Joel Gallagher1, Juan Adams1, Mary Hintermeyer1, Troy R Torgerson2, Jesus Lopez-Guisa2, Hans D Ochs2, Sara Szabo3, Mina Salib4, James Verbsky5, John Routes6. 1. Division of Asthma, Department of Pediatrics, Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, USA. 2. Department of Pediatrics, University of Washington School of Medicine and Seattle Children's Research Institute, Seattle, WA, USA. 3. Department of Pathology, Medical College of Wisconsin, Milwaukee, WI, USA. 4. Division of Pediatric Pulmonary and Sleep Medicine, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. 5. Division of Rheumatology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA. 6. Division of Asthma, Department of Pediatrics, Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, USA. jroutes@mcw.edu.
Abstract
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.
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.
Authors: S Lacroix-Desmazes; I Resnick; D Stahl; L Mouthon; T Espanol; J Levy; S V Kaveri; L Notarangelo; M Eibl; A Fischer; H Ochs; M D Kazatchkine Journal: J Immunol Date: 1999-05-01 Impact factor: 5.422
Authors: J Levy; T Espanol-Boren; C Thomas; A Fischer; P Tovo; P Bordigoni; I Resnick; A Fasth; M Baer; L Gomez; E A Sanders; M D Tabone; D Plantaz; A Etzioni; V Monafo; M Abinun; L Hammarstrom; T Abrahamsen; A Jones; A Finn; T Klemola; E DeVries; O Sanal; M C Peitsch; L D Notarangelo Journal: J Pediatr Date: 1997-07 Impact factor: 4.406
Authors: R Fuleihan; N Ramesh; R Loh; H Jabara; R S Rosen; T Chatila; S M Fu; I Stamenkovic; R S Geha Journal: Proc Natl Acad Sci U S A Date: 1993-03-15 Impact factor: 11.205
Authors: P Revy; T Muto; Y Levy; F Geissmann; A Plebani; O Sanal; N Catalan; M Forveille; R Dufourcq-Labelouse; A Gennery; I Tezcan; F Ersoy; H Kayserili; A G Ugazio; N Brousse; M Muramatsu; L D Notarangelo; K Kinoshita; T Honjo; A Fischer; A Durandy Journal: Cell Date: 2000-09-01 Impact factor: 41.582