PURPOSE OF THE STUDY.
The goal of this study was to investigate the clinical, laboratory, and molecular characteristics of patients with similar findings, including immunodeficiency, significant atopy, immune dysregulation, and neurocognitive developmental defects.
Eight patients from 2 different families underwent clinical, laboratory, and genetic evaluation.
Patients were assessed clinically followed by an immunologic evaluation and whole-exome sequencing, directed Sanger sequencing, and specific ex vivo biochemical studies.
All patients had a history of significant atopic dermatitis as well as other allergic findings, including asthma, food allergy, and/or environmental allergy. Staphylococcal soft tissue infections, recurrent sinopulmonary infections, low-level Epstein-Barr virus viremia, and other viral infections were characteristic of these patients. In addition, autoimmunity was found in the majority of the patients, primarily cutaneous leukocytoclastic vasculitis or membranoproliferative glomerulonephritis. Finally, neurologic impairment that developed early in life was present in all patients. Laboratory evaluation revealed elevated IgE levels, whereas IgG, IgA, IgM, and specific antibody production to vaccines were found to be normal. The patients also demonstrated varied degrees of cytopenias. Whole-exome evaluation in the affected patients from the first family revealed a large number of single nucleotide variants that after extensive software filtering yielded 1 candidate, an autosomal recessive defect in the gene encoding phosphoglucomutase 3 (PGM3). Application of the same strategy in the second family also yielded an autosomal recessive defect in the affected patients involving the same gene, and in both families, Sanger sequencing confirmed these results. The genetic results were followed by biochemical studies that demonstrated variable defects in O- and N-linked glycosylation, thus establishing that these genetic changes yielded functional abnormalities in glycosylation.
Patients with autosomal recessive defects in PGM3 have an immunologic disorder that includes severe atopic disease, autoimmunity, and intellectual disability as well as increased susceptibility to infection.
This report adds to a growing list of immune defects associated with immune dysregulation that present clinically with elevated IgE levels, atopic disease, and autoimmunity together with increased susceptibility to infection. The link between immune dysregulation and atopy is providing valuable new information regarding the underlying immunologic processes involved in the development of allergic disease. In addition, defects in glycosylation have typically been associated with neurologic disease but generally have not been linked with immune disorders. Conversely, ∼50% of the proteins in humans are glycosylated, and there is an evolving appreciation that protein glycosylation plays a role in immunologic development and response. This newly defined disorder provides support for this role, and an additional report of immunologic changes in the setting of genetic defects of glycosylation (Sadat MA, Moir S, Chun TW, et al. Glycosylation, hypogammaglobulinemia, and resistance to viral infections. N Engl J Med. 2014;370:1615–1625) strengthens this link.
- Copyright © 2014 by the American Academy of Pediatrics