QSOX2 Deficiency-induced short stature, gastrointestinal dysmotility and immune dysfunction

Avinaash V Maharaj; Miho Ishida; Anna Rybak; Reem Elfeky; Afiya Andrews; Aakash Joshi; Frances Elmslie; Anni Joensuu; Katri Kantojarvi; Raina Y Jia; John R. B Perry; Edel A O; Liam J McGuffin; Vivian Hwa; Helen L Storr

doi:10.1530/ey.22.4.3

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ESPE Yearbook of Paediatric Endocrinology (2025) 22 4.3 | DOI: 10.1530/ey.22.4.3

ESPEYB25 4. Growth and Growth Factors Novel Genetic Insights (3 abstracts)

4.3. QSOX2 Deficiency-induced short stature, gastrointestinal dysmotility and immune dysfunction

Avinaash V Maharaj , Miho Ishida , Anna Rybak , Reem Elfeky , Afiya Andrews , Aakash Joshi , Frances Elmslie , Anni Joensuu , Katri Kantojärvi , Raina Y Jia , John R. B Perry , Edel A O’Toole , Liam J McGuffin , Vivian Hwa & Helen L Storr

Nat Commun. 2024 Sep 28;15(1):8420. PMID: 39341815. doi: 10.1038/s41467-024-52587-w

Brief Summary: This study identifies and characterizes QSOX2 deficiency, a newly described autosomal recessive multi-system disorder. It investigates the genetic and phenotypic heterogeneity in patients presenting with short stature and other associated symptoms, a significant challenge in pediatric endocrinology where the molecular basis of growth failure often remains unidentified.

Five patients from 3 families presenting with short stature, immune dysfunction, atopic eczema, and gastrointestinal pathology were found to have recessive variants in the QSOX2 gene. QSOX2 encodes a nuclear membrane protein involved in disulphide isomerase and oxidoreductase activity. It localizes to the nuclear membrane/nucleoplasm and Golgi apparatus and shares homology with QSOX1, known for protection against oxidative stress. The study reveals that QSOX2 acts as a gatekeeper for regulating the stabilization and import of phosphorylated-STAT5B into the nucleus. STAT5B is a key effector in the GH receptor pathway, crucial for the production of insulin-like growth factor 1 (IGF-1). Loss of QSOX2 function disrupts GH-mediated STAT5B nuclear translocation, this attenuated nuclear localization of STAT5B impairs its transcriptional activities, leading to reduced expression of target genes like IGF-1.

This mechanism explains the observed partial GH insensitivity (GHI) in affected individuals, characterized by consistently low basal IGF-1 levels despite normal GH responses.

A trial of recombinant human GH therapy in 2 probands resulted in modest increases in height and weight SDS and normalized serum IGF-1 levels over 1.5 years. GH therapy did not improve gastrointestinal symptoms. Therapeutic recombinant insulin-like growth factor-1 (rhIGF-1) may be a more effective treatment for this condition.