X-linked Hyper IgM Syndrome Presenting as Pulmonary Alveolar Proteinosis.
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.



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



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.



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.
Division of Asthma, Department of Pediatrics, Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
Joel
J
Gallagher
Division of Asthma, Department of Pediatrics, Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
Juan
J
Adams
Division of Asthma, Department of Pediatrics, Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
Mary
M
Hintermeyer
Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, Seattle, WA, USA.
Troy R
TR
Torgerson
Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, Seattle, WA, USA.
Jesus
J
Lopez-Guisa
Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, Seattle, WA, USA.
Hans D
HD
Ochs
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA.
Sara
S
Szabo
Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
Mina
M
Salib
Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
James
J
Verbsky
Division of Asthma, Department of Pediatrics, Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, USA. jroutes@mcw.edu.
John
J
Routes
D015415:Biomarkers; D023201:CD40 Ligand / Q000235:genetics; D003937:Diagnosis, Differential; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000628:therapy; D007223:Infant; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008297:Male; D009154:Mutation; D010641:Phenotype; D011649:Pulmonary Alveolar Proteinosis / Q000175:diagnosis*; D013902:Radiography, Thoracic; D014057:Tomography, X-Ray Computed; D000073359:Exome Sequencing
D015415:Biomarkers; D023201:CD40 Ligand
CD40 ligand (CD40L); Hyper IgM Syndrome; Macrophage dysfunction; Pulmonary alveolar proteinosis