affected members of the family reported by Stern et al. (1970) showed a nonsense mutation (142959.0001) which converted a highly conserved tryptophan residue in the homeodomain of HOXA13 to a stop codon and truncated 20 amino acids from the protein (Mortlock and Innis, 1997).

Goodman et al. (2000) examined the HOXA13 gene in 2 new and 4 previously reported families with features of HFG syndrome. In 3 families, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produced typical limb and genitourinary abnormalities; in the fourth family, an expansion of an N-terminal polyalanine tract produced a similar phenotype; in the fifth family, a missense mutation, which altered an invariant domain, produced an exceptionally severe limb phenotype. In the sixth family, first reported by Hennekam (1989), in which limb abnormalities were atypical, no HOXA13 mutation was detected. In all families in which a mutation was detected, the limb abnormalities were fully penetrant, bilateral, and symmetrical, with analogous involvement of the hands and feet. In contrast, genitourinary abnormalities were incompletely penetrant and variably severe.