Omodysplasia 2

A number sign (#) is used with this entry because of evidence that omodysplasia-2 (OMOD2) is caused by heterozygous mutation in the FZD2 gene (600667) on chromosome 17q21.

Description

Omodysplasia-2 is a rare autosomal dominant skeletal dysplasia characterized by shortened humeri, dislocated radial heads, shortened first metacarpals, craniofacial dysmorphism, and variable genitourinary anomalies (Saal et al., 2015).

For a discussion of genetic heterogeneity of OMOD, see 258315.

Clinical Features

Under the designation omodysplasia, Maroteaux et al. (1989) described 3 cases of a 'new' congenital bone disorder associating facial anomalies (depressed nasal bridge, broad base of the nose, and long philtrum) with short humeri. (Omodysplasia etymologically means shoulder dysplasia: the 'omo' comes from the Greek word for shoulder.) The complex skeletal abnormalities consisted of a defect in the growth of the distal end of the humerus, a hypoplastic everted condyle, a proximal radioulnar diastasis, and an anterolateral dislocation of the head of the radius. A mother and her infant son were 2 of the 3 cases. Two other cases had micromelic dwarfism due to shortness of the long bones, particularly the femora; Maroteaux et al. (1989) considered that these cases represented variable expression of the same disorder; see OMOD1 (258315).

Venditti et al. (2002) described a family with mother-to-son transmission of omodysplasia. The mother, who had originally been diagnosed with Robinow syndrome (180700), had shortened humeri, shallow olecranon fossae with partially subluxed radii, shortened first metacarpals, and small, laterally displaced patellas. She also had a large forehead, hypertelorism, a depressed nasal bridge, maxillary hypoplasia, and hypoplastic genitalia. Her intellectual and motor development were normal. Prenatal ultrasound of her son at 13 to 14 weeks showed delayed humeral ossification. A repeat study at 20 weeks showed shortened humeri and genitalia that were not assignable to either gender. At birth, he was noted to have facial and skeletal features similar to those of his mother and hypoplastic genitalia with a small penis, bifid scrotum, and undescended testes.

Gordon et al. (2014) provided long-term observation of a 48-year-old woman with omodysplasia, who was first evaluated at age 9 years. She had short stature, prominent forehead, flat face, rhizomelic shortening of the upper and lower extremities, and inability to pronate and supinate the forearms. Radiographs revealed shortening of the humeri and ulnas, bowing and dislocation of the radial heads, short fifth metacarpals, and symmetric coxa valga. At age 11 years, 6 to 8 permanent teeth were extracted to relieve dental crowding due to a small maxilla and mandible. Radiographic evaluation at age 16 confirmed marked symmetric shortening of all tubular bones in the upper limbs; bones in the lower limbs were considered to be normal. At age 25, the patient underwent laparotomy for suspected ectopic pregnancy and was found to have a bicornuate uterus. Examination at age 48 showed low-set, posteriorly angulated ears with a Darwinian tubercle and overfolded helix, downslanting palpebral fissures, upturned short nose with broad base and hypoplastic alae, and underdeveloped but long philtrum. She had several small frenula between lower lip and gums, slightly tethered tongue, and hypoplastic uvula. Her thumbs were short and proximally implanted due to short first metacarpals. The authors stated that mild rhizomelic shortening of the lower extremities had not previously been reported in omodysplasia.

Saal et al. (2015) reported a mother and daughter with omodysplasia. Both had short humeri and radial dislocation with limitation of movement, and the daughter also showed widening of the femoral neck and lateral uncovering of the femoral head bilaterally, shortening of the ulnas and fibulas, and short first metacarpals. Both patients exhibited facial dysmorphism, including round face, frontal bossing, flat nasal bridge, and long philtrum, and the mother also had bilateral cleft lip and cleft palate. In addition, the mother showed hypoplastic genitalia and a didelphic uterus.

Molecular Genetics

In a mother and daughter with omodysplasia, Saal et al. (2015) performed next-generation exome sequencing and identified heterozygosity for a nonsense mutation in the FZD2 gene (W548X; 600667.0001) that was not found in the mother's unaffected parents or in an in-house database or in public variant databases. Functional analysis showed that the mutant protein had reduced ability to interact with downstream targets and, in contrast to wildtype FZD2, could not facilitate the cellular response to canonical WNT (see 164820) signaling.