PTEN hamartoma tumor syndrome in children: Identification of recurrent mutations, an unpublished variant and a case of cerebral cortical dysplasia co-occurring with pleuropulmonary blastoma. Review of PTEN-related malformations of cortical development

PTEN hamartoma tumor syndrome (PHTS) is caused by germline heterozygous pathogenic variants of the tumor suppressor PTEN gene, crucial for the regulation of the PI3K-AKT-mTOR pathway. PHTS encompasses several different syndromes with overlapping clinical features, such as PTEN-related macrocephaly and autism syndrome, Bannayan-Riley-Ruvalcaba, Cowden, Lhermitte-Duclos, Proteus and Proteus-like syndromes. In this study, the clinical and molecular findings of five children, aged 1.5-18 years, with PHTS confirmed by clinical exome sequencing are reported. Megalencephaly, delayed development, autism spectrum disorder, and intellectual disability were the main phenotypic features in four cases with missense variants (Pro95Leu, Cys136Arg, Arg173His, and Ile253Thr). One of these variants (Ile253Thr) is still unpublished. A truncating variant (Arg335Ter), however, was associated with an extended segmental cerebral cortical dysplasia, and pleuropulmonary blastoma, neither of them reported yet in association with this pathogenic PTEN variant. DICER1 mutation was not identified in the lung tumor; however, a PTEN somatic delin variant [c.197_200delins CG p.(Lys66ThrfsTer7)] causing frameshift as a second hit in the tumor co-occurred with the germline truncating variant. Conclusion: This study expands the clinical and molecular spectrum of PHTS in childhood, highlighting a novel variant. In addition, a unique co-occurrence of segmental cerebral cortical dysplasia and pleuropulmonary blastoma in association with the pathogenic Arg335Ter PTEN variant is described. A somatic PTEN variant, as a second hit might have contributed to the genesis of the lung tumor.