SG04 Early-onset superficial spreading melanoma and macrocephaly: think Cowden syndrome

Abstract PTEN hamartoma tumour syndrome (PHTS) is a rare genetic condition caused by germline mutations in the PTEN (phosphatase and tensin homolog) tumour suppressor gene on chromosome 10q23. It incorporates historically described clinical syndromes including Cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome, with variable expression and age-related penetrance. Cowden syndrome is a member of PHTS and usually presents with multiple benign hamartomas that can occur in multiple organs along with trichilemmomas. In addition to the mucocutaneous features described in Cowden syndrome, diagnostic criteria for PHTS include thyroid, breast and endometrial cancer, gastrointestinal hamartomas, macrocephaly > 97th centile and Lhermitte–Duclos disease as major criteria. Here we report the case of a 30-year-old man who was diagnosed with PHTS after his initial diagnosis of superficial spreading melanoma at the age of 22 years. He presented with pigmented lesions on the left ear pinna in 2017, left helix in 2018 and left scapula in 2022. All were excised and proven to be superficial spreading malignant melanoma pT1a, with Breslow thickness 0.5 mm. Leeds melanoma panel was negative (BAP1, BRCA2, CDK4, CDKN2A, POLE, POT1, TERT). Single gene sequencing of the PTEN gene identified a heterozygous variant c.529T>G p.(Tyr177Asp) classified as likely pathogenic after parental testing confirmed it was de novo. In infancy, he was investigated for macrocephaly (adult head circumference 65.5 cm) with computed tomography (CT) of the brain, which was unremarkable. Recent brain CT was performed as he presented with headaches, and revealed several lesions that could represent hamartomas. Magnetic resonance imaging of the brain identified prominent perivascular (Virchow–Robin) spaces consistent with PHTS. A diagnosis of PHTS was clinically suspected as he also presented with other supporting features including freckles on the glans penis and prepuce, mucosal neuromas of gums, early palmar keratosis, acanthosis nigricans and papilliform lesions on his tongue. In view of the risk of thyroid cancer in PHTS, a screening thyroid ultrasound scan was requested, which identified multiple thyroid nodules. Subsequent histology following thyroidectomy reported follicular adenoma, oncocytic variant and a well-circumscribed tumour with a background of mixed macro- and microfollicular architecture. There was no evidence of papillary thyroid carcinoma, but a lipoma was noted, which is a component of PHTS. Subsequent colonoscopies following a presentation with abdominal pain identified lymphoid hyperplasia and ganglioneuromatous polyps. He presented with hypertrophied tonsils in July 2024 causing sleep apnoea. Following tonsillectomy, histology identified reactive lymphoid hyperplasia, consistent with his PHTS diagnosis. In the literature, Cowden syndrome has been associated with breast cancer, thyroid cancer, endometrial cancer and a very small percentage of melanomas. However, this is the first report of Cowden syndrome that has been diagnosed after an early-onset superficial spreading melanoma.