Acheiropody

A number sign (#) is used with this entry because classic acheiropody (ACHP) as described in Brazil is caused by homozygous mutation in the LMBR1 gene (605522) on chromosome 7q36.

Description

Acheiropody is characterized by bilateral congenital amputations of the upper and lower extremities and aplasia of the hands and feet. Specific patterns of malformations consist of a complete amputation of the distal epiphysis of the humerus, amputation of the distal part of the tibial diaphysis, and aplasia of the radius, ulna, fibula, and of the carpal, metacarpal, tarsal, metatarsal, and phalangeal bones (summary by Ianakiev et al., 2001).

Clinical Features

Toledo and Saldanha (1969) described an inbred Brazilian kindred of Portuguese ancestry in which multiple members had absence of the hands and feet, with the arms and legs ending in stumps. Freire-Maia et al. (1975) stated that at least 22 sibships had been reported, all from Brazil. Consanguinity was found in 82% of parents.

The expressivity of the acheiropodia gene is rather variable (Grimaldi et al., 1983). For example, patients may or may not show a Bohomoletz bone, an elongated small bone in the tip of the upper limb remnant, parallel to the axis of the humerus. The origin of the bone is unclear; in some cases it looks like the proximal part of the ulna, whereas in others it is not sufficiently differentiated to allow identification. Fett-Conte and Richieri-Costa (1990) reported 4 new patients from Brazil, 2 of whom had a Bohomoletz bone.

In peromelia with micrognathism, or the Hanhart syndrome (103300), absence of the hands and feet occurs, making it a form of acheiropody.

Mapping

Escamilla et al. (2000) performed a complete genome screen of 7 members of an extended Brazilian pedigree that included 3 sibs with acheiropodia. Homozygosity mapping was used to identify regions most likely to harbor the gene for acheiropodia in this pedigree. In the 2 key regions (14p and 7q), further genotyping of 1 additional affected member of this pedigree plus 7 additional unaffected sibs provided evidence, through linkage analysis, that the 7q36 region contains the acheiropodia gene. In this region, a maximum 2-point lod score of 3.81 (4.2 with multipoint analysis) was achieved, and a homozygous haplotype spanning a region of 11.7 cM was seen in all affected members of the pedigree. Genotypic analysis of 2 additional cases of acheiropodia with no known relation to the other pedigree studied revealed homozygous sharing of a portion of the same haplotype on 7q36, which reduced the chromosomal location of the acheiropodia gene to an 8.6-cM region. Localization of this gene, at the screening level, by use of data from only 3 affected subjects, provided an example of how certain genes may be mapped by use of a minimal number of affected cases.

Inheritance

The transmission pattern of acheiropody in the families reviewed by Freire-Maia et al. (1975) was consistent with autosomal recessive inheritance.

Molecular Genetics

Ianakiev et al. (2001) identified a homozygous deletion in the human ortholog of the mouse Lmbr1 gene in all 5 Brazilian families with acheiropody studied, thus identifying the common acheiropody mutation; see 605522.0001. One of the families (pedigree 4) had been described by Toledo and Saldanha (1969).

Population Genetics

Freire-Maia et al. (1975) estimated the incidence of acheiropody in Brazil to be 1 in 250,000 births.

Nomenclature

Freire-Maia (1975) strenuously insisted that the name for this disorder should be acheiropodia, not acheiropody, and that it is unnecessary to qualify the disorder as Brazilian. In American English, polydactyly and syndactyly are preferred usage over polydactylia or syndactylia, and use of acheiropody can be defended on the grounds of consistency.