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X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis. J Clin Immunol 2016 08;36(6):564-70



Pubmed ID




Scopus ID

2-s2.0-84975263201   8 Citations


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.608Ga??>a??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.

Author List

Gallagher J, Adams J, Hintermeyer M, Torgerson TR, Lopez-Guisa J, Ochs HD, Szabo S, Salib M, Verbsky J, Routes J


James Verbsky MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

CD40 Ligand
Diagnosis, Differential
Hyper-IgM Immunodeficiency Syndrome, Type 1
Lymphocyte Activation
Lymphocyte Count
Lymphocyte Subsets
Pulmonary Alveolar Proteinosis
Radiography, Thoracic
Tomography, X-Ray Computed
Whole Exome Sequencing