Lim et al. Allergy Asthma Clin Immunol (2019) 15:2 Allergy, Asthma & Clinical Immunology https://doi.org/10.1186/s13223-018-0317-y CASE REPORT Open Access IL2RG hypomorphic mutation: identifcation of a novel pathogenic mutation in exon 8 and a review of the literature Che Kang Lim1,2†, Hassan Abolhassani1,3†, Sofa K. Appelberg1, Mikael Sundin4,5 and Lennart Hammarström1,6* Abstract Background: Atypical X-linked severe combined immunodefciency (X-SCID) is a variant of cellular immunodefciency due to hypomorphic mutations in the interleukin 2 receptor gamma (IL2RG) gene. Due to a leaky clinical phenotype, diagnosis and appropriate treatment are challenging in these patients. low Case presentation: We report a 16-year-old patient with a ­T ­B+ ­NK+ cellular immunodefciency due to a novel nonsense mutation in exon 8 (p.R328X) of the IL2RG gene. Functional impairment of the IL2RG was confrmed by IL2-Janus kinase 3-signal transducer and activator of transcription signaling pathway investigation. In addition, the characteristics of the mutations previously described in 39 patients with an atypical phenotype were reviewed and analyzed from the literature. Conclusion: This is the frst report of an atypical X-SCID phenotype due to an exon 8 mutation in the IL2RG gene. The variability in the phenotypic spectrum of classic X-SCID associated gene highlights the necessity of multi-disciplinary cooperation vigilance for a more accurate diagnostic workup. Keywords: Interleukin 2 receptor gamma, Atypical severe combined immunodefciency, Hypomorphic mutations Background mutations lead to the production of a nonfunctional γC Interleukin 2 receptor gamma (IL2RG) is an important or prevent the protein from being produced, resulting in signaling component for IL2, IL4, IL7, IL9, IL15, and an arrest in lymphocyte development. IL21 [1]. Te gene encodes a common gamma chain (γC) In typical X-SCID, the disease is characterized by an that is essential in the ontogeny and function of immune almost complete absence of T and NK cells, and nearly cells, in particular T and NK cells. Mutations in the gene normal or high numbers of functionally defcient B cells result in X-linked severe combined immunodefciency ­(T–B+NK− phenotype). Infants with X-SCID are highly (X-SCID) [2]. susceptibility to bacterial and opportunistic infections. Approximately 200 unique mutations in the IL2RG Additional features include protracted diarrhea, rash, gene have been identifed to date in more than 320 fever, pneumonia and sepsis. Te disease is usually lethal patients with X-SCID. Missense and nonsense mutations within the 1st year of life unless reconstitution of the comprise around 48%, while insertion/deletion and immune system is carried out. splicing mutations account for 29% and 23%, respectively Diferent mutations in the IL2RG gene have also been according to the mutation database (Table 1). Te shown to be associated with less severe phenotypic variants. Several patients having hypomorphic IL2RG mutation with a milder form of combined *Correspondence: [email protected] immunodefciency, termed “atypical X-SCID”, have †Che Kang Lim and Hassan Abolhassani contributed equally to this work 1 Division of Clinical Immunology and Transfusion Medicine, Department been described previously [3–9]. Some patients might of Laboratory Medicine, Karolinska Institutet at Karolinska University be less susceptible to infections, the reduction of T Hospital Huddinge, 141 86, Stockholm, Sweden cells is relatively moderate and a normal lymphocyte Full list of author information is available at the end of the article © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lim et al. Allergy Asthma Clin Immunol (2019) 15:2 Page 2 of 8 Table 1 Summary of IL2 RG unique mutation* and comparison with hypomorphic mutations Parameters Total unique mutation Total observed Typical SCID Atypical SCID p value Exons Exon 1 12 15 13 2 0.6642 Exon 2 23 28 28 0 0.0574 Exon 3 47 72 68 4 0.1377 Exon 4 38 47 45 2 0.1998 Exon 5 38 106 87 19 0.0046** Exon 6 19 36 34 2 0.4018 Exon 7 14 41 32 9 0.0253** Exon 8 9 11 10 1a 1.0000 Othersb 3 6 6 0 1.0000 Type of mutation Missense 61 138 108 30 < 0.0001** Nonsense 36 73 70 3 0.0533 Insertion 15 21 20 1 0.7113 Deletion 43 52 50 2 0.1386 Splicing 35 62 59 3 0.1692 Othersc 13 16 16 0 0.3929 Total 202 362 323 39 *Summary based on NCBI Clinvar database (http://www.ncbi.nlm.nih.gov/clinv ar/), LOVD gene database [25] (http://www.ncbi.nlm.nih.gov/lovd/home.php?selec t_db IL2RG ) and OMIM database (http://www.omim.org/) = **Fisher’s exact test was used to analyze the association of exons or mutation type in the distribution of diferent clinical phenotypes (Typical SCID vs Atypical SCID) observed and p 0.05 was regarded as signifcant ≤ a Patient in the present study b Includes large deletions c Includes complex mutations, disruption of poly-A addition, variants within the frst codon proliferation assay may be observed. In addition, some Case presentation of these patients might not be detected by newborn Te patient, a 16 years old male of Kurdish ethnicity, screening programs for SCID [10]. was admitted to the pediatric lung and allergy Due to poorly defned clinical and immunological service of Astrid Lindgren Children’s Hospital at phenotypes, the diagnosis is usually established later Karolinska University Hospital due to chronic airway in childhood or even in adulthood, and the appropriate hypersensitivity and recurrent sinopulmonary treatment is thus delayed. infections. He is the third child of consanguineous Here we describe a novel nonsense mutation in the parents with a family history of several early deaths IL2RG gene consisting of a single nucleotide substitution due to lung failure on the maternal side (Fig. 1). He had at exon 8, in which a normal count of NK cells was found a normal vaccination history but a medical history of in peripheral blood. four hospitalizations due to enteroviral infection (at Fig. 1 a Family pedigree of the patient(s). b Sanger sequencing Lim et al. Allergy Asthma Clin Immunol (2019) 15:2 Page 3 of 8 age 16 months presenting with skin rash and diarrhea), In order to identify the molecular defect, whole exome chronic cough and fever (at age 18 months due to sequencing (WES) was performed. As the patient was Moraxella catarrhalis), otitis media, adenopathy and born in a consanguineous family and showed a family shingles (leading to tympanostomy at the age of 2), history of recurrent infections and early death on the pneumonia and an asthmatic reaction (at the age of 6). maternal side, an autosomal recessive or X-linked At the age of 8 years, a computed tomography was inheritances pattern was expected. Analysis of all performed due to a progression of his pulmonary variants were performed according to a standard pipeline disease which revealed bronchiectasis and a right described previously [12]; we identifed 2 homozygous middle lobe atelectasis. Immunologic profles were (autosomal) and 5 hemizygous (X-linked) variants which investigated as previously described [11]. Although were absent from dbSNP database and 1000 Genome a complete blood count and immunoglobulin levels database (Additional fle 1: Table S1). Comparing with were normal, lymphocyte populations were measured. the primary immunodefciency genes database, the only Low CD4+ and CD8+ T cell numbers, with normal variant consistent with the patient’s immunological numbers of B and NK cells were detected (Fig. 1 and phenotype was a novel nonsense mutation, p.R328X Table 2). Te patient had low specifc cell-mediated (c.982C>T) in exon 8 of the IL2RG gene (Fig. 1). Based immune response in activated whole blood using on this fnding, the therapeutic plan of the patient mitogens and antigen, such as pokeweed mitogen was changed and he became a potential candidate for (PWM), candida antigen etc. (Table 3). However, allogeneic hematopoietic stem cell transplantation. normal response to mitogens phytohemagglutinin Since the mutation causes a 42 amino acid truncation (PHA) and concanavalin A (Con A) by CD4+ T cells, of the intracellular domain of the γC, including of but not CD8+ T cells were detected. Te observation the Janus kinase 3 (JAK3) binding site (Fig. 2), we suggested that PHA and ConA stimulations for CD4+ investigated the expression of members of the IL2/ T cells may be diferent from CD8+ T cells. Despite JAK3 signaling pathway by western blot. Western blot his combined immunodefciency, the patient was (Fig. 3) demonstrated absence of IL2RG, suggesting free from opportunistic infections and his condition that the mutation caused degradation of the molecule. improved with temporary substitution of subcutaneous In addition, IL2 stimulation activated JAK3 and signal immunoglobulin and prophylactic antibiotics. transducer and activator of transcription signaling 5 Table 2 Immunologic characteristics of the patient with hypomorphic/atypical X-linked severe combined immunodefciency Parameters 2004a (5 years) 2010a, b (8 years) 2011c