Outcomes of pediatric cancer predisposition syndromes identified by phenotype directed recognition: an Indian cohort

Outcomes of pediatric cancer predisposition syndromes identified by phenotype directed recognition: an Indian cohort | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Outcomes of pediatric cancer predisposition syndromes identified by phenotype directed recognition: an Indian cohort Aditi Tulsiyan, Dr Nita Radhakrishnan, Dr Anuj Singh, Dr Hari Gaire, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7723362/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version 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. Cancer predisposition syndromes Pediatric cancer Phenotype-directed recognition Genetic testing Treatment modification Introduction Childhood cancer is an important cause of morbidity and mortality worldwide and represents an increasing health burden in India, where approximately 50,000 new cases are diagnosed annually [ 1 ]. Although the majority of childhood cancers are traditionally regarded as sporadic, germline predisposition contributes to 8–10% of cases, as confirmed in large genomic sequencing studies [ 2 , 3 ]. Cancer predisposition syndromes (CPS) include diverse entities such as Li-Fraumeni syndrome, Ataxia-Telangiectasia, telomere biology disorders, and constitutional trisomy 21. These syndromes not only increase susceptibility to malignancy but also result in multisystem disease manifestations that complicate therapy [ 4 , 5 ]. Early recognition of CPS is essential. In the oncologic setting, knowledge of a child’s underlying predisposition may lead to treatment modifications, such as avoidance of radiotherapy in Ataxia-Telangiectasia or dose reduction in telomere biology disorders, thereby preventing life-threatening toxicity [ 6 ]. Equally important, diagnosis enables structured surveillance programs that improve survival through early detection of subsequent malignancies, as demonstrated in Li-Fraumeni syndrome [ 7 ]. Family implications are profound, as parents and siblings may require genetic counseling, cascade testing, and prenatal or preimplantation genetic diagnosis in future pregnancies. Despite these benefits, universal germline sequencing remains inaccessible in most LMICs due to economic, infrastructural, and workforce constraints [ 8 , 9 ]. Therefore, phenotype-directed testing triggered by dysmorphism, family history, unusual tumor patterns, or excessive treatment toxicity remains the only pragmatic strategy [ 10 ]. However, this approach underestimates the prevalence of CPS and may delay recognition until after toxicity or secondary complications occur. We report an eight-year experience of CPS diagnosed by phenotype-directed testing at a tertiary pediatric oncology center in India, with a focus on outcomes, treatment modifications, and family impact. Methods This retrospective cohort study was conducted at the Department of Pediatric Hematology-Oncology, PGICH, Noida, between April 2017 and March 2025. Children aged 0–18 years with a diagnosis of malignancy were included if they had clinical suspicion of CPS and a confirmed germline mutation. Clinical suspicion was based on physical dysmorphism, positive family history, atypical cancer presentation, or unusual toxicity during treatment. Genetic confirmation was obtained using next-generation sequencing (NGS) multigene panels; The staging and risk stratification evaluation for cancer was as per standard of care. Additional investigations such as immunological studies and imaging were performed where appropriate. Variants were classified according to American College of Medical Genetics guidelines [ 11 ]. Clinical records were reviewed for demographics, cancer diagnosis, CPS subtype, genetic findings, non-oncologic manifestations, treatment modifications, and outcomes. Data were summarized descriptively. The study was approved by the Institutional Ethics Committee of the Post Graduate Institute of Child Health, Noida (Approval number: 2023-10-EM-43; Title: Evaluation of medical and psychosocial outcome of children undergoing treatment for cancer ) and the study adhered to the Declaration of Helsinki. Waiver of consent was taken as it was retrospective chart review with no identifying information reported. Follow-up was recorded from the date of cancer diagnosis until last documented contact or death, and overall survival (OS) and event-free survival (EFS) were estimated as of 31 August 2025, with patients lost to follow-up censored at the date of last contact. Results During the eight-year study period, 855 children with malignancy were registered at the center. Fourteen patients (1.6%) were diagnosed with an underlying CPS. The triggers for evaluation were dysmorphism (n = 6), unusual clinical presentation (n = 4), family history (n = 1), treatment-related toxicity (n = 2), and molecular findings on disease work-up (n = 1). The identified syndromes represented both classical and emerging entities. Classical CPS included Li-Fraumeni syndrome (TP53), Ataxia-Telangiectasia (ATM), and Down syndrome-associated AML. Emerging disorders included GATA2 deficiency, Dyskeratosis congenita (RTEL1, TINF2), SAMD9L-associated ataxia–pancytopenia syndrome, mosaic variegated aneuploidy (BUB1B), and mismatch repair deficiency (PMS2). Other syndromes comprised Denys-Drash (WT1), WAGR (WT1-PAX6), Sotos (NSD1), common variable immunodeficiency, and an NLRP2 variant. The details of diagnosis of CPS, cancer associated, treatment modifications and outcome are detailed in Table 1 . Table 1 Outcome of the cancer and underlying predisposition syndromes Sl. No Age Sex Year of diagnosis Cancer diagnosis Cancer Predisposition Genetic mutation Reason for testing for CPS Non oncological manifestations Treatment modification for cancer Outcome of cancer Outcome of underlying CPS 1 1.5 M 2024 Neuroblastoma Sotos Syndrome NSD1 Dysmorphism Hemihypertrophy Nil Remission Alive on follow up 2 10 M 2017 Hodgkins Lymphoma Ataxia Telangiectasia ATM Infections Ataxia, Tremors, Recurrent infections Avoided Bleomycin/ Low dose radiation exposure for CT scan Remission Died of pneumonia 3 4 M 2018 Wilms Tumor WAGR Syndrome LMO2 HIPK3 WT1 PAX6. ELP4 Dysmorphism Aniridia Developmental delay Nil Remission Died following seizures 4 3 F 2023 Wilms Tumor Denys Drash Syndrome WT1 Renal dysfunction Steroid refractory Nephrotic Syndrome Dose modification for renal dysfunction, Veno Occlusive Disease Remission Died of progressive renal dysfunction 5 5 M 2019 Acute Lymphoblastic leukemia Ataxia Pancytopenia Syndrome SAMD9L Toxicity – Infections, Prolonged cytopenia Infective complications – Abscesses, Empyema, Cervical abscess with paraplegia Radiotherapy avoided Remission Lost to follow up 6 17 M 2023 Acute Myeloid Leukemia (Myelodysplastic Syndrome) Dyskeratosis Congenita RTEL MDS Pancytopenia Nil Died of progressive disease 7 14 M 2019 Acute Myeloid Leukemia (Monosomy 7) GATA2 haploinsufficiency GATA 2 Progressive lymphopenia, Infections Life threatening Infections Nil Remission Died of pneumonia 8 0.9 M 2022 Wilms Tumor Mosaic variegated Aneuploidy BUB1B, TINF2 Dysmorphism Microcephaly Horseshoe kidney FTT/Developmental Delay Dose modifications for weight Remission Alive on follow up 9 10 M 2017 T Lymphoblastic Lymphoma CVID No pathogenic mutation identified Recurrent lung infections Bronchopneumonia Nil Remission Alive, Chronic lung disease 10 13 F 2023 Acute Lymphoblastic leukemia Li Fraumeni Syndrome TP53 Very early relapse Disease Relapse Nil Died of progressive disease 11 6 F 2021 Acute Lymphoblastic leukemia NLRP2 NLRP2 Dysmorphism Failure to thrive Generalized Eczema Dose modification for weight Remission Died of infection 12 2 F 2024 Wilms Tumor Denys Drash Syndrome WT1 Dysmorphism Nephrotic syndrome Coarse facies No Remission Alive on follow up 13 13 M 2024 T Lymphoblastic Lymphoma Mismatch repair defect PMS2 Family history Family history No Remission Alive on follow up 14 1 M 2025 Acute Myeloid Leukemia Down syndrome Trisomy 21 Dysmorphism Facies Hypothyroidism DS-AML protocol Remission Alive on follow up The child was diagnosed with WAGR in early infancy on the basis of congenital aniridia and genitourinary anomalies and genetic testing (MLPA) confirmed a large heterozygous 11p13 deletion involving PAX6 and WT1. Under a structured surveillance programme (renal ultrasound every 3 months) a Wilms tumor was detected at 1.5 years; the patient received neoadjuvant chemotherapy followed by nephrectomy with an uncomplicated early oncologic course. Of note, at approximately 3.5 years the child developed an acute, relapsing encephalopathy characterized by CSF pleocytosis and MRI changes consistent with acute disseminated encephalomyelitis (ADEM); infectious and metabolic causes were excluded, and the child showed a prompt clinical and radiologic response to high-dose corticosteroids. The child with AML and GATA2 haploinsufficiency was diagnosed at 14-years of age with high-risk acute myeloid leukemia with monosomy 7. He tolerated standard AML treatment, and achieved remission, but developed recurrent infections, persistent diarrhea with Cryptosporidium parvum, progressive lymphopenia and near-absent circulating B- and NK-cell populations. Next-generation sequencing identified a heterozygous frameshift GATA2 variant (chr3:128205727: TG > T; c.147del, p.Phe49LeufsTer31) consistent with GATA2 haploinsufficiency; allogeneic HSCT was advised but could not be undertaken and the child later succumbed to a rapid pulmonary event [ 12 ]. The child with AT presented in early childhood with recurrent infections and progressive cerebellar signs (clumsiness and frequent falls) leading to a clinical and laboratory diagnosis of ataxia-telangiectasia. Over the subsequent years the patient had multiple hospital admissions for infectious complications and, later, developed mediastinal lymphadenopathy; fine-needle aspiration biology confirmed Hodgkin lymphoma (documented as Stage III). The clinical course was complicated by invasive fungal sepsis (Candida) and recurrent bronchopneumonia, and he died in 2025 after a severe pulmonary event. Treatment was modified in six patients to prevent severe toxicity. Bleomycin was avoided in Ataxia-Telangiectasia, cranial irradiation was omitted in SAMD9L-associated ALL, and chemotherapy doses were adjusted in Denys-Drash and mosaic aneuploidy. Children with DS-AML were treated with adapted protocols. These interventions were essential to avoid fatal complications. While 2 children died of progressive disease (MDS-AML and ALL-TP53), the rest (n = 12) attained remission and there were no relapses noted in the cohort. Deaths that occurred further were due to CPS related issues such as infections (Ataxia-Telangiectasia, GATA2 deficiency, NLRP mutation), seizures (WAGR) and progressive renal failure (Denys-Drash syndrome). Survivors continue to face significant CPS-related morbidity, including renal disease, immunodeficiency, chronic pulmonary disease, and developmental delay, necessitating multidisciplinary follow-up. As of 31 August 2025, overall survival (OS) and event-free survival (EFS) for the cohort were both 50% (7/14), or 54% (7/13) when restricted to known outcomes, with the single patient lost to follow-up censored at last contact; no relapses were observed, and all recorded events were deaths due either to progressive malignancy or CPS-related complications. Discussion This study highlights the outcomes of children with CPS identified through phenotype-directed testing in a resource-limited setting. Although the observed prevalence of 1.6% was much lower than the 8–10% reported in prospective genomic studies [ 2 , 4 ], recognition of CPS had tangible impacts on patient outcomes. Early diagnosis facilitated treatment modifications, reduced the risk of life-threatening therapy-related toxicity, and enabled tailored follow-up. Early testing for cancer-predisposition syndromes (CPS) at or soon after a cancer diagnosis is critically important because it changes management for the index patient and for relatives: identifying a germline CPS enables syndrome-specific cancer surveillance that can detect second or metachronous tumours early (for example, whole-body MRI and biochemical surveillance in Li-Fraumeni syndrome with demonstrated survival benefit) [ 7 ]. It also determines donor suitability and transplant strategy; several DNA-repair disorders (e.g., Fanconi anemia) and immunodeficiency-associated predisposition syndromes require genetic testing of potential family donors and mandate reduced-intensity or radiation-sparing conditioning regimens to avoid catastrophic toxicity [ 13 ]. Because germline CPS are not uncommon among children with cancer (large series found pathogenic variants in ~ 8–9% of pediatric cancer patients), early testing identifies at-risk relatives who should enter targeted surveillance and cascade testing, enabling cancer prevention, earlier detection and informed reproductive counselling [ 3 ]. Finally, knowledge of an underlying CPS frequently requires immediate treatment adaptations for the patient; for example, avoiding or minimizing ionizing radiation and certain alkylating/topoisomerase agents in DNA-repair syndromes, so that therapy is both effective and safe. Disease related outcome in select cases While neurodevelopmental abnormalities are a recognized component of the WAGR/PAX6 contiguous-gene syndrome, autoimmune demyelinating encephalopathy such as ADEM has not, to our knowledge, been previously described in association with WAGR and may represent either a coincidental post-infectious event or a hitherto under-recognized manifestation of the contiguous-gene deletion. This observation highlights the need for vigilance for new neurologic symptoms in children with WAGR: early neurological investigation (MRI, CSF analysis) and prompt specialist referral are warranted, and clinicians should include inflammatory/autoimmune causes in the differential in addition to structural or developmental explanations. We suggest that long-term follow-up of WAGR cohorts explicitly capture acute neurologic events so the spectrum and incidence of such complications can be better defined, and that multidisciplinary care plans for WAGR incorporate a low threshold for neurologic assessment. The child with GATA2 haploinsufficiency highlights the protean phenotype of germline GATA2 deficiency in which hematologic malignancy (frequently MDS/AML with monosomy 7) coexists with profound immunodeficiency (monocytopenia, B- and NK-cell loss) and susceptibility to opportunistic infections (HPV, mycobacteria, cryptosporidium) and pulmonary complications [ 12 ]. Recognition of the syndrome is critical because allogeneic HSCT is the only curative therapy for both the hematologic and immunologic defects and because family members considered as donors require genetic evaluation. Therefore, it is recommended to test for germline GATA2 defects in children with monosomy-7 MDS/AML or with the combination of cytopenias, recurrent or atypical infections and characteristic skin/lymphatic findings, and early multidisciplinary referral for transplant planning, infection surveillance and family counselling. This case with AT highlights two hallmark and interacting features of A-T; progressive neurodegeneration and clinically important immunodeficiency and focuses important management challenges. Children with A-T are predisposed to lymphoid malignancies but are also highly vulnerable to life-threatening infections and display cellular radiosensitivity, which complicates standard oncologic approaches (radiation avoidance or extreme caution and chemotherapy dose individualization are often required). The combined risks of infection, treatment-related toxicity and neurodegeneration contribute to high morbidity and mortality and underscore the need for early immunologic assessment, aggressive infection surveillance and prophylaxis, multidisciplinary care (neurology, immunology, oncology, physiotherapy), and individualized, risk-adapted cancer therapy planning in A-T patients. Systematic long-term follow-up is critical to detect both oncologic and non-oncologic complications early and to optimize supportive interventions Implications for family Our findings further highlight the implications for families. Identification of CPS necessitates genetic counseling, cascade testing of at-risk relatives, and guidance regarding reproductive options [ 13 ]. A qualitative multi–family-member interview study found that parents generally regarded germline genetic testing in childhood cancer as valuable but often experienced its psychosocial effects as intertwined with the overall stress of the child’s illness [ 14 ]. Five recurring themes were identified: family communication about testing, strengthened togetherness, differing coping styles between partners, feelings of guilt and forgiveness, and sustained worries about relatives’ future health. The authors recommend proactive, family-centered counselling and psychosocial support integrated into pre- and post-test care to address these family-level impacts. In many LMIC settings, families lack access to genetic services, exacerbating the psychosocial and medical consequences of undiagnosed CPS. Establishing national registries and expanding access to genetic counseling are therefore critical steps in closing this gap. Published literature from high-income countries consistently shows that between 8–15% of children with cancer harbor an underlying cancer predisposition syndrome, with prevalence varying by sequencing strategy and cohort design [ 1 , 2 , 15 , 16 , 17 , 18 ]. In contrast, data from low- and middle-income countries remain sparse; the recent Indian cohort [ 8 ], using a structured checklist has shown a higher diagnostic yield in selected patients. Together, these studies highlight both the under-recognition of CPS in LMICs and the need for systematic strategies that balance feasibility with comprehensive detection. Table 2 summarizes study design, number of children tested, and prevalence of CPS reported by published studies from high-income countries (HIC) and LMICs. A pragmatic framework includes systematic clinical triage for CPS red flags, stepwise use of targeted panels, and broader sequencing only in unresolved but high-risk cases [ 8 , 19 ]. Investment in clinician training to recognize CPS features is also essential. Table 2 Published studies reporting germline CPS in pediatric cancer Author / Year/ Reference Country Design (as reported) Children tested CPS prevalence reported Zhang et al 2015 [ 3 ] USA (High income) Multiple cohorts 1,120 across cohorts 8.5% Byrjalsen et al 2020 [ 17 ] Denmark (High income) Prospective, nationwide cohort 198 consecutive patients 14.6% Bolanos et al 2023 [ 19 ] International (High income) Cohort synthesis Various cohorts ~ 10–15% Dangoni et al 2024 [ 18 ] International (High income) Retrospective, syndromic only Cohort 14% Singh et al 2024 [ 8 ] India (LMIC) Prospective 60 8.3% In our cohort, 10 of 12 children who attained remission remained disease-free, demonstrating that with appropriate tailored therapy, good outcomes are achievable; however, the substantial burden of CPS-related morbidity highlights the need for lifelong, multidisciplinary care. The limitations of our study include its retrospective design, small sample size, and reliance on clinical triggers, which likely underestimated the true CPS burden. The prevalence figure identified here likely represent an underestimation, as most data are derived from retrospective series rather than systematic prospective testing. Nonetheless, this report adds valuable evidence from South Asia, a region where systematic data on CPS remain sparse, and underscores the urgent need for improved diagnostic capacity. Conclusions Phenotype-directed testing identifies only a minority of cancer predisposition syndromes in children with malignancy. Nevertheless, early recognition, even in limited-resource settings, enables critical treatment modifications, reduces therapy-related mortality, and informs long-term survivorship care. Equally, CPS diagnosis benefits families through genetic counseling and cascade testing. Expansion of genetic testing capacity and development of pragmatic, context-specific screening protocols are essential to improve outcomes for children with CPS in LMICs. Declarations Author contribution: All authors contributed to patient care, were involved in preparing the manuscript and its revisions. Conflict of interest: No conflict of interest Ethics approved statement : Study protocol number: 2023-10-EM-43, Institute: Post Graduate Institute of Child Health, Noida Acknowledgements: We thank the support received from Lok Bharti Educational Society for supporting the cost of whole exome sequencing for few of the patients. Declaration of interest: The authors have no relevant financial or non-financial interests to disclose Funding declaration : There was no funding for this work. References Arora RS, Eden TO, Kapoor G. Epidemiology of childhood cancer in India. Indian J Cancer. 2009 Oct-Dec;46(4):264-73. doi: 10.4103/0019-509X.55546. 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15:47:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":614677,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7723362/v1/739cf92a-5e42-4fc4-a296-8310da968a4f.pdf"},{"id":93667142,"identity":"ae505b27-73cc-4b33-84ca-005abc604dc6","added_by":"auto","created_at":"2025-10-16 09:21:15","extension":"pptx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":91903,"visible":true,"origin":"","legend":"","description":"","filename":"7.Graphicabstract.pptx","url":"https://assets-eu.researchsquare.com/files/rs-7723362/v1/f788ea02a64b4f9d885a701a.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Outcomes of pediatric cancer predisposition syndromes identified by phenotype directed recognition: an Indian cohort","fulltext":[{"header":"Introduction","content":"\u003cp\u003eChildhood cancer is an important cause of morbidity and mortality worldwide and represents an increasing health burden in India, where approximately 50,000 new cases are diagnosed annually [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although the majority of childhood cancers are traditionally regarded as sporadic, germline predisposition contributes to 8–10% of cases, as confirmed in large genomic sequencing studies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Cancer predisposition syndromes (CPS) include diverse entities such as Li-Fraumeni syndrome, Ataxia-Telangiectasia, telomere biology disorders, and constitutional trisomy 21. These syndromes not only increase susceptibility to malignancy but also result in multisystem disease manifestations that complicate therapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eEarly recognition of CPS is essential. In the oncologic setting, knowledge of a child’s underlying predisposition may lead to treatment modifications, such as avoidance of radiotherapy in Ataxia-Telangiectasia or dose reduction in telomere biology disorders, thereby preventing life-threatening toxicity [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Equally important, diagnosis enables structured surveillance programs that improve survival through early detection of subsequent malignancies, as demonstrated in Li-Fraumeni syndrome [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Family implications are profound, as parents and siblings may require genetic counseling, cascade testing, and prenatal or preimplantation genetic diagnosis in future pregnancies.\u003c/p\u003e\u003cp\u003eDespite these benefits, universal germline sequencing remains inaccessible in most LMICs due to economic, infrastructural, and workforce constraints [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Therefore, phenotype-directed testing triggered by dysmorphism, family history, unusual tumor patterns, or excessive treatment toxicity remains the only pragmatic strategy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, this approach underestimates the prevalence of CPS and may delay recognition until after toxicity or secondary complications occur. We report an eight-year experience of CPS diagnosed by phenotype-directed testing at a tertiary pediatric oncology center in India, with a focus on outcomes, treatment modifications, and family impact.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis retrospective cohort study was conducted at the Department of Pediatric Hematology-Oncology, PGICH, Noida, between April 2017 and March 2025. Children aged 0–18 years with a diagnosis of malignancy were included if they had clinical suspicion of CPS and a confirmed germline mutation. Clinical suspicion was based on physical dysmorphism, positive family history, atypical cancer presentation, or unusual toxicity during treatment. Genetic confirmation was obtained using next-generation sequencing (NGS) multigene panels; The staging and risk stratification evaluation for cancer was as per standard of care. Additional investigations such as immunological studies and imaging were performed where appropriate. Variants were classified according to American College of Medical Genetics guidelines [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Clinical records were reviewed for demographics, cancer diagnosis, CPS subtype, genetic findings, non-oncologic manifestations, treatment modifications, and outcomes.\u003c/p\u003e\u003cp\u003eData were summarized descriptively. The study was approved by the Institutional Ethics Committee of the Post Graduate Institute of Child Health, Noida (Approval number: 2023-10-EM-43; Title: \u003cem\u003eEvaluation of medical and psychosocial outcome of children undergoing treatment for cancer\u003c/em\u003e) and the study adhered to the Declaration of Helsinki. Waiver of consent was taken as it was retrospective chart review with no identifying information reported. Follow-up was recorded from the date of cancer diagnosis until last documented contact or death, and overall survival (OS) and event-free survival (EFS) were estimated as of 31 August 2025, with patients lost to follow-up censored at the date of last contact.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eDuring the eight-year study period, 855 children with malignancy were registered at the center. Fourteen patients (1.6%) were diagnosed with an underlying CPS. The triggers for evaluation were dysmorphism (n\u0026thinsp;=\u0026thinsp;6), unusual clinical presentation (n\u0026thinsp;=\u0026thinsp;4), family history (n\u0026thinsp;=\u0026thinsp;1), treatment-related toxicity (n\u0026thinsp;=\u0026thinsp;2), and molecular findings on disease work-up (n\u0026thinsp;=\u0026thinsp;1).\u003c/p\u003e\u003cp\u003eThe identified syndromes represented both classical and emerging entities. Classical CPS included Li-Fraumeni syndrome (TP53), Ataxia-Telangiectasia (ATM), and Down syndrome-associated AML. Emerging disorders included GATA2 deficiency, Dyskeratosis congenita (RTEL1, TINF2), SAMD9L-associated ataxia\u0026ndash;pancytopenia syndrome, mosaic variegated aneuploidy (BUB1B), and mismatch repair deficiency (PMS2). Other syndromes comprised Denys-Drash (WT1), WAGR (WT1-PAX6), Sotos (NSD1), common variable immunodeficiency, and an NLRP2 variant. The details of diagnosis of CPS, cancer associated, treatment modifications and outcome are detailed in Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eOutcome of the cancer and underlying predisposition syndromes\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSl. No\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eYear of diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCancer diagnosis\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCancer Predisposition\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGenetic mutation\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eReason for testing for CPS\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNon oncological manifestations\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eTreatment modification for cancer\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eOutcome\u003c/p\u003e\u003cp\u003eof cancer\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eOutcome of underlying CPS\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eNeuroblastoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSotos Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNSD1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDysmorphism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHemihypertrophy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eAlive on follow up\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHodgkins Lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAtaxia Telangiectasia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eATM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eInfections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAtaxia, Tremors, Recurrent infections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eAvoided Bleomycin/ Low dose radiation exposure for CT scan\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eDied of pneumonia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2018\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWilms Tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eWAGR Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eLMO2 HIPK3 WT1\u003c/p\u003e\u003cp\u003ePAX6. ELP4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDysmorphism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eAniridia\u003c/p\u003e\u003cp\u003eDevelopmental delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eDied following seizures\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWilms Tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDenys Drash Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eWT1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eRenal dysfunction\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSteroid refractory Nephrotic Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDose modification for renal dysfunction, Veno Occlusive Disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eDied of progressive renal dysfunction\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAcute Lymphoblastic leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eAtaxia Pancytopenia Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eSAMD9L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eToxicity \u0026ndash; Infections, Prolonged cytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eInfective complications \u0026ndash; Abscesses, Empyema, Cervical abscess with paraplegia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eRadiotherapy avoided\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eLost to follow up\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAcute Myeloid Leukemia (Myelodysplastic Syndrome)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDyskeratosis Congenita\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eRTEL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMDS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003ePancytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eDied of progressive disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2019\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAcute Myeloid Leukemia (Monosomy 7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eGATA2 haploinsufficiency\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eGATA 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eProgressive lymphopenia, Infections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eLife threatening Infections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eDied of pneumonia\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWilms Tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMosaic variegated Aneuploidy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eBUB1B, TINF2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDysmorphism\u003c/p\u003e\u003cp\u003eMicrocephaly\u003c/p\u003e\u003cp\u003eHorseshoe kidney\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFTT/Developmental Delay\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDose modifications for weight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eAlive on follow up\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eT Lymphoblastic Lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eCVID\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNo pathogenic mutation identified\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eRecurrent lung infections\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eBronchopneumonia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eAlive, Chronic lung disease\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAcute Lymphoblastic leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eLi Fraumeni Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTP53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVery early relapse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eDisease Relapse\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNil\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eDied of progressive disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2021\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAcute Lymphoblastic leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eNLRP2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eNLRP2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDysmorphism\u003c/p\u003e\u003cp\u003eFailure to thrive\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eGeneralized Eczema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDose modification for weight\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eDied of infection\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eWilms Tumor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDenys Drash Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eWT1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDysmorphism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eNephrotic syndrome\u003c/p\u003e\u003cp\u003eCoarse facies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eAlive on follow up\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eT Lymphoblastic Lymphoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMismatch repair defect\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ePMS2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eFamily history\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFamily history\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eAlive on follow up\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAcute Myeloid Leukemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003eDown syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003eTrisomy 21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eDysmorphism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFacies\u003c/p\u003e\u003cp\u003eHypothyroidism\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eDS-AML protocol\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003eRemission\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003eAlive on follow up\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe child was diagnosed with WAGR in early infancy on the basis of congenital aniridia and genitourinary anomalies and genetic testing (MLPA) confirmed a large heterozygous 11p13 deletion involving PAX6 and WT1. Under a structured surveillance programme (renal ultrasound every 3 months) a Wilms tumor was detected at 1.5 years; the patient received neoadjuvant chemotherapy followed by nephrectomy with an uncomplicated early oncologic course. Of note, at approximately 3.5 years the child developed an acute, relapsing encephalopathy characterized by CSF pleocytosis and MRI changes consistent with acute disseminated encephalomyelitis (ADEM); infectious and metabolic causes were excluded, and the child showed a prompt clinical and radiologic response to high-dose corticosteroids.\u003c/p\u003e\u003cp\u003eThe child with AML and GATA2 haploinsufficiency was diagnosed at 14-years of age with high-risk acute myeloid leukemia with monosomy 7. He tolerated standard AML treatment, and achieved remission, but developed recurrent infections, persistent diarrhea with Cryptosporidium parvum, progressive lymphopenia and near-absent circulating B- and NK-cell populations. Next-generation sequencing identified a heterozygous frameshift GATA2 variant (chr3:128205727: TG\u0026thinsp;\u0026gt;\u0026thinsp;T; c.147del, p.Phe49LeufsTer31) consistent with GATA2 haploinsufficiency; allogeneic HSCT was advised but could not be undertaken and the child later succumbed to a rapid pulmonary event [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe child with AT presented in early childhood with recurrent infections and progressive cerebellar signs (clumsiness and frequent falls) leading to a clinical and laboratory diagnosis of ataxia-telangiectasia. Over the subsequent years the patient had multiple hospital admissions for infectious complications and, later, developed mediastinal lymphadenopathy; fine-needle aspiration biology confirmed Hodgkin lymphoma (documented as Stage III). The clinical course was complicated by invasive fungal sepsis (Candida) and recurrent bronchopneumonia, and he died in 2025 after a severe pulmonary event.\u003c/p\u003e\u003cp\u003eTreatment was modified in six patients to prevent severe toxicity. Bleomycin was avoided in Ataxia-Telangiectasia, cranial irradiation was omitted in SAMD9L-associated ALL, and chemotherapy doses were adjusted in Denys-Drash and mosaic aneuploidy. Children with DS-AML were treated with adapted protocols. These interventions were essential to avoid fatal complications. While 2 children died of progressive disease (MDS-AML and ALL-TP53), the rest (n\u0026thinsp;=\u0026thinsp;12) attained remission and there were no relapses noted in the cohort.\u003c/p\u003e\u003cp\u003eDeaths that occurred further were due to CPS related issues such as infections (Ataxia-Telangiectasia, GATA2 deficiency, NLRP mutation), seizures (WAGR) and progressive renal failure (Denys-Drash syndrome). Survivors continue to face significant CPS-related morbidity, including renal disease, immunodeficiency, chronic pulmonary disease, and developmental delay, necessitating multidisciplinary follow-up.\u003c/p\u003e\u003cp\u003eAs of 31 August 2025, overall survival (OS) and event-free survival (EFS) for the cohort were both 50% (7/14), or 54% (7/13) when restricted to known outcomes, with the single patient lost to follow-up censored at last contact; no relapses were observed, and all recorded events were deaths due either to progressive malignancy or CPS-related complications.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study highlights the outcomes of children with CPS identified through phenotype-directed testing in a resource-limited setting. Although the observed prevalence of 1.6% was much lower than the 8\u0026ndash;10% reported in prospective genomic studies [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], recognition of CPS had tangible impacts on patient outcomes. Early diagnosis facilitated treatment modifications, reduced the risk of life-threatening therapy-related toxicity, and enabled tailored follow-up.\u003c/p\u003e\u003cp\u003eEarly testing for cancer-predisposition syndromes (CPS) at or soon after a cancer diagnosis is critically important because it changes management for the index patient and for relatives: identifying a germline CPS enables syndrome-specific cancer surveillance that can detect second or metachronous tumours early (for example, whole-body MRI and biochemical surveillance in Li-Fraumeni syndrome with demonstrated survival benefit) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. It also determines donor suitability and transplant strategy; several DNA-repair disorders (e.g., Fanconi anemia) and immunodeficiency-associated predisposition syndromes require genetic testing of potential family donors and mandate reduced-intensity or radiation-sparing conditioning regimens to avoid catastrophic toxicity [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Because germline CPS are not uncommon among children with cancer (large series found pathogenic variants in ~\u0026thinsp;8\u0026ndash;9% of pediatric cancer patients), early testing identifies at-risk relatives who should enter targeted surveillance and cascade testing, enabling cancer prevention, earlier detection and informed reproductive counselling [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Finally, knowledge of an underlying CPS frequently requires immediate treatment adaptations for the patient; for example, avoiding or minimizing ionizing radiation and certain alkylating/topoisomerase agents in DNA-repair syndromes, so that therapy is both effective and safe.\u003c/p\u003e\u003cp\u003eDisease related outcome in select cases\u003c/p\u003e\u003cp\u003eWhile neurodevelopmental abnormalities are a recognized component of the WAGR/PAX6 contiguous-gene syndrome, autoimmune demyelinating encephalopathy such as ADEM has not, to our knowledge, been previously described in association with WAGR and may represent either a coincidental post-infectious event or a hitherto under-recognized manifestation of the contiguous-gene deletion. This observation highlights the need for vigilance for new neurologic symptoms in children with WAGR: early neurological investigation (MRI, CSF analysis) and prompt specialist referral are warranted, and clinicians should include inflammatory/autoimmune causes in the differential in addition to structural or developmental explanations. We suggest that long-term follow-up of WAGR cohorts explicitly capture acute neurologic events so the spectrum and incidence of such complications can be better defined, and that multidisciplinary care plans for WAGR incorporate a low threshold for neurologic assessment.\u003c/p\u003e\u003cp\u003eThe child with GATA2 haploinsufficiency highlights the protean phenotype of germline GATA2 deficiency in which hematologic malignancy (frequently MDS/AML with monosomy 7) coexists with profound immunodeficiency (monocytopenia, B- and NK-cell loss) and susceptibility to opportunistic infections (HPV, mycobacteria, cryptosporidium) and pulmonary complications [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Recognition of the syndrome is critical because allogeneic HSCT is the only curative therapy for both the hematologic and immunologic defects and because family members considered as donors require genetic evaluation. Therefore, it is recommended to test for germline GATA2 defects in children with monosomy-7 MDS/AML or with the combination of cytopenias, recurrent or atypical infections and characteristic skin/lymphatic findings, and early multidisciplinary referral for transplant planning, infection surveillance and family counselling.\u003c/p\u003e\u003cp\u003eThis case with AT highlights two hallmark and interacting features of A-T; progressive neurodegeneration and clinically important immunodeficiency and focuses important management challenges. Children with A-T are predisposed to lymphoid malignancies but are also highly vulnerable to life-threatening infections and display cellular radiosensitivity, which complicates standard oncologic approaches (radiation avoidance or extreme caution and chemotherapy dose individualization are often required). The combined risks of infection, treatment-related toxicity and neurodegeneration contribute to high morbidity and mortality and underscore the need for early immunologic assessment, aggressive infection surveillance and prophylaxis, multidisciplinary care (neurology, immunology, oncology, physiotherapy), and individualized, risk-adapted cancer therapy planning in A-T patients. Systematic long-term follow-up is critical to detect both oncologic and non-oncologic complications early and to optimize supportive interventions\u003c/p\u003e\u003cp\u003eImplications for family\u003c/p\u003e\u003cp\u003eOur findings further highlight the implications for families. Identification of CPS necessitates genetic counseling, cascade testing of at-risk relatives, and guidance regarding reproductive options [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. A qualitative multi\u0026ndash;family-member interview study found that parents generally regarded germline genetic testing in childhood cancer as valuable but often experienced its psychosocial effects as intertwined with the overall stress of the child\u0026rsquo;s illness [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Five recurring themes were identified: family communication about testing, strengthened togetherness, differing coping styles between partners, feelings of guilt and forgiveness, and sustained worries about relatives\u0026rsquo; future health. The authors recommend proactive, family-centered counselling and psychosocial support integrated into pre- and post-test care to address these family-level impacts. In many LMIC settings, families lack access to genetic services, exacerbating the psychosocial and medical consequences of undiagnosed CPS. Establishing national registries and expanding access to genetic counseling are therefore critical steps in closing this gap.\u003c/p\u003e\u003cp\u003ePublished literature from high-income countries consistently shows that between 8\u0026ndash;15% of children with cancer harbor an underlying cancer predisposition syndrome, with prevalence varying by sequencing strategy and cohort design [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In contrast, data from low- and middle-income countries remain sparse; the recent Indian cohort [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], using a structured checklist has shown a higher diagnostic yield in selected patients. Together, these studies highlight both the under-recognition of CPS in LMICs and the need for systematic strategies that balance feasibility with comprehensive detection. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes study design, number of children tested, and prevalence of CPS reported by published studies from high-income countries (HIC) and LMICs. A pragmatic framework includes systematic clinical triage for CPS red flags, stepwise use of targeted panels, and broader sequencing only in unresolved but high-risk cases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Investment in clinician training to recognize CPS features is also essential.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePublished studies reporting germline CPS in pediatric cancer\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAuthor / Year/ Reference\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCountry\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDesign (as reported)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eChildren tested\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCPS prevalence reported\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eZhang et al 2015 [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eUSA (High income)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMultiple cohorts\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,120 across cohorts\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8.5%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eByrjalsen et al 2020 [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDenmark (High income)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProspective, nationwide cohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e198 consecutive patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14.6%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBolanos et al 2023 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInternational (High income)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCohort synthesis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eVarious cohorts\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e~\u0026thinsp;10\u0026ndash;15%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDangoni et al 2024 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eInternational (High income)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eRetrospective, syndromic only\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCohort\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e14%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSingh et al 2024 [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIndia (LMIC)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eProspective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e8.3%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eIn our cohort, 10 of 12 children who attained remission remained disease-free, demonstrating that with appropriate tailored therapy, good outcomes are achievable; however, the substantial burden of CPS-related morbidity highlights the need for lifelong, multidisciplinary care. The limitations of our study include its retrospective design, small sample size, and reliance on clinical triggers, which likely underestimated the true CPS burden. The prevalence figure identified here likely represent an underestimation, as most data are derived from retrospective series rather than systematic prospective testing. Nonetheless, this report adds valuable evidence from South Asia, a region where systematic data on CPS remain sparse, and underscores the urgent need for improved diagnostic capacity.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003ePhenotype-directed testing identifies only a minority of cancer predisposition syndromes in children with malignancy. Nevertheless, early recognition, even in limited-resource settings, enables critical treatment modifications, reduces therapy-related mortality, and informs long-term survivorship care. Equally, CPS diagnosis benefits families through genetic counseling and cascade testing. Expansion of genetic testing capacity and development of pragmatic, context-specific screening protocols are essential to improve outcomes for children with CPS in LMICs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution:\u003c/strong\u003e All authors contributed to patient care, were involved in preparing the manuscript and its revisions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest:\u003c/strong\u003e No conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approved statement\u003c/strong\u003e: Study protocol number: 2023-10-EM-43, Institute: Post Graduate Institute of Child Health, Noida\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e We thank the support received from Lok Bharti Educational Society for supporting the cost of whole exome sequencing for few of the patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of interest:\u003c/strong\u003e The authors have no relevant financial or non-financial interests to disclose\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding declaration\u003c/strong\u003e: There was no funding for this work.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eArora RS, Eden TO, Kapoor G. Epidemiology of childhood cancer in India. Indian J Cancer. 2009 Oct-Dec;46(4):264-73. doi: 10.4103/0019-509X.55546.\u003c/li\u003e\n \u003cli\u003eBrodeur GM, Nichols KE, Plon SE, Schiffman JD, Malkin D. Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr. Clin Cancer Res. 2017 Jun 1;23(11):e1-e5. doi: 10.1158/1078-0432.CCR-17-0702.\u003c/li\u003e\n \u003cli\u003eZhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBakhuizen JJ, Hopman SMJ, Bosscha MI, Dommering CJ, van den Heuvel-Eibrink MM, Hol JA et al. Assessment of Cancer Predisposition Syndromes in a National Cohort of Children With a Neoplasm. JAMA Netw Open. 2023 Feb 1;6(2):e2254157. doi: 10.1001/jamanetworkopen.2022.54157.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKratz CP, Jongmans MC, Cav\u0026eacute; H, Wimmer K, Behjati S, Guerrini-Rousseau L et al. Predisposition to cancer in children and adolescents. Lancet Child Adolesc Health. 2021 Feb;5(2):142-154. doi: 10.1016/S2352-4642(20)30275-3.\u003c/li\u003e\n \u003cli\u003eBrodeur GM, Nichols KE, Plon SE, Schiffman JD, Malkin D. Pediatric Cancer Predisposition and Surveillance: An Overview, and a Tribute to Alfred G. Knudson Jr. Clin Cancer Res. 2017 Jun 1;23(11):e1-e5. doi: 10.1158/1078-0432.CCR-17-0702. PMID: 28572261; PMCID: PMC5553563.\u003c/li\u003e\n \u003cli\u003eVillani A, Shore A, Wasserman JD, Stephens D, Kim RH, Druker H et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol. 2016 Sep;17(9):1295-305. doi: 10.1016/S1470-2045(16)30249-2.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSingh M, Bhatia P, Sharma P, Trehan A, Jain R. Assessment of cancer predisposition syndromes in children with leukemia and solid tumors: germline-genomic profiling and clinical features in a series of cases. Pediatr Hematol Oncol. 2024 Nov;41(8):620-632. doi: 10.1080/08880018.2024.2411321. Epub 2024 Oct 12. PMID: 39394854.\u003c/li\u003e\n \u003cli\u003eParambil BC, Moulik NR, Gollamudi VRM, Srinivasan S, Dhamne C, Chichra A et al. Changing paradigms in pediatric cancer care - the contemporary landscape and perspectives for India. Ecancermedicalscience. 2025 Jun 24;19:1931. doi: 10.3332/ecancer.2025.1931.\u003c/li\u003e\n \u003cli\u003eRoganovic J. Genetic predisposition to childhood cancer. World J Clin Pediatr. 2024 Sep 9;13(3):95010. doi: 10.5409/wjcp.v13.i3.95010. PMID: 39350900; PMCID: PMC11438921.\u003c/li\u003e\n \u003cli\u003eHampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL; Guideline Development Group, American College of Medical Genetics and Genomics Professional Practice and Guidelines Committee and National Society of Genetic Counselors Practice Guidelines Committee. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015 Jan;17(1):70-87. doi: 10.1038/gim.2014.147.\u003c/li\u003e\n \u003cli\u003eRadhakrishnan N, Singh S, Nath D, Madan J. GATA 2 Haploinsufficiency in Acute Myeloid Leukemia: Looking Beyond the Obvious. Indian Pediatr. 2020 Jun 15;57(6):570-571.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eEbens CL, MacMillan ML, Wagner JE. Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations. Expert Rev Hematol. 2017 Jan;10(1):81-97. doi: 10.1080/17474086.2016.1268048.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVan Hoyweghen S, Claes KBM, de Putter R, Wakefield CE, Van Poucke M, Van Schoors M et al. Family-Level Impact of Germline Genetic Testing in Childhood Cancer: A Multi Family Member Interview Analysis. Cancers (Basel). 2025 Feb 4;17(3):517. doi: 10.3390/cancers17030517.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eSchiffman JD, Geller JI, Mundt E, Means A, Means L, Means V. Update on pediatric cancer predisposition syndromes. Pediatr Blood Cancer. 2013 Aug;60(8):1247-52. doi: 10.1002/pbc.24555.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKaffai S, Angelova-Toshkin D, Weins AB, Ickinger S, Steinke-Lange V, Vollert K et al. Cancer predisposing syndromes in childhood and adolescence pose several challenges necessitating interdisciplinary care in dedicated programs. Front Pediatr. 2024 Jun 3;12:1410061. doi: 10.3389/fped.2024.1410061.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eByrjalsen A, Hansen TVO, Stoltze UK, Mehrjouy MM, Barnkob NM, Hjalgrim LL et al. Nationwide germline whole genome sequencing of 198 consecutive pediatric cancer patients reveals a high incidence of cancer prone syndromes. PLoS Genet. 2020 Dec 17;16(12):e1009231. doi: 10.1371/journal.pgen.1009231.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDangoni GD, Teixeira ACB, da Costa SS, Scliar MO, Carvalho LML, Silva LN et al. Germline mutations in cancer predisposition genes among pediatric patients with cancer and congenital anomalies. Pediatr Res. 2024 Apr;95(5):1346-1355. doi: 10.1038/s41390-023-03000-7.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eFuentes Bolanos NA, Padhye B, Daley M, Hunter J, Hetherington K, Warby M et al. Protocol for a comprehensive prospective cohort study of trio-based whole-genome sequencing for underlying cancer predisposition in paediatric and adolescent patients newly diagnosed with cancer: the PREDICT study. BMJ Open. 2023 May 30;13(5):e070082. doi: 10.1136/bmjopen-2022-070082.\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Cancer predisposition syndromes, Pediatric cancer, Phenotype-directed recognition, Genetic testing, Treatment modification","lastPublishedDoi":"10.21203/rs.3.rs-7723362/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7723362/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eCancer predisposition syndromes (CPS) are implicated in 8\u0026ndash;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.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe performed a retrospective cohort study at the Post Graduate Institute of Child Health (PGICH), Noida, from April 2017 to March 2025. Children aged 0\u0026ndash;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.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAmong 855 pediatric cancer patients, 14 (1.6%) had confirmed CPS, including Li\u0026ndash;Fraumeni, Ataxia-Telangiectasia, GATA2 deficiency, Dyskeratosis congenita, Denys\u0026ndash;Drash, WAGR, Sotos, SAMD9L-associated ataxia\u0026ndash;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.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003ePhenotype-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.\u003c/p\u003e","manuscriptTitle":"Outcomes of pediatric cancer predisposition syndromes identified by phenotype directed recognition: an Indian cohort","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-16 09:21:11","doi":"10.21203/rs.3.rs-7723362/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6df08f4f-4db9-4efd-87f6-aae10e834bf6","owner":[],"postedDate":"October 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-27T14:32:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-16 09:21:11","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7723362","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7723362","identity":"rs-7723362","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}