Why study human limb malformations?

Abstract

Congenital limb malformations occur in 1 in 500 to 1 in 1000 human live births and include both gross reduction defects and more subtle alterations in the number, length and anatomy of the digits. The major causes of limb malformations are abnormal genetic programming and intra-uterine disruption to development. The identification of causative gene mutations is important for genetic counselling and also provides insights into the mechanisms controlling limb development. This article illustrates some of the lessons learnt from the study of human limb malformation, organized into seven categories. These are: (1) identification of novel genes, (2) allelic mutation series, (3) pleiotropy, (4) qualitative or (5) quantitative differences between mouse and human development, (6) physical and teratogenic disruption, and (7) unusual biological phenomena.

Fig. 1

Human limb phenotypes in Greig and Apert syndromes. A, Greig syndrome is caused by heterozygous loss-of-function mutations in GLI3. Note the postaxial polydactyly of the hand with cutaneous syndactyly between digits 3 and 4 (left); by contrast, in the feet (right) the polydactyly is classically pre-axial. B, Apert syndrome is caused by specific heterozygous missense mutations in FGFR2. Note syndactyly between the three central digits of the hand (left). The radiograph of the hands in another patient (right) shows a different pattern of syndactyly, unusual for this disorder, in which digit 2 is separate but the tips of digits 3–5 form a syndactylous mass. Note the fusion of the proximal and middle phalanges and the bilateral symmetry of the malformations.

Fig. 2

A genotype–phenotype series in FGFR2. The heterozygous state for five different mutations of a serine–proline dipeptide in the linker between the extracellular immunoglobulin-like domians IgII and IgIII has been described. The mutations S252W, S252F and P253R lead to severe syndactyly (Apert syndrome) but the intermediate mutations S252L and S252F;P253S do not (Oldridge et al. 1997). Abbreviations: IgI, IgII, IgIII, immunoglobulin-like domains I, II, III, respectively.

Fig. 3

Identical mutations in mouse and human give rise to different phenotypes. A, the heterozygous state for an Arg > Gln substitution at position 5 of the paired-type homeodomain of Alx4 causes hindlimb polydactyly in the lst mouse (above, forelimb; below, hindlimb); the skull is normal (not shown). B, in the human, the identical mutation of ALX4 causes paired defects in the skull bones (parietal foramina); the limbs are normal (not shown). Part A from Qu et al. (1998); reproduced with permission.

Fig. 4

Gestational age of chorionic villus sampling according to level of reduction defect in most severely affected limb (1 = defect in humerus/femur; 5 = defect in terminal phalanx or nail). Filled circles: isolated limb defects (n = 56); unfilled circles: cases with additional oromandibular hypogenesis (n = 19). From Firth et al. (1994); reproduced with permission.