Pediatric cancer predisposition syndromes identified by phenotype directed recognition: an Indian cohort

Abstract Background Cancer predisposition syndromes (CPS) are implicated in 8–10% of childhood cancers in large prospective studies. Early recognition informs therapy, reduces treatment-related toxicity, and enables surveillance and family-level interventions. In low- and middle-income countries (LMICs), universal germline sequencing is seldom feasible, and phenotype-directed testing is the most practical approach. Methods We performed a retrospective cohort study at the Post Graduate Institute of Child Health (PGICH), Noida, from April 2017 to March 2025. Children aged 0–18 years with malignancy and clinical suspicion of CPS underwent germline next-generation sequencing. Clinical triggers included dysmorphism, family history, atypical presentation, or treatment-related toxicity. Data on demographics, CPS subtype, treatment modifications, and outcomes were collected. Results Among 855 pediatric cancer patients, 14 (1.6%) had confirmed CPS, including Li–Fraumeni, Ataxia-Telangiectasia, GATA2 deficiency, Dyskeratosis congenita, Denys–Drash, WAGR, Sotos, SAMD9L-associated ataxia–pancytopenia, mosaic variegated aneuploidy, common variable immunodeficiency, mismatch repair deficiency, Down syndrome, and an NLRP2 variant. Treatment was modified in six patients, with changes such as omission of radiotherapy or bleomycin and dose adjustments for renal function or regimen intensity. As of 31 August 2025, overall and event-free survival were both 50% (7/14), or 54% (7/13) when restricted to known outcomes. No relapses were observed; all events were deaths due to progressive cancer or CPS-related complications. Conclusions Phenotype-directed testing detects fewer CPS than universal sequencing but yields clinically meaningful benefits. Early CPS recognition facilitated tailored therapy, reduced toxicity, and enabled family counseling. Wider access to germline testing is urgently needed in LMICs, but systematic phenotype-directed screening remains a valuable interim strategy.