Megalencephaly secondary to a novel germline missense variant p.Asp322Tyr in AKT3 associated with growth hormone deficiency and central hypothyroidism: A case report

Germline gain of function variations in the AKT3 gene cause brain overgrowth syndrome with megalencephaly and diffuse bilateral cortical malformations. Here we report a child with megalencephaly, who is a carrier of a novel heterozygous missense variant in the AKT3 gene NM_005465.7:c.964G>T,p.Asp322Tyr. The phenotype of this patient is associated with pituitary deficiencies diagnosed at 2 years of age: growth hormone (GH) deficiency responsible for growth delay and central hypothyroidism. After 6 months of GH treatment, intracranial hypertension was noted, confirmed by the observation of papilledema and increased intracranial pressure, requiring the initiation of acetazolamide treatment and the discontinuation of GH treatment. This is the second reported patient described with megalencephaly and AKT3 gene variant associated with GH deficiency . Other endocrine disorders have also been reported in few cases with hypothyroidism and hypoglycemia. Pituitary deficiency may be a part of the of megalencephaly phenotype secondary to germline variant in the AKT3 gene. Special attention should be paid to growth in these patients and search for endocrine deficiency is necessary in case of growth retardation or hypoglycemia.