title: Humoral Immunodeficiency with Hypotonia, Feeding Difficulties, Enteropathy, and Mild Eczema Caused by a ClassicalFOXP3Mutation.
abstract: We describe here the case of a boy who presented with pulmonary infections, feeding difficulties due to velopharyngeal insufficiency and gastroesophageal reflux, myopathy, and hypotonia soon after birth. Later, he was also found to have an elevated immunoglobulin (Ig) E and mild eczema and was diagnosed with inflammatory bowel disease. Further immunological screening at the age of 7 years showed low B and NK cell numbers but normal CD4+and CD8+T cells and notably, normal numbers of CD4+regulatory T (Treg) cells. Serum IgG, IgA, and IgM were low to normal, but he had a deficient response to a pneumococcal polysaccharide vaccine and thus a humoral immunodeficiency. To our surprise, whole exome sequencing revealed a mutation inforkhead box protein 3 (FOXP3), encoding an essential transcription factor for the development and function of Treg cells. This classical mutation is associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Furtherin vitrostudies indeed showed defective function of Treg cells despite normal FOXP3 protein expression and nuclear localization. The boy underwent hematopoietic stem cell transplantation at 11 years of age and despite the temporary development of diabetes while on prednisone is now doing much better, IgE levels have declined, and his fatigue has improved. This case illustrates that a classical pathogenic mutation inFOXP3can lead to a clinical phenotype where the diagnosis of IPEX syndrome was never considered because of the lack of diabetes and the presence of only mild eczema, in addition to the normal Treg cell numbers and FOXP3 expression.
authors.affiliation: Department of Pediatric Hematology, Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Tuijnenburg
authors.affiliation: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, University of Amsterdam , Amsterdam , Netherlands.
authors.forename: Eloy
authors.initials: E
authors.lastname: Cuadrado
authors.affiliation: Department of Metabolic Disorders, Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam , Amsterdam , Netherlands.
authors.forename: Annet M
authors.initials: AM
authors.lastname: Bosch
authors.affiliation: Department of Pediatric Gastroenterology, Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam , Amsterdam , Netherlands.
authors.forename: Angelika
authors.initials: A
authors.lastname: Kindermann
authors.affiliation: Department of Pediatric Hematology, Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands; Department of Experimental Immunology, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Machiel H
authors.initials: MH
authors.lastname: Jansen
authors.affiliation: Department of Clinical Genetics, Academic Medical Center (AMC), University of Amsterdam , Amsterdam , Netherlands.
authors.forename: Marielle
authors.initials: M
authors.lastname: Alders
authors.affiliation: Department of Experimental Immunology, Academic Medical Center (AMC), University of Amsterdam , Amsterdam , Netherlands.
authors.forename: Ester M M
authors.initials: EM
authors.lastname: van Leeuwen
authors.affiliation: Department of Pediatric Hematology, Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands; Department of Clinical Genetics, Academic Medical Center (AMC), University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
keywords: FOXP3; IPEX syndrome; Treg; WES; autoimmunity; immunodeficiency