Two Monogenetic Disorders, Activated PI3-Kinase-δ Syndrome 2 and Smith–Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling

Abstract

Activated PI3-kinase-δ syndrome 2 (APDS2) is caused by autosomal dominant mutations in the PIK3R1 gene encoding the p85α, p55α, and p50α regulatory subunits. Most diagnosed APDS2 patients carry mutations affecting either the splice donor or splice acceptor sites of exon 11 of the PIK3R1 gene responsible for an alternative splice product and a shortened protein. The clinical presentation of APDS2 patients is highly variable, ranging from mild to profound combined immunodeficiency features as massive lymphoproliferation, increased susceptibility to bacterial and viral infections, bronchiectasis, autoimmune manifestations, and occurrence of cancer. Non-immunological features such as growth retardation and neurodevelopmental delay have been reported for APDS2 patients. Here, we describe a patient suffering from an APDS2 associated with a Smith–Magenis syndrome (SMS), a complex genetic disorder affecting, among others, neurological manifestations and review the literature describing neurodevelopmental impacts in APDS2 and other PIDs/monogenetic disorders associated with dysregulated PI3K signaling.

How can same-gene mutations promote both cancer and developmental disorders?

“…PI3Kδ isoform mostly expresses in lymphocytes. APDS can also promote T cell senescence and a rare primary immunodeficiency disorder ( 120 ). PIK3CD mutations elevate basal activity through enhanced membrane binding of p110δ.…”

Inborn errors of immunity present with neuropsychiatric symptoms overlapping with autistic behavioral symptoms

“…In addition to symptoms associated with immunodeficiency, APDS patients also manifest autoimmune conditions typically after the first decade of life: cytopenia and glomerulonephritis are common, along with an increase in the risk of malignant complications [88] . Since both APDS1/APDS2 are inherited in an AD pattern, despite the recent identification of APDS, the frequency of this condition is expected to be fairly high; a total of 243 APDS patients were reported in the systemic review published in 2020 [89] . We already follow two APDS patients in our clinic and it is not unusual for these patients to be found in other immunology clinics.…”

“…PI3Kδ coded by PIK3CD is upregulated in developing brains, and developmental delay and ASD-like behavioral symptoms have been described in APDS patients, more commonly in APDS2 patients [89] . Neurodevelopmental delay may manifest as mild cognitive impairment and/or learning disabilities [90] .…”