Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome Q87.22

Megalencephaly-polydactyly-polymicrogyria-hydrocephalus syndrome is a rare genetic syndrome characterized by a variety of anomalies, such as primary megalencephaly, vascular capillary malformations of the skin, prenatal overgrowth, connective tissue dysplasia, digital anomalies, body asymmetry with pronounced brain imaging features such as polymicrogyria, asymmetry of the lateral ventricles, hydrocephalus, polymicrogyria, large cerebellum leading to an overcrowded posterior fossa, cerebellar tonsil hernia or ectopia, thick corpus callosum and other features (Mirzaa GM et al. 2012).

A newer classification was proposed by Mirzaa et al. in 2012, which is commonly used for diagnosis. Neuroimaging features associated with this disease include cerebral asymmetry, increased white matter signals, cavum septum pellucidum, "hydropic" appearing optic nerve sheaths, cortical dysgenesis/dysplasia, dilated perivascular spaces of cortical veins, and venous sinus thrombosis (Conway RL et al. 2007). The disease is associated with dynamic changes, such as ventriculomegaly, which can develop into hydrocephalus, cerebellar tonsil ectopy and mega-corpus callosum, which is why follow-up MRI is required.

Rivière JB et al (2012) found that de novo postzygotic or germline mutations in the AKT3, PIK3R2 and PIK3CA genes are associated with MCAP, and also pointed to the essential role of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in brain, vascular and limb development.

Familial cases of MCAP are also known, suggesting germline mosaicism or autosomal recessive inheritance in the parents.

Currently, there is no specific treatment for MCAP, but ARQ 092, an allosteric AKT inhibitor, has shown antiproliferative effects in overgrowth syndromes including MCAP due to inhibition of the PI3K/AKT signaling pathway.

Supportive treatment includes drug therapy to control seizures and other symptoms, physiotherapy, speech, occupational and physical therapy to improve daily functioning.

Surgical treatment includes shunt placement for hydrocephalus and posterior fossa decompression for symptomatic cerebellar tonsil ectopia, especially if there are signs of brainstem compression or syringomyelia.

Only a few similar MCAP cases have been registered in the Johns Hopkins Online Medillian Inheritance of Man (OMIM) with different clinical and imaging manifestations. Initially, 13 unrelated cases with abnormalities of somatic growth, face, brain, vasculature and connective tissue were described by Moore et al. in 1997 and collectively classified as megalencephaly-cutis marmorata telangiectasia congenita (MCMTC). Further cases were subsequently described. As there was overlap between megalencephaly, polymicrogyria-polydactyly-hydrocephalus syndrome and capillary malformation, Gripp et al. proposed the term megalencephaly-polydactyly-polymicrogyria-hydrocephalus-capillary malformation (MPPH-CM) for this phenotype spectrum (Gripp KW et al. (2009). About 21 cases of MPPH have also been described in the OMIM literature, with most cases reported by Mirzaa et al. in 2014, and there was a significant phenotypic overlap and common genetic basis between these two by Nakamura et al. in 2014.

Other syndromes simulating brain overgrowth include megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndrome, in which megalencephaly occurs in association with distal limb abnormalities such as postaxial polydactyly and hydrocephalus. Other diseases associated with megalencephaly and skin manifestations include congenital lipomatous overgrowths, vascular malformations, epidermal nevi(CLOVE syndrome) and Bannayan-Riley-Ruvalcaba syndrome (BRRS) (Sarma K et al. 2022).

1. Clayton-Smith J et al. (1997) Macrocephaly with cutis marmorata, haemangioma and syndactyly--a distinctive overgrowth syndrome. Clin Dysmorphol 6:291-302.
2. Conway RL et al. (2007) Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients. Am J Med Genet A 143A:2981-3008.
3. Giuliano F et al. (2004) Macrocephaly-cutis marmorata telangiectatica congenita: seven cases including two with unusual cerebral manifestations. Am J Med Genet A 126A:99-103.
4. Gripp KW et al. (2009) Significant overlap and possible identity of macrocephaly capillary malformation and megalencephaly polymicrogyria-polydactyly hydrocephalus syndromes. Am J Med Genet A. 149A:868-876.
5. Mirzaa GM et al. (2012) Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am J Med Genet 158A:269-291.
6. Moore CA et al. (1997) Macrocephaly-cutis marmorata telangiectatica congenita: a distinct disorder with developmental delay and connective tissue abnormalities. Am J Med Genet 70:67-73.
7. Nakamura K et al. (2014) AKT3 and PIK3R2 mutations in two patients with megalencephaly-related syndromes: MCAP and MPPH. Clin Genet 85:396-398.
8. Rivière JB et al. (2012) De novo germline and postzygotic mutations in AKT3, PIK3R2 and PIK3CA cause a spectrum of related megalencephaly syndromes. Nat Genet 44:934-940.
9. Sarma K et al. (2022) Megalencephaly-Capillary Malformation-Polymicrogyria Syndrome (MCAP): A Rare Dynamic Genetic Disorder. Cureus 14:e25123.