Clinical and immunological assessment of APDS2 with features of the SHORT syndrome related to a novel mutation in PIK3R1 with reduced penetrance

Abstract

Monoallelic loss-of-function (LOF) mutations in the phosphatidylinositol 3-kinase (PIK3R1) gene affecting the inter-Src homology 2 domain of the p85α regulatory subunit of phosphoinositide-3-kinase δ (PI3Kδ) cause the activated PI3K δ syndrome (APDS2). APDS2 is defined as a primary antibody deficiency, developmental abnormalities within the B and T lymph cell compartments, and immune dysregulation. The genetic defect of APDS2 is shared with that of the SHORT syndrome, characterized by short stature, joint hyperextensibility, ocular depression, Rieger anomaly, and delayed tooth eruption. LOF variants in an intronic splice site (c.1425+1G.C/A/T) in the PI3KR1 gene have been identified in patients affected with both APDS2 and SHORT syndrome. Herein, we report a novel c.1644-1648del (p.Asp548Glufs*6) variant in a pediatric patient with the APDS2-related immunodeficiency, who presents with mild phenotypic fea-tures of the SHORT syndrome, congenital chest wall deformity, and IgE-mediated food allergy. The same variant was also identified in the patient’s hitherto asymptomatic mother, implicating an incomplete penetrance. Regular monitoring by a multidisciplinary team under the pediatric clinical immunologist’s supervision to implement appropriate diagnostic procedures and treatment modalities is of paramount importance. Further studies are required to better define the genotype-phenotype correlation in patients with the PIK3R1 gene mutations and to better delineate the mutual relationship between APDS2 and the SHORT syndrome.

Hematopoietic stem cell transplantation in a patient with activated phosphoinositide 3‑kinase δ syndrome: A case report and literature review

“…We observed a positive response to the conservative treatment regimen in a patient with APDS 2 who received immunoglobulins and remained in a good general condition. This patient has been described by our colleagues from Poznan [ 25 ].…”

Paradoxical dominant negative activity of an immunodeficiency-associated activatingPIK3R1variant

“…In contrast to SHORT syndrome, mutations in the inter SH2 domain of PIK3R1, mostly leading to skipping of exon 11, were shown in 2014 to activate PI3K in vitro and to cause immunodeficiency (APDS2) (Deau et al ., 2014; Lucas et al ., 2014b) similar to that caused by activating mutations in p110δ (APDS1) (Angulo et al ., 2013; Lucas et al ., 2014a). Neither overgrowth nor metabolic features of APDS2 have been described to suggest p110α hyperactivation, and indeed short stature is common in APDS2 (Elkaim et al ., 2016; Jamee et al ., 2020; Maccari et al ., 2023; Olbrich et al ., 2016; Petrovski et al ., 2016), with a growing number of APDS2 patients described with features of SHORT syndrome (Bravo Garcia-Morato et al ., 2017; Maccari et al ., 2023; Nguyen et al ., 2023; Petrovski et al ., 2016; Ramirez et al ., 2020; Szczawinska-Poplonyk et al ., 2022). Moreover mice with the common APDS2 causal Pik3r1 variant knocked in show impaired growth and in utero survival, unclike APDS2 murine models(Nguyen et al ., 2023).…”

“…It features reduced linear growth, insulin resistance, and dysmorphic features (Avila et al , 2016). In recent years, both case reports (Bravo Garcia-Morato et al , 2017; Petrovski et al , 2016; Ramirez et al , 2020; Szczawinska-Poplonyk et al , 2022) and larger series (Elkaim et al , 2016; Jamee et al , 2020; Maccari et al , 2023; Nguyen et al , 2023; Olbrich et al , 2016; Petrovski et al ., 2016) have established that many people with APDS2 have overt features of SHORT syndrome, while, more generally, linear growth impairment is common in APDS2, but not in APDS1. These clinical observations are bolstered by the impaired linear growth and increased in utero mortality reported in mice with knock in of the common causal APDS2 mutation in Pik3r1(Nguyen et al ., 2023).…”

Prevalence and Concentration of Mycotoxins in Animal Feed in the Middle East and North Africa (MENA): A Systematic Review and Meta-Analysis

“…However, allergies to mycotoxins in animal feed are relatively rare but can occur in animals with a hypersensitive immune system. These allergies can manifest in various ways, such as respiratory problems, skin irritation, and digestive issues, which can lead to reduced growth rates, weight loss, and in severe cases, mortality [ 41 , 42 , 43 , 44 , 45 , 46 ]. To prevent allergies to mycotoxins in animal feed, it is essential to maintain proper storage conditions, regularly test feed for mycotoxin contamination, and use appropriate detoxification techniques before feeding animals.…”