APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant
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ORIGINAL ARTICLE
APDS2 and SHORT Syndrome in a Teenager with PIK3R1 Pathogenic Variant Lourdes Ramirez 1
&
Wendy Tamayo 2 & Hanadys Ale 3
Received: 6 April 2020 / Accepted: 6 August 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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-offunction 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. Keywords APDS . SHORT syndrome . PIK3R1 . primary immunodeficiencies
Introduction Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency caused by heterozygous germline mutations in genes encoding the phosphoinositide-3-kinase δ (PI3Kδ). PI3Kδ belongs to the family of class IA phosphatidylinositol 3-kinases (PI3Ks) which are involved in many cellular functions such as cell growth, proliferation, metabolism, and apoptosis. These kinases exist as heterodimers composed of a regulatory subunit and a catalytic subunit. The role of the regulatory subunit, p85α, is to stabilize and inhibit the kinase function of its catalytic subunit, * Lourdes Ramirez [email protected] 1
Department of Pediatrics, Joe DiMaggio Children’s Hospital, 1005 Joe DiMaggio Dr, Hollywood, FL 33021, USA
2
Department of Medicine, Herbert Wertheim College of Medicine, 11200 SW 8th St, Miami, FL 33199, USA
3
Department of Pediatric Allergy and Immunology, Joe DiMaggio Children’s Hospital, 1005 Joe DiMaggio Dr, Hollywood, FL 33021, USA
p110δ. Together, they form the PI3Kδ lipid kinase which interacts with multiple immune system players including the T cell receptor, B cell receptor, and multiple cytokine receptors [1–4]. APDS1 occurs as a result of heterozygous gain-of-function mutations in PIK3CD, affecting the catalytic subunit p110δ, resulting in activated PI3Kδ [1, 3, 5–8]. APDS2 is caused by heterozygous
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