Editor's comment: This is an exciting contribution to the rapidly growing fund of information regarding the molecular causes of growth failure in children. It is not uncommon for a pediatric endocrinologist to be faced with extremely sholt children for whom no endocrinopathy can be identified. The work by Ayling and colleagues describes an additional genetic mutation that could present as growth hormone insensitivity syndrome. We look forward to studies of other families in hopes of determining the clinical magnitude of this new finding. The implications for potential treatment with insulin-like growth factor (IGF-1) are obvious, although the availability of IGF-1 as a therapeutic agent seems far distant in the future.

Ayling and colleagues report the identification of a new dominant-negative mutation in the growth hormone receptor (GHR) in a mother and daughter with short stature. This mutation (876-1 G~ C transversion affecting the 3'splice acceptor site preceding exon 9) was not detected in maternal grandparents. The mutation results in a premature stop codon or a truncated GHR. The GHR belongs to a cytokine family of receptors that depend on JAK tyrosine kinases for activation. It is predicted that a truncated receptor would be incapable of association with JAK and, therefore, would have a dominant-negative effect on the GHR. The clinical significance of this mutation relates to the phenotypic differences of the individuals from those with the Laron syndrome, in which midfacial hypoplasia, blue sclera, limited elbow extension, hypoglycemia, truncal adiposity, etc are often observed. In the latter, the mutations of the GHR have been primarily in the extracellular domain. In the 2 patients reported here, the GHBP, the extracellular portion of the GH binding receptor, was normal. The authors suggest that this new dominant GHR mutation should be looked for in children with familial short stature who have normal William L. Clarke, MD