Short stature in carriers of recessive mutation causing familial isolated growth hormone deficiency

Isolated growth hormone deficiency (IGHD) IB is an autosomal recessive diso rder characterized by a good response to exogenous growth hormone (GH) trea tment without development of anti-GH antibodies, Patients with IGHD LB were found to be compound heterozygotes for deletion and frameshift mutations a s well as homozygotes for splicing mutations in the GH-1 gene. Recently, a novel splicing mutation in the GH-1 gene was identified in an extended, con sanguineous Arab-Bedouin family from Israel with IGHD IB, Prior to the iden tification of this mutation, a considerable number of children with short s tature in this family were found normal on pharmacological stimulation for GH release. This observation prompted a genotype/phenotype correlation of p otential heterozygotes in the family. Carriers of the mutant GH-1 allele we re found as a group to have a significantly shorter stature than normal hom ozygote (mean standard deviation scores, 1.67 and -0.40, respectively, P < 0.05), Moreover, 11 of 33 (33%) heterozygotes, but only 1 of 17 (5.9%) norm al homozygotes, had their height at 2 or more SD below the mean. Overall, 4 8.5% of studied heterozygotes were found to be of appreciably short stature with height at or lower than the 5th centile (greater than or equal to -1. 7 SD), whereas only 5.9% of the normal homozygotes did (P < 0.004), This ph enomenon of heterozygotes for a recessive mutation in the GH-1 gene manifes ting short stature, might imply that some such mutations may account for no n-GH deficiency reduced height in the general population. (C) 2000 Wiley-Li ss, Inc.