Spondylometaepiphyseal Dysplasia, Short Limb-Hand Type

A number sign (#) is used with this entry because of evidence that spondylometaepiphyseal dysplasia, short limb-hand type, is caused by homozygous mutation in the DDR2 gene (191311) on chromosome 1q23.

Clinical Features

Borochowitz et al. (1993) described 3 cases of a 'new' severe short-limb bone dysplasia, which they termed spondylometaepiphyseal dysplasia, short limb-hand type. The 3 unrelated patients were born into 2 separate Sephardic Jewish families and a Puerto Rican family. Abnormalities included small stature with short limbs and short hands, a short nose with wide nasal bridge and wide nostrils, a long philtrum, ocular hypertelorism, retro/micrognathia, and a narrow chest. Radiologic abnormalities included platyspondyly, short tubular bones with very abnormal metaphyses and epiphyses beyond early infancy, short ribs, and a typical evolution of bony changes. Histologic findings were described in 1 patient. The parents were related in 1 of the Sephardic Jewish families in which, in addition to the patient described, 2 other sibs, who did not survive infancy, were affected.

Langer et al. (1993) reported 8 additional cases of this short-limb dysplasia with a rather typical clinical appearance including similar facies and seemingly characteristic deformity of the anterior thorax and sternum. Because of abnormal premature calcification in cartilaginous structures, Langer et al. (1993) referred to the condition as the short limb-abnormal calcification type of SMED. Atlantoaxial instability resulting in cord damage and death occurred in 4 of the 8 patients of Langer et al. (1993). Seven of the 8 patients were Puerto Rican; of these, there was 1 pair of affected sibs and another family with 3 affected sibs. The stippled calcification might suggest chondrodysplasia calcificans punctata but the other features serve to differentiate the condition. Calcification of the falx cerebri was noted in 1 patient at age 20 months. Calcification of costochondral cartilages is presumably responsible for the unusual and perhaps characteristic deformity of the anterior chest and sternum. Parental consanguinity was established in 1 of the Puerto Rican families reported by Langer et al. (1993).

Al-Gazali et al. (1996) described 2 affected sibs (a girl and a boy), born of a consanguineous Egyptian couple. Both children showed extensive calcification of epiphyses, ligaments, and chondral tissues. Intellectual development of both patients was normal. Ali et al. (2010) reported that both of the sibs had died, one at age 13 years from respiratory complications and the other suddenly at age 8 years from cord compression.

Bargal et al. (2009) reported 8 patients with SMED-SL, bringing the total number of reported patients to 20. They confirmed that this dysplasia is progressive with respect to the severity of the bowing of the lower limbs and to the appearance of the calcifications.

Smithson et al. (2009) described a 7-year-old boy from Pakistan with clinical and radiologic features of a relatively mild case of SMED-SL.

Dias et al. (2009) described 2 female sibs with clinical and radiographic features consistent with SMED-SL, who died suddenly in infancy from cord compression because of foramen magnum stenosis. Dias et al. (2009) suggested that the characteristic shape of the metacarpals and phalanges seen at a young age in SMED-SL provide an important diagnostic handle so that appropriate management may be instituted early.

Inheritance

Consanguinity in 13 of 17 reported families segregating SMED-SL and the occurrence of the disorder in sibs confirms autosomal recessive inheritance (Bargal et al., 2009).

Mapping

Using a homozygosity mapping strategy to study 3 unrelated Arab Muslim patients with SMED-SL, Bargal et al. (2009) identified an identical homozygous 2.4-Mb region on chromosome 1q23 between markers rs12059277 and rs10799915. The discoidin domain receptor-2 gene (DDR2; 191311) had been mapped within this region and was considered a strong candidate because of the similarity between the phenotype of the Ddr2 knockout mouse and that of SMED-SL patients.

Molecular Genetics

In 8 patients from 7 different consanguineous families with SMED-SL, Bargal et al. (2009) identified missense mutations in exon 17 of the DDR2 gene: 6 Arab Muslims from the Jerusalem area were homozygous for an R752C substitution (191311.0001), and 1 Algerian and 1 Pakistani patient were homozygous for an I726R (191311.0002) and a T713I (191311.0003) substitution, respectively. Bargal et al. (2009) also identified a splice site mutation (191311.0004) in the DDR2 gene, which resulted in the skipping of exon 17, in one of the consanguineous Jewish families originally reported by Borochowitz et al. (1993).

Ali et al. (2010) reported a novel DDR2 missense mutation (E113K; 191311.0005) that caused SMED-SL in 2 sibs of Pakistani origin. They also detected the R752C mutation (191311.0001), identified by Bargal et al. (2009), in the 2 Egyptian sibs described by Al-Gazali et al. (1996).