Case report end-stage cystic fibrosis with fatal outcome in two siblings from a Chinese family: a 15-year diagnostic odyssey.

BACKGROUND: Cystic fibrosis (CF) remains severely underdiagnosed in China due to the absence of newborn screening, limited sweat chloride testing capacity, and low clinical awareness. Diagnostic delay results in irreversible lung damage and precludes timely genotype-directed therapy. CASE PRESENTATION: A 16-year-old Chinese boy presented with end-stage CF lung disease after a 15-year diagnostic odyssey. He had recurrent lower respiratory tract infections since infancy, progressive bronchiectasis, CF-associated liver disease with portal hypertension, and chronic Pseudomonas aeruginosa/Burkholderia cepacia co-infection. Sweat chloride was 102 mmol/L. Whole-exome sequencing identified compound heterozygous CFTR variants: c.579 + 1_579+2insACAT (a canonical splice-site insertion, predicted null) inherited from the father, and c.1766 + 5G>T (CF-causing in CFTR2, near-complete exon 13 skipping) inherited from the mother. Fecal elastase was preserved (525 μg/g), confirming pancreatic sufficiency; this finding is consistent with but does not prove residual CFTR function. CFTR modulator therapy was unavailable. He died of cardiopulmonary failure approximately 1 year after diagnosis while awaiting lung transplantation. Cascade testing confirmed the same genotype in his 11-year-old sister (sweat chloride 111 mmol/L), who also died of cardiopulmonary failure within months. Their eldest brother had died at age two of severe pneumonia without CF being suspected. CONCLUSION: This family illustrates the convergence of three pharmacologically relevant barriers in underserved CF populations: prolonged diagnostic delay precluding specialized care, uncharacterized population-specific variants lacking theratyping data, and inaccessibility of CFTR modulators. The preserved pancreatic function despite end-stage lung disease is compatible with residual CFTR activity, but the contribution of either allele and potential responsiveness to CFTR modulators require transcript, protein, and functional characterization. This underscores the urgent need for systematic theratyping of under-characterized CFTR variants reported in East Asian populations. Expansion of sweat chloride testing, clinician education, and international collaborative theratyping efforts are needed to break this cycle.