Coexisting PTEN and SDHB Mutations in a Pediatric Patient with PTEN Hamartoma Tumor Syndrome: a case report

Phenotypic variability in PTEN hamartoma tumor syndrome (PHTS) remains incompletely understood, and the contribution of additional rare genetic variants has rarely been functionally investigated.

We report a 9-year-old girl with macrocephaly, gastrointestinal manifestations, hypogammaglobulinemia, and lymphocyte abnormalities. Thyroid function and biochemical screening for SDHB-associated tumors were normal. Trio-based whole-exome sequencing identified a de novo pathogenic PTEN variant, c.464A > G (p.Tyr155Cys), together with a de novo SDHB variant, c.719T > C (p.Leu240Pro). Functional studies showed an increased succinate-to-fumarate ratio and reduced succinate dehydrogenase activity, consistent with impaired mitochondrial complex II function. Structural modeling further suggested that the p.Leu240Pro substitution may reduce SDHB protein stability. Functional evidence fulfilled ACMG/AMP PS3 criteria and supported the proposed reinterpretation of the SDHB variant from a variant of uncertain significance to likely pathogenic using the OddsPath framework.

This case expands the molecular spectrum of PHTS by describing the coexistence of pathogenic PTEN and functionally supported SDHB variants. Although the phenotype is largely attributable to PHTS, the potential contribution of SDHB dysfunction remains speculative and warrants further investigation. These findings underscore the importance of functional variant interpretation and genotype-informed longitudinal surveillance in rare genetic disorders.