1 - Paediatric Unit, Hospital Dona Estefânia, CHULC, Lisboa, Portugal,
2 - Primary Immunodeficiencies Unit, Paediatric Department, Hospital Dona Estefânia, CHULC, Lisboa, Portugal,
3 - Primary Immunodeficiencies Unit, Paediatric Department, Hospital Dona Estefânia, CHULC, Lisboa, Portugal,
4 - Paediatric Haematology Unit, Hospital Dona Estefânia, CHULC, Lisboa, Portugal, 5Gastrenterology Unit, Hospital Dona Estefânia, CHULC, Lisboa, Portugal
- Poster, XXXVI Reunião Anual da Sociedade Portuguesa de Gastrenterologia, Hepatologia e Nutrição Pediátrica, Porto, 14-15 de março de 2024
- Poster, 56th Annual Meeting of the European Society for Pediatric Gastroenterology, Hepatology and Nutricion (ESPGHAN), Milão, 15-18 de maio 2024
RESUMO:
Objectives and Study: SOCS1 is an intracellular protein that downregulates cytokine signaling by inhibiting the JAKSTAT pathway. Recently, rare heterozygous germline mutations in the SOCS1 gene leading to haploinsufficiency were associated with early onset autoimmune manifestations.
Methods: We report the first description of the Tyr80* mutation in SOCS1 leading to poliautoimmunity.
Results: 17-year old female initially diagnosed with autoimmune hemolytic anemia, responsive to corticosteroid treatment, presented 7 months later with fever, abdominal pain and vomiting. Examination revealed hepatomegaly and splenomegaly. Blood tests showed thrombocytopenia and elevated AST and ALT levels (peaking at 1792 U/L and 1271 U/L, respectively). Extensive workup for liver disease included normal ceruloplasmin and negative ANA, SMA, LKM1, SLA and LC1 antibodies. Abdominal ultrasound exhibited a heterogeneous liver and splenomegaly, while elastography indicated severe liver fibrosis. Liver biopsy revealed panacinar and submassive necrosis, lymphoplasmacytic infiltrate in portal spaces, extensive interface hepatitis, piecemeal necrosis and lesions of endotheliitis, indicative of autoimmune hepatitis. Liver function was slightly impaired (maximum INR 1.95, minimum albumin 21.3 mg/dL). Intravenous immunoglobulin (2g/Kg) and prednisolone (60mg) resulted in progressively reduced transaminases and recovery of synthetic function. Immunological workup revealed a hyper-IgM-like phenotype, as well as global lymphopenia and reduced class-switched memory B cells and naive CD4+ T cells (13% CD4 CD45RA). NGS panel for primary immunodeficiencies identified a novel nonsense variant of the SOCS 1 gene p.(Tyr80*), impacting the downregulation of the JAKSTAT pathway. MRCP showed a slight focal distortion of the hepatic duct related to early stage sclerosing cholangitis. She currently maintains stability with normal LFT´s under azathioprine, prednisolone and UDCA.
Conclusions: With fewer than 20 patients reported, SOCS1 haploinsufficiency has been associated with different autoimmune features, caused by abnormal control of the JAKSTAT signaling pathway. A proper diagnosis will allow the use of personalized treatment with JAK inhibition in the probable case of relapse or new autoimmune phenomena.