Signal transducer and activator transcription 5B (STAT5B) is a critical mediator of multiple cytokines (e.g., IL-2 and IL-7) and growth hormone signaling and plays a key role in hematopoiesis, particularly in lymphocyte development, proliferation, and survival. Loss-of-function and dominant-negative mutations in STAT5B have been associated with growth failure and immune dysregulation, including atopy. While short stature has been reported in individuals with heterozygous loss-of-function mutations (haploinsufficiency), allergic manifestations have not been reported in depth.
The proband is an adult female who presented with neonatal-onset atopic dermatitis, which progressively worsened to severe, diffuse involvement of her face and extremities by adulthood (SCORAD of 59) and was refractory to topical corticosteroids. She was ultimately started on dupilumab with significant improvement. Initial evaluation revealed markedly elevated IgE (20,756 IU/mL) and mild eosinophilia (660 cells/μL). Her medical history was notable for slightly reduced height, moderate asthma, seasonal allergies managed with immunotherapy, and peanut allergy. Her family history was notable for moderate-severe atopic dermatitis affecting her father, sister, and niece. There was no history of recurrent infections, enteropathy, endocrine abnormalities, autoimmune disease, or malignancy. Detailed immunophenotyping revealed reduced central memory CD4+ and CD8+ T lymphocytes, increased effector memory CD4+ T lymphocytes, and a high proportion of TEMRA CD4+ and CD8+ cells. Immunoglobulin levels and vaccine titers were within normal limits. Genetic sequencing identified a heterozygous nonsense variant in the STAT5B gene (c.361C>T, p.R121*) that has not previously been reported in publicly available datasets. This variant segregated with atopic dermatitis in the proband’s sister and niece. Consistent with impairment in STAT5B signaling in vivo, IGF1 levels were low, while GH and IGFBP3 levels were within normal limits. Western blot analysis confirmed reduced total p-STAT5 and STAT5B expression in primary dermal fibroblasts.
This study identifies a novel heterozygous nonsense variant in the STAT5B gene that results in haploinsufficiency associated with severe atopic dermatitis and mild growth impairment with notably absent autoimmune endocrinopathy or other immune dysregulation. These findings expand the phenotypic spectrum of STAT5B-associated disorders and highlight the importance of targeted therapeutic interventions.
Reduced p-STAT5 and STAT5B expression in dermal fibroblasts (M42).
