Modern Pediatrics. Ukraine. (2023). 6(134): 133-141. doi 10.15574/SP.2023.134.133
Dorosh O. I.^1,2,3, Tymchyshyn S. M.¹, Melko I. P.^1,4, Voloshchuk V. B.¹, Lizarov Yu. V.⁵, Kreminska О. S.⁶, Mykh A. M.¹, Seredych L. P.¹, Kitsera N. I.^7
1СNE of Lviv Regional Council «Western Ukrainian Specialized Pediatric Medical Centre», Ukraine
²Danylo Halytsky Lviv National Medical University, Ukraine
³Hematology Clinic DrSmart, Lviv, Ukraine
⁴Center for Medical Innovations NOVO, Lviv, Ukraine
⁵The Municipal Enterprise «Volyn Regional Territorial Mother and Child Health Care Center» of the Volyn Regional Council, Lutsk, Ukraine
⁶CSD LAB Medical Laboratory, Kyiv, Ukraine
⁷Institute of Hereditary Pathology of the NAMS of Ukraine, Lviv

For citation: Dorosh OI, Tymchyshyn SM, Melko IP, Voloshchuk VB, Lizarov YuV, Kreminska ОS et al. (2023). Genetic verification of an autoinflammatory syndrome caused by a heterozygous mutation in the SOCS1 gene masquerading as hemoblastosis. Clinical case. Modern Pediatrics. Ukraine. 6(134): 133-141. doi 10.15574/SP.2023.134.133.
Article received: Jul 13 2023. Accepted for publication: Oct 10, 2023.

Familial autoinflammatory syndrome with or without immunodeficiency (AISIMD), caused by a heterozygous mutation in the SOCS1 gene on chromosome 16p13, is characterized by the appearance of various autoimmune signs usually in the first decades of life, although later onset has been reported. Typical features of AISIMD include autoimmune cytopenia, thrombocytopenia, hemolytic anemia and lymphadenopathy, possible alterations in cellular immunity, and hypogammaglobulinemia.
Purpose – to present a combination of clinical, imaging and laboratory signs in a nine-year-old patient with autoinflammatory syndrome and mild immunodeficiency caused by a heterozygous mutation in the SOCS1 gene; to emphasise the importance of genetic tests for definitive diagnosis.
Clinical case. Features of diagnosis of autoinflammatory syndrome caused by heterozygous mutation in the SOCS1 gene in a 9-year-old boy are described. The disease was manifested in the laboratory by leukopenia with neutropenia, monocytosis, thrombocytopenia, an increase in markers of inflammation – C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), impaired cellular immunity (inverse CD4/CD8 ratio, reduced number of NK cells (CD3-CD16+CD56+), decrease in CD19, increase in the per cent of double-negative T-lymphocytes (Neg. In T- Double LF (CD3+CD4-CD8-); clinical: hyperthermia, recurrent aphthous stomatitis, irritable bowel syndrome, progressive generalized lymphoproliferative syndrome. Differential diagnosis with hemoblastosis was carried out, which was denied. Subsequently the presence of an ulcer in the ileum and mucinous metaplasia in the covering epithelium gave grounds to diagnose an inflammatory bowel disease: Crohn's disease with damage to the terminal part of the small intestine. Verification of the final diagnosis of an autoinflammatory syndrome caused by a heterozygous mutation in the SOCS1 gene took place using genome sequencing.
The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies.
No conflict of interests was declared by the authors.
Keywords: autoinflammatory/autoimmune syndrome, heterozygous mutation in the SOCS1 gene, genome sequencing, cytopenia, lymphoproliferative syndrome, immunodeficiency, children.
REFERENCES

1. Afzal W, Owlia MB, Hasni S, Newman KA. (2017). Autoimmune Neutropenia Updates: Etiology, Pathology, and Treatment. South Med J. 110 (4): 300-307. https://doi.org/10.14423/SMJ.0000000000000637; PMid:28376530

2. Beaurivage C, Champagne A, Tobelaim WS, Pomerleau V, Menendez A, Saucier C. (2016). SOCS1 in cancer: An oncogene and a tumor suppressor. Cytokine. 82: 87-94. https://doi.org/10.1016/j.cyto.2016.01.005; PMid:26811119

3. Chen SS, Wu WZ, Zhang YP, Huang WJ. (2020). Gene polymorphisms of SOCS1 and SOCS2 and acute lymphoblastic leukemia. Eur Rev Med Pharmacol Sci. 24 (10): 5564-5572. doi: 10.26355/eurrev_202005_21342.

4. Grimbacher B, Schäffer AA, Holland SM, Davis J, Gallin JI, Malech HL et al. (1999). Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. 65 (3): 735-744. https://doi.org/10.1086/302547; PMid:10441580 PMCid:PMC1377980

5. GTEx Consortium. (2020). The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. 369 (6509): 1318-1330. https://doi.org/10.1126/science.aaz1776; PMid:32913098 PMCid:PMC7737656

6. Hadjadj J, Castro CN, Tusseau M, Stolzenberg MC, Mazerolles F, Aladjidi N et al. (2020). Early-onset autoimmunity associated with SOCS1 haploinsufficiency. Nat Commun. 11 (1): 5341. https://doi.org/10.1038/s41467-020-18925-4; PMid:33087723 PMCid:PMC7578789

7. Hale RC, Owen N, Yuan B, Chinn IK; SOCS1 Study Group. (2023). Phenotypic Variability of SOCS1 Haploinsufficiency. J Clin Immunol. 43 (5): 902-906. https://doi.org/10.1007/s10875-023-01460-4; PMid:36890397

8. Körholz J, Gabrielyan A, Sowerby JM, Boschann F, Chen LS, Paul D et al. (2021). One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency. Front Immunol. 12: 680334. https://doi.org/10.3389/fimmu.2021.680334; PMid:34421895 PMCid:PMC8375263

9. Lee PY, Platt CD, Weeks S, Grace RF, Maher G, Gauthier K et al. (2020). Immune dysregulation and multisystem inflammatory syndrome in children (MIS-C) in individuals with haploinsufficiency of SOCS1. J Allergy Clin Immunol. 146 (5): 1194-1200.e1. https://doi.org/10.1016/j.jaci.2020.07.033; PMid:32853638 PMCid:PMC7445138

10. Mart G, Malkan UY, Buyukasik Y. (2022). Determination of etiology in patients admitted due to isolated leukopenia. Medicine (Baltimore). 101 (33): e30116. https://doi.org/10.1097/MD.0000000000030116; PMid:35984149 PMCid:PMC9387957

11. Michniacki TF, Walkovich K, DeMeyer L, Saad N, Hannibal M, Basiaga ML et al. (2022). SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition. J Clin Immunol. 42 (8): 1766-1777. https://doi.org/10.1007/s10875-022-01346-x; PMid:35976468 PMCid:PMC9381392

12. Mottok A, Renné C, Willenbrock K, Hansmann ML, Bräuninger A. (2007). Somatic hypermutation of SOCS1 in lymphocyte-predominant Hodgkin lymphoma is accompanied by high JAK2 expression and activation of STAT6. Blood. 110 (9): 3387-3390. https://doi.org/10.1182/blood-2007-03-082511; PMid:17652621

13. Ryu JY, Oh J, Kim SM, Kim WG, Jeong H, Ahn SA et al. (2022). SOCS1 counteracts ROS-mediated survival signals and promotes apoptosis by modulating cell cycle to increase radiosensitivity of colorectal cancer cells. BMB Rep. 55 (4): 198-203. https://doi.org/10.5483/BMBRep.2022.55.4.191; PMid:35321782 PMCid:PMC9058468

14. Schmiedel BJ, Singh D, Madrigal A, Valdovino-Gonzalez AG, White BM, Zapardiel-Gonzalo J et al. (2018). Impact of Genetic Polymorphisms on Human Immune Cell Gene Expression. Cell. 175 (6): 1701-1715.e16. https://doi.org/10.1016/j.cell.2018.10.022; PMid:30449622 PMCid:PMC6289654

15. Schuhmacher B, Bein J, Rausch T, Benes V, Tousseyn T, Vornanen M et al. (2019). JUNB, DUSP2, SGK1, SOCS1 and CREBBP are frequently mutated in T-cell/histiocyte-rich large B-cell lymphoma. Haematologica. 104 (2): 330-337. https://doi.org/10.3324/haematol.2018.203224; PMid:30213827 PMCid:PMC6355500

16. Thaventhiran JED, Lango Allen H, Burren OS, Rae W, Greene D, Staples E et al. (2020). Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature. 583 (7814): 90-95. https://doi.org/10.1038/s41586-020-2265-1; PMid:32499645 PMCid:PMC7334047

17. Ying J, Qiu X, Lu Y, Zhang M. (2019). SOCS1 and its Potential Clinical Role in Tumor. Pathol Oncol Res. 25 (4): 1295-1301. https://doi.org/10.1007/s12253-019-00612-5; PMid:30761449