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Short stature caused by a natural growth hormone antagonist
K Chihara1, Y Takahashi, H Kaji
1Department of Internal Medicine, Kobe University School of Medicine, Hyogo, Japan.
Insights
A rare growth hormone (GH) gene mutation caused severe short stature in a child. This mutation created a GH antagonist, preventing normal growth and response to GH therapy, defining a new short stature syndrome.
Area of Science:
- Genetics
- Endocrinology
- Molecular Biology
Background:
- Severe short stature in children can stem from genetic mutations affecting growth hormone (GH).
- Understanding the molecular mechanisms of GH action is crucial for diagnosing and treating growth disorders.
Observation:
- A male child presented with severe short stature, a prominent forehead, and saddle nose, with bone age significantly lagging behind chronological age.
- Biochemical tests revealed low Insulin-like Growth Factor 1 (IGF-1), IGF Binding Protein 3 (IGFBP-3), and GH Binding Protein (GHBP), alongside high nocturnal urinary GH excretion.
- Genetic analysis identified a missense mutation (R77C) in the GH-1 gene, leading to an abnormal GH variant.
Findings:
- The R77C mutant GH exhibited a 6-fold higher affinity for GHBP and a 10-fold greater potency in inhibiting tyrosine phosphorylation, indicating a dominant-negative antagonistic effect.
- The child's lack of IGF-1 response to exogenous human GH (hGH) administration confirmed the mutant GH's antagonistic properties.
- This case differs from typical Kowarski syndrome, characterized by bioinactive GH, and represents a novel syndrome caused by a natural GH antagonist.
Implications:
- This discovery expands the known spectrum of genetic causes for short stature.
- The identification of a natural GH antagonist highlights the complexity of GH signaling pathways.
- This finding may inform the development of targeted therapies for specific GH-related growth disorders.
Abstract:
Severe short stature in a male child due to a single mutation in the GH-1 gene was first reported in 1996 by Takahashi et al. [N Engl J Med 1996;334:432-436]. This missense mutation was predicted to convert codon 77 from arginine (R) to cysteine (C). The child's chronological age was 4 years and 11 months, and his bone age 2 years and 6 months, i.e., equal to only 51% of his chronological age. Body proportions were normal except for the prominent forehead and saddle nose. Pituitary size was normal on magnetic resonance imaging examinations. Serum IGF-1, IGFBP-3 and GHBP were all decreased or at the lower limit of the normal range. Nocturnal urinary growth hormone (GH) excretion was high. Isoelectric focusing analysis revealed the presence of an abnormal GH peak in addition to the normal one. The R77C mutant GH possessed a 6 times greater affinity to GHBP than the wild-type GH, and inhibited tyrosine phosphorylation in IM-9 cells 10 times more potently than the wild-type GH, showing an antagonistic or a dominant negative action. In agreement with the antagonistic property of the mutant GH exhibited, the child did not show any increase in serum IGF-1 levels after exogenous hGH administration. It should be noted that the child in this study is not a typical case of Kowarski syndrome in which endogenous GH is found to be simply bioinactive, as in the patient we recently described elsewhere. Therefore, this patient's condition should be categorized as a new syndrome of short stature caused by a natural GH antagonist.