Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: SH2B3

Red List (low evidence)

Blombery et al. described 2 patients from 2 kindreds, harboring biallelic loss-of-function mutations in the SH2B3 gene. They presented with early-onset developmental delay, hepatosplenomegaly, multi-organ autoimmunity (including autoimmune thyroiditis and hepatitis), bone marrow myeloproliferation, and severe thrombotic complications. The underlying mechanism was validated ex vivo using patient-derived fibroblasts, demonstrating that upon stimulation with various cytokines (including IL-3, GH, GM-CSF, and EPO), the mutant cells exhibited significantly increased phosphorylation and hyperactivation of JAK2 and STAT5 signaling. The phenotype and mechanism were further validated in vivo using CRISPR-Cas9 engineered zebrafish animal models (sh2b3 F0 crispants). These models successfully recreated the myeloproliferative phenotype, presenting with a significantly increased number of macrophages and thrombocytes. Furthermore, rescue and treatment experiments demonstrated that administering the JAK1/2 inhibitor ruxolitinib to the mutant fish successfully intercepted and resolved the myeloproliferative defect.
Sources: Literature, Expert list

Created: 17 Jun 2026, 4:38 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Myeloproliferative disorder; Autoimmunity; Hepatosplenomegaly; Thrombosis; Autoimmune thyroiditis; Autoimmune hepatitis; Global developmental delay

Publications

• 37206266