Variant PIK3R1 Hypermorphic Mutation and Clinical Phenotypes in a Family with Short Statures, Mild Immunodeficiency and Lymphoma

Abstract

Heterozygous point mutations in the GT splice donor consensus sequence of exon 11 of the PIK3R1 gene (coding for p85α, p55α, and p50α regulatory subunits of PI3K) lead to exon skipping and thereby to an aberrant protein that leaves PI3K hyperactivated. Several patients with this particular variant of PI3 kinase delta syndrome (APDS) suffering from sinopulmonary infections and lymphoproliferation have been described. (Whole exome) sequencing, evaluation of cellular and clinical phenotypes. We here report a family with a new heterozygous mutation in this gene, a 9 bp deletion (c.1418_1425+1del) that, however, leads to the same skipping of exon 11. The clinical phenotypes of their members partly overlap features of patients of other reports. We found a new mutation in PIK3R1 and show how broad the resulting clinical spectrum can be.

Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency

“…The clinical spectrum of APDS1, APDS2, and APDS-L is largely overlapping and consists mostly of immunological abnormalities (Table 1 ), although growth retardation has also been reported APDS2 and, less frequently, APDS1 ( 10 , 12 – 14 , 17 , 21 , 24 , 26 , 27 , 29 – 33 , 37 ). Recurrent upper and lower respiratory tract infections are the most common clinical features affecting 98% of APDS patients and often resulting in progressive airway damage.…”

“…Because of the recurrent sinopulmonary infections, antibiotics are often given prophylactically, and immunoglobulin replacement is commonly used, although recurrent infections have been reported despite this treatment ( 15 , 20 , 26 ). Chemo- and/or radiotherapy are often used for lymphomas, a major cause of death in APDS patients (about 62% of deaths) ( 11 , 14 , 17 – 19 , 24 , 30 , 31 , 37 ). Beyond the treatment of these specific symptoms, hematopoietic stem-cell transplantation has proven beneficial for restoration of immune function in 67% of APDS patients receiving this therapy, which requires availability of an HLA-compatible donor and is particularly risky in the setting of EBV infection ( 10 , 14 , 15 , 18 , 24 , 31 , 34 , 36 ).…”

Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome

“…In one E1021K APDS1 kindred ( 26 ) in which three individual affected family members exhibited a mild, intermediate, and severe spectrum respiratory infections, there seemed to be a broad association of severer phenotype with more suppressed IgG and lower class-switched memory B cells. However, this correlation was not observed in other affected families ( 2 , 27 ) and does not seem to be recapitulated in larger cohort studies. To date, no circulating biomarker has been reliably linked to respiratory phenotypes, but larger longitudinal studies may enable such correlation to be identified in future.…”

“…While occasional case reports have highlighted significant tonsillar hypertrophy in APDS1 ( 6 , 24 ), it seems to be noted more frequently, and to be more severe in APDS2 [e.g., Ref. ( 12 , 14 , 27 , 45 )]. Tonsillar biopsies from two APDS2 patients demonstrated small B cell follicles rather than the atypical follicular hyperplasia reported in biopsies of lymph nodes/mucosal follicular hyperplasia from APDS1 ( 7 , 20 ) and APDS2 ( 14 ), but other features such as reduced mantle layers and infiltration with PD1 +ve T cells were concordant, suggesting a related immunopathogenesis.…”

“…There are little available data on the efficacy of these interventions; Coulter et al ( 20 ) stated that there was “reported benefit in most cases,” with none of the other case series specifically addressing this issue. Case reports have suggested that some patients exhibit marked ( 14 , 23 , 30 , 36 ) or partial improvements ( 27 ), but others have flagged patients who had significant ongoing respiratory sepsis in the face of these treatments ( 15 , 18 ). Of note, 42/68 patients currently listed on the APDS registry are currently receiving immunoglobulin replacement (see text footnote 1), with an overall reported decrease in respiratory infection and no withdrawals from therapy.…”