Microcephaly-Micromelia Syndrome

A number sign (#) is used with this entry because of evidence that microcephaly-micromelia syndrome (MIMIS) is caused by homozygous mutation in the DONSON gene (611428) on chromosome 21q22.

Biallelic mutation in the DONSON gene can also cause microcephaly, short stature, and limb abnormalities (MISSLA; 617604), a less severe disorder.

Description

Microcephaly-micromelia syndrome (MIMIS) is a severe autosomal recessive disorder that usually results in death in utero or in the perinatal period. Affected individuals have severe growth retardation with microcephaly and variable malformations of the limbs, particularly the upper limbs. Defects include radial ray anomalies, malformed digits, and clubfeet (summary by Evrony et al., 2017).

Clinical Features

Ives and Houston (1980) reported 14 infants with similar congenital malformations resulting in perinatal death who were born in a highly inbred, predominantly Cree Indian community in northern Saskatchewan, Canada. Features included intrauterine growth retardation (IUGR), marked microcephaly, craniosynostosis, and severe malformation of the limbs, especially the arms. Elbows were fused, forearms were greatly shortened and usually contained only a single bone, and the hands were abnormal with only 2 to 4 malformed digits.

Evrony et al. (2017) provided follow-up of the family reported by Ives and Houston (1980) and identified multiple additional cases from related families from the same population. The affected individuals had marked IUGR, with low birth weight (average -6.5 SD), length (average -7.4 SD), and head circumference (average -7.4 SD). They had characteristic facial appearance with a broad and beaked nose, short palpebral fissures, microstomia, micrognathia, low-set ears, and short neck. Upper limb abnormalities included underdevelopment or even absence of the radius and/or ulna, humeroradial synostosis, oligodactyly with absent thumbs, and absent or poorly developed fifth fingers. Lower limb abnormalities included limb shortening with underdeveloped fibulae, clubfeet, and toe abnormalities, such as short great toes, abnormally placed great toes, and abnormal metatarsal bones. Additional skeletal anomalies included craniosynostosis or absence of 1 or 2 rib pairs. Brain imaging showed profound microcephaly with only primary sulci and gyri, diminished white matter, and hypoplastic or absent corpus callosum. Microscopic analysis of the cerebral cortex showed decreased cells in the subventricular zone and a disorganized distribution of cells. Some patients had cleft palate and cardiac, gastrointestinal, or genitourinary defects. The lungs were severely hypoplastic with anomalous lobation, and most patients were either stillborn or died within the first week of life due to respiratory failure. Two died at ages 3 months and 2 years.

Reynolds et al. (2017) reported 2 sibs, born of consanguineous Saudi Arabian parents (family P21), with a phenotype similar to that reported by Evrony et al. (2017). The patients died in utero. They had severe microcephaly (-7.8 and -8.5 SD), narrow chest, absent ulna and radius, hypoplastic femur and tibia, and severe talipes. Other features included oligohydramnios, cystic hygroma, low-set ears, micrognathia, and microphthalmia.

Inheritance

Recessive inheritance of the microcephaly-micromelia syndrome was indicated by parental consanguinity, sex ratio close to 1, and a 25% segregation ratio (Ives and Houston, 1980).

The transmission pattern of MIMIS in the family reported by Reynolds et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In tissue samples derived from at least 12 patients of Cree descent with MIMIS, Evrony et al. (2017) identified a homozygous splice site mutation in the DONSON gene (c.1047-9A-G; 611428.0001). Most patients belonged to a large consanguineous pedigree of First Nations origin in Saskatchewan, whereas the others belonged to the same population and were known to be descendants of the founders of this pedigree, although the exact relationships were unknown. The variant, which was found by transcriptome sequencing and confirmed by Sanger sequencing, segregated with the disorder in all families. Patient and carrier cells showed decreased transcript levels of DONSON compared to controls, consistent with nonsense-mediated decay. However, a small fraction of transcripts were correctly spliced, suggesting that it is a hypomorphic allele. Evrony et al. (2017) noted that the mutation was not identified by comprehensive exome or genome sequencing initially, which prompted the use of RNA sequencing to identify this noncoding variant. Using public proteomic and gene expression databases, Evrony et al. (2017) found that DONSON is associated with multiple components of the DNA replication and replication fork machinery. Knockdown of DONSON in HeLa cells resulted in disturbance of components of the cell cycle, arrest of the cell cycle, and impaired cellular proliferation.

Reynolds et al. (2017) identified homozygosity for the c.1047-9A-G mutation in the DONSON gene in 2 sibs from a consanguineous Saudi Arabian family with MIMIS.