Balkan Journal of Medical Genetics

PHENOTYPIC VARIABILITY OF COWDEN SYNDROME WITHIN A SINGLE FAMILY: IMPACT ON DIAGNOSIS, MANAGEMENT AND GENETIC COUNSELLING
Ilic N1, Mitrovic N2, Radeta R3, Krasić S4,5, Vukomanović V4,5, Samardzija G2, Vasic M6, Vlahovic A5,6, Sarajlija A1,5
*Corresponding Author: *Corresponding Author: Ass. Prof. Dr. Adrijan Sarajlija MD, PhD, Clinical Genetics Outpatient Clinic, Mother and Child Health Care Institute “Dr Vukan Čupić”, Radoja Dakića 6-8, 11070 Novi Beograd, Serbia; University of Belgrade, Faculty of Medicine, Belgrade, Serbia; e-mail: adrijans2004@yahoo.com
page: 95

INTRODUCTION

Cowden syndrome (CS), also known as PTEN ham- artoma tumor syndrome (PHTS), is a rare autosomal domi- nant disorder caused by germline mutations in the PTEN gene located on chromosome 10q23.3 (1). The PTEN gene encodes a tumor suppressor protein that plays a critical role in maintaining genomic stability, regulating cell pro- liferation, and facilitating apoptosis (2). Loss-of-function mutations in PTEN disrupt these processes, leading to the unregulated growth of cells and the development of hamartomas and malignancies across multiple tissues (3). The PTEN gene negatively regulates the PI3K/AKT signal- ling pathway, essential for cell growth and metabolism. Germline PTEN mutations are heterogeneous, including nonsense, missense, and splice-site variants, with over 300 mutations described (4). These mutations cause vari- able expressivity and incomplete penetrance, even among family members (5). De novo mutations are identified in 10–20% of cases (1). CS is part of the PTEN hamartoma tumor spectrum (PHTS), which includes Bannayan-Riley- Ruvalcaba syndrome (BRRS) and Lhermitte-Duclos dis- ease (5). The clinical manifestations of CS are diverse, involving hamartomas in the skin, thyroid, gastrointestinal tract, and other tissues (1). Genotype-phenotype correla-tions in PTEN disorders show significant variability caused by mutations and phenotypic interactions (4,5).

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