Mutations in the GHRH-R gene account for approximately 10% of the patients with familial isolated GHD. In both our patients a homozygous G-> C transition at the splice donor site of intron VII was found, altering the first basepair of the intervening intronic sequence after exon 7. This mutation interrupts the signal transduction of GHRH, causes GHD and consequently severe postnatal growth retardation. Our patients were diagnosed at the ages of 16 and 14.9 years, respec- tively, and they both showed signs of advanced puberty. We hypothesized that GH treatment alone at this advanced stage of puberty would accelerate bone matura- tion progressively and thereby limit the effect on final height, while administration of GnRHa might delay the process of epiphyseal fusion by inhibiting the secretion of gonadotropins and gonadal sex steroids. Our cases illustrate that severely GH deficient adolescents can greatly benefit from the combination GH and GnRHa treatment, even at an advanced age, bone age and pubertal stage.
The large height gain on GH and GnRHa treatment as we experienced in our patients is far beyond the average additional effect of GnRHa in group analyses (approximately 7 cm) (13-17). Also in individual patients with GH deficiency we are not aware of reports on such extremely good result. We speculate that, in our cases, who have a severe GH deficiency caused by a well-defined genetic disorder, the intact GH –IGF-I axis downstream the level of the GHRH-R resulted in maximal GH sensitivity. This is supported by the significant rise of IGF-I seen in the IGF-I
Large height gain by GH and GnRH therapy in GHRH-R mutation
47
response to GH therapy in those patients (2-5, 18). The good sensitivity allows optimal catch-up growth, while the absence of estrogen restricts epiphyseal mat- uration. The only report on GH and GnRHa therapy in a boy with a GHRH-R mutation also showed a positive effect on linear growth, but this was limited to a few centimeters (19).
The TSH response to TRH was suboptimal in our patients, suggesting mild secondary hypothyroidism. A blunted TSH response was also reported in other
patients with a GHRH-R mutation (18).One could hypothesize that hypoplasia
of the pituitary is one of the contributing factors, however the pituitary size was normal in the brother. Another possible explanation for the blunted TSH response is that GHRH is necessary for maximal TSH production, although the normal TRH test at adult age argues against this. The low T4 levels after the start of GH therapy were probably the result of the positive effect of GH on 5’deiodinase activity, the enzyme converting T4 into T3 (20). In general, treatment is not necessary as T4 levels recover spontaneously, but in our cases levothyroxine treatment was started to create optimal conditions for growth.
In conclusion, this report shows that in patients with isolated GH deficiency due to a GHRH-R mutation, combined treatment of GH and GnRHa can have a great effect on adult height, even if started at an advanced bone age and pubertal stage.
Chapter 3
48
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