Brachydactyly, Type E1

A number sign (#) is used with this entry because of evidence that a skeletal malformation with features overlapping those of brachydactyly types E and D (BDD; 113200) is caused by heterozygous mutation in the HOXD13 gene (142989) on chromosome 2q31.

Another form of brachydactyly type E, BDE2 (613382), is caused by heterozygous mutation in the PTHLH gene (168470) on chromosome 12p11.

Also see the hypertension and brachydactyly syndrome (112410).

Clinical Features

In type E brachydactyly, shortening of the fingers is mainly in the metacarpals and metatarsals. Wide variability in the number of digits affected occurs from person to person, even in the same family. Male-to-male transmission of type E brachydactyly has been observed (McKusick and Milch, 1964).

Hertzog (1968) suggested that there are at least 3 subtypes of BDE: E1, in which shortening is limited to fourth metacarpals and/or metatarsals (Hortling et al., 1960); E2, in which variable combinations of metacarpals are involved, with shortening also of the first and third distal and the second and fifth middle phalanges (McKusick and Milch, 1964); and E3, a dubious category which may have a variable combination of short metacarpals without phalangeal involvement.

Some individuals with BDE are moderately short of stature and have round facies but do not have ectopic calcification (or ossification), mental retardation or cataract as in pseudohypoparathyroidism (103580) which is otherwise a clinically similar entity. This phenotype occurs with a chromosomal aberration, the XO Turner syndrome. Also see brachydactyly-nystagmus-cerebellar ataxia (Biemond syndrome I), a probable dominant trait. Poznanski et al. (1977) concluded that 'brachydactyly E is indistinguishable radiologically from the PHP-PPHP syndrome'.

Newcombe and Keats (1969) described an extensively affected kindred with a dominant pedigree pattern (their pedigree II) as having peripheral dysostosis. The description resembled that in the family of McKusick and Milch (1964) except for cone epiphyses. The authors thought that the presence of cone epiphyses in their family was a distinguishing feature.

In a family reported by Gorlin and Sedano (1971), type E brachydactyly was associated with multiple impacted teeth. Gorlin and Sedano (1971) gave the designation 'cryptodontic metacarpalia' to type E brachydactyly associated with multiple impacted teeth. The clavicles were unusually straight and short. Whether this is a distinct entity is not clear.

Cytogenetics

Wilson et al. (1995) found a cytogenetically visible de novo deletion of 2q37 in 4 patients in whom brachydactyly type E was combined with mental retardation to produce a picture simulating Albright hereditary osteodystrophy (see 600430). A fifth patient, who was cytogenetically normal, was found to have a microdeletion at 2q37. It is possible that these patients suffered from a contiguous gene syndrome involving the locus for brachydactyly type E and one or more other loci.

Molecular Genetics

Johnson et al. (2003) performed a mutation screen of the HOXD13 gene in a family previously classified as having brachydactyly type E (Brailsford, 1945; Oude Luttikhuis et al., 1996) and identified a heterozygous ser308-to-cys mutation (S308C; 142989.0005). The patients showed selective shortening of metacarpals 3, 4, and 5 and metatarsals 1 and 4, as well as shortening of the distal phalanges of the thumb. The hand phenotype showed wide intrafamilial variation of the features, which overlapped those described in brachydactyly types D (113200) and E. No family member had syndactyly, but foot radiographs of several affected individuals showed an abnormally broad first metatarsal.