Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome

Abstract

Hand-foot-genital syndrome (HFGS) is a rare, dominantly inherited condition affecting the distal limbs and genitourinary tract. A nonsense mutation in the homeobox of HOXA13 has been identified in one affected family, making HFGS the second human syndrome shown to be caused by a HOX gene mutation. We have therefore examined HOXA13 in two new and four previously reported families with features of HFGS. In families 1, 2, and 3, nonsense mutations truncating the encoded protein N-terminal to or within the homeodomain produce typical limb and genitourinary abnormalities; in family 4, an expansion of an N-terminal polyalanine tract produces a similar phenotype; in family 5, a missense mutation, which alters an invariant domain, produces an exceptionally severe limb phenotype; and in family 6, in which limb abnormalities were atypical, no HOXA13 mutation could be detected. Mutations in HOXA13 can therefore cause more-severe limb abnormalities than previously suspected and may act by more than one mechanism.

Figure 1

Pedigree drawings. A, Family 1; B, family 2; C, family 3; D, family 4; and E, family 5. Black shading of the left half of symbols indicates hand and foot abnormalities. Gray shading of the right half of symbols indicates genital abnormalities (hypospadias or other penile abnormality in males; uterine and/or vaginal abnormalities in females). An asterisk (*) above a symbol indicates that the individual had a urinary tract abnormality on diagnostic imaging.

Figure 2

Limb abnormalities in II.2 from family 1 at age 8 years. Photographs of left hand (A), showing short, proximally placed thumb, ulnar deviation of the second finger, and clinodactyly of the fifth finger; and left foot (B), showing short, medially deviated hallux. Radiographs of both hands (C), showing short first metacarpals, small pointed first distal phalanges, hypoplastic second and fifth middle phalanges, proximal pseudoepiphyses of the second metacarpals and delayed ossification of the carpal centers; and both feet (D), showing short first metatarsals, small triangular first proximal and distal phalanges, absent ossification of the third to fifth middle phalanges, and hypoplasia/absence of the distal phalanges.

Figure 3

Limb abnormalities in II.1 from family 5. Photographs at age 1 mo of left hand (A), showing extremely small thumb; and right foot (B ), showing absence of hallux. Radiographs at age 5 years of both hands (C), showing extremely short first metacarpals, small pointed first distal phalanges, marked hypoplasia of all middle phalanges, especially the second and fifth, pseudoepiphyses of the third and fourth middle phalanges and the first and second metacarpals, and delayed ossification of the carpal centers; and both feet (D), showing absence of first digits apart from rudimentary bases of the first metatarsals, hypoplasia/absence of all middle phalanges, lack of epiphyses associated with the middle and distal phalanges, and abnormal tarsals with absent or fused cuneiforms.

Figure 4

Mutations in HOXA13. A, Genomic structure of HOXA13, showing sites of the five mutations identified in this study. B, Wild-type HOXA13 protein. C–F, Predicted truncated mutant proteins in family 1 (C), lacking the last 253 amino acids; family 2 (D), lacking the last 193 amino acids; family 3 (E), lacking the last 24 amino acids; and family previously investigated by Mortlock and Innis (1997) (F), lacking the last 20 amino acids. G, Stable truncated mutant protein in the Hypodactyly mouse (Post et al. 2000), caused by a frameshift mutation in exon 1 of Hoxa13; the first 25 amino acids are followed by 275 amino acids with no wild-type counterpart and a premature stop codon.