STAT5B germline heterozygous variant presenting with lymphadenopathy, atopy, and short stature
Abstract
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.
Get full access to this article
View all available purchase options and get full access to this article.
REFERENCES
Ando T., Xiao W., Gao P., Namiranian S., Matsumoto K., Tomimori Y., Hong H., Yamashita H., Kimura M., Kashiwakura J.-I., Hata T.R., Izuhara K., Gurish M.F., Roers A., Rafaels N.M., Barnes K.C., Jamora C., Kawakami Y., and Kawakami T. (2014). Critical role for mast cell Stat5 activity in skin inflammation. Cell Rep. 6(2): 366–376.
Awasthi N., Liongue C., and Ward A.C. (2021). STAT proteins: a kaleidoscope of canonical and non-canonical functions in immunity and cancer. J. Hematol. Oncol. 14(1).
Fagerberg L., Hallström B.M., Oksvold P., Kampf C., Djureinovic D., Odeberg J., Habuka M., Tahmasebpoor S., Danielsson A., Edlund K., Asplund A., Sjöstedt E., Lundberg E., Szigyarto C.A.-K., Skogs M., Takanen J.O., Berling H., Tegel H., Mulder J., Nilsson P., Schwenk J.M., Lindskog C., Danielsson F., Mardinoglu A., Sivertsson A., Feilitzen K.V., Forsberg M., Zwahlen M., Olsson I., Navani S., Huss M., Nielsen J., Ponten F., and Uhlén M. (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell. Proteomics. 13(2): 397–406.
Hoelbl A., Kovacic B., Kerenyi M.A., Simma O., Warsch W., Cui Y., Beug H., Hennighausen L., Moriggl R., and Sexl V. (2006). Clarifying the role of Stat5 in lymphoid development and Abelson-induced transformation. Blood, 107(12): 4898–4906.
Hu X., li J., Fu M., Zhao X., and Wang W. (2021). The JAK/STAT signaling pathway: from bench to clinic. Signal Trans. Target. Therapy 6(1): 402.
Hwa V., Nadeau K., Wit J.M., and Rosenfeld R.G. (2011). STAT5b deficiency: Lessons from STAT5b gene mutations. Best Pract. Res. 25(1): 61–75.
Kanai T., Jenks J., and Nadeau K.C. (2012). The STAT5b pathway defect and autoimmunity. Front. Immunol. 3(AUG).
Kasap N., Aslan K., Karakurt L.T., Bozkurt H., Canatan H., Cavkaytar O., Eken A., and Arga M. (2022). A novel gain-of-function mutation in STAT5B is associated with treatment-resistant severe atopic dermatitis. Clin. Experiment. Aller. 52(7): 907–910.
Kawakami T., Ando T., and Kawakami Y. (2015). Hypothetical atopic dermatitis-myeloproliferative neoplasm syndrome. Front. Immunol. 6.
Klammt J., Neumann D., Gevers E.F., Andrew S.F., Schwartz I.D., Rockstroh D., Colombo R., Sanchez M.A., Vokurkova D., Kowalczyk J., Metherell L.A., Rosenfeld R.G., Pfäffle R., Dattani M.T., Dauber A., and Hwa V. (2018). Dominant-negative STAT5B mutations cause growth hormone insensitivity with short stature and mild immune dysregulation. Nat. Comm. 9(1).
Kofoed E.M., Hwa V., Little B., Woods K.A., Buckway C.K., Tsubaki J., Pratt K.L., Bezrodnik L., Jasper H., Tepper A., Heinrich J.J., and Rosenfeld R.G. (2003). Growth Hormone Insensitivity Associated with a STAT5b Mutation. New England J. Med. 349(12): 1139–1147.
Ma C.A., Xi L., Cauff B., DeZure A., Freeman A.F., Hambleton S., Kleiner G., Leahy T.R., O’Sullivan M., Makiya M., O’Regan G., Pittaluga S., Niemela J., Stoddard J., Rosenzweig S.D., Raffeld M., Klion A.D., and Milner J.D. (2017). Somatic STAT5b gain-of-function mutations in early onset nonclonal eosinophilia, urticaria, dermatitis, and diarrhea. Blood, 129(5): 650–653.
Maurer B., Kollmann S., Pickem J., Hoelbl-Kovacic A., and Sexl V. (2019). STAT5A and STAT5B—twins with different personalities in hematopoiesis and leukemia. Cancers, 11(11).
Pelham S.J., Caldirola M.S., Avery D.T., Mackie J., Rao G., Gothe F., Peters T.J., Guerin A., Neumann D., Vokurkova D., Hwa V., Zhang W., Lyu S.-C., Chang I., Manohar M., Nadeau K.C., Gaillard M.I., Bezrodnik L., Iotova V., Zwirner N.W., Gutierrez M., Al-Herz W., Goodnow C.C., Vargas-Hernández A., Satter L.R.F., Hambleton S., Deenick E.K., Ma C.S., Tangye S.G., and Tangye S.G. (2022). STAT5B restrains human B-cell differentiation to maintain humoral immune homeostasis. J. Aller. Clin. Immunol. 150(4): 931–946.
Shahmarvand N., Nagy A., Shahryari J., and Ohgami R.S. (2018). Mutations in the signal transducer and activator of transcription family of genes in cancer. Cancer Sci. 109(4): 926–933.
Smith M.R., Satter L.R.F., and Vargas-Hernández A. (2023). STAT5b: A master regulator of key biological pathways. Front. Immunol. 13.
Information & Authors
Information
Published In
LymphoSign Journal
Volume 11 • Number 1 • March 2024
Pages: 12 - 18
History
Received: 16 October 2023
Accepted: 8 November 2023
Accepted manuscript online: 27 November 2023
Version of record online: 27 November 2023
Copyright
© 2024.
Authors
Metrics & Citations
Metrics
Other Metrics
Citations
Cite As
Laura AbregoFuentes and MaianRoifman. 2024. STAT5B germline heterozygous variant presenting with lymphadenopathy, atopy, and short stature. LymphoSign Journal.
11(1): 12-18. https://doi.org/10.14785/lymphosign-2023-0010
Export Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download.
There are no citations for this item
View Options
Get Access
Login options
Check if you access through your login credentials or your institution to get full access on this article.
