APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant

• Published in: Journal of clinical immunology 2020-10, Vol.40 (7), p.1020-1025
• Main Authors: Ramirez, Lourdes, Tamayo, Wendy, Ale, Hanadys
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Biomedical and Life Sciences; Biomedicine; Genetic screening; Hypogammaglobulinemia; Immune system; Immunodeficiency; Immunology; Infectious Diseases; Internal Medicine; Medical Microbiology; Mutation; Original Article; Primary immunodeficiencies
• ISSN: 0271-9142; 1573-2592
• DOI: 10.1007/s10875-020-00843-1

Activated PI3K δ syndrome (APDS) is a primary immunodeficiency caused by heterogeneous germline gain-of-function mutations which ultimately lead to the hyperactivation of the phosphoinositide-3-kinase δ (PI3K δ). PI3K δ exists as a heterodimer composed of a catalytic and a regulatory subunit. APDS type 2 is caused by mutations in the PIK3R1 gene affecting the p85α regulatory subunit. SHORT syndrome is a rare multisystem disorder characterized by short stature, hyperextensible joints, ocular depression, Rieger anomaly, and tooth eruption delay. The primary causes of SHORT syndrome are heterozygous loss-of-function mutations in the PIK3R1 gene. The combination of APDS2 and SHORT syndrome is rare, with few cases reported to date. Here we describe a 17-year-old female with phenotypic features consistent with SHORT syndrome and history of sinopulmonary infections and hypogammaglobulinemia. Invitae immunodeficiency panel genetic testing revealed a pathogenic loss-of-function variant in an intronic splice site in the gene PIK3R1 (c.1425 + 1G > C). This pathogenic variant had been previously associated with APDS2; however, it had not been associated with SHORT syndrome. The exact mechanisms linking both conditions are yet to be identified. This case report emphasizes the importance of screening for comorbidities associated with SHORT syndrome in APDS2 patients and vice versa.