Clinical and Molecular Spectrum of PIK3CA-Related Overgrowth Syndrome: A Turkish Cohort

Öz

Background: PIK3CA-related overgrowth spectrum (PROS) includes a group of mosaic overgrowth disorders caused by postzygotic gain-of-function variants in the PIK3CA gene. These variants lead to upregulation of the PI3K/AKT/mTOR signaling pathway, resulting in dysregulated cell growth, proliferation, and vasculogenesis. Disorders such as KTWS and CLOVES syndrome share overlapping clinical features such as segmental overgrowth, vascular and lymphatic malformations, and cutaneous involvement. Methods: A cohort of five Turkish patients with clinical findings consistent with PROS was evaluated. High-depth next-generation sequencing (NGS) was performed on affected tissue samples, and the identified variants on PIK3CA gene were interpreted according to ACMG/AMP criteria. Clinical, radiological, and molecular data were integrated to assess genotype–phenotype correlations. Results: Five distinct somatic PIK3CA variants were identified. Four were in the C-terminal helical and kinase domains—known mutational hotspots—while one variant was found in the N-terminal adaptor-binding (PI3K-ABD) domain. Four variants were missense substitutions, and one was an in-frame deletion. The mean sequencing depth was approximately 1100×, and the lowest variant allele frequency (VAF) detected was 2%. No correlation was observed between VAF and disease severity. Conclusion: This Turkish cohort highlights the clinical and molecular heterogeneity of PROS and emphasizes the importance of tissue-targeted, high-depth sequencing in detecting low-level mosaic variants. Molecular confirmation of PIK3CA mosaicism is essential for accurate diagnosis and therapeutic decision-making. Considering the recent evidence supporting the efficacy of Alpelisib in both pediatric and adult PROS patients, early recognition and molecular characterization of these cases are critical for guiding precision therapy and improving clinical outcomes.

Anahtar Kelimeler

• PIK3CA
• overgrowth
• segmental
• somatic
• mosaic

PIK3CA-İlişkili Aşırı Büyüme Sendromlarının Klinik ve Moleküler Spektrumu: Türk Hasta Kohortu

Öz

Arka Plan: PIK3CA-ilişkili aşırı büyüme spektrumu (PROS), PIK3CA geninde postzigotik dönemde ortaya çıkan işlev kazandırıcı (‘gain-of-function’) varyantlardan kaynaklanan mozaik aşırı büyüme sendromlarını kapsar. Bu varyantlar, PI3K/AKT/mTOR sinyal yolunun aktivasyonuna yol açarak hücre büyümesi, proliferasyonu ve damar gelişiminin düzeninin bozulmasına neden olur. Alt tiplerinden olan KTWS ve CLOVES sendromu gibi tablolar; segmental aşırı büyüme, vasküler ve lenfatik malformasyonlar ile deri tutulumunu içeren örtüşen klinik özellikler gösterir. Yöntemler: PROS ile uyumlu klinik bulgulara sahip beş Türk hastadan oluşan bir kohort değerlendirildi. Etkilenen doku örneklerinden yüksek derinlikli yeni nesil dizileme (NGS) analizi yapıldı ve saptanan PIK3CA gen varyantları ACMG/AMP kriterlerine göre yorumlandı. Klinik, radyolojik ve moleküler veriler entegre edilerek genotip–fenotip ilişkileri incelendi. Bulgular: Toplam beş farklı somatik PIK3CA varyantı tanımlandı. Dördü C-terminal helikal ve kinaz bölgelerinde (bilinen mutasyonel sıcak noktalar), biri ise N-terminal adaptor-bağlanma (PI3K-ABD) bölgesinde yer almaktaydı. Dört varyant ‘missense’ değişimi, biri ise çerçeve kayması oluşturmayan (‘in-frame’) delesyondu. Ortalama dizileme derinliği yaklaşık 1100× olup, saptanan en düşük varyant alel frekansı (VAF) %2 idi. VAF ile hastalık şiddeti arasında belirgin bir ilişki gözlenmedi. Sonuç: Bu Türk kohortu, PROS’un klinik ve moleküler heterojenitesini vurgulamakta ve düşük düzeydeki mozaik varyantların saptanmasında dokuya özgü, yüksek derinlikli dizilemenin önemini ortaya koymaktadır. PIK3CA mozaisizminin moleküler olarak doğrulanması, doğru tanı ve uygun tedavi seçimi açısından kritik öneme sahiptir. Hem pediatrik hem de erişkin PROS olgularında Alpelisib tedavisinin etkinliğini destekleyen güncel veriler göz önüne alındığında, bu hastaların erken tanınması ve moleküler olarak karakterize edilmesi, hedefe yönelik tedavi ve klinik sonuçların iyileştirilmesi açısından büyük önem taşımaktadır.

Anahtar Kelimeler

• PIK3CA
• aşırı büyüme
• segmental
• somatik
• mozaik

Kaynakça

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