Spondyloepimetaphyseal Dysplasia, Aggrecan Type

A number sign (#) is used with this entry because of evidence that the aggrecan type of spondyloepimetaphyseal dysplasia (SEMDAG) is caused by homozygous or compound heterozygous mutation in the ACAN gene (155760) on chromosome 15q26.

Clinical Features

Tompson et al. (2009) described a Mexican family in which 2 brothers and a sister had a newly recognized autosomal recessive form of spondyloepimetaphyseal dysplasia characterized by severe short stature and a novel constellation of radiographic findings. The sibs, aged 16, 19, and 24 years, had a height ranging between 66 and 71 cm. Craniofacial abnormalities included relative macrocephaly, severe midface hypoplasia with almost absent nasal cartilage, relative prognathism, and slightly low-set, posteriorly rotated ears. They had short necks and barrel chests and exhibited a mild lumbar lordosis. Their extremities showed rhizomelia and mesomelia with no bowing of any segment. Hand findings included significant brachydactyly with short, broad thumbs, horizontal nails, and telescoping interphalangeal joints. Radiographic features included long bones with generalized irregular epiphyses with widened metaphyses, especially at the knees; platyspondyly; and multiple cervical-vertebral clefts. The mother and father were 150 cm and 152 cm tall, respectively. An unaffected half sister was 150 cm tall and an unaffected full sib was 178 cm tall. The authors raised the possibility of a carrier phenotype of mild proportionate short stature.

Fukuhara et al. (2019) reported a 45-year-old man with the aggrecan type of spondyloepimetaphyseal dysplasia. He was born to nonconsanguineous parents and his weight and length at birth were within the normal range. At age 6 years, he was noted to have short stature. When evaluated at 42 years of age, his height was 118.3 cm (-9.1 SD) and his head circumference was 59.4 cm (+2 SD). He had acromesomelic limb shortening and relative macrocephaly. No midface hypoplasia, prognathism, or low-set ears were noted. On radiologic examination, his phenotype was consistent with SEMD. He had moderate platyspondyly with cervical lordosis and thoracolumbar kyphosis. Vertebral bodies were rectangular in shape, except for a wedge-shaped deformity of L1. Acetabula were shallow and degenerative joint disease of the large joints, especially the hips, was significant. Long bones were short and relatively broad with metaphyseal flaring. Generalized brachydactyly was remarkable. The authors noted that his skeletal phenotype was milder than that previously reported with this phenotype.

Inheritance

The aggrecan type of SEMD is an autosomal recessive disorder (Tompson et al., 2009).

Mapping

Tompson et al. (2009) found homozygosity for a haplotype that was identical by descent between 2 of the 3 affected sibs in the Mexican family segregating SEMDAG and identified a locus for the disease within a 17.4 Mb interval on chromosome 15.

Molecular Genetics

In 3 sibs with SEMDAG, Tompson et al. (2009) identified homozygosity for a missense mutation in the ACAN gene (D2267N; 155760.0002) that affected the C-type lectin domain of the protein. The mutation segregated with the phenotype in the family.

In a 45-year-old male with SEMDAG, who was born to nonconsanguineous parents, Fukuhara et al. (2019) identified compound heterozygosity for missense mutations in the ACAN gene (S1687R, 155760.0014 and V1380F, 155760.0015) that affected chondroitin sulfate domains. No DNA from his parents was available for segregation analysis. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the ESP6500 or 1000 Genomes Project databases.