Acromesomelic Dysplasia, Hunter-Thompson Type

A number sign (#) is used with this entry because of evidence that the Hunter-Thompson type of acromesomelic dysplasia (AMDH) is caused by homozygous mutation in the CMPD1 gene (GDF5; 601146) on chromosome 20q11. One such family has been reported.

Description

The Hunter-Thompson type of acromesomelic dysplasia is characterized by skeletal abnormalities restricted to the limbs; the craniofacial skeleton and axial skeletal structures are normal. The severity of the long bone shortening progresses in a proximal to distal direction. The hands and feet are most severely affected, but the distal phalanges are relative normal. Affected individuals have joint dislocations but the number of joints involved is not constant (summary by Thomas et al., 1996).

Clinical Features

Beighton (1974) observed acromelic dysplasia in 5 sisters, the offspring of consanguineous unaffected parents. Campailla and Martinelli (1971) described 2 sibs with limb shortening, which was most pronounced in the forearms and lower legs (as is characteristic of mesomelic dwarfism), associated with dysplasia of the tubular bones of the hands and feet. In each of 2 sibships, 2 sisters were affected. The parents were double first cousins in one of these. Intelligence was normal. The nose was somewhat pugged. Precocious osteoarthritic changes developed in the hips. The patients were dwarfed. See acrodysostosis (101800) and peripheral dysostosis (170700). Langer et al. (1977) concluded that the 3 sib pairs reported as peripheral dysostosis by Hall (1969) and the sisters reported as recessive peripheral dysostosis by Goodman et al. (1974) actually had acromesomelic dwarfism.

Langer et al. (1989) described a severe autosomal recessive form of acromesomelic dysplasia, which they called the Hunter-Thompson type (AMDH). Abnormalities were limited to the limbs, with the middle and distal segments being most affected and the lower limbs more affected than the upper. Hunter and Thompson (1976) had reported a patient who appeared to have had the same condition. In all 3 patients, dislocations of the elbows and ankles were present; dislocations of the hips and knees were present in 2.

Individuals with either AMDH or Grebe chondrodysplasia (AMDG; 200700) have normal axial skeletons and missing or fused skeletal elements within the hands and feet. This contrasts with the radiologic features of the Maroteaux type of acromesomelic dysplasia. In patients with the Maroteaux type of acromesomelic dysplasia (AMDM; 602875), all skeletal elements are present, but they have abnormal rates of linear growth. In addition, axial skeletal involvement occurs in individuals with AMDM, characterized by wedging of vertebral bodies, with the dorsal margins being shorter than the ventral margins (Langer and Garrett, 1980). Langer et al. (1989) pointed to similarities between AMDH and AMDG but concluded that radiologic analysis demonstrated differences. Langer et al. (1989) also considered AMDH to be distinct from AMDM.

Clarke et al. (1994) reported bilateral central corneal opacities in a patient with clinical and radiographic features consistent with acromesomelic dysplasia. Transmission electron micrography of the cornea demonstrated disorganization of collagen bundles secondary to the accumulation of fibillogranular material, with increased cellularity and abundant rough-surfaced endoplasmic reticulum in fibrocytes. Both corneas showed scarring through 20% of the thickness, and the child was successfully treated by full-thickness keratoplasty and corneal grafting on the right and lamellar keratoplasty on the left.

Thomas et al. (1996) described affected individuals from the family with AMDH previously reported by Langer et al. (1989). Skeletal abnormalities were limited to the limbs; the craniofacial skeleton and axial skeletal structures were normal. The forearms and hands were relatively shorter than the upper arms, and the lower leg shorter than the thighs. The feet were very short, and the third, fourth, and fifth toes were ball-shaped and functionless. Joint dislocations involved ankles, hips, elbows, and knees.

Molecular Genetics

In affected members of the family described by Langer et al. (1989) from the Choco District of Colombia with Hunter-Thompson type chondrodysplasia, Thomas et al. (1996) demonstrated homozygosity for a 22-bp tandem duplication frameshift mutation (601146.0001) in the GDF5 gene (601146.0001).