Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome 3

A number sign (#) is used with this entry because megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome-3 (MPPH3) is caused by heterozygous mutation in the CCND2 gene (123833) on chromosome 12p13.

Description

This disorder comprises macrocephaly, megalencephaly, ventriculomegaly, polymicrogyria, and polydactyly. Most affected individuals have severely delayed psychomotor development (summary by Mirzaa et al., 2014).

For a discussion of genetic heterogeneity of MPPH, see MPPH1 (603387).

Clinical Features

Mirzaa et al. (2014) reported 12 unrelated patients with an enlarged head circumference (up to +4.5 SD) associated with ventriculomegaly or hydrocephalus and megalencephaly apparent at birth or in early infancy. Brain imaging showed bilateral perisylvian polymicrogyria or frontoparietal polymicrogyria. All but 1 patient had severely delayed psychomotor development, and many had no language acquisition. One patient, age 13 years at the time of the report, was more mildly affected. All except 1 had postaxial polydactyly of the hands and/or feet. Only 1 patient had a thick corpus callosum. In several patients, head circumference increased with age (up to +7.5 SD). Several of the patients had previously been reported by Mirzaa et al. (2012).

Inheritance

Almost all patients with MPPH3 have de novo mutations. However, Mirzaa et al. (2014) reported 1 severely affected child whose mother appeared to carry the same mutation as a mosaic. The mother had a large head circumference, hypertelorism, and borderline intelligence, but did not undergo brain imaging.

Molecular Genetics

In 12 probands with MPPH, Mirzaa et al. (2014) identified 7 different heterozygous mutations in the CCND2 gene (e.g., 123833.0001-123833.0006). The mutations in the first 3 patients were found by whole-exome sequencing; the mutations in 9 additional patients were found by conventional Sanger sequencing. All of the mutations either altered conserved residues surrounding thr280, a GSK3B (605004) phosphorylation target necessary for subsequent protein degradation, or truncated the mutation before this phosphorylation site. Transfection of the CCND2 mutations into HEK293 cells resulted in abnormal accumulation of unphosphorylated, degradation-resistant cyclin D2. In utero electroporation of the T280A (123833.0001) or P281R (123833.0005) mutations into mouse embryos resulted in increased numbers of actively dividing cells in the cortical plate compared to wildtype. These phosphodeficient mutants were more effective in promoting mitosis and were associated with decreased exit from the cell cycle compared to wildtype. Cells from individuals with megalencephaly due to PIK3CA (171834), PIK3R2 (603157), or AKT3 (611223) mutations showed similar CCND2 accumulation, which indicated that activation of the PI3K-AKT pathway resulting in increased CCND2 is a unifying mechanism in these related disorders. The findings were consistent with a gain-of-function effect of the CCND2 mutations, and Mirzaa et al. (2014) suggested that the expansion of neuronal progenitor populations underlies the megalencephaly as well as the polymicrogyria observed in the disorder.