A number sign (#) is used with this entry because of evidence that immunodeficiency-36 (IMD36) is caused by heterozygous mutation in the PIK3R1 gene (171833) on chromosome 5q13.Description
IMD36 is a primary immunodeficiency with a highly heterogeneous clinical phenotype, characterized primarily by recurrent respiratory tract infections, lymphoproliferation, and antibody deficiency. Other features include growth retardation, mild neurodevelopmental delay, and autoimmunity. The major complication is development of B-cell lymphoma (Elkaim et al., 2016).Clinical Features
Deau et al. (2014) reported 4 patients from 3 unrelated families with a primary immunodeficiency. A mother and son were affected in 1 of the families. Two patients presented with recurrent respiratory infections at age 6 months, a third at age 2 years, and the fourth at age 13 years. All had bacterial infections, but only 1 patient had chronic viremia with Epstein-Barr virus (EBV) and cytomegalovirus (CMV). None had features of allergy, autoimmunity, splenomegaly, or lymphadenopathy. Lymphocyte counts were in the normal range, but there were decreased numbers of naive CD4+ and CD8+ T cells. Two patients had a deficiency of memory B cells. One patient had almost complete absence of switched memory B cells, whereas the other 3 patients had increased transitional B cells. All had impaired B-cell function with hypogammaglobulinemia associated with increased IgM. T-cell blasts displayed enhanced activation-induced cell death, and B cells showed weak proliferation in response to activation via the B-cell receptor and TLR9 (605474). Three patients were on Ig replacement therapy.
Lucas et al. (2014) studied 4 patients from 3 unrelated families with immunodeficiency, including a 32-year-old Turkish woman (family A), a Caucasian American 43-year-old mother and her 17-year-old son (family B), and a 5-year-old Chinese boy (family C). The patients showed a similar phenotype involving recurrent sinopulmonary infections, poor production of class-switched antibodies, and lymphoproliferation, with splenomegaly present in 3 of the 4 patients. All had low serum IgG and IgA levels; however, IgM was elevated in the Turkish woman, normal in the Caucasian American boy, and low in the Chinese boy. Additional features included the development of arthritis and inflammatory bowel disease in adulthood in the Turkish woman, and severe juvenile arthritis in the Chinese boy. All required intravenous immunoglobulin supplementation and had a low CD4/CD8 ratio due to expansion of CD8 T cells. The authors noted that the clinical features of immunodeficiency, lymphoproliferation, poor immunoglobulin responses, and expansion of CD8 T cells with susceptibility to inflammatory disease were consistent with immunodeficiency-14 (IMD14; 615513).
Lougaris et al. (2015) reported 4 unrelated children from Albania, Italy, and Sweden, with immunodeficiency and mutations in the PIK3R1 gene. All had hypogammaglobulinemia with elevated serum IgM levels, and all exhibited lymphoproliferation, with 2 developing severe tonsillar hypertrophy and 1 having splenomegaly; 3 of the 4 patients also showed poor growth. In addition, 2 exhibited an abnormal expansion of immature B cells with a concomitant reduction of mature B cells, which the authors stated was a pattern not previously reported in PIK3R1-mutated patients.
Elkaim et al. (2016) retrospectively analyzed 36 patients with PIK3R1-associated immunodeficiency, including the 8 patients previously reported by Deau et al. (2014) and Lucas et al. (2014). The most common features were recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%), including adenopathy (75%), splenomegaly (43%), and upper respiratory tract lymphoid hyperplasia (48%). Growth retardation was frequently observed (45%). Other complications were mild neurodevelopmental delay (31%), malignant diseases (28%) consisting mostly of B-cell lymphomas, autoimmunity (17%), bronchiectasis (18%), and chronic diarrhea (24%). The predominant immunologic features included decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells. The majority of patients (89%) received immunoglobulin replacement. Five patients died, including 4 from lymphoma. Elkaim et al. (2016) designated the immunodeficiency disorder 'activated phosphoinositide 3-kinase delta syndrome-2' (APDS2) or PASLI-R1; see IMD14, 615513.Inheritance
The transmission pattern of IMD36 in the families reported by Deau et al. (2014) was consistent with autosomal dominant inheritance.Molecular Genetics
In 4 patients from 3 families with a primary immunodeficiency, Deau et al. (2014) identified heterozygous mutations in the PIK3R1 gene (171833.0007 and 171833.0008). The mutations, which were found by whole-exome sequencing, affected the same nucleotide and resulted in the same splicing defect. The mutations were predicted to cause a loss of p85-mediated inhibition of p110 activity, and patient lymphocytes showed increased PI3K activity and enhanced phosphorylation of AKT (see 164730), consistent with a gain of function. The phenotype was similar to that of patients with IMD14 (615513) carrying gain-of-function mutations in the PIK3CD gene (602839). The findings suggested that PI3K activity is tightly regulated in T and B lymphocytes and that various defects in the PI3K-triggered pathway can cause primary immunodeficiencies.
In 4 patients from 3 families with immunodeficiency, who exhibited clinical features consistent with immunodeficiency-14 but who were negative for mutation in the PIK3CD gene (602839), Lucas et al. (2014) performed whole-exome sequencing and identified heterozygosity for point mutations at the same splice donor site in the PIK3R1 gene that was reported by Deau et al. (2014): c.1425+1G-C (171833.0008) in families A and B, and c.1425+1G-A (171833.0009) in the proband from family C. Analysis of patient CD8 T cells in families A and B showed expansion, terminal differentiation, and senescence similar to that seen in PIK3CD-associated immunodeficiency.
In a 9-month-old Albanian girl with pneumonia, poor growth, progressive lymphadenopathy, and a hyper-IgM-like phenotype (see HIGM1, 308230) including hypogammaglobulinemia with elevated IgM levels and reduced switched memory B cells, who was negative for mutation in HIGM-associated genes, Lougaris et al. (2015) performed whole-exome sequencing and identified the previously reported PIK3R1 c.1425+1G-A splice site mutation. Screening of the PIK3R1 gene in 102 additional patients with an HIGM-like phenotype but no mutations in known causative genes revealed de novo splice site mutations in 3 more patients, 2 with the same c.1425+1G-A mutation and 1 with the c.1425+1G-T mutation (171833.0007). Lougaris et al. (2015) reviewed the 12 reported patients with PIK3R1 mutations at c.1425+1 and noted that elevated IgM serum levels and recurrent respiratory infections were common features, whereas lymph node enlargement and tonsillary hypertrophy were less consistent. Poor growth was present in 6 of the 8 patients in whom the parameter was assessed, suggesting that it might be a clinically relevant feature in this disorder.
By next-generation sequencing in a set of 50 patients with immunodeficiency, Petrovski et al. (2016) identified 4 unrelated patients who carried the c.1425+1G-A mutation in the PIK3R1 gene. All 4 had been diagnosed clinically with hyper-IGM syndrome and had low IgG and IgA with elevated IgM levels, lymphadenopathy, and short stature. One of the patients exhibited features of SHORT syndrome (269880), including facial dysmorphism, delayed eruption of secondary teeth, conductive hearing loss, joint laxity, lack of subcutaneous fat, and a learning disability. Further analysis did not reveal any additional mutations in that patient; the authors noted that no results of immune studies had been reported for SHORT syndrome patients.
Elkaim et al. (2016) studied 36 patients with PIK3R1-associated immunodeficiency, including 8 previously reported patients (Deau et al., 2014; Lucas et al., 2014), and noted that the previously described substitutions at c.1425+1 were detected in 84% of patients, with G-A identified in 42%, G-C in 29%, and G-T in 13%. In addition, 4 patients had mutations involving c.1425+2, including 2 with a T-A change (171833.0010), 1 with a T-G mutation (171833.0011), and 1 with a TG deletion (171833.0012). Another patient had a G-C substitution at the -1 position of the splice acceptor site of exon 11 (171833.0013). Analysis of patient mRNA demonstrated that all of the mutations cause skipping of exon 11 (coding exon 10).