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

CASE SERIES

This case series involves members of a nonconsan- guineous Serbian family. Detailed exploration of the fam- ily tree revealed that at least five family members exhibited clinical presentations consistent with CS. These manifesta- tions included recurrent benign tumors, atypical vascular malformations, and hamartomatous lesions involving soft tissues and internal organs (Figure 1). Patient 1 The first family member brought to medical attention was an 8-year-old girl, the third child from a regularly monitored pregnancy. She was born at term via natural delivery, with a birth weight of 3200 g and Apgar scores of 9 and 10. The patient initially presented in December 2016 to the surgical outpatient clinic with a noticeable lesion in the right axillary region. On examination, the lesion measured 4 cm in diameter and was circular and localized. Ultrasound revealed a prominent mass in the right anterior axillary line consistent with fatty tissue, with no involvement of underlying bone or muscle structures. The lesion was closely monitored, but after significant growth was noted, it was surgically excised in March 2017. The excised mass measured 6 × 5 cm, and histopathologi- cal (HP) findings confirmed a lipoma. For the next four years, the patient was lesion-free until December 2021, when swelling in the medial aspect of the right knee was reported following an injury. An MRI of the knee region revealed a tumor within the vastus lateralis and medialis muscles, raising concerns for a myofibroblastic or synovial tumor, with sarcoma considered as a differential diagnosis. A subsequent evaluation by a pediatric hematologist included full blood count, biochemical tests, coagulation screening, immunoglobulins, and ultrasound of the left in- guinal region due to regional lymphadenopathy. A chest CT scan in May 2022 showed no evidence of pulmonary consolidation or lymphadenopathy but revealed a 1.2 cm hy- podense lesion in the spleen, prompting further monitoring. In May 2022, the patient underwent excision of the right thigh tumor. Histopathological evaluation identified the tissue as benign soft-tissue angiomatosis. However, in February 2023, follow-up imaging suggested tumor recurrence in the right knee region. The recurrence was surgically removed in November 2023, and HP analysis confirmed identical findings to the prior assessment. In June 2024, the patient presented with pain in the left inguinal region and thigh. Examination revealed two freely mobile subcutaneous masses, measuring 8 × 4 cm near the left iliac crest and 5 × 3 cm in the anterior inner thigh. Both masses were surgically excised. Macroscopic examination of the subcutaneous tissue showed hyperlobu- lated adipose tissue with densely packed vascular compo- nents forming a cribriform structure. Histopathological analysis revealed a complex soft tissue lesion composed of disorganized mesenchymal tissues, including atypical combined vascular malformations, proliferative lipoma- tous components, and fibrous elements. Immunohisto- chemistry (CD31, CD34, D2-40, smooth muscle actin, desmin, S-100 protein, Ki-67) supported the diagnosis of PHOST (Figure 2). Genetic testing via whole exome sequencing identified a heterozygous pathogenic variant c.48T>A (p.Tyr16Ter) in the PTEN gene, confirming a diagnosis of CS type 1. Following diagnosis, regular multidisciplinary monitor- ing by a plastic surgeon, hematologist, and geneticist was initiated. There have been no new lesions detected to date. Patient 2 The patient’s 9-year-old older sister presented in De- cember 2023 with a soft tissue mass in the lumbar region. MRI revealed a lipomatous lesion involving muscle and aponeurotic structures. In May 2024, the mass was sur- gically excised, preserving muscle and nerve function. Postoperative HP analysis confirmed a benign lipomatous lesion. However, follow-up imaging revealed recurrence of the tumor at the initial site. Genetic testing confirmed the presence of the familial PTEN variant c.48T>A (p.Tyr16Ter), and the diagnosis of CS was extended to the older sister. She is now under regular multidisciplinary surveillance. Patient 3 Clinical examination of the children’s father revealed plantar keratosis. Genetic testing confirmed the same PTEN variant (c.48T>A, p.Tyr16Ter) as in his daughters. Given the genetic findings, the father was referred for endocrine and hematological evaluations, as well as regular cancer surveillance. To date, he has not developed malignancies but remains under continuous monitoring. Patient 4 The paternal grandfather of the siblings, now a 78-year-old man, was identified as Patient 4. Based on anamnesis and photographic analysis, he was noted to have two large soft tissue masses located in the neck and interscapular regions. Although genetic testing was not performed, these findings, along with the confirmed fa- milial PTEN variant in his descendants, strongly suggest that he is affected by CS. To date, he has not reported any significant health issues potentially associated with the CS spectrum. As a precautionary measure, he was advised to undergo regular surveillance, including monitoring for potential malignancies, in alignment with current recom- mendations for individuals with CS. Patient 5 Patient 5 is the 70-year-old paternal great-aunt of the two sisters. She has a long-standing history of medical follow-up due to benign central nervous system tumor, adrenal tumors, and diffuse intestinal polyposis. Anam- nesis indicates that she has undergone multiple surgical interventions over the years for these conditions. While no documentation confirms whether genetic testing has been performed, the clinical presentation aligns with features of CS, particularly given the familial history of a confirmed PTEN pathogenic variant. She has been advised to con- tinue regular monitoring under the care of a hematologist, with emphasis on multidisciplinary surveillance for the potential CS complications. Anamnestic data further suggests that the great- grandfather of the proband passed away in his late 70s due to liver cancer. However, no reliable medical records are available to confirm the diagnosis or precisely assess contributing risk factors such as alcohol consumption or underlying conditions. While this observation could be relevant to the familial context, its significance remains uncertain.

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