一例新生儿筛查结果正常后偶然诊断的经典型同型半胱氨酸尿症

Classical homocystinuria (HCY) due to cystathionine beta-synthase (CBS) deficiency is included in many newborn screening programs, which traditionally use dried blood spot (DBS) methionine as the primary biomarker. However, some patients have normal or only mildly elevated methionine in the neonatal period, leading to false-negative results. We report a four-month-old male infant referred for sagittal craniosynostosis, whose metabolic evaluation revealed markedly elevated plasma methionine and total homocysteine concentrations. Genetic analysis identified a homozygous, pathogenic variant (c.1007G>A) in the CBS gene, confirming HCY. On retrospective review, the DBS sample had been collected at 48 h of life, and methionine was within the reference range. Consequently, the screening algorithm had not triggered second-tier total homocysteine testing. Sanger sequencing of the original DBS sample confirmed the same homozygous CBS variant, ruling out sample swap and establishing the case as a true false-negative result. Treatment with pyridoxine and folic acid rapidly normalized biochemical parameters, consistent with a pyridoxine-responsive phenotype. This case illustrates that normal neonatal methionine does not exclude CBS deficiency and that genomic newborn screening approaches could detect this disease more reliably.