A Novel RAC2 Variant Presenting as Severe Combined Immunodeficiency
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LETTER TO EDITOR
A Novel RAC2 Variant Presenting as Severe Combined Immunodeficiency Heather Stern 1 & Agnes Donkó 2 & Teresa Shapiro 3 & Amy P. Hsu 4 & Thomas L. Leto 2 & Steven M. Holland 4 & Doerthe Adriana Andreae 1 Received: 24 June 2020 / Accepted: 5 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
To the editor, Severe combined immunodeficiency (SCID) is characterized by profound impairment of T and B cell development and function. About 5% of SCIDs do not have a known molecular diagnosis [1]. An absence of both neutrophils and T cells is highly suspicious for reticular dysgenesis (RD), a type of SCID, caused by an adenylate kinase 2 (AK2) mutation. Recently, patients with this clinical presentation but normal AK2 have been reported and were found to have missense mutations in the RAC2 gene [1]. Recent reports on RAC2 mutations have widened our understanding of the clinical presentations that range from the newborn period into adulthood. Reported patients present with varying degrees of lymphopenia and neutrophil dysfunction. To date, there are 17 reported patients with RAC2 mutations. Two patients were diagnosed in infancy with dominant loss-of-function mutations [2, 3], two siblings with homozygous null mutations [4], and 13 patients with activating mutations [1, 5–8]. Unique to this cohort are 3 patients who presented as newborns with a severe phenotype of frequent
* Doerthe Adriana Andreae [email protected] 1
Department of Pediatrics, Division of Allergy and Immunology, Penn State Children’s Hospital, 600 University Drive, Hershey, PA 17036, USA
2
Molecular Defenses Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
3
Department of Pediatrics, Division of Pediatric Hematology and Oncology, Penn State Children’s Hospital, 600 University Drive, Hershey, PA 17036, USA
4
Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology (LCIM), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD, USA
infections and profound leukopenia. These patients were found to have severe bone marrow involvement caused by a dominant RAC2 activating mutation, p.G12R [1]. We report a novel RAC2 mutation, p.Q61R, presenting as a severe immunodeficiency in the newborn period. This is the 18th reported patient with a RAC2 mutation. A 2-day-old male infant presented with temperature instability and hyperbilirubinemia and subsequently underwent a sepsis work-up at which time agranulocytosis and severe lymphopenia without associated anemia or thrombocytopenia were noted. Infection was ruled out. Further work-up revealed severe leukopenia involving both neutrophils and lymphocytes; severe T, B, and NK cell lymphopenia undetectable IgM; and decreased proportion of naive CD4+ T cells (Table 1). An initial chest x-ray showed the absence of a thymus but no other patholog
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