SG18 When telomeres are too long: multiple melanoma in situ revealing a germline POT1 mutation

Abstract

Pathogenic germline mutation in the protection of telomeres 1 gene (POT1) predisposes individuals to a range of malignancies, most notably cutaneous melanoma. We present a case of POT1-associated syndrome, highlighting the importance of multidisciplinary surveillance. A 50-year-old woman with a history of multiple melanoma in situ, asthma and a previously excised hibernoma (brown fat lipoma) was admitted for evaluation of two discrete brain lesions identified during investigations for right-sided hearing loss. Dermatology review identified two additional skin lesions histologically confirmed as MIS. Subsequent investigations during her admission revealed papillary thyroid carcinoma, cerebral telangiectasia and recurrence of the hibernoma. The patient had undergone germline genetic testing, which confirmed a pathogenic mutation in the POT1 gene. This was inherited from her mother, who had a history of sarcoma, breast cancer, thyroid cancer and multiple primary melanomas. POT1 encodes a critical component of the shelterin complex, essential for telomere protection and regulation of telomere length. Germline POT1 mutations were initially described in chronic lymphocytic leukaemia (CLL) and are inherited in an autosomal dominant pattern, with age-dependent penetrance and genetic anticipation. First-degree relatives have 50% risk of inheritance. Unlike the typical telomere shortening seen with ageing, people carrying POT1 mutations exhibit relative preservation of telomere length, a mechanism hypothesized to promote oncogenesis. Associated malignancies include cutaneous melanoma, sarcomas, gliomas and CLL. Historically, surveillance strategies for those with POT1 mutations have been limited. However, 2025 UK clinical practice guidelines advise baseline full-skin examination and patient education for asymptomatic carriers. Annual dermatological surveillance is reserved for those with a personal history of melanoma or additional risk factors as seen in this case. This case illustrates the complex phenotypic diversity of POT1-associated malignancies. Clinician awareness is vital to ensure appropriate screening for associated internal malignancies and to guide the frequency of dermatological ­follow-up in high-risk patients.