Megalencephaly Polymicrogyria Polydactyly Hydrocephalus (MPPH): A Case Report and Review of Literature

Abstract

Megacephaly polymicrogyria, polydactyly, hydrocephalus (MPPH) is an extremely rare condition caused by a defect in the AKT3, CCND2, or PIKR2 genes. Although the prevalence of the syndrome is very low, there is a significant clinical and radiological variation in the syndrome. We present a case with MPPH admitted to the hospital due to an increase in seizure frequency. The patient had a history of cerebral palsy, global developmental delay, spasticity, and hypoglycemic episodes. MRI findings revealed ventriculomegaly, polymicrogyria, abnormal encephalon, and pachygyria. The addition of clobazam and alprazolam diminished the seizures' frequency and the patient's spasticity, respectively. To highlight the clinical and radiological variation of the syndrome, we review cases of MPPH with clinical and radiological variants. Pachygyria and cerebral palsy are new associations not previously described before in MPPH. Pachygyria and cerebral palsy could be worsening the seizures and the global delay in this patient. Hypoglycemic episodes are probably related to the AKT3 gene, promoting more glucose consumption. Spasticity is most probably related to an upper motor sign due to the patient's cerebral palsy. This case highlights the clinical and radiological variation of the syndrome. More cases of MPPH need to be described to consolidate the knowledge and have a better understanding of the clinical and radiological variation of the syndrome.

The somatic p.T81dup variant in AKT3 gene underlies a mild cerebral phenotype and expands the spectrum including capillary malformation and lateralized overgrowth

“…[28][29][30][31] Germline variants, on the other hand, are associated with syndromic conditions such as MCAP and MPPH, where most of the MCDs are bilateral perisylvian (BPP) PMG associated with ventriculomegaly (VMEG). 2,18 In Figure 1A are shown the AKT3 pathogenetic variants identified so far in 35 cases, 23 of which carrying germinal mutations 1,2,8,[18][19][20][21]32,33 and the remaining 12 with p.E17K postzygotic mutation. 6,8,12,24,30,31,34 Most of the reported variants in AKT3 gene are within the PH or Kinase domain, except for p.R465W, which localizes into the C-terminal region.…”

“…In Figure 1A are shown the AKT3 pathogenetic variants identified so far in 35 cases, 23 of which carrying germinal mutations 1,2,8,18–21,32,33 and the remaining 12 with p.E17K postzygotic mutation 6,8,12,24,30,31,34 . Most of the reported variants in AKT3 gene are within the PH or Kinase domain, except for p.R465W, which localizes into the C‐terminal region.…”

“…These variants are usually activating and result in disruptions in critical stages of cortical development, including neuronal proliferation, migration, and organization, often associated with brain overgrowth and cellular dysplasia: although rare, they represent a major cause of intellectual disability, autism, epilepsy, and cerebral palsy 6,13–16 . Most cases of MCDs/FCDs, including isolated or syndromic forms like the megalencephaly‐polymicrogyria‐polydactyly‐hydrocephalus (MPPH) syndrome and the megalencephaly‐capillary malformation (MCAP) syndrome, are caused by heterozygous germline or somatic variants in AKT3 , CCND2 , or PIK3R2 1,2,5,7,9,17–22 . MPPH is a rare autosomal dominant syndrome that presents with multiple clinical and radiological features, such as perisylvian polymicrogyria (PMG), megalencephaly, postaxial polydactyly, and hydrocephalus.…”

“…6,[13][14][15][16] Most cases of MCDs/FCDs, including isolated or syndromic forms like the megalencephaly-polymicrogyria-polydactylyhydrocephalus (MPPH) syndrome and the megalencephaly-capillary malformation (MCAP) syndrome, are caused by heterozygous germline or somatic variants in AKT3, CCND2, or PIK3R2. 1,2,5,7,9,[17][18][19][20][21][22] MPPH is a rare autosomal dominant syndrome that presents with multiple clinical and radiological features, such as perisylvian polymicrogyria (PMG), megalencephaly, postaxial polydactyly, and hydrocephalus. MCAP phenotype overlap MPPH, including also lateralized body overgrowth and vascular capillary malformations.…”

Shared Biological Pathways and Processes in Patients with Intellectual Disability: A Multicenter Study

“…Although the AKT3 and PIK3R2 genes are associated with megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome, a "nonsyndromic" megalencephaly which is a condition without the distinctive hallmarks of defined megalencephaly syndromes but only nonspecific neurodevelopmental features including ID and ASD, was reported in very few patients. 33,34 Besides, these three genes, together with the ACTG1, CTNNB1, and SLC2A1 genes, links thyroid hormone signaling pathway with hepatocellular carcinoma and central carbon metabolism in cancer pathways. Comprehensive functional studies that will enable the discovery of shared molecules for targeted therapy are needed.…”