Microphthalmia/coloboma And Skeletal Dysplasia Syndrome

A number sign (#) is used with this entry because of evidence that microphthalmia and/or coloboma, with or without rhizomelic skeletal dysplasia, is caused by heterozygous mutation in the MAB21L2 gene (604357) on chromosome 4q31. One family with a homozygous mutation has also been reported.

Clinical Features

Rainger et al. (2014) described 8 patients from 5 unrelated families with mutations in the MAB21L2 gene who had microphthalmia with coloboma or clinical anophthalmia, with or without rhizomelic skeletal dysplasia. In 1 family (family 1463), there were 9 affected individuals spanning 3 generations; all but 1 had isolated microphthalmia and coloboma. The 13-year-old male proband also exhibited skeletal involvement, with bowing of both legs noted in infancy; he had joint contractures of the knees and hips bilaterally and bilateral hypoplastic femoral condyles and pes cavus as well as hypospadias and wasting of the calf muscles. A 10-year-old Norwegian girl (family 676) and an unrelated 24-year-old man (family 4480), both with clinical anophthalmia, had severe bilateral rhizomelia as well as contractures of all large joints; additional findings in the girl included macrocephaly and precocious puberty at age 7 years, and in the man, hypoplastic femoral condyles. Both had moderate intellectual disability, and the girl also exhibited features of autistic spectrum disorder. A 39-year-old man (family 131) with bilateral microphthalmia, coloboma, and microcornea had fairly good vision until 11 years of age, after which he became blind over a period of 2 years. There was no evidence of retinal detachment; no retinal electrophysiology was available. He exhibited minor skeletal dysmorphism, with recurrent dislocations of the patella and soft tissue syndactyly of fingers 3 and 4 and toes 2 and 3; he also had bilateral undescended testes. Two brothers, aged 3 and 5 years, who were born of consanguineous parents (family 4468), had bilateral coloboma, but only the younger brother had microphthalmia, which was unilateral. They both exhibited facial dysmorphism, including prominent forehead, periorbital fullness, long eyelashes, epicanthus, and long and prominent philtrum, and both had unilateral strabismus. The younger brother had mild shortening of the long bones with decreased tubulation, but the older brother exhibited no skeletal changes. Their unaffected first-cousin parents had normal vision, and examination revealed no evidence of an asymptomatic structural eye malformation. Horn et al. (2015) provided additional clinical details on the probands of families 676 and 4480.

Deml et al. (2015) reported a 3-generation family in which a 32-year-old man and his sister, brother, and 2 nephews had coloboma, microcornea, cataracts, and skeletal dysplasia. The proband had bilateral microcornea, iris and chorioretinal coloboma, corectopia, nystagmus, and cataract, and also exhibited rhizomelic shortening of the upper and lower limbs, and mild contractures of the knees and elbows. Ultrasound measurements of the proband's eyes revealed axial lengths to be within the normal range; axial lengths of other affected family members were not reported.

Molecular Genetics

In 3 independent exome-sequencing projects, Rainger et al. (2014) identified 4 different missense mutations in the MAB21L2 gene (604357) in 8 patients from 5 unrelated families with bilateral microphthalmia and coloboma or clinical anophthalmia with or without rhizomelic skeletal dysplasia. The mutations segregated with disease in each family and were not found in public databases, including those of the 1000 Genomes Project and the NHLBI Exome Variant server. In 4 of the families, the mutations were heterozygous and located near each other, involving R51 in 3 families (R51H, 604357.0001; R51C, 604357.0002) and E49 (E49K; 604357.0003); however, 2 brothers, born of consanguineous parents, were homozygous for an R247Q mutation (604357.0004) for which their unaffected parents were both heterozygous. Rainger et al. (2014) stated that the restricted repertoire of mutations in the monoallelic cases strongly suggested an unusual genetic mechanism beyond simple loss of function, and further noted that the 2 patients with homozygous mutations were the least severely affected.

In a 3-generation family with coloboma, microcornea, cataracts, and skeletal dysplasia, Deml et al. (2015) identified heterozygosity for a missense mutation in the MAB21L2 gene (R51G; 604357.0005) that segregated with disease and was not found in public variant databases. The proband's unaffected mother appeared to have low-level mosaicism for the mutation. Analysis of whole-exome data from 276 patients with developmental ocular conditions revealed no additional mutations in MAB21L2. In 125 patients derived from the UK10K Rare Coloboma project, the R51H mutation was detected in 2 patients; the authors noted that these 2 patients were members of the family (family 1463) previously studied by Rainger et al. (2014) in which the R51H mutation had been identified.