General Medical Information

Hand-Foot-Genital Syndrome

Joe Leigh Simpson

Hand-foot-genital (HFG) syndrome is an autosomal dominant disorder in which incomplete müllerian fusion is a major feature. First reported by Stern and associates, multiple kindreds have now been recognized. The HFG syndrome is characterized by skeletal (hand and foot) malformations and either incomplete müllerian fusion in females or hypospadias in males (thus, “hand-foot-genital” has replaced the original appellation “hand-foot-uterus”). Limb abnormalities include short first metacarpals, small distal phalanges on the thumbs, short middle phalanges on the small finger, and fusion of the wrist bones. The great toe is shortened due to a shortened metatarsal; the distal phalanx is small and pointed.

Urinary system anomalies in HFG syndrome include urinary incontinence in females, ventrally displaced urethral meatus (male and female), and malposition of the ureteral orifices in the bladder wall (females). These urologic anomalies differ from those associated with isolated incomplete müllerian fusion. Moreover, vertebral anomalies do not seem characteristic of the HFG syndrome.

Even with a negative family history, HFG syndrome should be considered present if an individual with incomplete müllerian fusion has any of the skeletal or genital anomalies characteristic of HFG syndrome. Given that variable expressivity is characteristic of all autosomal dominant disorders, it also would be expected that some females with the HFG gene would manifest only uterine anomalies or only skeletal anomalies, whereas others in the same kindred show both.

HOXA13 is an attractive candidate gene for human HFG). A HOXA13 mutation was detected in a member of the original family reported by Stern, and a HOXA13 nonsense mutant was found in other HFG families. The manner by which perturbation of HOXA13 produces HFG still is uncertain.

HFG is not the only multiple malformation syndrome associated with incomplete müllerian fusion. Table 1.4 provides a more complete list. Many different genes as well as nonmendelian factors must remain intact for normal müllerian development. Whether wild-type genes for these syndromes are integral for normal müllerian differentiation remains unclear. The uterine anomalies merely could arise secondary to connective tissue or vascular perturbations.