The clinical and phenotypic spectrum of PTEN hamartoma tumor syndrome: a retrospective cohort study

PTEN Hamartoma Tumor Syndrome (PHTS) is a rare condition characterized by a complex phenotype including gastrointestinal hamartomas and increased lifetime malignancy risk. To characterize the clinical phenotype, genetic landscape, and spectrum of malignancies within a large cohort of adult PHTS carriers. A retrospective cohort study of adult patients (≥ 18 years) followed at specialized high-risk clinics who met PHTS diagnostic criteria based on either: (1) identification of a germline PTEN pathogenic/likely pathogenic variant, or (2) fulfillment of clinical criteria according to National Comprehensive Cancer Network (NCCN) guidelines. A total of 62 individuals were included (62.9% male; median age at inclusion 39.5, IQR, 28-52). All fulfilled diagnostic criteria for PHTS. PTEN pathogenic or likely pathogenic variant were identified in 50 individuals (80.6%). Colonic polyps were present in 40 patients. Malignancies were reported in 61% (n = 38), most frequently breast (n=13) and thyroid (n=7). Three individuals (4.8%) had rare soft tissue tumors: one with a desmoid tumor at age 18, one with concurrent axillary osteosarcoma and bilateral chest liposarcoma, and one with a skull-base sarcoma. Macrocephaly was observed in 33.8% (n = 21), and developmental delay, including autism spectrum disorder, in 8 patients (12.9%). One case of PTEN mosaicism was identified through tumor sequencing after negative blood genetic testing. Five individuals (8%) were treated with Sirolimus. This large cohort highlights the broad clinical spectrum and substantial cancer burden in PHTS, including rare soft tissue tumors. Constitutional mosaicism should be considered when clinical suspicion persists despite negative germline testing.