Post-receptor Growth Hormone Insensitivity (GHI) associated with Severe Immune Dysfunction Caused by a Novel Bioinactive STAT5b.

PAULA A, SCAGLIA; ALICIA S. MARTÍNEZ; EVA FEIGERLOVA; PENG FANG; LILIANA BEZRODNIK; MARIA GAILLARD; DANIELA DI GIOVANNI; MARIA G. BALLERINI; HÉCTOR G. JASPER; JUAN J HEINRICH; RON G. ROSENFELD; VIVIAN HWA; HORACIO M. DOMENÉ

Boston, Massachussets

Congreso; 93rd Annual Meeting, The Endocrine Society; 2011

The Endocrine Society

Endocr Rev, Vol. 32 (03_MeetingAbstracts): OR42-3 Copyright © 2011 by The Endocrine Society Post-Receptor Growth Hormone Insensitivity (GHI) Associated with Severe Immune Dysfunction Caused by a Novel Bioinactive STAT5b Paula Scalia, MS1, Alicia S Martinez, MS1, Eva Feigerlova, MD, PhD2, Peng Fang, PhD2, Liliana Bezrodnik, MD1, Maria I Gaillard, MD1, Daniela Di Giovanni, MD1, Maria G Ballerini, MS1, Hector G Jasper, MD1, Juan J Heinrich, MD, PhD1, Ron G Rosenfeld, MD2, Vivian Hwa, PhD2 and Horacio M Domene, MS1 1, Alicia S Martinez, MS1, Eva Feigerlova, MD, PhD2, Peng Fang, PhD2, Liliana Bezrodnik, MD1, Maria I Gaillard, MD1, Daniela Di Giovanni, MD1, Maria G Ballerini, MS1, Hector G Jasper, MD1, Juan J Heinrich, MD, PhD1, Ron G Rosenfeld, MD2, Vivian Hwa, PhD2 and Horacio M Domene, MS1 Centro de Investigaciones Endocrinológicas (PS,ASM,LB,MIG,DDG,MGB,HGJ,JJH,HMD), Hospital de Niños "Ricardo Gutiérrez", Buenos Aires Argentina Pediatrics (EF,PF,RGR,VH), Oregon Health & Science University, Portland, OR The mouse Stat5b-/- knock-out model and rare human STAT5B gene mutations identified to date have demonstrated the critical involvement of STAT5b in both growth and immunity. Patients with STAT5b deficiency show GH insensitivity (GHI) and a variable degree of immune dysregulation which results in a broad spectrum of skin and respiratory infections.Patient: We describe a girl, adopted at four days of age, with severe cutaneous eczema, who presented with several infections associated with failure to thrive since the first year of life. Immunological evaluation revealed T lymphopenia (low CD3/CD4, CD8 and Treg cell numbers), poor proliferative response after antigen stimulation, and normal B cell counts. The patient was also severely growth retarded, reaching an adult height of 122.7 cm (-6.14 SDS). Endocrine evaluations indicated GHI, which was confirmed by a normal GH response to provocative tests (GHmax: 27.1 ng/ml), low levels of serum IGF-I (16 ng/ml; -3.7 SDS) and IGFBP-3 (0.84 mg/L; -4.5 SDS) and a negative IGF-I/IGFBP-3 generation test. Prolactin levels were significantly elevated (83 ng/ml; reference values <25 ng/ml).Results: The phenotype of the patient was consistent with STAT5b deficiency. Sequencing of the STAT5B gene was undertaken and revealed a novel homozygous T to C transition in exon 16, which resulted in a p.F646S missense mutation. F646, a highly conserved residue throughout the human STAT family of proteins, is within the critical SH2 domain, a region necessary for STAT5b to dock to activated receptors, to dimerize and to stabilize interactions with DNA. Preliminary reconstitution studies indicate that the regenerated N-terminally FLAG-tagged STAT5b:F646S, is readily over-expressed in HEK293(GHRfl) cells, is immunodetectable and of normal size, although expression is considerably lower than that of wild-type FLAG-STAT5b. The expressed mutant FLAG-STAT5b:F646S cannot be phosphorylated or activated by GH.Conclusion: A novel missense STAT5B mutation, p.F646S, has been identified in a patient who presented with a complex phenotype consistent with STAT5b deficiency. Only the second STAT5B missense mutation to be identified to date, the new mutation resulted in a bioinactive STAT5b variant that was not well expressed. The phenotype of our patient, together with previously described cases, confirms the crucial role of STAT5b in normal postnatal growth as well as normal immunity. Stat5b-/- knock-out model and rare human STAT5B gene mutations identified to date have demonstrated the critical involvement of STAT5b in both growth and immunity. Patients with STAT5b deficiency show GH insensitivity (GHI) and a variable degree of immune dysregulation which results in a broad spectrum of skin and respiratory infections.Patient: We describe a girl, adopted at four days of age, with severe cutaneous eczema, who presented with several infections associated with failure to thrive since the first year of life. Immunological evaluation revealed T lymphopenia (low CD3/CD4, CD8 and Treg cell numbers), poor proliferative response after antigen stimulation, and normal B cell counts. The patient was also severely growth retarded, reaching an adult height of 122.7 cm (-6.14 SDS). Endocrine evaluations indicated GHI, which was confirmed by a normal GH response to provocative tests (GHmax: 27.1 ng/ml), low levels of serum IGF-I (16 ng/ml; -3.7 SDS) and IGFBP-3 (0.84 mg/L; -4.5 SDS) and a negative IGF-I/IGFBP-3 generation test. Prolactin levels were significantly elevated (83 ng/ml; reference values <25 ng/ml).Results: The phenotype of the patient was consistent with STAT5b deficiency. Sequencing of the STAT5B gene was undertaken and revealed a novel homozygous T to C transition in exon 16, which resulted in a p.F646S missense mutation. F646, a highly conserved residue throughout the human STAT family of proteins, is within the critical SH2 domain, a region necessary for STAT5b to dock to activated receptors, to dimerize and to stabilize interactions with DNA. Preliminary reconstitution studies indicate that the regenerated N-terminally FLAG-tagged STAT5b:F646S, is readily over-expressed in HEK293(GHRfl) cells, is immunodetectable and of normal size, although expression is considerably lower than that of wild-type FLAG-STAT5b. The expressed mutant FLAG-STAT5b:F646S cannot be phosphorylated or activated by GH.Conclusion: A novel missense STAT5B mutation, p.F646S, has been identified in a patient who presented with a complex phenotype consistent with STAT5b deficiency. Only the second STAT5B missense mutation to be identified to date, the new mutation resulted in a bioinactive STAT5b variant that was not well expressed. The phenotype of our patient, together with previously described cases, confirms the crucial role of STAT5b in normal postnatal growth as well as normal immunity.