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 in forkhead 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. Further in vitro studies 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 in FOXP3 can 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.
Highlights
A boy born at term of Caucasian non-consanguineous parents presented with respiratory insufficiency immediately after birth due to tracheomalacia and a diaphragmatic paresis
Polyendocrinopathy, enteropathy X-linked syndrome (OMIM304790) is an X-linked genetic disorder characterized by enteropathy, insulin-dependent type-1 autoimmune diabetes mellitus (IDDM1), and eczema
A previous comparative genomic hybridization (CGH) array did not yield any relevant finding, and we did not diagnose the patient until Whole exome sequencing (WES) was performed, which to our surprise resulted in the identification of a classical mutation in the forkhead box protein 3 (FOXP3) gene which fits the diagnosis of IPEX syndrome
Summary
A boy born at term of Caucasian non-consanguineous parents presented with respiratory insufficiency immediately after birth due to tracheomalacia and a diaphragmatic paresis. IDDM1 is common (>80%) and is diagnosed early, often within the first 1–3 months of life [6,7,8,9,10,11] It was found in 4% of neonatal permanent diabetes among males [2]. Other prominent symptoms due to profound immune dysregulation in males with IPEX syndrome include eczema/dermatitis (~65%), failure to thrive (~50%), thyroiditis (~30%), and recurrent infections (~20%). Autoimmune phenomena such as nephropathy, pneumonitis, hepatitis, vasculitis, arthritis, myositis, alopecia, and autoimmune cytopenias may be present [11, 12]. The severe watery diarrhea and life-threatening infections reduce the lifespan of these patients, and they usually die in the first years of life
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