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Clinical and Biochemical Characteristics of a Male Patient with a Novel Homozygous STAT5b Mutation

Departments of Endocrinology and Metabolic Diseases (S.V., A.M.P., M.K., H.A.v.D., F.R., J.A.R.), Pediatrics (M.J.E.W., M.K., H.A.v.D., M.F.K., J.M.W.), and Infectious Diseases (J.v.Di., R.J.) and Center for Human and Clinical Genetics (S.W., M.H.B.), Leiden University Medical Center, Leiden, The Netherlands; and Department of Metabolic and Endocrine Disorders (J.v.Do.), University Medical Center Utrecht, Utrecht, The Netherlands

Address all correspondence and requests for reprints to: M. J. E. Walenkamp, Department of Pediatrics J6-S, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. E-mail: m.j.e.walenkamp{at}lumc.nl.

Context: GH insensitivity can be caused by defects in the GH receptor (GHR) or in the postreceptor signaling pathway. Recently, two female patients with severe growth retardation and pulmonary and immunological problems were described with a defect in STAT5b, a critical intermediary of downstream GHR signaling.

Objective: The objective was to determine the functional characteristics of a novel STAT5b mutation and describe the phenotype.

Patient: We describe an adult male patient with short stature [–5.9 SD score (SDS)], delayed puberty, and no history of pulmonary or immunological problems. GH-binding protein level as well as GH secretion characteristics were normal. Plasma prolactin level was elevated. Extremely low levels of IGF-I (–6.9 SDS), IGF-binding protein-3 (–12 SDS), and acid-labile subunit (–7.5 SDS) were found.

Results: We found a homozygous frameshift mutation in the STAT5b gene (nucleotide 1102–3insC, Q368fsX376), resulting in an inactive truncated protein, lacking most of the DNA binding domain and the SH2-domain.

Conclusions: This report confirms the essential role of STAT5b in GH signaling in the human. We show for the first time that immunological or pulmonary problems or elevated GH secretion are not obligatory signs of STAT5b deficiency, whereas hyperprolactinemia appears to be part of the syndrome. Therefore, in patients with severe short stature, signs of GH insensitivity, and a normal GHR, analysis of the STAT5b gene is recommended.

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