Interstitial lung disease in infancy: an unusual presentation of CD40 ligand deficiency

Introduction: Childhood interstitial lung disease (chILD) syndrome describes findings of respiratory symptoms and diffuse abnormalities on lung imaging. Immunodeficiency and immune dysregulation are increasingly recognized as potential causes of these clinical findings. Patients with CD40 ligand (CD40L) deficiency typically present with sinopulmonary and opportunistic infections secondary to impairments in both humoral and cellular immunity. chILD syndrome has not previously been reported as a presenting feature of this disease. Objectives: We describe a patient with CD40L deficiency, caused by a novel mutation in CD40LG (c.464 T>A, p.Leu155Gln), who presented in infancy with chILD syndrome and lung biopsy findings of chronic interstitial pneumonitis and patchy pulmonary glycogenosis. Methods: A left lingula wedge lung biopsy was fixed with formalin and stained for analysis. Whole blood samples from the patient and parents were sent for whole exome sequencing. Flow cytometry to assess CD40L expression on activated CD3+CD8− T cells was performed. Results: Lung biopsy demonstrated lymphoid aggregates and patchy pulmonary interstitial glycogenosis. Whole exome sequencing revealed maternal inheritance of a novel mutation in CD40LG (c.464 T>A, p.Leu155Gln). Functional studies demonstrated absent CD40L expression on activated CD3+CD8− T cells. Conclusion: This novel mutation in CD40LG, c.464 T>A, is disease-causing based on the patient’s clinical features and absent CD40L expression. This is the first report of CD40L deficiency presenting as chILD syndrome. Statement of novelty: The missense mutation observed in our patient (c.464 T>A, p.Leu155Gln), is novel; CD40L deficiency secondary to a different missense variant at the same amino acid position has been described (c.464 T>P, p.Leu155Pro). To our knowledge, this is the first report of CD40L deficiency with an initial clinical picture consistent with interstitial lung disease.