Immundeficiency 14A (autosomal dominant), Mutation in PIK3CD D81.4

Autosomal dominant immunodeficiency-14A (IMD14A), is a primary immunodeficiency characterized by the occurrence of recurrent sinopulmonary and other infections in early childhood. It is caused by a heterozygous mutation in the PIK3CD gene (602839) on chromosome 1p36.

Laboratory studies show defects in both the B- and T-cell populations, with Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infection not controlled. Patients' CD8+ T cells are shifted toward differentiation and senescence. Many patients develop lymphadenopathy, mucosal lymphoid aggregates, and/or elevated serum IgM levels. There is also increased susceptibility to B-cell lymphoma (Lucas CL et al 2014).

A biallelic mutation in the PIK3CD gene causes autosomal recessive IMD14B (619281).

Jou et al (2006) reported a Taiwanese boy of Chinese descent with primary B-cell immunodeficiency. He suffered from hypogammaglobulinemia and recurrent sinopulmonary infections since he was 7 months old. He was an only child, and there was no family history of similar disease.

Angulo et al (2013) identified 17 patients from 7 families with a primary immunodeficiency characterized by recurrent respiratory infections and progressive airway damage. While the immunologic phenotype was largely consistent among the patients, the clinical presentation and disease course were variable. All patients had recurrent respiratory and ear infections caused by H. influenzae and S. pneumoniae. Twelve of 16 (75%) had bronchiectasis or mosaic attenuation airway disease on CT. Ninety-one percent had low or intermittently low serum IgG2 levels and 82% had high or intermittently high serum IgM levels. All had low antibody levels to S. pneumoniae and 80% had low antibody levels to H. influenzae type B. 10 of 17 had recurrent infections (erysipelas, abscesses) and splenomegaly before onset. 4 of 17 (24%) suffered from infections caused by herpes viruses (HSV, CMV, VZV, and EBV). One patient was diagnosed with marginal zone lymphoma. 12 of 17 had a decrease in circulating T cells (total CD3+) and/or CD4+ and/or CD8+ T cells. 12 of 17 also had a decrease in circulating B cells (total CD19+). 14 of 16 patients (88%) had increased circulating transitional B cells (CD19+CD38+IgM+). Half of the patients had decreased circulating class-specific memory B cells (CD19+CD27+IgD-).

Lucas et al (2014) reported 9 patients from 7 unrelated families with IMD14A. All presented with recurrent sinopulmonary infections and EBV viremia in childhood, and most had chronic CMV infection. Two patients developed EBV-positive lymphoma. Other features included lymphadenopathy and mucosal lymphoid aggregates. Laboratory studies revealed decreased numbers of CD4+ T cells and increased numbers of CD8+ effector T cells. Mitogenic responses of T cells in vitro were low. There was a deficiency of CD27+ memory B cells and an accumulation of immature transitional B cells. Most patients had hypogammaglobulinemia and 4 had elevated IgM levels, suggesting impairment of class-distinct immunoglobulin isotypes.

Lucas et al (2014) identified three different heterozygous gain-of-function mutations in the PIK3CD gene (602839.0001-602839.0003). The mutations were found by whole-exome sequencing and targeted Sanger sequencing

Crank et al (2014) reported 3 patients from 2 unrelated families with IMD14A. Each had recurrent infections since childhood associated with elevated serum IgM levels but low levels of other antibodies. CD4+ T cells were decreased. All 3 patients had a history of lymphadenopathy and also developed non-EBV B-cell lymphomas. In 3 patients from 2 unrelated families with IMD14A manifesting as hyper-IgM and B-cell lymphoma, the authors identified 2 heterozygous "gain-of-function mutations!" in the PIK3CD gene (602839.0001 and 602839.0004).

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