Szymon Lulek1
Katarzyna Bąbol-Pokora2Monika Radwańska3Daniel Popiel4Magdalena Reich5,6
Wojciech Młynarski2
Radosław Chaber3,6*- 1Students’ Scientific Association at the Department of Pediatric Hematology and Oncology, Department of Pediatrics, University of Rzeszów, Rzeszów, Poland
- 2Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland
- 3Clinic of Pediatric Oncology and Hematology, State Hospital 2, Rzeszow, Poland
- 4Clinic of Intensive Care and Anesthesiology, State Hospital 2, Rzeszow, Poland
- 5Clinic of Pediatrics and Pediatric Gastroenterology, State Hospital 2, Rzeszow, Poland
- 6Department of Pediatrics, Faculty of Medicine, University of Rzeszow, Rzeszow, Poland
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome that may arise secondary to genetic or acquired triggers. Although HLH has been reported in patients with adenosine deaminase 2 (ADA2) deficiency, to date it has not been reported in individuals harboring pathogenic variants in ERCC6L2, a gene typically linked to inherited bone marrow failure. We report a fatal case of HLH in a 2-year-old girl with persistent fever, cytopenias, hepatosplenomegaly, liver failure, and multiorgan dysfunction. Despite targeted HLH therapy, the disease progressed rapidly. Genetic testing identified a homozygous pathogenic variant in ERCC6L2 and a heterozygous ADA2 variant, which we interpret as indicating a susceptibility background to immune dysregulation, with HLH most plausibly occurring as a secondary, trigger-dependent event. No functional validation was performed, and causal inference cannot be made on this basis. To our knowledge, this is the first documented case of HLH in a patient with a homozygous pathogenic ERCC6L2 variant. The co-occurrence of a heterozygous ADA2 variant may have modulated the hyperinflammatory response. These observations highlight the importance of genetic evaluation and suggest—while not proving—a broader spectrum of genetic contexts associated with pediatric HLH; confirmation will require functional studies and replication.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome characterized by persistent fever, cytopenias, hepatosplenomegaly, coagulopathy, and markedly elevated biomarkers, including ferritin and soluble interleukin-2 receptor (sIL-2R). HLH results from dysregulated immune responses, particularly impaired granule-mediated cytotoxicity of NK and CD8+ T lymphocytes, leading to uncontrolled macrophage activation and excessive cytokine release. The disorder is classified into primary forms—associated with mutations in genes such as PRF1, UNC13D, STX11, and STXBP2—and secondary forms triggered by infections, malignancies, or autoimmune conditions (1).
Excision repair cross-complementing 6-like 2 (ERCC6L2) has recently been recognized as a critical gene implicated in inherited bone marrow failure (BMF) syndromes. Biallelic germline defects in ERCC6L2 impair DNA repair and increase oxidative stress. The clinical course is typically characterized by erythroid predominance and progression to acute erythroid leukemia, which carries a poor prognosis (2).
Pathogenic variants ADA2 have been associated with autoinflammatory disorders, including HLH (3). Unlike ADA1 deficiency (loss of intracellular ADA), ADA2 deficiency results from malfunction of the extracellular, growth factor-like enzyme, which is required for myeloid differentiation and immune regulation. HLH in the context of ADA2 variants shows variable severity and is often precipitated by infectious triggers (4).
Here, we report a 2-year-old girl with severe HLH in whom we identified a homozygous pathogenic ERCC6L2 variant together with a heterozygous ADA2 variant. To our knowledge, this is the first documented case of HLH in a patient with a homozygous pathogenic ERCC6L2 variant.
2 Case report
A 2-year-old girl was admitted with persistent fever lasting more than five days, progressive apathy, poor oral intake, and markedly reduced urine output.
At 7 months of age she experienced severe COVID-19 pneumonia; at 10 months, roseola infantum complicated by leukopenia and thrombocytopenia; and at 20 months, severe varicella with secondary bacterial skin infection. Prior records documented transient, infection-associated abnormalities in peripheral blood counts during earlier illnesses. Between episodes, values returned to age-adjusted reference ranges, and no transfusion dependence was noted. One week before admission, she received the measles–mumps–rubella (MMR) vaccine. Family history was notable for the sudden death of a male relative (the child of a paternal great-uncle) following polio vaccination.
The patient appeared severely ill and somnolent, with periorbital and peripheral edema, jaundice, and tachycardia (150–160 bpm). The abdomen was distended with palpable splenomegaly.
Initial tests revealed profound leukopenia (WBC 2.25 ×109/L), thrombocytopenia (PLT 63 ×109/L), anemia (HGB 91 g/L), and markedly elevated inflammatory markers: CRP >100 mg/l; (ref. <10); procalcitonin 4.78 µg/L, (ref. <0.5); IL-6 2,061.6 ng/L (ref. < 4.4). Metabolic acidosis was evident: HCO3− 15.4 mmol/l, (ref. 21,2-27,0); lactate 2.2–2.4 mmol/L, (ref. 0,56–1,33). Liver dysfunction was severe, with elevated aminotransferases: ALT 171 U/L, (ref. 13 – 45); AST 535 U/L, (ref. 28 – 57), hyperbilirubinemia: total bilirubin 103 μmol/L (ref. 5.1–20.5), and hypoalbuminemia: 23.8 g/L, (ref. 34 – 42). Coagulopathy was indicated by prolonged INR (1.62), low fibrinogen: 1.07 g/l, (ref. 2,0 - 4,0); and markedly elevated D-dimers: 54.2 mg/L, (ref. 0-0.5). Ferritin exceeded 4,000 μg/L, (ref. 10-290).
Abdominal ultrasound demonstrated splenomegaly, gallbladder wall thickening, increased renal cortical echogenicity, and ascites. By day 11 of hospitalization, hepatomegaly was also observed. Chest CT revealed bilateral perihilar infiltrates and echocardiography identified a moderate pericardial effusion.
Blood culture grew Staphylococcus hominis (methicillin-resistant coagulase-negative staphylococcus, MRCoNS). Serology was negative for Mycoplasma, EBV, HAV, HBV, HIV, Rotavirus, Adenovirus, and Campylobacter but positive for CMV IgG and Parvovirus B19 IgG.
Bone marrow aspiration revealed hypocellular marrow with absent megakaryocytes. The erythroid lineage (6%) showed normoblastic maturation; granulocytes (55%) displayed dysplastic features; lymphocytes accounted for 37%. Overall, findings were consistent with an aplastic marrow pattern. No hemophagocytosis was observed.
Cerebrospinal fluid was clear, straw-colored, with a nucleated cell count of 5 cells/µL, elevated protein (1.314 g/L; ref. 0,15–0,45), and normal glucose and chloride levels. Pandy’s test was positive, the Nonne–Apelt test equivocal, and the Weichbrodt test negative. Cytology showed exclusively mononuclear cells, consistent with blood–brain barrier dysfunction, with no cytologic evidence of purulent meningitis.
Clinical and laboratory findings met the HLH-2004 diagnostic criteria (5)— fever >38.5°C, cytopenias, hypertriglyceridemia, splenomegaly, and hyperferritinemia (≥500 µg/L)— establishing the diagnosis of HLH. Germline testing identified a homozygous pathogenic ERCC6L2 variant (NM_001010895.2:c.1930C>T; p.(Arg644*)), introducing a premature termination codon at position 644, together with a heterozygous ADA2 missense variant (NM_001282225.2:c.1078A>G; p.(Thr360Ala)) resulting in a threonine-to-alanine substitution at position 360. No functional assays (e.g., ERCC6L2 transcript/protein quantification, DNA-damage–response readouts or ADA2 enzymatic activity) were performed.
Despite intensive therapy—including broad-spectrum antibiotics (cefotaxime, vancomycin), antifungals (fluconazole), diuretics, intravenous fluids, albumin infusion, and electrolyte correction—the patient’s condition remained critical. The HLH-2004 regimen was initiated with dexamethasone at 10 mg/m²/day; cyclosporine A at 6 mg/kg/day in two divided doses; and intravenous etoposide (first dose 75 mg/m²/day due to hepatic/renal dysfunction, followed by 150 mg/m²/day). In addition, two doses of tocilizumab (12 mg/kg iv each) were administered as immunomodulatory therapy. Nevertheless, extensive inflammatory changes developed in the lungs. On hospital day 8, acyclovir was introduced for suspected varicella/herpetic reactivation, and antibiotics were escalated to meropenem and amikacin with the addition of amphotericin B. Despite these measures, the child developed progressive multiorgan failure, accompanied by persistently elevated inflammatory markers (Table 1, Figure 1). On hospital day 19, she suffered cardiac arrest and died.
Table 1. Serial laboratory parameters during hospitalization.
Figure 1. Trends of selected inflammatory and organ function markers.
3 Discussion
This case illustrates the extreme severity and diagnostic complexity of HLH in the setting of coexisting genetic abnormalities. To our knowledge, this is the first report of HLH in a patient with a homozygous pathogenic ERCC6L2 variant, accompanied by a heterozygous ADA2 variant.
HLH may arise sporadically or in association with genetic disorders of immune regulation (6). Familial HLH results from biallelic defects in genes involved in NK- and T-cell cytotoxicity (e.g., PRF1, UNC13D), whereas secondary HLH typically lacks an identified monogenic defect and is most often triggered by infection or malignancy. However, mounting evidence indicates that some patients categorized as “secondary” HLH carry heterozygous variants in HLH-related genes or other germline immune defects (7). Notably, HLH has rarely been reported in inherited BMF syndromes, although a recent case described HLH as the initial presentation of telomerase-related BMF (8).
Deficiency of DADA2, an autosomal-recessive disorder caused by biallelic loss-of-function variants in ADA2, has been identified as one HLH-associated autoinflammatory condition (9). Its clinical spectrum ranges from systemic inflammation to immunodeficiency and cytopenias (10). Hematologic manifestations occur in approximately 20–25% of patients, whereas HLH is rare but severe, reported in <1% of cases (11). Additionally, ADA2 deficiency skews monocytes toward a pro-inflammatory M1 phenotype and disrupts NK/T-cell regulatory interactions, creating a cytokine-rich milieu characterized by elevated TNF-α, IL-6, and type I interferons (12, 13). Moreover, ADA2-deficient cytotoxic lymphocytes exhibit impaired granzyme release, which may predispose to HLH in the context of viral triggers (14).
Classic DADA2 requires biallelic variants, and heterozygous carriers are usually asymptomatic. Exceptions have been reported: Wouters et al. (2024) demonstrated that certain heterozygous variants exert dominant-negative effects on ADA2 activity, dimerization, or secretion (15). Several reports describe symptomatic heterozygous carriers with presentations ranging from immunodeficiency to inflammatory and vascular phenotypes (16–19). Pulvirenti et al. (2023) reported a heterozygous carrier who developed fatal multiorgan failure, supporting the hypothesis that single-allele pathogenic variants may contribute to severe inflammation (10). In our patient, the heterozygous ADA2 variant alone does not fulfil criteria for DADA2 but may have facilitated immune dysregulation. Partial ADA2 impairment could have lowered the threshold for hyperinflammation, acting synergistically with ERCC6L2-related marrow stress as a “second hit.”
ERCC6L2 encodes a helicase central to transcription-coupled nucleotide-excision repair and the genomic integrity of hematopoietic stem cells (20). Biallelic germline variants cause an inherited BMF syndrome that often progresses to MDS/AML. Moreover, approximately 90% of affected patients acquire somatic TP53 variations during the BMF/MDS phase, driving rapid evolution to high-risk AML with a median survival of 3 months after transformation (2, 21, 22). HLH has not previously been described in ERCC6L2-related disease, but sustained marrow stress and apoptotic turnover could leave cytotoxic effectors quantitatively and functionally compromised, favoring dysregulated macrophage activation. Consistent with this framework, preclinical ERCC6L2-deficiency models show upregulated TP53 signaling and remodeling of the marrow microenvironment (23). Although these changes do not implicate ERCC6L2 in the perforin–granule pathway that defines classic familial HLH, they may lower the threshold for infection- or vaccine-driven hyperinflammation. Taken together, and in the absence of functional validation or confirmation of ERCC6L2 loss of function in other patients with HLH, it is not possible to establish a direct link between homozygous ERCC6L2 variants and the development of HLH. It is plausible that this episode represents vaccine-triggered HLH occurring in the setting of a homozygous pathogenic ERCC6L2 variant, with a heterozygous ADA2 variant acting as a potential modifier.
Notably, this case highlights the need for careful pre-vaccination assessment in children with unexplained cytopenias and recurrent infections suggestive of immune dysfunction. In such patients, live-attenuated vaccines can trigger uncontrolled immune activation, warranting genetic evaluation and close clinical monitoring. This observation also supports considering ERCC6L2 testing in HLH when “classic” pathogenic variants are not identified.
4 Conclusions
This fatal case illustrates the genetic complexity and likely multifactorial pathogenesis of HLH. Our literature review identified no previous reports of HLH in ERCC6L2-related bone-marrow failure indicating that this association is exceedingly rare. Although a direct causal relationship between homozygous ERCC6L2 variants and HLH cannot be established from a single observation, the coexistence of homozygous ERCC6L2 deficiency and a heterozygous ADA2 variant—together with a recent exposure to a live-attenuated vaccine—may have acted as disease modifiers that lowered the threshold for hyperinflammation. These considerations support including ERCC6L2 in the genetic work-up of HLH when “classic” predisposing variants are not identified. Further research, including functional studies and replication in independent cases, is needed to determine whether this represents a rare coincidence or whether similar oligogenic gene–environment interactions underlie a subset of currently “idiopathic” HLH.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Ethics statement
Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements. Written informed consent was obtained from the minor’s legal guardian for the publication of any potentially identifiable images or data included in this article.
Author contributions
SL: Writing – review & editing. KB-P: Writing – review & editing. MRa: Writing – review & editing. DP: Writing – review & editing. MRe: Writing – review & editing. WM: Writing – review & editing. RC: Writing – original draft.
Funding
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Conflict of interest
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References
1. Canna SW and Marsh RA. Pediatric hemophagocytic lymphohistiocytosis. Blood. (2020) 135:1332–43. doi: 10.1182/blood.2019000936
2. Hakkarainen M, Kaaja I, Douglas SPM, Vulliamy T, Dokal I, Soulier J, et al. The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia. Blood. (2023) 141:2853–66. doi: 10.1182/blood.2022019425
3. Andriessen MVE, Legger GE, Bredius RGM, van Gijn ME, Hak AE, Hissink Muller PCE, et al. Clinical symptoms, laboratory parameters and long-term follow-up in a national DADA2 cohort. J Clin Immunol. (2023) 43:1581–96. doi: 10.1007/s10875-023-01521-8
4. Pilania RK, Banday AZ, Sharma S, Kumrah R, Joshi V, Loganathan S, et al. Deficiency of human adenosine deaminase type 2 - A diagnostic conundrum for the hematologist. Front Immunol. (2022) 13:869570. doi: 10.3389/fimmu.2022.869570
5. Henter J-I, Horne A, Aricò M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. (2007) 48:124–31. doi: 10.1002/PBC.21039
6. Janka G and zur Stadt U. Familial and acquired hemophagocytic lymphohistiocytosis. Hematol Am Soc Hematol Educ Program. (2005) 2005:82–8. doi: 10.1182/asheducation-2005.1.82
7. Paolino J, Berliner N, and Degar B. Hemophagocytic lymphohistiocytosis as an etiology of bone marrow failure. Front Oncol. (2022) 12:1016318. doi: 10.3389/fonc.2022.1016318
8. Medina-Neira D, Alvarado-Gamarra G, Huamaní-Condori B, Purizaca-Rosillo N, Atamari-Anahui N, Matos-Villena E, et al. Hemophagocytic lymphohistiocytosis as the initial manifestation of bone marrow failure in a child with a TERC variant telomere biology disorder. Ther Adv Rare Dis. (2025) 6:26330040241311621. doi: 10.1177/26330040241311621
9. Drago E, Garbarino F, Signa S, Grossi A, Schena F, Penco F, et al. Case Report: Susceptibility to viral infections and secondary hemophagocytic lymphohistiocytosis responsive to intravenous immunoglobulin as primary manifestations of adenosine deaminase 2 deficiency. Front Immunol. (2022) 13:937108. doi: 10.3389/fimmu.2022.937108
10. Pulvirenti F, Cinicola BL, Ferrari S, Guadagnolo D, Sculco E, Capponi M, et al. Case Report: Interindividual variability and possible role of heterozygous variants in a family with deficiency of adenosine deaminase 2: are all heterozygous born equals? Front Immunol. (2023) 14:1156689. doi: 10.3389/fimmu.2023.1156689
11. Maccora I, Maniscalco V, Campani S, Carrera S, Abbati G, Marrani E, et al. A wide spectrum of phenotype of deficiency of deaminase 2 (DADA2): a systematic literature review. Orphanet J Rare Dis. (2023) 18:117. doi: 10.1186/s13023-023-02721-6
12. Caorsi R, Penco F, Grossi A, Insalaco A, Omenetti A, Alessio M, et al. ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: A multicentre national study. Ann Rheum Dis. (2017) 76:1648–56. doi: 10.1136/annrheumdis-2016-210802
13. Carmona-Rivera C, Khaznadar SS, Shwin KW, Irizarry-Caro JA, O’Neil LJ, Liu Y, et al. Deficiency of adenosine deaminase 2 triggers adenosine-mediated NETosis and TNF production in patients with DADA2. Blood. (2019) 134:395–406. doi: 10.1182/blood.2018892752
14. Signa S, Bertoni A, Penco F, Caorsi R, Cafaro A, Cangemi G, et al. Adenosine deaminase 2 deficiency (DADA2): A crosstalk between innate and adaptive immunity. Front Immunol. (2022) 13:935957. doi: 10.3389/fimmu.2022.935957
15. Wouters M, Ehlers L, Van Eynde W, Kars ME, Delafontaine S, Kienapfel V, et al. Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers. J Exp Med. (2025) 222:e20250499. doi: 10.1101/2024.12.09.24317629
16. Moi L, Schnider C, Riccio O, Hershfield MS, and Candotti F. Common variable immunodeficiency in a carrier of the ADA2 R169Q variant: coincidence or causality? J Clin Immunol. (2022) 42:959–61. doi: 10.1007/s10875-022-01271-z
17. Rama M, Duflos C, Melki I, Bessis D, Bonhomme A, Martin H, et al. A decision tree for the genetic diagnosis of deficiency of adenosine deaminase 2 (DADA2): A French reference centres experience. Eur J Hum Genet. (2018) 26:960–71. doi: 10.1038/s41431-018-0130-6
18. Nihira H, Izawa K, Ito M, Umebayashi H, Okano T, Kajikawa S, et al. Detailed analysis of Japanese patients with adenosine deaminase 2 deficiency reveals characteristic elevation of type II interferon signature and STAT1 hyperactivation. J Allergy Clin Immunol. (2021) 148:550–562.
19. Izumo H, Ishikawa N, Kobayashi Y, Doi T, and Okada S. A successful infliximab treatment of a pediatric case of severe polyarteritis nodosa with a cerebral infarction and a decreased adenosine deaminase 2 activity. Cureus. (2023) 15:e47952. doi: 10.7759/cureus.47952
20. Tummala H, Kirwan M, Walne AJ, Hossain U, Jackson N, Pondarre C, et al. ERCC6L2 mutations link a distinct bone-marrow-failure syndrome to DNA repair and mitochondrial function. Am J Hum Genet. (2014) 94:246–56. doi: 10.1016/j.ajhg.2014.01.007
21. Baccelli F, Leardini D, Cerasi S, Messelodi D, Bertuccio S, and Masetti R. ERCC6L2-related disease: a novel entity of bone marrow failure disorder with high risk of clonal evolution. Ann Hematol. (2023) 102:699–705. doi: 10.1007/s00277-023-05128-2
22. Haroon A, Al-Jefri A, Jaradi M, Alotaibi AS, Alfayez M, Alzahrani H, et al. First description of new variant of germline ERCC6L2 mutations causing bone marrow failure, a single center report of 11 cases in 7 families. Blood. (2024) 144:5706. doi: 10.1182/blood-2024-193282
Keywords: hemophagocytic lymphohistiocytosis (HLH), ERCC6L2, ADA2/DADA2 deficiency, cytopenias, immunodeficiency, genetic predisposition, hyperinflammation
Citation: Lulek S, Bąbol-Pokora K, Radwańska M, Popiel D, Reich M, Młynarski W and Chaber R (2026) A fatal course of hemophagocytic lymphohistiocytosis in a child with homozygous ERCC6L2 defect and heterozygous ADA2 variant: a case report. Front. Immunol. 16:1717567. doi: 10.3389/fimmu.2025.1717567
Received: 02 October 2025; Accepted: 18 November 2025; Revised: 31 October 2025;
Published: 03 February 2026.
Edited by:
Randy Q. Cron, University of Alabama at Birmingham, United StatesReviewed by:
Rakesh Kumar Pilania, Post Graduate Institute of Medical Education and Research, IndiaXiangmin Wang, The Affiliated Hospital of Xuzhou Medical University, China
Copyright © 2026 Lulek, Bąbol-Pokora, Radwańska, Popiel, Reich, Młynarski and Chaber. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Radosław Chaber, cmNoYWJlckB1ci5lZHUucGw=