Background: Signal Transducers and Activators of Transcription (STAT) proteins are fundamental for multiple cellular processes, including immunity. STAT5B serves as a signal transducer downstream of cytokine and growth factor-mediated activation. Aberrations in STAT5B are associated with the development of atopy, immunodeficiencies, autoimmunity, cancers, hematological disease, growth disorders, and lung disease. Biallelic STAT5B variants are associated with loss-of-function of the gene, and cause a recessive disorder characterized by growth hormone insensitivity and immune dysregulation. Clinically significant heterozygous variants result in either dominant negative or gain-of-function effects; these latter variants are rare and their impact on the immune system is less clearly delineated than those responsible for the recessive form of the condition.

Aim: We describe the presentation, immune workup, and genetic findings in a pediatric patient with a novel STAT5B heterozygous variant.

Methods: A thorough retrospective review of the patient’s chart was performed.

Results: A four-year-old male presented with history of lymphadenopathy, eczema, asthma, food allergy, short stature, and recurrent upper and lower respiratory tract infections. Clinical trio whole exome sequencing identified a novel heterozygous variant (c.1A>G; p. Met1?) in STAT5B. His mother harbours the same heterozygous variant and has a history remarkable for atopy. Immune investigations on the child revealed persistent elevated IgE. The patient’s variant targets the STAT5B N-terminal domain, and represents the first case with a heterozygous variant affecting this region.

Conclusion: We present a novel STAT5B variant associated with a dominantly-inherited growth and immune phenotype. This is the first report of a heterozygous variant affecting the N-terminal domain in association with a clinical phenotype, expanding the genotypic landscape of this disorder. Further investigations and follow up responses to growth hormone replacement are needed to better delineate the functional effect of the variant identified in this family.

Statement of Novelty: We report a novel germline heterozygous STAT5B variant in a paediatric patient with lymphadenopathy, atopy, and short stature.