Correlation between exon 3 polymorphism of growth hormone receptor gene and the responses to rhGH therapy

Objective: To investigate the correlation between the exon 3 polymorphism of growth hormone receptor (GHR) gene and the responses to the recombinant human growth hormone (rhGH) therapy in children with short stature. Methods: Forty-five growth hormone deficiency (GHD) children (male: 30, female: 15, aged 10.39±2.73 yrs) and twenty-five idiopathic short stature (ISS) children (male: 15, female: 10, aged 10.58±2.56 yrs) admitted to our hospital were included. The polymorphism of exon 3 of GHR gene was determined using multiple PCR amplification. Treatment duration for each subject was at least 12 months. On this basis, we evaluated the correlation between treatment efficiency of rhGH therapy and GHR exon 3 polymorphism, GHD, and treatment duration. Results: Significant difference was noted in the growth velocity (GV) of GHD children with a genotype of GHRfl compared with those with a genotype of GHRd3 (9.44±2.35 vs. 11.36±2.49, P < 0.05). Meanwhile, the GV of ISS patients with a genotype of GHRfl were remarkably decreased compared with those with a genotype of GHRd3 (8.74±2.36 vs. 11.18±2.44, P < 0.05). For the children with peak GH response of less than 5 ng/ml, statistical difference was noted in the GV of children with a genotype of GHRfl compared with those with a genotype of GHRd3 (9.55±2.76 vs. 10.84±1.53, P < 0.05). For the patients with peak GH response to clonidine or pyridostigmine bromide of > 5 ng/ml, a satisfactory response to rhGH therapy was noted in children with a genotype of GHRd3 compared with those of GHRfl (P < 0.05). Conclusions: GHRd3 was correlated with the response to rhGH therapy in children with short stature. For the patients with the same genotype, GHD caused no obvious effects on the final height. However, for the patients with peak GH response of > 5 ng/ml, a satisfactory response to rhGH therapy was noted in children with a genotype of GHRd3 compared with those of GHRfl (P < 0.05). A higher treatment efficiency was obtained in those received rhGH at an early age.     

Growth hormone deficiency and growth hormone therapy in Ullrich-Turner-Syndrome

Summary In a girl with Ullrich-Turner-Syndrome (gonadal dysgenesis 45, XO) and growth hormone deficiency, 10 U of human growth hormone/m² body surface area/week increased the growth rate from 2.0 to 4.1 cm/year. Doses of up to 36 U/m²/week did not improve the growth rate in 4 girls with Ullrich-Turner-Syndrome who had normal plasma growth hormone concentration and incretion. We conclude that growth hormone therapy is unsuccessful in dwarfism in Ullrich-Turner-Syndrome and should be reserved for patients with proven growth hormone deficiency.Supported by Deutsche Forschungsgemeinschaft, SFB 51/C10     

Growth and growth hormone therapy in children with achondroplasia: A two-year experience

The efficacy and safety of recombinant human growth hormone (hGH) administration was studied in children with achondroplasia. Fifteen children with achondroplasia, seven boys (4.8–12.2 years of age) and 12 girls (5.7–2.2 years of age), were treated daily with hGH at a dosage of 1 IU/kg/week. Auxological assessments were performed 6 months before, at initiation of, and at 6, 12, and 24 months following initiation of growth hormone (GH) therapy. Before initiating GH therapy, hypothalamic-pituitary and thyroid functions were evaluated. Levels of serum insulin-like growth factor (IGF)-I and IGF binding protein (BP)-3 (IGFBP-3) were assessed, as was GH response to provocative stimuli. GH responses in two stimulation tests were normal for all but three children. During the first semester of GH treatment, a significant increase in height velocity (HV), from 3.2 to 8.3 cm/year, was observed in all children. However, during the second semester, a relative decrease in growth rate was observed. By the end of the first year, HV had increased from 3.2 to 6.9 cm/year (mean, 3.7 cm/year; range, 1.1–8 cm/year) in 13 children and remained unchanged in two children. HV declined progressively during the next 12 months and, by the end of the second year of treatment, had increased in seven of the nine children who had completed 2 years of therapy (mean increase, 3.1 cm/year); two children did not respond to GH therapy, as shown by the lack of increase in HV. Sitting-height (SH) to standing-height ratio % (SH%) remained unchanged throughout GH therapy, and no significant change in skeletal maturation was observed. In conclusion, hGH treatment resulted in an increased growth rate in some children with achondroplasia; however, this increase waned during the second year of treatment. Children with the lowest pretreatment HVs seemed to benefit most from GH therapy. Nonetheless, the usefulness of GH treatment in achondroplasia will be known only when a study of final height is completed. Am. J. Med. Genet. 72:71–76, 1997. © 1997 Wiley-Liss, Inc.     

16例伴生长激素缺乏的多种垂体激素缺乏患者的临床特点及生长激素治疗效果分析

目的探讨伴生长激素缺乏(GHD)的多种垂体激素缺乏症(MPHD)患者的临床特点以及生长激素(GH)治疗效果。方法回顾性分析16例伴有生长激素缺乏的多种垂体激素缺乏患者的临床资料。结果本研究纳入了16例MPHD的患者,其中伴甲状腺功能减退症9例、伴低促性腺激素性性腺功能低减13例和伴肾上腺皮质功能减退6例。臀位、足先露和难产等不良生产史患者10例。骨龄(11.0±3.5)岁,明显落后实际年龄。L-Dopa-GH激发试验GH峰值为(0.14±0.17)ng/m L,GH治疗平均剂量(0.11±0.02)IU/kg。治疗后IGF-1水平及生长速度均明显增加。结论排除下丘脑、垂体占位等病变后,伴GH缺乏的MPHD患者在纠正其他轴系激素缺乏后,使用GH治疗可明显改善身高,并且无严重不良事件发生。     

Transient growth hormone therapy to rats with low protein-inflicted intrauterine growth restriction does not prevent elevated blood pressure in later life

Intrauterine growth restriction (IUGR) is a risk factor for the development of hypertension in later life. Insulin-like growth factor I and growth hormone (GH) have the potential to improve metabolic syndrome after IUGR in adult animals. The objective of the present study was to examine whether transient GH treatment of pups after weaning can prevent the development of arterial hypertension in adult rats.

IUGR was induced in Wistar rats by isocaloric protein restriction in pregnant dams and litter size was reduced to six male neonates after birth. Recombinant human GH was applied by daily subcutaneous injections at a dose of 3 μg/g body weight between days 24 and 60 of life. Control animals received vehicle treatment (VEH) only.

Birth weight was significantly lower in low protein (LP) animals than in normal protein (NP) animals (5.1 ± 0.3 g vs. 5.9 ± 0.7 g, p < 0.05). Until weaning at day 23, LP animals reached similar body length, but had reduced body weight compared to NP animals. Intraarterially measured mean arterial blood pressure at day 120 was elevated in LP-VEH compared to NP-VEH animals (113 ± 6 mmHg vs. 101 ± 6 mmHg, p < 0.01). However, transient GH-treatment did not prevent arterial hypertension in LP animals (112 ± 5 mmHg).

Our data suggest that GH treatment between days 24 and 60 of life does not or at least not permanently reprogram blood pressure elevation after IUGR.     

基因重组人生长激素治疗特发性身材矮小儿童的临床观察

目的为了了解基因重组人生长激素(r-hGH)治疗特发性身材矮小儿童时其对身高、青春期的影响.方法我们对14例特发性身材矮小(ISS)儿童采用r-hGH治疗3～12月,比较其治疗前后的年生长速率和青春发育情况.结果经r-hGH治疗,特发性身材矮小儿童的年生长速率有显著提高,身高年龄的增长明显快于生活年龄和骨龄的增长,但没有明显青春期加速的现象.结论r-hGH可显著改善特发性身材矮小儿童的身高,且青春期、骨龄均不提前.     

GH-1 gene splicing mutations: Molecular basis of hereditary isolated growth hormone deficiency in children

Children, residents of the Russian Federation, with congenital isolated growth hormone deficiency, were screened for mutations of GH-1 gene, the main gene of this deficiency. Twenty-eight children from 26 families with total congenital isolated growth hormone deficiency were examined. Direct sequencing of GH-1 detected five splicing mutations in intron 2, intron 3, and exon 4, two of them were never described previously. Three dominant negative mutations of GH-1 splicing, the basis for autosomal dominant isolated growth hormone deficiency (type II), are presented: IVS2 −2A>T, IVS3 +2T>C, and IVS3 +1G<A. GH-1 is the main gene of type II isolated growth hormone deficiency in patients living in the Russian Federation. All detected mutations of GH-1 impair splicing processes, which distinguishes them from mutations in other forms of isolated growth hormone deficiency. The detected variety of GH-1 splicing mutations attests to allele genetic heterogeneity of this pathology. The “hot spot” of mutations is 5′-donor splicing site of GH-1 intron 3, while IVS3 +1G>A mutation can be regarded as the most incident in type II isolated growth hormone deficiency in the Russian population. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 141, No. 3, pp. 324–329, March, 2006     

完全性生长激素缺乏患儿大脑皮质脑沟深度与曲率变化的MRI研究

目的 探讨完全性生长激素缺乏(CGHD)患儿与特发性矮小(ISS)患儿大脑皮质脑沟深度与曲率的差异。方法 纳入2015年1月-2019年1月山东大学附属省立医院确诊的CGHD与ISS患儿各12例进行回顾性队列研究。CGHD组男8例、女4例,年龄5~14岁,生长激素刺激释放试验的峰值水平<5.0 μg/L;ISS组男9例、女3例,年龄5~14岁,生长激素的峰值水平>10.0 μg/L。选取患者首诊时所采集的颅脑T₁WI MRI数据进行后处理分析。双侧半球与全脑皮质的脑沟深度与曲率均值应用FreeSurfer软件获得。将同一脑区的脑沟深度与曲率测量值进行组内平均与组间相减,以分别获得每个脑区该测量值的组内均值分布图与组间差异值分布图。两组患儿上述测量均值的组间差异应用协方差分析。结果 两组患儿的年龄与性别分布差异均无统计学意义(P值均>0.05)。CGHD组左、右侧半球与全脑的脑沟深度分别为(0.405±0.073)mm、(0.416±0.073) mm、(0.411±0.060)mm;左、右侧半球与全脑的曲率(×10)分别为(0.264±0.023)mm^-1、(0.259±0.017)mm^-1、(0.261±0.019)mm^-1。ISS组左、右侧半球与全脑的脑沟深度分别为(0.493±0.069)mm、(0.502±0.062) mm、(0.497±0.057)mm;左、右侧半球与全脑的曲率(×10)分别为(0.250±0.021)mm^-1、( 0.247±0.025)mm^-1、(0.249±0.022)mm^-1。两组患儿的双侧大脑半球与全脑脑沟深度比较(F_左=9.288、F_右=8.874、F_全=12.545)、左侧半球与全脑曲率比较(F_左=4.688、F_全=5.132),差异均有统计学意义(P值均<0.05)。两组患儿脑沟深度与曲率在全脑的分布规律相似,但存在脑区间测量值大小与分布范围的差异。结论 CGHD患儿与ISS患儿大脑皮质脑沟深度与曲率的MRI测量值存在差异,这可能与其运动、智力或其它相关功能发育相对落后相关。     

Syndrome of hypoparathyroidism,growth hormone deficiency,and multiple minor anomalies

A 5 1/2-year-old Saudi Arabian girl presented with a syndrome of intrauterine growth retardation, minor anomalies, hypoparathyroidism, and growth hormone deficiency. She was the product of a consanguineous mating. Her minor anomalies and delayed development were similar to findings in a previously reported Saudi Arabian patients with hypoparathyroidism and growth deficiency. There were substantial differences in findings from a series of Kuwaiti children. Parathyroid hormone was undetectable, but the renal response to infused parathyroid hormone was normal, indicating primary hypoparathyroidism. In response to arginine stimulation, her GH rose to 5.8 ng/ml (5.8 μg/L) (nl > 10), and to 2.3 ng/ml (2.3 μg/L) after L-dopa. Following clonidine it rose to 15 ng/ml (15 μg/L) at 120 minutes. She responded normally to infusions of GHRH (GH rose to 22 ng/ml (22 μg/L) at 75 minutes) and TRH (TSH rose to 37 μu/ml, 37 mlU/L). On treatment with recombinant human growth hormone, she showed an increase in height and weight. Hypocalcemia was well controlled with supplemental 1-α-cholecalciferol. © 1994 Wiley-Liss, Inc.     

Growth hormone does not increase the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary

A growing body of information now supports the existence of a complete intraovarian insulin-like growth factor I (IGF-I) system. Although the precise role of IGF-I in the context of ovarian physiology remains to be determined, it is likely that IGF-I may engage in the amplification of gonadotrophin hormonal action. These facts and experiments with animals establishing the ovaries of multiple species as a site of growth hormone (GH) reception and action have led to the use of recombinant GH (rGH) as an adjunctive agent to potentiate ovulation induction by exogenous gonadotrophins. Whether intraovarian IGF-I plays an intermediary role in GH hormonal action at the ovarian level remains uncertain at present. The aim of this study was to evaluate whether rGH administration to pre-menopausal women could modify the expression of the IGF-I gene in the ovary. The expression of the IGF-I gene was examined in a time-dependent manner in normal pre-menopausal ovaries obtained from nine women treated with rGH and nine control women treated with placebo, using solution hybridization/RNase protection assays. Ovarian tissue samples were obtained 24 h (six women) and 7 days (12 women) following rGH/placebo injection. Total RNA (20 microg) from whole pre-menopausal ovaries (with or without rGH treatment) as well as from human granulosa cells was hybridized with a human IGF-I antisense RNA. IGF-I peptide, but not oestradiol, serum concentrations increased significantly 24 h after rGH injection. IGF-I gene, however, was not expressed in the luteinized granulosa cells and whole pre-menopausal ovaries irrespectively of rGH treatment in ovarian samples analysed both 1 and 7 days following rGH injection. On the contrary, IGF-II mRNA transcribed from the fetal or fetal-neonatal IGF-II promoter and IGF-I receptor mRNA (both used as hybridization control) were both found in whole pre-menopausal ovary and luteinized granulosa cells. Nevertheless, no changes in the hybridization patterns were seen in the absence or presence of rGH. These studies demonstrate that rGH administration to normal premenopausal women does not change the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary. Furthermore, these results provide further evidence against locally produced IGF-I as responsible for any ovarian effects seen in systemic rGH administration.     

两种不同剂型基因重组人生长激素治疗生长激素缺乏性矮小的临床研究

目的观察基因重组人生长激素（rhGH）水剂与粉剂治疗生长激素缺乏性矮小的效果。方法将36例生长激素缺乏性矮小儿童随机分为A、B两组,分别采用rhGH水剂与粉剂治疗6个月,比较其治疗前后的年生长速率和青春期发育情况,及不良反应的发生率。结果经rhGH治疗,A、B两组生长激素缺乏性矮小儿童的年生长速率均明显的提高,身高年龄的增长明显快于生活年龄和骨龄的增长,A、B两组组间比较无统计学差异（P〉0.05）,没有明显青春期加速的现象。A、B两组胰岛素样生长因子-1（IGF-1）及其结合蛋白-3（IGFBP-3）含量,与治疗前相比差异有显著性（P〈0.01）;但两组组间比较无统计学差异（P〉0.05）。结论两种剂型rhGH均可显著改善生长激素缺乏性矮小儿童的身高,且青春期、骨龄均不提前。但粉剂治疗费用低于水剂,更易临床推广。     

The 3C syndrome: Evolution of the phenotype and growth hormone deficiency

The 3C syndrome (cranio-cerebello-cardiac dysplasia or the Ritscher-Schinzel syndrome) is a recently delineated condition involving abnormalities of the cranium (large head with prominent forehead), cerebellum (Dandy-Walker cyst and vermis hypoplasia), and cardiac (primarily septal) defects. At least 20 individuals with this condition have been reported in the past 11 years. We report on a girl with the 3C syndrome who at 13 years of age is the oldest patient reported to date. She has been followed since birth, allowing us to show the evolution of her phenotype over time. In addition, she has documented growth hormone deficiency. We suggest that growth hormone deficiency should be considered as a possible cause of the short stature often seen in this condition. Am. J. Med. Genet. 87:61–64, 1999. © 1999 Wiley-Liss, Inc.     

完全性生长激素缺乏患儿大脑皮质形态变化的3.0 T MRI研究

目的 探讨完全性生长激素缺乏(CGHD)患儿与特发性矮小(ISS)患儿大脑结构的灰质体积、皮层表面积及皮层厚度的差异。方法 回顾性队列研究。纳入2015年1月—2019年1月山东省立医院确诊的12例CGHD患儿(男8例、女4例,年龄5~14岁,生长激素刺激释放试验峰值小于5.0 μg/L)与12例ISS患儿(男9例、女3例,年龄5~14岁,生长激素刺激释放试验峰值大于10.0 μg/L)。在首次就诊时采集患者高分辨率、高信噪比三维T₁WI MRI。利用FreeSurfer软件图像后处理方法获得两组患儿左右大脑半球及全脑灰质体积、皮层表面积与皮层厚度值,统计分析组间的差异情况。将每组患儿的上述形态学参数值分别进行平均以获得该组患儿的均值分布图。将两组患儿的测量均值进行相减,即获得两组患儿该测量均值的差异值分布图。结果 CGHD患儿左、右侧大脑半球的灰质体积分别为(228.50±36.72)cm³、 (229.10±34.95)cm³;皮层表面积分别为(737.02±140.48)cm²、(738.68±135.26)cm²;皮层厚度分别为(2.43±0.09)mm、(2.44±0.09)mm。ISS患儿左、右侧大脑半球的灰质体积分别为(272.36±34.77)cm³、 (272.54±32.76)cm³;皮层表面积分别为(841.88±141.75)cm²、(839.98±135.69)cm²;皮层厚度分别为(2.55±0.18)mm、(2.57±0.17)mm。CGHD患儿与ISS患儿的双侧半球与全脑的灰质体积(F_左=17.884, F_右=20.115, F_全=19.009)、皮层表面积(F_左=11.105, F_右=11.453, F_全=11.337)及皮层厚度(F_左=5.907, F_右=6.109, F_全=6.066)的差异均有统计学意义(P值均<0.05)。测量值的均值分布图与均值的差异值分布图显示两组患儿的灰质体积、皮层表面积与皮层厚度在诸多脑区存在差异。结论 CGHD患儿较ISS患儿的大脑灰质体积、皮层表面积与皮层厚度均较小,这可能与其智力、运动或其它功能发育相对落后相关。     

Growth retardation and growth hormone deficiency in patients with Ataxia telangiectasia

Abstract

Background: Ataxia telangiectasia (A-T) is a devastating human recessive disorder characterised by progressive cerebellar ataxia, immunodeficiency, genetic instability, and cancer susceptibility. In addition, many patients suffer from growth failure. Methods: We analyzed growth and IGF-1/BP3 levels of 24 A-T-patients compared with an age-matched group of healthy controls (n?=?36). Results: Ten (41.7%) A-T patients and none of healthy controls had an IGF-1 level below the 3rd percentile for age. The growth hormone (GH) stimulation tests revealed a severe GH deficiency with no increase of >5?ng/ml in six of the ten A-T patients. The IGF-1 generation tests revealed normal increases in IGF-1 values in all patients. Conclusion: Our results show that a disturbance in the GH/IGF-1 axis was present in 58.3% of A-T patients. Low levels of GH were the result of reduced central GH secretion. GH treatment may be a therapeutic option for A-T patients with severe growth failure.     

6例Noonan综合征患者临床特点及重组人生长激素治疗效果分析

目的 本研究将总结6例Noonan综合征(NS)患者的临床特点、基因诊断结果及对重组人生长激素(rh GH)治疗的反应。方法 回顾性总结2009年5月至2015年8月在北京协和医院内分泌科矮小门诊的6例NS患者的临床特点。5例以0.1 IU/(kg·d)为起始剂量应用rh GH,进行定期随访,并与年龄/性别相匹配的同期应用rh GH的10例特纳综合征(TS)和10例生长激素缺乏症(GHD)患者进行比较。结果 6例患者均存在NS的典型临床表现;5例经rh GH治疗后,年生长速度显著增加(P0.01);NS与TS患者rh GH疗效相似,随访各点均无显著性差异;但GHD患者相比,在应用rh GH后疗效欠佳;不良事件:2例NS在随访期出现亚临床甲状腺功能减低。结论 NS患者具有典型的临床表现,基因检查有助于明确诊断,rh GH治疗有显著疗效及较高的安全性。     

Evaluation of growth hormone axis and responsiveness to growth stimulation of short children with osteogenesis imperfecta

We present four individuals with Gerodermia Osteodysplastica in a Jewish family from Morocco confirming the autosomal recessive inheritance of the disorder. Three previously unreported findings are described: (a) enlarged funnel-shaped mandibular lingula; (b) extension of the mandibular premolar and molar roots below the inferior dental canal, and of the second molars into the lower border of mandibular cortical bone; and (c) hypercementosis of the maxillary incisors and mandibular molars surrounded by a radiolucent halo in several teeth. The facial deformity resulting from maxillary hypoplasia and mandibular prognathism was corrected by orthognathic surgery: Le Fort I maxillary osteotomy and vertical mandibular osteotomy. © 1993 Wiley-Liss, Inc.     

重组人生长激素对烟雾吸人性损伤大鼠肺泡Ⅱ型细胞的增殖及Bcl-2和Bax蛋白表达的影响

目的研究重组人生长激素（ recombinant human growth hormone, rhGH ）对烟雾吸入性损伤大鼠肺泡Ⅱ型细胞（ATⅡ）增殖及Bcl-2和Bax蛋白表达的影响。方法清洁级雄性SD大鼠70只，体重160～180g，采用随机数字表法随机分为3组：正常对照组（C组）、单纯吸入性损伤组（I组）和吸入性损伤＋rhGH治疗（R组），后2组各再分为6、10、14日亚组。烟雾造成吸入性肺损伤模型，rhGH经腹部皮下注入（1．33U／kg），连续应用7d。各时相点剖胸取肺，行常规病理切片进行病理形态学观察并用免疫组化方法观察肺泡Ⅱ型细胞（ATⅡ）增殖以及Bcl-2和Bax蛋白表达的变化。结果rhGH能显著增加新增殖ATⅡ数量；正常大鼠肺组织Bcl-2和Bax mRNA无表达，皮下注射rhGH后6、10、14日R组Bcl-2蛋白表达阳性细胞分别为（31．01±2．70）、（52．34±3．44）、（50．15±4．00）个／HP，明显高于I组的（24．76±2．82）、（37．92±4．28）、（35．58±3．64）个／HP（P〈0．05）；R组Bax蛋白表达阳性细胞为（21．16±2．79）、（31．22±5．62）、（26．27±5．41）个／HP，明显低于I组[（26．51±2．61）、（41．50±4．14）、（34．55±2．94）个／HP，P〈0．05]。结论经皮下注入外源性rhGH能有效刺激ATⅡ的增殖，上调Bcl-2蛋白表达及下调Bax蛋白表达，改变Bcl-2／Bax的比值从而抑制细胞凋亡。     

A polymorphism in the leptin receptor gene at position 223 is associated with growth hormone replacement therapy responsiveness in idiopathic short stature and growth hormone deficiency patients

We hypothesized that responses to growth hormone (GH) therapy by idiopathic short stature (ISS) and growth hormone deficiency (GHD) patients were associated with single nucleotide polymorphisms (SNPs) in the leptin (LEP) and leptin receptor (LEPR) genes. We retrospectively enrolled ISS (n = 32) and GHD (n = 38) patients and forty healthy age-and gender-matched children. They were genotyped for the LEP promoter at nt.-2548, and LEPR K109R and LEPR Q223R polymorphisms. Clinical and laboratory variables were determined before and after 2 years of GH treatment. ISS patients with G/A or A/A genotypes of the LEPR Q223R SNP had a significantly higher height velocity (cm/y) than ISS patients with the G/G genotype at 2 years after GH treatment. For GHD patients, G/A or A/A genotype of the LEPR K109R SNP was associated with higher body weight, higher BMI, and higher weight velocity than patients with the G/G genotype before GH treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher body weight, higher height velocity before treatment, but not after GH treatment. G/A or A/A genotype of the LEPR Q223R SNP was associated with a significantly higher weight velocity before treatment, but a significantly lower weight velocity was found at 2 years after GH treatment. These results suggest LEPR Q223R SNP (rs1137101) is associated with outcomes of GH replacement therapy in ISS and GHD patients.