Desai Meena P, Upadhye Pradnya S, Kamijo Takashi, Yamamoto Michiyo, Ogawa Masamichi, Hayashi Yoshitaka, Seo Hisao, Nair Shilpa R
Sir Hurkisondas Nurrotumdas Medical Research Society, Sir H.N. Hospital & Research Centre, Mumbai, India.
J Pediatr Endocrinol Metab. 2005 Oct;18(10):955-73. doi: 10.1515/jpem.2005.18.10.955.
Various mutations of the growth hormone releasing hormone receptor (GHRH-R) gene have been recently described to cause familial isolated growth hormone (GH) deficiency (FIGHD), with the GHRH-R nonsense mutation E72X reported in patients with FIGHD from South Asia. The molecular genetic basis of FIGHD in Indian children is not known.
To look for the GHRH-R E72X non-sense mutation in our patients with FIGHD and describe its clinical phenotype.
A total of 31 patients from 22 families diagnosed 4-20 years previously, 20 patients with familial IGHD-IB from 11 families and 11 patients with non-familial isolated GH deficiency (NFIGHD) (phenotypes IGHD-IB in eight patients and -IA in three) were included. Twenty-eight of 31 patients with IGHD-IB came from two states of Western India, 27 of them Hindus from 18 families (three consanguineous) and one from an inbred Moslem kindred.
Twenty-two of the patients (71%) (18 FIGHD and four NFIGHD) had a homozygous G-->T transversion in exon 3, with this GHRH-R gene mutation E72X in 90% (18/20) of patients with FIGHD, 36% (4/11) of NFIGHD, altogether 78% (22/28) with phenotype IB. One parent pair with IGHD had homozygous E72X mutation, the rest were heterozygous carriers. Two siblings with IGHD due to homozygous E72X mutation were also heterozygous carriers for GH-1 gene 6.7 kb deletion, inherited from their mother, heterozygous for both GH-1 and GHRH-R mutations. Initial chronological age was 10.89 +/- 3.69 years, bone age 6.4 +/- 3.4 years, and mean height SDS was -5.83 +/- 1.41. The clinical phenotype, with sharp features, lean habitus, lack of frontal bossing or hypoglycemia, was characteristic. The mean peak GH was 1.25 +/- 0.75 ng/ml, IGF-I and IGFBP-3 below -2 SDS with no response to GHRH in those tested. MRI (n = 10) showed pituitary hypoplasia, mean vertical height 2.61 +/- 0.76 mm. Among the other 7/11 NFIGHD patients, four with phenotype IB were negative for genotypes tested in this study; of three patients with phenotype IA, two had the GH-1 gene 6.7 kb deletion, and one was a compound heterozygote with 6.7 and 7.6 kb deletions.
The majority of patients with FIGHD from different communities belonged to non-consanguineous Hindu families from Western India. The GHRH-R gene E72X mutation was found in 71% of this series, in 90% of FIGHD, 36% of NFIGHD, and in 78% with phenotype IB. The characteristic phenotype helped in suspecting this mutation. GHRH-R gene mutations may be the most reasonable candidate for IGHD-IB with the E72X mutation predominating in the Indian subcontinent. More extensive studies need to be undertaken.
最近已描述生长激素释放激素受体（GHRH-R）基因的各种突变可导致家族性孤立性生长激素（GH）缺乏症（FIGHD），在来自南亚的FIGHD患者中报告了GHRH-R无义突变E72X。印度儿童FIGHD的分子遗传基础尚不清楚。
在我们的FIGHD患者中寻找GHRH-R E72X无义突变并描述其临床表型。
纳入了22个家庭中总共31例4至20年前诊断的患者，11个家庭中的20例家族性IGHD-IB患者和11例非家族性孤立性GH缺乏症（NFIGHD）患者（8例为IGHD-IB表型，3例为-IA表型）。31例IGHD-IB患者中有28例来自印度西部的两个邦，其中27例为印度教徒，来自18个家庭（3个近亲家庭），1例来自近亲穆斯林家族。
22例患者（71%）（18例FIGHD和4例NFIGHD）在第3外显子中有纯合的G→T颠换，该GHRH-R基因突变E72X在90%（18/20）的FIGHD患者、36%（4/11）的NFIGHD患者中出现，总计78%（22/28）具有IB表型。一对患有IGHD的父母为E72X纯合突变，其余为杂合携带者。两名因E72X纯合突变而患有IGHD的兄弟姐妹也是GH-1基因6.7 kb缺失（从其母亲遗传而来）的杂合携带者，同时携带GH-1和GHRH-R突变。初始实足年龄为10.89±3.69岁，骨龄6.4±3.4岁，平均身高标准差为-5.83±1.41。临床表型特征为面容消瘦、体型纤细、无额部突出或低血糖，具有特征性。平均GH峰值为1.25±0.75 ng/ml，IGF-I和IGFBP-3低于-2个标准差，且在接受检测的患者中对GHRH无反应。MRI（n = 10）显示垂体发育不全，平均垂直高度为2.61±0.76 mm。在其他7/11例NFIGHD患者中，4例IB表型患者在本研究中检测的基因型为阴性；3例IA表型患者中，2例有GH-1基因6.7 kb缺失，1例为6.7 kb和7.6 kb缺失的复合杂合子。
来自不同社区的大多数FIGHD患者属于印度西部非近亲的印度教家庭。本系列中71%的患者发现有GHRH-R基因E72X突变，在90%的FIGHD患者、36%的NFIGHD患者以及78%的IB表型患者中存在该突变。特征性表型有助于怀疑该突变。GHRH-R基因突变可能是IGHD-IB最合理的候选病因，E72X突变在印度次大陆占主导。需要进行更广泛的研究。
