The phosphatase and tensin homologue (PTEN) gene is located on chromosome 10q23.31 and is a tumor suppressor which regulates cell growth by inhibiting the mTOR (mammalian target of Rapamycin) pathway. Both germline and de novo variants of the PTEN gene can cause pathological cell growth, resulting in PTEN Hamartoma Tumor Syndrome, which is inherited in an autosomal dominant manner. This syndrome is an umbrella term for various overlapping syndromes with phenotypes including a high risk for benign and malignant tumors (breast, endometrium, and thyroid cancers), macrocephaly and autism, congenital malformations and hamartomatous overgrowth of multiple tissues. Hemimegalencephaly is a rare manifestation of this syndrome, with few cases reported in the literature.

Case discussion and literature review. 

Our patient, a baby girl, was born at 37 weeks gestation via Cesarean section with a prenatal diagnosis of ventriculomegaly. The initial physical exam was notable for profound macrocephaly, diffuse hypotonia, right patellar hyperreflexia, and sustained right ankle clonus. MRI brain revealed gross enlargement and lissencephaly of the left parietal, left temporal, and left occipital lobes, with compression of the contralateral hemisphere. At twenty-two hours of life, she developed focal left-sided motor seizures. Continuous EEG revealed seizures involving both hemispheres. She was burst suppressed with a pentobarbital infusion with epilepsy surgery deferred based on the bi-hemispheric origin of seizures. She went on to develop intractable epilepsy with daily seizures. Whole genome sequencing revealed a de novo heterozygous pathogenic variant in PTEN (c.738del, p.L247Yfs*9), consistent with clinical picture of hemimegalencephaly.

The typical neurophenotype for PTEN variants is macrocephaly and autism, but the spectrum of neurological manifestations is broad, ranging from neurodevelopment delay to brain malformations.