X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis

J Clin Immunol. 2016 Aug;36(6):564-70. doi: 10.1007/s10875-016-0307-0. Epub 2016 Jun 20.


Purpose: X-linked hyper IgM syndrome (XHIGM) is a combined immunodeficiency caused by mutations in the CD40 ligand (CD40L) gene that typically results in decreased or absent CD40L expression on activated T cells, leading to defective class switching and somatic hypermutation. We describe an infant who presented with respiratory failure due to pulmonary alveolar proteinosis (PAP) with a novel damaging missense mutation in the CD40L gene.

Methods: Whole exome sequencing (WES) was used to identify a mutation in the CD40L gene. CD40L expression and function were determined by flow cytometry.

Results: A 5-month-old previously-healthy male presented with respiratory failure and diffuse pulmonary ground glass opacities on CT scan of the chest. Laboratory evaluation revealed an undetectable IgG, normal IgA, and elevated IgM. A bronchoalveolar lavage demonstrated pulmonary alveolar proteinosis. WES demonstrated a c.608G > C mutation in the CD40L gene resulting in p.R203T. Flow cytometry demonstrated normal CD40L expression on activated T cells but absent binding of CD40-Ig to CD40L on activated patient T cells.

Conclusions: The clinical manifestations of XHIGM in our patient had several unique features, including the presentation with PAP, normal serum IgA, and expression of non-functional CD40L on activated T cells. To our knowledge, this is the first published case of PAP in a patient with XHIGM.

Keywords: CD40 ligand (CD40L); Hyper IgM Syndrome; Macrophage dysfunction; Pulmonary alveolar proteinosis.

Publication types

  • Case Reports

MeSH terms

  • Biomarkers
  • CD40 Ligand / genetics
  • Diagnosis, Differential
  • Exome Sequencing
  • Humans
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / diagnosis*
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / genetics
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / immunology
  • Hyper-IgM Immunodeficiency Syndrome, Type 1 / therapy
  • Infant
  • Lymphocyte Activation / immunology
  • Lymphocyte Count
  • Lymphocyte Subsets / immunology
  • Lymphocyte Subsets / metabolism
  • Male
  • Mutation
  • Phenotype*
  • Pulmonary Alveolar Proteinosis / diagnosis*
  • Radiography, Thoracic
  • Tomography, X-Ray Computed


  • Biomarkers
  • CD40 Ligand