A number sign (#) is used with this entry because of evidence that autosomal recessive immunodeficiency-14B (IMD14B) is caused by homozygous mutation in the PIK3CD gene (602839) on chromosome 1p36.

Heterozygous mutation in the PIK3CD gene causes autosomal dominant IMD14A (615513).

Autosomal recessive primary immunodeficiency-14B (IMD14B) is characterized by onset of recurrent infections in early childhood. Most patients have respiratory infections, but some may develop inflammatory bowel disease or osteomyelitis. Laboratory studies tend to show hypogammaglobulinemia and decreased levels of B cells. Although NK cell and T cell numbers are normal, there may be evidence of impaired immune-mediated cytotoxicity and defective T-cell function (summary by Sogkas et al., 2018 and Cohen et al., 2019).

Sogkas et al. (2018) reported 2 brothers, born of consanguineous Pakistani parents, with IMD14B. The older brother presented at age 2 years with recurrent sinopulmonary infections associated with hypogammaglobulinemia. He later developed chronic diarrhea with gastrointestinal inflammation and died of sepsis at 13 years of age. His younger brother presented with osteomyelitis at age 2 months. At age 8, he had inflammatory colitis diagnosed as Crohn disease, and at 12, he developed recurrent respiratory tract infections. Laboratory studies in both patients showed hypogammaglobulinemia with decreased B-cell counts. T-cell and NK-cell counts were normal, but NK-cell function was decreased and there was impaired cytotoxic immunity.

Cohen et al. (2019) reported a boy, born of consanguineous Pakistani parents, with IMD14B. He tolerated vaccination in early childhood and was well until age 6 years when he presented with chronic diarrhea associated with colitis and polyarticular arthritis. He later developed features of inflammatory bowel disease. Laboratory studies showed leukocytosis, neutrophilia, monocytosis, and thrombocytosis. Serum IgG and IgA were decreased. Calcium flux in response to anti-CD3 crosslinking on patient T cells was decreased, although T-cell proliferative response was normal. The patient died at age 14 years of severe pneumonia and sepsis. Family history revealed a similarly affected brother who died of sepsis at 6 months of age.

The transmission pattern of IMD14B in the family reported by Sogkas et al. (2018) was consistent with autosomal recessive inheritance.

In 2 brothers, born of consanguineous Pakistani parents, with IMD14B, Sogkas et al. (2018) identified a homozygous frameshift mutation in the PIK3CD gene (602839.0006). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient T cells showed impaired AKT (164730) phosphorylation after stimulation with an anti-CD3 antibody, suggesting a loss of PIK3CD function.

In a boy, born of consanguineous Pakistani parents, with IMD14B, Cohen et al. (2019) identified a homozygous frameshift mutation in the PIK3CD gene (602839.0007). The mutation, which was found by whole-exome sequencing, was predicted to disrupt the ATP binding site in the catalytic domain. The mutation was not found in the 1000 Genomes Project, ExAC, or Exome Sequencing Project databases. In vitro functional expression studies in HEK293T cells transfected with the mutation showed that the truncated protein was expressed, but lacked kinase activity, consistent with a loss of function. Patient T cells showed decreased calcium flux after CD3 stimulation compared to controls, suggesting impaired cellular immunity. Noting that dominant gain-of-function mutations in the PIK3CD gene can cause IMD14A, both Sogkas et al. (2018) and Cohen et al. (2019) concluded that precise regulation of PIK3CD activity is required for proper immune function.