Smith-Mccort Dysplasia 2

A number sign (#) is used with this entry because Smith-McCort dysplasia-2 (SMC2) is caused by homozygous or compound heterozygous mutation in the RAB33B gene (605950) on chromosome 4q31.

Description

Smith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short trunk dwarfism with a barrel-shaped chest, rhizomelic limb shortening, and specific radiologic features including marked platyspondyly with double-humped end-plates, kyphoscoliosis, metaphyseal irregularities, laterally displaced capital femoral epiphyses, and small pelvis with a lace-like appearance of iliac crests. These clinical and radiologic features are also common to Dyggve-Melchior-Clausen syndrome (DMC; 223800), which is distinguished from SMC by the additional feature of mental retardation (summary by Dupuis et al., 2013).

For a discussion of genetic heterogeneity of Smith-McCort dysplasia, see SMC1 (607326).

Clinical Features

Alshammari et al. (2012) reported a consanguineous Saudi family in which 4 sibs and 2 first cousins had Dyggve-Melchior-Clausen syndrome and normal intelligence (Smith-McCort dysplasia). All were short and had variable degrees of progressive pectus carinatum deformity, limitation of joint mobility, and lumbar lordosis. The index patient had significant short stature and no gross craniofacial dysmorphism. He had a short neck, significant pectus carinatum, exaggerated lumbar lordosis, and limitation of elbow extension and interphalangeal joint flexion with difficulty making a fist. There was genu valgus and no evidence of organomegaly.

Salian et al. (2017) reported 3 unrelated probands with Smith-McCort dysplasia. All had short trunk, barrel chest, limited extension of elbow joints, brachydactyly, and normal intelligence. Radiography in all 3 showed playtspondyly with double humps of the vertebral bodies, short and broad ilia with basilar hypoplasia and lacy iliac crests, short metacarpals, and dysplastic carpal bones. The first patient was a 7-year-old Indian boy who had short stature (-2 SD) and pes planus. The second patient was a 12-year-old Indian boy who had no sonographic findings of skeletal abnormalities at 34-35 weeks' gestation, short stature (-4 SD), normal motor and sensory milestones at age 4 years, coarse facial features, small forehead, posteriorly rotated ears, mild prognathism, and lumbar lordosis. The third patient was a 31-year-old Korean man with short stature (-8 to -9 SD), hip joint pain and weakness, myopia, atlantoaxial instability and compressive myelopathy, ligamentous laxity, thoracolumbar kyphosis, and small hands and feet.

Mapping

By linkage analysis in a consanguineous Saudi family segregating Smith-McCort syndrome in which mutation in the DYM gene (607461) had been excluded, Alshammari et al. (2012) found linkage of the disorder to a 19-Mb region on chromosome 4 between SNPs rs6844366 and rs2215748 (maximum lod of 3.25).

Molecular Genetics

By exome sequencing of the proband in a consanguineous Saudi family segregating Smith-McCort syndrome linked to chromosome 4, Alshammari et al. (2012) identified a homozygous missense mutation in the RAB33B gene (K46Q; 605950.0001). Immunoblot analysis showed severe deficiency of RAB33B in patient cells compared with control cells, and patient fibroblasts also displayed a marked reduction in the immunofluorescence signal corresponding to RAB33B but comparable signal intensity to the Golgi marker giantin (602500).

In a Turkish patient with Smith-McCort syndrome in whom Neumann et al. (2006) had found no mutation in the DYM gene (607461), Dupuis et al. (2013) identified a homozygous missense mutation in the RAB33B gene (N148K; 605950.0002). By Western blot analysis and immunofluorescence studies, Dupuis et al. (2013) found marked reduction of the RAB33B protein.

In 3 unrelated patients with Smith-McCort syndrome who did not have a mutation in the DYM gene (607461), Salian et al. (2017) identified homozygous or compound heterozygous mutations in the the RAB33B gene (605950.0003-605050.0006). The mutations, which included a missense mutation and 3 truncating mutations, segregated with the disorder in each family.