Immunodeficiency 23

A number sign (#) is used with this entry because immunodeficiency-23 (IMD23) is caused by homozygous or compound heterozygous mutation in the PGM3 gene (172100) on chromosome 6q14.

Description

IMD23 is an autosomal recessive primary immunodeficiency syndrome characterized by recurrent respiratory and skin infections beginning in early childhood. Laboratory studies are notable for increased serum IgE. Affected individuals also show developmental delay or cognitive impairment of varying severity (summary by Zhang et al., 2014).

Clinical Features

Hay et al. (2004) reported a family in which 5 sibs, including a pair of identical male twins, had an immune disorder and nonprogressive neurologic abnormalities. The parents were unrelated. The patients presented with severe dermatitis in infancy or early childhood, as well as with severe recurrent upper and lower respiratory infections. All also had low-average IQ (70-80), oral motor deficits, dysarthria, and cortical myoclonus. Four had ataxia and/or sensory impairment with hyporeflexia of the ankles. Other features included high-arched palate, unilateral narrow palpebral fissures, conductive hearing loss, and cutaneous vasculitis. Laboratory studies showed increased serum IgE, IgA, and IgG. Hay et al. (2004) proposed the designation 'immunodeficiency-vasculitis-myoclonus syndrome' (IVMS).

Zhang et al. (2014) presented a follow-up of the family reported by Hay et al. (2004) and also reported 3 affected males from a consanguineous Egyptian family. Patients had atopic dermatitis and atopic diatheses, including asthma and allergies, associated with increased serum IgE. Skin infections were a prominent feature. Some patients had Epstein-Barr virus viremia, which was associated with lymphoma in 2 patients. Autoimmune and immune-mediated disease was common, manifest as cutaneous leukocytoclastic vasculitis, membranoproliferative glomerulonephritis, and autoimmune neutropenia/hemolytic anemia. Five of 7 patients had rheumatoid factor. Neurologic features included developmental delay, ataxia, dysarthria, sensorineural hearing loss, and cortical myoclonus. One patient had seizures. Laboratory studies showed neutropenia and leukopenia, with particularly decreased levels of CD8 (see 186910)-positive T cells and CD27 (TNFRSF7; 186711) memory B cells, as well as increased IgE, IgG, and IgA. In vitro studies showed that stimulation of patient CD4 (186940)-positive T cells resulted in increased levels of certain cytokines, including IL4 (147780), IL5 (147850), IL13 (147683), and IL17 (IL17A; 603149), compared with controls. Stimulation of peripheral blood cells resulted in increased proliferation of CD4-positive and CD8-positive T cells compared with controls. There was also evidence of a glycosylation defect, with decreased UDP-GalNAc and hyposialylation of O-linked serum glycans. However, glycosylation of serum transferrin (TF; 190000) was normal.

Sassi et al. (2014) reported 9 patients from 4 consanguineous families with IMD23. One of the families had previously been reported by Ayed et al. (1987). The patients presented in the first year of life with recurrent respiratory infections and dermatitis, often with abscesses. Fungal, viral, and bacterial infections were present. Most patients had failure to thrive as well as delayed psychomotor development, and some had dysmorphic facial features. Laboratory studies showed increased serum IgE and eosinophils and a decreased CD4-positive to CD8-positive T-cell ratio. T-cell differentiation and proliferation were impaired in vivo.

Stray-Pedersen et al. (2014) reported 3 unrelated children of different ethnicities with IMD23. All patients presented soon after birth with recurrent infections associated with a severe combined immunodeficiency (SCID) phenotype with low numbers of B and T cells, neutropenia, and normal NK cells. Only 1 patient had increased serum IgE levels. Other features included eczema and gastroesophageal reflux. None of the patients had glycosylation defects of serum transferrin or APOC3 (107720). Two patients received successful hematopoietic stem cell transplants; the third died before transplant. In addition to immunodeficiency, 2 patients had skeletal anomalies resembling Desbuquois dysplasia (DBQD1; 251450), including short stature, brachydactyly, dysmorphic facial features, and intellectual disability. Stray-Pedersen et al. (2014) proposed designating this variant DBQD type 3.

Inheritance

The transmission pattern of IMD23 in the families reported by Zhang et al. (2014) and Sassi et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In affected members of the family reported by Hay et al. (2004), Zhang et al. (2014) identified compound heterozygous mutations in the PGM3 gene (172100.0001 and 172100.0002). Three Egyptian males with the disorder were homozygous for another pathogenic mutation (172100.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families.

In 9 affected members of 4 consanguineous families of North African origin with IMD23, Sassi et al. (2014) identified 3 different homozygous mutations in the PGM3 gene (172100.0004-172100.0006). The mutations in the first 2 families were found by homozygosity mapping and candidate gene sequencing. The second 2 probands were found by direct sequencing of the PGM3 gene in 32 unrelated patients with a similar phenotype. Patient neutrophils showed decreased levels of complex tri- and tetra-antennary N-glycans and an accumulation of bi-antennary N-glycans compared with controls, indicating decreased PGM3 function and impaired glycosylation.

In 3 unrelated patients with IMD23, Stray-Pedersen et al. (2014) identified biallelic mutations in the PGM3 gene (172100.0007-172100.0010). In vitro functional expression assays in E. coli showed that all of the mutations resulted in reduced phosphate-group transfer from GlcNAc-6-P to GlcNAc-1-P, consistent with a loss of PGM3 enzyme function.