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Background: H syndrome is a rare genetic disorder caused by pathogenic variants in the SLC29A3 gene. It is increasingly recognized as an auto-inflammatory disease within the group of histiocytosis, characterized by multisystem involvement [1, 2].
Objectives: This study aims to expand the clinical, genetic, and immunopathological spectrum of H syndrome by analyzing a large patient cohort. It evaluates the disease’s long-term progression and describes the use of emerging therapies, such as IL-6 antagonists and MEK inhibitors.
Methods: This retrospective and prospective study reviewed clinical and genetic data from patients diagnosed with SLC29A3 mutations between 2012 and 2024. Patients were identified through multidisciplinary networks across France. Referring physicians and principal investigator contributed anonymized data via the secured database “Histiobase”. This study is conducted in accordance with current legislation and regulations. The CCTIRS approval number is 09 6 191 , and the CNIL registration number is 909027.
Results: On December 2024, data were collected from 33 patients spanning 28 families, with a median age of 23 years (range: 0.5–66) and a sex ratio of 1.29 M/F.
Key findings include:
Histiocytic infiltrations (71%) leading to retroperitoneal or mediastinal fibrosis, compressive masses located in heart or kidney leading to pyelocalyceal dilatation, and renal failure.
Sensorineural hearing loss was reported in 70% of patients.
Hepatosplenomegaly and lymphadenopathies (69%).
Dermatological features (65%), including hyperpigmentation, hypertrichosis, and telangiectasia.
Musculoskeletal involvement in over half the patients, with joint contractures, tenosynovitis, myositis, and arthritis.
Ophthalmologic manifestations (44%) such as anterior granulomatous uveitis.
Hematological abnormalities (20%), including pure red cell anemia, autoimmune cytopenia, and hemophagocytic lymphohistiocytosis.
Biological findings revealed elevated inflammatory markers in 87% and hypergammaglobulinemia in 70%. A small number of adult patients (n=3) presented with a monoclonal peak, while another had hypogammaglobulinemia associated with severe respiratory infections requiring immunoglobulin supplementation. Memory B-cell deficiency was observed in 6 of 7 tested patients. Autoimmunity was detected in 25% of the cohort, with both specific and non-specific autoantibodies, such as those associated with diabetes mellitus or anti-SSA antibodies, leading to sicca syndrome. Additionally, anti-MPO antibodies were found, associated with ANCA vasculitis. Genetic analysis confirmed pathogenic SLC29A3 mutations in all patients. Somatic mutations in the MAP kinase pathway, such as MAP2K1 and NRAS, were identified in biopsies from 3 patients. Many patients were initially misdiagnosed with various rheumatologic and immunologic conditions, highlighting the significant diagnostic challenges associated with the syndrome. Regarding the therapeutic insights, IL-6 antagonists proved effective in inflammatory symptoms, including fever, arthritis, and skin hyperpigmentation, in 16 patients. However, MEK inhibitors, such as Cobimetinib, demonstrated superior results in addressing organ infiltration and proliferative lesions in a smaller group of patients (n=5), achieving complete responses in cases where IL-6 antagonists provided only partial relief or where symptoms reappeared after prolonged treatment.
Conclusion: This study expands the clinical spectrum of H syndrome, underscoring its classification as both a genetic histiocytosis and a multisystem inflammatory disorder. It highlights autoimmune features, potential immunodeficiency, and a predisposition to fibrosis, which contribute to significant morbidity and mortality. Promising therapeutic options, including MEK inhibitors and IL-6 antagonists, offer hope for better disease management and improved patient outcomes.
REFERENCES: [1] Jacquot R, Jouret M, Valentin MG, Richard M, Jamilloux Y, Rousset F, et al. H syndrome treated with Tocilizumab: two case reports and literature review. Front Immunol. 11 août 2023;14:1061182.
[2] Shiloh R, Lubin R, David O, Geron I, Okon E, Hazan I, et al. Loss-of-function of ENT3 drives histiocytosis and inflammation through TLR-MAPK signaling. Blood J. 22 sept 2023;blood.2023020714.
Acknowledgements: NIL.
Disclosure of Interests: None declared.
© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license (