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

Main Article Content

Aleksandra Szczawińska-Popłonyk
Katarzyna Bernat-Sitarz
Eyal Schwartzmann
Michał Piechota
Magdalena Badura-Stronka


APDS2, immune dysregulation, immunodeficiency, PIK3R1, SHORT syndrome


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 features 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.

Abstract 329 | PDF Downloads 309 HTML Downloads 44 XML Downloads 2


1. Avila M, Dyment DA, Sagen JV, St-Onge J, Moog U, Chung BHY, et al. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: towards recommendations for molecular testing and management. Clin Genet. 2016;89(4):501–6. 10.1111/cge.12688

2. Bonnel S, Dureau P, LeMerrer M, Dufier JL. SHORT syndrome: a case with high hyperopia and astigmatism. Ophthalmic Genet. 2000;21(4):235–8. 10.1076/1381-6810(200012)2141-HFT235

3. Solheim MH, Clermont AC, Winnay JN, Hallstensen N, Molven A, Njolstad PR, et al. Iris malformation and anterior segment dysgenesis in mice and humans with mutations in PI 3-kinase. Invest Ophthalmol Vis Sci. 2017;58(7):3100–06. 10.1167/iovs.16-21347

4. Klatka M, Rysz I, Kozyra K, Polak A, Kołłątaj W. SHORT syndrome in a two-year-old girl–case report. Ital J Pediatr. 2017;43(1):44. 10.1186/s13052-017-0362-z

5. Sun L, Zhang Q, Li Q, Tang Y, Wang Y, Li X, et al. A novel PIK3R1 mutation of SHORT syndrome in a Chinese female with diffuse thyroid disease: a case report and review of the literature. BMC Med Genet. 2020;21(1):215. 10.1186/s12881-020-01146-3

6. Singh A, Arora R, Singh P, Kapoor S. Short syndrome-an expanding phenotype. Indian Pediatr. 2013;50(4):414–16. 10.1007/s13312-013-0099-8

7. Zhang Y, Ji B, Li J, Li Y, Zhang M, Ban B. SHORT syndrome in two Chinese girls: a case report and review of the literature. Mol Genet Genomic Med. 2020;8(9):e1385. 10.1002/mgg3.1385

8. Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, et al. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet. 2013;93(1):141–9. 10.1016/j.ajhg.2013.05.019

9. Singh A, Joshi V, Jindal AK, Mathew B, Rawat A. An updated review on activated PI3 kinase delta syndrome (APDS). Genes Dis. 2020;7(1):67–74. 10.1016/j.gendis.2019.09.015

10. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702–14. 10.1038/nri.2016.93

11. Petrovski S, Parrott RE, Roberts JL, Huang H, Yang J, Gorentla B, et al. Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature. J Clin Immunol. 2016;36(5):462–71. 10.1007/s10875-016-0281-6

12. Ramirez L, Tamayo W, Ale H. APDS2 and SHORT syndrome in a teenager with PIK3R1 pathogenic variant. J Clin Immunol. 2020;40(7):1020–25. 10.1007/s10875-020-00843-1

13. Bravo Garcia-Morato M, Garcia-Minaur S, Molina Garicano J, Santos Simarro F, Del Pino Molina L, Lopez-Granados E, et al. Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. Clin Immunol. 2017;179:77–80. 10.1016/j.clim.2017.03.004

14. Olbrich P, Lorenz M, Cura Daball P, Lucena JM, Rensing-Ehl A, Sanchez B, et al. Activated PI3Kδ syndrome type 2: two patients, a novel mutation, and review of the literature. Pediatr Allergy Immunol. 2016;27(6):640–44. 10.1111/pai.12585

15. Ahmed AA, El Shahaway AA, Hussien SA. Activated PI3K-delta syndrome in an Egyptian pediatric cohort with primary immune deficiency. Allergol Immunopathol. 2020;48(6):686–93. 10.1016/j.aller.2019.12.006

16. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606. 10.1016/j.jaci.2016.06.021

17. Ewertowska M, Grześk E, Urbańczyk A, Dąbrowska A, -Bąbol-Pokora K, Łęcka M, et al. Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS1 and APDS2): similarities and differences based on clinical presentation in two boys. Allergy Asthma Clin Immunol. 2020;16:22. 10.1186/s13223-020-00420-6

18. Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9): 3923–3928. 10.1172/JCI75746

19. Yazdani R, Hamidi Z, Babaha F, Azizi G, Fekrvand S, Abolhassani H, et al. PIK3R1 mutation associated with hyper IgM (APDS2 syndrome); a case report and review of the literature. Endocr Metab Immune Disord Drug Targets. 2019;19(7):941–958. 10.2174/1871530319666190225114739

20. Fekrvand S, Delavari S, Chavoshzadeh Z, Sherkat R, Mahdaviani SA, Sadeghi Shabestari M, et al. The first Iranian cohort of pediatric patients with activated phosphoinositide 3-kinase-δ (PI3Kδ) syndrome (APDS). Immunol Invest. 2021;1–16. 10.1080/08820139.2020.1863982

21. Tang P, Upton JEM, Barton-Forbes MA, Salvadori MI, Clynick MP, Price Ak. Autosomal recessive agammaglobulinemia due to a homozygous mutation in PIK3R1. J Clin Immunol. 2018;38(1):88–95. 10.1007/s10875-017-0462-y

22. Elkaim E, Neven B, Bruneau J, Mitsui-Sekinaka K, Stanislas A, Heurtier L, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138(1):210–218. 10.1016/j.jaci.2016.03.022

23. Michalovich D, Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy. Front Immunol. 2018;9:369. 10.3389/fimmu.2018.00369

24. Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinikova O, Bangs C, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome: the European Society for Immunodeficiencies-activated phosphoinositide 3-kinase δ syndrome registry. Front Immunol. 2018;9:543. 10.3389/fimmu.2018.00543

25. Nunes-Santos CJ, Uzel G, Rosenzweig SD. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676–87. 10.1016/j.jaci.2019.03.017

26. Avery DT, Kane A, Nguyen T, Lau A, Nguyen A, Lenthall H, et al. Germline-activating mutations in PIK3CD compromise B cell development and function. J Exp Med. 2018;215(8):2073–95. 10.1084/jem.20180010

27. Cannons JL, Preite S, Kapnick SM, Uzel G, Schwarzberg PL. Genetic defects in phosphoinositide 3-kinase delta influence CD8+ T cell survival, differentiation, and function. Front Immunol. 2018;9:3174. 10.3389/fimmu.2018.01758

28. Bloomfield M, Klocperk A, Zachova R, Milota T, Kanderova V, Sediva A. Natural course of activated phosphoinositide 3-kinase delta syndrome in childhood and adolescence. Front Pediatr. 2021;9:697706. 10.3389/fped.2021.697706

29. Thouenon R, Moreno-Corona N, Poggi L, Durandy A, Kracker S. Activated PI3Kinase delta syndrome–a multifaceted disease. Front Pediatr. 2021;9:652405. 10.3389/fped.2021.652405

30. Baleydier F, Bernard F, Ansari M. The possibilities of immunotherapy for children with primary immunodeficiencies associated with cancers. Biomolecules. 2020;10:1112. 10.3390/biom10081112

31. Baleydier F, Ranza E, Schappi M, Rougemont A, Merlini L, Ansari M, et al. Activated phosphoinositide 3 kinase delta syndrome (APDS): a primary immunodeficiency mimicking lymphoma. J Pediatr Hematol Oncol. 2019;41(8):521–24. 10.1097/MPH.0000000000001328

32. Pham MN, Cunningham-Rundles C. Evaluation of lymphoproliferative disease and increased risk of lymphoma in activated phosphoinositide 3 kinase delta syndrome: a case report with discussion. Front Pediatr. 2018;6:402. 10.3389/fped.2018.00402

33. Coulter TI, Cant AJ. The treatment of activated PI3Kδ syndrome. Front Immunol. 2018;9:2043. 10.3389/fimmu.2018.02043