Novel RAD50 variants lead to Nijmegen Breakage Syndrome-like disorder and unplanned recombinant human growth hormone treatment response.

BACKGROUND: Human RAD50 gene mutations cause Nijmegen Breakage Syndrome-like disease, characterized by severe prenatal and postpartum growth retardation and microcephaly. It is very rare (less than 5 cases) with limited clinical data and treatment experience. METHODS: Clinical information was collected on a boy with microcephaly and severe growth restriction, including birth history, clinical features, unplanned response to recombinant human growth hormone treatment, and five-year follow-up after growth hormone discontinuation. The child underwent trio-based whole-exome sequencing and Sanger sequencing to validate the mutation. Constructed variant plasmids were used for in vitro functional experiments and Western blots to evaluate the potential impact of the variants. RESULTS: The boy was born at full term, with substantial growth retardation from infancy to early childhood. At the age of 4.5 years, the child with syndromic short stature was prescribed recombinant human growth hormone for height correction by junior resident physicians, with no genetic evaluation performed prior to treatment. After 5 years and 9 months of recombinant human growth hormone treatment, genetic analysis was done due to his evident microcephaly and distinctive facial features. Two novel variants (p.His1269Argfs2 and p.Ser844Asn) were identified in the RAD50 gene. Western blotting revealed the presence of the Flag-tag and EGFP in RAD50-wt, but not in RAD50-mut (p.His1269Argfs2), indicating the frameshift mutation may markedly impair RAD50 protein expression or stability. Although recombinant human growth hormone significantly improved the patient's growth rate (from -3.35 SD to -1.28 SD), these variants may serve as a potential molecular basis for Nijmegen Breakage Syndrome-like disease and could also increase the risk of tumor formation. Treatment with recombinant human growth hormone was discontinued when the patient was 10 years and 3 months old. A five-year follow-up showed no evidence of a tumor was observed; The 15-year-old patient's height ceased to increase and remained at 151.5 cm. CONCLUSION: In the current study, we identified and characterized a patient with two RAD50 mutations. This report expands the clinical and genetic scope of RAD50 mutations. For the first time, it describes the response to unplanned recombinant human growth hormone therapy and the risk of long-term tumors. This report is intended to raise clinical awareness of the risk-benefit balance of recombinant human growth hormone therapy for syndromic short stature.