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Background: The Megalencephaly Capillary Malformation syndrome (MCAP) is a genetic overgrowth disorder characterized by brain overgrowth, polymicrogyria, vascular malformations, and segmental somatic overgrowth secondary to activating mutations in the PI3K-AKT-mTOR pathway (PIK3CA). Congenital macrosomia and postnatal asymmetric overgrowth is typical in this condition, however both growth failure and hypoglycemia have been reported in a significant fraction of affected children raising the concern for growth hormone deficiency (GHD). Methods: We performed an observational multi-institution study of children with MCAP and GHD. Medical records were abstracted including growth trajectories, laboratory data, and treatment response to growth hormone (GH), if applicable. Results: Eight participants (4 female, 4 male) were diagnosed with GHD at mean age of 3.2 years. All had very low or undetectable insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGF-BP3) concentrations. Four underwent GH stimulation testing and all had insufficient responses with a median peak GH of 3.1 ng/ml (range 1.1-7.3). Growth patterns revealed a drastic decline in height z-scores within the first year of life from greater than 2.0 at birth to less than -2.0 z-score by 12 months of age. Growth velocity was in the low-normal range between 1-4 years of age therefore height z-scores were stable but remained low. Four of the 8 had hypoglycemia with fasting. Central hypothyroidism was diagnosed in one and adrenal insufficiency in another. Brain MRI reports were available in 7 children and all had a structurally normal pituitary gland. Three children were treated with GH; one became inconsolable after one week of treatment and it was discontinued. The other two children have continued on GH with excellent responses in linear growth velocity. Conclusion: Profound GHD is a notable feature of MCAP, a condition with gain-of-function mutations promoting cell growth and proliferation. Therefore, children with MCAP and either hypoglycemia and/or postnatal growth failure should be evaluated for GHD. The universally low IGF-BP3 levels in this cohort were striking given this is an unusual finding even in GHD. Additional research is needed into the mechanisms underlying this phenomenon as well as whether treatment with GH is effective and safe in this condition.

The clinical diagnosis of malformations of cortical development (MCDs) is often challenging due to the complexity of the brain malformation by neuroimaging, the rarity of individual malformation syndromes, and the rapidly evolving genetic landscape of these disorders facilitated with the use of Next Generation Sequencing (NGS) methods. While the clinical and molecular diagnosis of severe cortical malformations, such as classic lissencephaly, is often straightforward, the diagnosis of more subtle and complex types of cortical malformations, such as pachygyria and polymicrogyria (PMG), can be more challenging due to limited knowledge regarding their genetic etiologies. Here, we report two individuals with the same de novo KIF5C mutation who present with subtle malformations of cortical development, early onset epilepsy and significant neurodevelopmental and behavioral issues including absent language. Our data, combined with the limited literature on KIF5C mutations, to date, support that KIF5C mutations are associated with a neurodevelopmental disorder characterized by infantile onset epilepsy, and subtle but recognizable types of brain malformations. We also show that the spectrum of KIF5C mutations is narrow, as five out of the six identified individuals have mutations affecting amino acid Glu237. Therefore, the identification of the clinical and neuroimaging features of this disorder may strongly facilitate rapid and efficient molecular diagnosis.