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

DISCUSSION

Clinical Manifestations The clinical manifestations of CS are diverse, in- volving hamartomas in the skin, thyroid, gastrointestinal tract, and other tissues (1). Macrocephaly, often present at birth or early infancy, is a key diagnostic feature in children, accompanied by facial dysmorphism such as a high anterior hairline and hypertelorism (6). Develop- mental delays and ASD, seen in up to 25% of patients, are frequent neurological findings, with brain imaging sometimes revealing structural anomalies, often white matter lesions (6, 7). The clinical manifestations of CS are diverse, involving hamartomas in the skin, thy- roid, gastrointestinal tract, and other tissue (8–10). Recognizable dermatological traits include trichilem- momas around the nose and mouth, oral papillomas, and acral keratoses (9, 10). Sclerotic fibromas and lipomas, presenting as soft, mobile masses on the torso or ex- tremities, further define the dermatological profile (8, 9). Gastrointestinal polyps affect up to 80% of patients, causing symptoms like abdominal pain or rectal bleed- ing. Though mostly benign, routine colonoscopic sur- veillance is recommended due to a small malignancy risk (11, 12). Less common vascular anomalies, such as arteriovenous malformations, can cause functional issues depending on their size and location (3, 13). In the case of our female patients, there were no elements of macrocephaly or dyscrania, and psychomotor devel- opment was normal. The characteristic skin changes as- sociated with the syndrome were also absent. The only findings that contributed to the diagnosis were the presence of characteristic tissue tumor changes. Screening of other organs and organ systems revealed no signs of visceral involvement typically seen in CS. At this point, it is chal- lenging to speculate on the genotype-phenotype correla- tion, given that this particular genotype, to our knowledge, has not been phenotypically described in any previously published case report in the available literature. Genotype-Phenotype Correlation and Penetrance in CS The PTEN variant identified in this family, c.48T>A (p.Tyr16Ter), represents a nonsense mutation associated with a truncated, non-functional protein. We confirmed by the thorough review of the available literature that the PTEN variant c.48T>A (p.Tyr16Ter) is a previously recognized pathogenic mutation. However, a detailed search of medical articles available online has not identified any publications to date presenting the clini- cal features of patients harboring this specific genotype. Genotype-phenotype correlations in CS demonstrate sig- nificant variability in clinical presentations, with features ranging from benign hamartomas to malignant transforma- tions (14, 15). For example, catalytic domain mutations are strongly associated with severe neurodevelopmental outcomes, including ASD and intellectual disability (6, 14). Beyond genotypic effects, traits such as macrocephaly, vascular anomalies, and lipomatous changes suggest po- tential phenotypic synergy, where certain characteristics amplify others (15). This interplay may result from shared developmental pathways disrupted by PTEN dysfunc- tion. Macrocephaly, for instance, often correlates with altered brain architecture, predisposing to neurodevelop- mental disorders (7). Similarly, vascular anomalies like angiomatosis or arteriovenous malformations may exac- erbate tissue overgrowth, contributing to complex lesions like PTEN hamartoma of soft tissue (PHOST) (8, 13). Incomplete penetrance and variable expressivity are im- portant characteristics of PTEN-related disorders, with up to 15% of carriers remaining asymptomatic throughout life (16). Modifier genes, environmental influences, and epi- genetic factors likely contribute to this variability, as sug- gested by studies in other hamartomatous syndromes such as Peutz-Jeghers and juvenile polyposis syndrome(15) Malignant Alterations in CS and Age-Related Observations CS is associated with an elevated lifetime risk of malignancies, particularly breast, thyroid, and endometrial cancers, with risk estimates reaching 85% for breast cancer in females and 35% for thyroid cancer (6, 17). However, in this family, two older members (the paternal grandfa- ther and the great-aunt) have not developed malignancies despite their advanced age. This observation could be ex- plained by the incomplete penetrance and suggests possible protective factors that warrant further investigation. Age at onset of malignancies in CS varies, with breast cancer often developing by the fourth decade and thyroid malignancies potentially occurring earlier (14, 17). Other common malignancies include thyroid (especially follicu- lar carcinoma) and endometrial cancers, warranting regular thyroid ultrasounds and gynecological evaluation (5, 18). Risks of renal cell carcinoma and colorectal cancer further emphasize the need for comprehensive cancer surveillance protocols (19). Interestingly, hepatic tumors have been reported in older individuals with CS, particularly in the context of non-alcoholic steatohepatitis (NASH) (20). The absence of malignancies in older family members suggests the need for personalized surveillance plans tailored to individual risk factors. Regular screening, including breast MRI and thyroid ultrasound, is therefore essential, even in asymptomatic carriers (5, 17). Therapeutic and Surveillance Considerations While surgical management of benign tumors pro- vides effective short-term relief, recurrence is common, as seen in this case. The use of pharmacological approaches, including mTOR inhibitors such as sirolimus and everoli- mus, offers a promising strategy for reducing tumor burden by targeting dysregulated cell growth pathways in PTEN- mutant cells. Hormonal therapies, such as tamoxifen, may also be considered for risk reduction in individuals predis- posed to breast and endometrial cancers, though their use in pediatric populations remains under investigation (21–24). In cases where malignancies arise, targeted therapies, such as tyrosine kinase inhibitors, may complement stan- dard oncological treatment, particularly when molecular pathways contributing to tumor growth are identified (25). Genetic Counseling and Family Segregation Analysis The autosomal dominant inheritance of CS puts im- perative on genetic counselling for affected families. In this case, segregation analysis confirmed the familial PTEN mutation in the proband’s sister and father. Early identifi- cation of mutation carriers enables the implementation of individualized surveillance programs, which are critical for minimizing cancer risk and improving outcomes. For at- risk family members, genetic analysis is indicated. In case of positive findings, regular monitoring and imaging are essential components of the clinical approach (1, 17, 26).

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