Case Report: Clinical manifestations of uncommon monogenic disorders: revisiting activated phosphoinositide 3-kinase delta syndrome 2

Abstract

Aim: Pediatricians are trained to identify recurrent or unusual infections in children, prompting evaluation for inborn errors of immunity (IEI). Some monogenic IEI, however, may present atypically. This study describes our experience with children diagnosed with activated phosphoinositide 3-kinase delta syndrome (APDS2) including unusual presentations.

Methods: A retrospective review was conducted on two children diagnosed with APDS2 at Shaare Zedek and Sheba Tel-Hashomer Medical Centers in Israel. Both patients underwent immune assessments, genetic testing, and treatment between 2019 and 2024.

Results: Two patients, a 17-year-old female (P1) and a 7-year-old male (P2), were diagnosed with APDS2 after presenting with recurrent juvenile parotitis (P1) and severe lymphadenopathy (P2). Immunologic evaluation revealed hypogammaglobulinemia and combined immune deficiency. Genetic testing identified PIK3R1 variants (c.1425 + 1G > T in P1 and c.1425 + 1G > C in P2). Both received intravenous immunoglobulins and prophylactic antibiotics. P2 was treated with rapamycin, leading to resolution of lymphadenopathy.

Conclusion: This report highlights the clinical presentation of APDS2, a rare monogenic IEI in children, including the atypical manifestation of RJP and the common feature of lymphadenopathy. Pediatricians should stay vigilant for red flags of IEI during clinical evaluations, as early diagnosis and multidisciplinary care are crucial for effective management.

Keywords: APDS2; PIK3R1; combined immune deficiencies; inborn errors of immunity; primary immune deficiencies (PID).

Figure 1

Clinical characteristics of the patients with APDS2. (A,B) Family pedigrees of P1 and P2, respectively. (C) Sanger sequencing demonstrating the PIK3R1variants found in P2 and P1. (D) Lymphadenopathy as demonstrated by ultrasound (US) scans of P2. Severely enlarged bilateral submandibular lymph nodes including small jugular lymph nodes can be seen. Non-homogenous pattern with some liquefication. The lengths of right and left submandibular lymph nodes are 4.36 and 2.1 cm, respectively. (E,F) US images of P1 of the right and left parotid glands showing hypoechoic round small (3–5 mm) regions, which may be compatible with sialectasis. (G,H) Bilateral sialo-cone beam computed tomography (sialo-CBCT) parotid gland image of P1 showing smooth main duct without sausaging (in left side mild dilatation in the distal 1 cm of the main duct) with few secondary ducts (ductopenia); (G) right showing numerous sialectasis, compatible with recurrent juvenile parotitis (RJP); (H) few clustered of sialectasis, without demonstrating the whole gland, compatible with RJP with secondary gland atrophy. (I) Scout image showing remaining contrast medium right main duct and sialectasis, left in main duct, thus demonstrating impaired bilateral gland activity.

Figure 2

Immunological workup of the APDS2 patients. (A,B) T-cell receptor (TCR) V-β repertoires the APDS2 patients. (A) A restrictive pattern with the expansion of Vβ1, Vβ3 and Vβ5.1 clones and (B) a normal/polyclonal distribution are evident in P1 and P2, respectively.

Figure 3

Response of lymphadenopathy to rapamycin treatment. (A) Severely enlarged bilateral submandibular lymph nodes as viewed by US upon P2's first examination. Length of right submandibular lymph node is measured 4.36 cm. (B) Two months following rapamycin treatment. A marked decrease of the right submandibular lymph node can be seen (3.6 × 1.1 × 1.4 cm) without abscess formation. (C) Following 1.5 years of rapamycin treatment, continuing decrease in the size of the right submandibular lymphadenopathy is noted (2.1 × 0.6 × 1 × 0.41 cm).