Approaches to Thyroid Nodules in Paediatric Cancer Predisposition Syndromes

To summarise current evidence and practical management considerations for thyroid nodules in children and adolescents with cancer predisposition syndromes (CPS), focusing on follicular cell-derived nodules and non-medullary thyroid carcinoma (NMTC).

We synthesised current paediatric guideline recommendations and recent cohort, pathology, and molecular studies addressing CPS-associated nodular thyroid disease including PTEN hamartoma tumour syndrome, DICER1 syndrome, familial adenomatous polyposis, and related endocrine neoplasia syndromes.

Evidence quantifying syndrome-stratified malignancy risk among paediatric CPS patients presenting with nodules remains limited and is largely derived from mixed-age or retrospectively ascertained cohorts with surveillance and verification bias. High-resolution ultrasound (US) is central to risk stratification. US-guided fine-needle aspiration (FNA) is a cornerstone of evaluation yet frequently yields indeterminate results, particularly in follicular-patterned and encapsulated lesions (e.g. PHTS, DICER1), and sampling error is accentuated in polyclonal multinodular disease. Molecular testing may aid aetiologic clarification and, in selected settings, risk refinement. However, panels optimised for sporadic adult disease may have reduced "rule-out" utility in CPS. Biochemical assessment (TSH ± free thyroxine) complements imaging, while routine thyroglobulin is not recommended and thyroid autoantibodies should be viewed as adjunctive rather than directive markers in CPS.

Management of thyroid nodules in paediatric CPS is best approached through integrated, multidisciplinary risk assessment that combines expert ultrasound, context-aware cytology and molecular interpretation, and shared decision-making. This review proposes a CPS-adapted, multidisciplinary risk-assessment framework and highlights the need for prospective multicentre registries and harmonised protocols to define syndrome-specific outcomes and evidence-based thresholds for surveillance and intervention.