Brachydactyly, Type D

A number sign (#) is used with this entry because a skeletal malformation with features overlapping those of brachydactyly types D and E (BDE; 113300) can be caused by mutation in the HOXD13 gene (142989).

Clinical Features

This type of brachydactyly is characterized by short and broad terminal phalanges of the thumbs and big toes. Thomsen (1928) described this anomaly. In a unilateral case he pointed out that the epiphyseal line at the base of the anomalous phalanx was obliterated but was still demonstrable in the corresponding position on the normal thumb. Goodman et al. (1965) also studied this 'normal' morphologic trait in detail. The trait has picturesque designations such as 'potter's thumb' and 'murderer's thumb.' It occurs as part of the Rubinstein syndrome (180849). Gray and Hurt (1984) concluded that penetrance is complete in females and incomplete in males. About three-fourths of affected persons, both males and females, express the trait bilaterally.

Robin et al. (1999) studied 6 affected individuals from a 4-generation family with brachydactyly type D. All affected individuals had either bilateral and symmetric or unilateral first distal phalangeal hypoplasia. Metacarpal-phalangeal profiles showed that some affected individuals also had a more generalized involvement of the apical skeleton. However, other than first distal phalangeal hypoplasia, there was no consistent pattern of associated skeletal involvement. Linkage analysis with 6 loci known to contain genes involved in apical skeletal patterning showed no significant linkage.

Molecular Genetics

The HOXD13 gene, the most 5-prime gene of the HOXD cluster, encodes a homeodomain transcription factor with important functions in limb patterning and growth. Heterozygous mutations of HOXD13, encoding polyalanine expansions or frameshifts, appear to act by dominant-negative or haploinsufficiency mechanisms and are predominantly associated with synpolydactyly phenotypes. Johnson et al. (2003) described 2 mutations in the homeodomain of HOXD13, ile314 to leu (I314L; 142989.0004) and ser308 to cys (S308C; 142989.0005), which were associated with distinctive limb phenotypes in which brachydactyly of specific metacarpals, metatarsals, and phalangeal bones was the most constant feature, exhibiting overlap with brachydactyly types D and E (113300).