Case Report: Congenital pulmonary airway malformation associated with a germline DICER1 splicing variant

Abstract

Background Congenital pulmonary airway malformation type IV (CPAM IV) and pleuropulmonary blastoma (PPB) exhibit significant radiographic and histopathological overlap, making their differentiation challenging. While DICER1 mutations are known to predispose individuals to the PPB spectrum, the molecular association between CPAM IV and early-stage PPB remains controversial. Case presentation We report a girl pathologically diagnosed with CPAM IV. Whole-exome sequencing (WES) of the lesion tissue identified a heterozygous splicing variant in the DICER1 gene (c.4206 + 1G > T). Sanger sequencing subsequently confirmed this variant to be germline, inherited from her asymptomatic father. Bioinformatic analysis predicted that this variant disrupts the highly conserved donor splice site of intron 22. Functional validation by RT-PCR demonstrated that the c.4206 + 1G > T variant results in exon fragment deletion. According to the ACMG/AMP guidelines, this variant was classified as likely pathogenic. Additionally, a somatic DICER1 hotspot mutation (c.5438A > G p.E1813G) was detected in the tissue, consistent with the two-hit tumorigenesis model. At the 22-month postoperative follow-up, although chest CT revealed a small cystic lucency with surrounding calcification, the patient remained clinically stable, without evidence of malignant progression or extrapulmonary involvement. Conclusion This article reports a case of CPAM IV carrying a pathogenic germline variant and a somatic hotspot mutation in the DICER1 gene. Our findings support the view that DICER1-associated CPAM IV may represent an early stage within the PPB disease spectrum. Given the incomplete penetrance of DICER1 syndrome and an approximately 50% risk of transmission to offspring, we propose that DICER1 genetic testing could be considered for selected pediatric patients diagnosed with CPAM IV, regardless of family history. This approach may aid in early and accurate differentiation, inform surgical management, and guide the development of appropriate long-term surveillance strategies.