PHENOTYPIC VARIABILITY OF COWDEN SYNDROME WITHIN A SINGLE FAMILY: IMPACT ON DIAGNOSIS, MANAGEMENT AND GENETIC COUNSELLING

Abstract

Cowden syndrome (CS) represents a rare autosomal dominant disorder caused by mutations in the PTEN gene located on chromosome 10q23.3. This entity belongs to the PTEN hamartoma tumor syndrome (PHTS) spectrum. The PTEN gene encodes a tumor suppressor protein crucial for regulating cell growth, survival, and apoptosis. Pathogenic mutations in PTEN result in dysregulated cell proliferation, manifesting clinically as benign and malignant growths across various tissues. CS is characterized by a predisposition to multiple hamartomas and an elevated risk of cancers, most notably in the skin, soft tissues, thyroid, breast, and gastrointestinal tract. In pediatric patients, macrocephaly is frequently the earliest feature, often accompanied by developmental delays and neurological deficits. This case series details the clinical evolution and multidisciplinary management of two siblings with CS and normal psychomotor development. Genetic testing identified a familial PTEN mutation, with multiple affected relatives, including the siblings’ father, paternal aunt and paternal grandfather, each displaying distinct phenotype. This familial clustering highlights the autosomal dominant inheritance of CS and points out the critical importance of early genetic testing, vigilant surveillance, and tailored counselling for at-risk relatives. Phenotypic variability observed between members of the same family points out the difficulties in predicting transgenerational outcomes and complicates genetic counselling. © 2024 Ilic N et al., published by Sciendo.