Familial Isolated Growth Hormone Deficiency Type II: Not So Isolated After All

Isolated growth hormone deficiency (IGHD) is thought to be familial in 5% to 30% of cases. Familial IGHD is categorized into 4 types: IA is autosomal recessive with absent endogenous GH; IB is autosomal recessive with decreased GH; type II is autosomal dominant with decreased GH; and type III is X-linked with decreased GH. Type II IGHD results from GH-1 gene mutations¹ that lead to missplicing and subsequent loss of exon 3; the resultant 17.5-kDa GH variant acts as a dominant negative inhibitor of the normal 22-kDa GH isoform (from the wild-type allele) by disrupting the Golgi apparatus, impairing trafficking of GH and other hormones, and reducing stability of the 22-kDa GH isoform.

Mullis and colleagues studied 57 subjects from 19 families with type II IGHD resulting from different splice site and missense mutations in GH-1. Thirty-three had received GH treatment, and 24 were untreated. Those who had been treated during childhood stopped treatment for 2 months when reaching near adult height and underwent pituitary retesting; the untreated subjects underwent similar testing. Several interesting findings arose. First, subjects with a splice site mutation in the first 2 bp of the third intron (5´ IVS +1/+2 bp) seemed to have a worse phenotype than those whose splice site mutation occurred in the 5th or 6th bps of the same intron (5´ IVS +5/+6). The former had lower mean serum cortisol and ACTH concentrations and were more likely to have lower TSH levels. They also had a significantly smaller pituitary height (–2.59 SDS vs –1.56 SDS, P<0.01) when reaching adult height. One patient with a missense mutation (P89L GH) also presented with ACTH and TSH deficiencies, and another (R183H GH) had a small pituitary size at age 73 years.

Pituitary height in affected GH-treated subjects at diagnosis as well as at the end of growth. The age-dependent heights of the adenohypophysis, which was determined in a strict midline positioned sagittal scan, are shown. Because MRI was performed at different ages and the size of the normal pituitary increases with age the –2.0 and +2.0 SDS are shown as lines. In each subject 2 measurements were performed: at the beginning/diagnosis and at near AH after the GH treatment was stopped for 2 months. Green/closed squares, Patients with 5´IVS-3 +5/+6 bp splice site mutation; red/closed circles/ dots, patients with 5´IVS-3 +1/+2 bp splice site mutation; blue/closed triangle, R183H GH. *, P < 0.01. Reprinted with permission Mullis PE, et al. J Clin Endocrinol Metab. 2005; 90:2089-2096. Copyright ©2005. The Endocrine Society. All rights reserved.

The authors concluded that the phenotype was partially genotype-related. On one hand, children with splice site mutations were younger at diagnosis (mean age 3 years) than those with missense mutations (mean age 9.3 years), and the splice site mutation in the first 2 bps of intron 3 presented with more pituitary dysfunction in adulthood than mutation in bps 5 or 6 of the same intron. However, there was still considerable phenotypic variability among individuals within the same family with the same mutation. Consistent with transgenic mouse models, it seems the phenotype is dose-dependent (ie, the ratio of mutant 17.5 kDa GH to wild-type 22 kDa GH). Transgenic mice with high-copy number IGHD II also developed pituitary hypoplasia and multiple hormone deficiencies (prolactin, TSH and in males only, LH).

Editor’s Comment: I agree with the authors that the most important lesson from this study is the need for long-term monitoring of pituitary function in patients with type II IGHD. Interestingly, the hormonal deficiencies and pituitary hypoplasia manifested later. The difference in pituitary size among patients with the 2 splice site mutations (+1/+2 vs +5/+6) was not significant at the time of diagnosis (−1.1 and −1.5 SDS, respectively), but became significant by the time near adult height was reached (−2.59 and −1.56 SDS) (Figure). Although type II IGHD is supposed to have isolated GHD by definition, the onset of additional pituitary deficiencies in adulthood warrants attention. This is reminiscent of the finding of central adrenal insufficiency in adults who had been treated for idiopathic GHD in childhood.² Unrecognized and under-treated adrenal insufficiency contributes to the increased mortality of individuals with GHD.


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