Crouzon综合征合并生长激素缺乏症1例报告及重组人生长激素治疗随诊

目的报告1例Crouzon综合征合并生长激素缺乏症(GHD)患儿及其重组人生长激素(rhGH)治疗结果。方法回顾分析患儿以rhGH治疗2年的临床资料。结果患儿女性,5岁4月龄时身高98.2 cm(P_3),有特殊面容(舟状头、突眼、反颌畸形等)。基因检测示FGFR2基因存在c.1061CG(p.Ser354Cys)杂合变异,源自母亲,为已知的致病变异,诊断为Crouzon综合征。同时相关检查提示患儿合并GHD。给予rhGH治疗2年,身高117 cm,平均生长速率为9.4 cm/a。治疗期间,头颅磁共振监测提示侧脑室及第三脑室略扩张等表现未进展,眼科随诊示左眼视盘水肿程度较前减轻,未发现不良反应。结论矮小可能是Crouzon综合征的表型,rhGH治疗可以改善Crouzon综合征合并GHD患儿的身高,且未引起患儿颅内压增高等不良反应。     

Growth hormone deficiency in Dubowitz syndrome

Severe short stature as a result of intra-uterine growth retardation is one of the characteristics of Dubowitz syndrome. There have been few reports elaborating growth hormone secretory status in this syndrome. A child with Dubowitz syndrome, who was found to have complete growth hormone (GH) deficiency and who responded to growth hormone therapy, is described. This appears to be the first documentation of GH deficiency in this syndrome.     

1例Bartter综合征的家系基因突变分析和产前诊断

目的对1例Bartter综合征的家系进行相关致病基因突变分析和产前诊断。方法应用高通量捕获测序技术、PCR-Sanger测序法从基因组水平对先证者进行Bartter综合征相关致病基因的检测及家系分析;明确遗传学病因后进一步对已妊娠5个月的先证者母亲抽取羊水进行产前诊断。结果先证者编码氯通道蛋白CLC-Kb的CLCNKB基因存在c.88CT(p.Arg30*)和c.968+2TA复合杂合突变,其中c.88CT(p.Arg30*)为已报道的致病突变,c.968+2TA为新突变。家系分析显示这两个突变分别源自其母亲和父亲。产前诊断结果显示胎儿未遗传其父母的突变,为两个位点均正常的健康个体,随诊显示出生的婴儿健康,证实了基因诊断及产前诊断的准确性。结论 CLCNKB基因的复合杂合突变c.88CT(p.Arg30*)和c.968+2TA为先证者的病因,产前诊断可以预防该家系Bartter综合征的再发风险。     

Central precocious puberty and growth hormone deficiency in a boy with Prader-Willi syndrome

In Prader-Willi syndrome (PWS) hypothalamic dysfunction is the cause of hormonal disturbances, such as growth hormone deficiency (GHD), hypogonadism, and delayed or incomplete puberty. Only a few cases of central precocious puberty (CPP) have been reported. We describe an 8.8-year-old PWS boy, with microdeletion of chromosome 15q, who developed CPP. On admission, height was 131.1 cm (+0.17 SD), BMI 26.2 kg/m², pubic hair (Ph) 2, and testis 4.5 ml. We found increased growth velocity (7 cm/year), high testosterone levels, pubertal response to GnRH test, and advanced bone age (10.6 years). An evaluation of growth hormone (GH) secretion revealed a deficiency. Pituitary MRI was normal. LHRH analogue therapy (Leuproreline 3.75 mg/28 days i.m.) was started at 8.9 years and discontinued at 11.3 years, when the patient had bone age of 13 years. During therapy, growth velocity, testosterone, FSH, and LH peak decreased significantly, with no pubertal progression. Growth hormone therapy (0.24 mg/kg/week) was started at 9.5 years and discontinued at 15.3 years because the patient had bone age of 17 years. After interrupting LHRH therapy the patient demonstrated spontaneous pubertal progression with pubertal gonadotropin and testosterone. At 16.3 years, height was 170 cm (−0.48 SDS), BMI 36.3 kg/m², Ph 4, testis volume 10 ml and there was a combined hypothalamic and peripheral hypogonadism hormonal pattern (normal LH even with low testosterone and undetectable inhibin B with high FSH). To our knowledge this is the fourth male patient with genetically-confirmed PWS demonstrating CPP and GHD and the first with a long follow-up to young adulthood.     

Growth hormone deficiency in Sturge-Weber syndrome

Sturge-Weber syndrome (SWS) is a disorder involving central nervous system abnormalities that may increase the risk of hypothalamic-pituitary dysfunction. Records of 19 patients with suspected growth hormone deficiency (GHD), identified from a registry of 1653 patients with SWS, were reviewed; nine patients with GHD were found.     

Smith-Magenis syndrome and growth hormone deficiency

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome including physical and neurobehavioural features. The disease is commonly associated with a ca. 3.7 Mb interstitial deletion of chromosome 17p11.2, while a 1.1 Mb critical region has been identified, containing about 20 genes expressed in multiple tissues. Haploinsufficiency of one of them, RAI1, seems to be responsible for the neurobehavioural, craniofacial and otolaryngological features of the syndrome, but not for short stature, commonly seen in SMS patients with chromosome deletion, implying the role of other genes in the 17p11.2 region. Growth failure is a final result of several different mechanisms involving decreased growth hormone (GH) production, reduced tissue response to GH, or impaired activity of epistatic factors. To our knowledge, the association of GH deficiency with SMS has never been reported and rarely investigated, despite the very short stature of SMS patients. We describe a girl with a full SMS phenotype and a typical 3.7 Mb deletion of 17p11.2 who also has GH deficiency. After starting replacement therapy, growth has significantly improved, her stature being now above both the 10th percentile and her genetic target. Conclusion:we suggest that an investigation of both growth hormone secretion and function is carried out in patients with Smith-Magenis syndrome and 17p11.2 deletion.Abbreviations FISH fluorescent in situ hybridisation - GH growth hormone - SMS Smith-Magenis syndrome     

Comparison of growth hormone releasing hormone therapy and growth hormone therapy in growth hormone deficiency

Seven children with growth hormone deficiency of hypothalamic origin responded to an i.v. bolus of growth hormone releasing hormone (GHRH) (1–29)-NH2 with a mean serum increase of 10.7 ng/ml growth hormone (GH) (range 2.5–29.3 ng/ml). Continuous s.c. administration of GHRH of 4–6 g/kg twice daily for at least 6 months did not improve the growth rate in five of the patients. One patient increased his growth rate from 1.9 to 3.8 cm/year and another from 3.5 to 8.2 cm/year; however, the growth rate of the latter patient then decreased to 5.4 cm/year. When treatment was changed to recombinant human growth hormone (rhGH) in a dose of 2 U/m² daily, given s.c. at bedtime, the growth rate improved in all patients to a mean of 8.5 cm/year (range: 6.2 to 14.6). Presently GHRH cannot be recommended for the routine therapy of children with growth hormone deficiency since a single daily dose of rhGH produced catch-up growth which GHRH therapy did not.Abbreviations GH growth hormone - GHD growth hormone deficiency - GHRH growth hormone releasing hormone - hGH human growth hormone - rhGH recombinant human growth hormone - SM C/IGF I somatomedin C/insulin-like growth factor I On the occasion of the 85th birthday of Prof. Dr.Dr.h.c. mult. Adolf Butenandt     

Neonatal Bartter syndrome with cholelithiasis and hydrocephalus: Rare association

Neonatal Bartter syndrome (NBS) is a rare autosomal recessive renal tubular disorder. This disease is characterized by hypokalemia, hypochloremia, and metabolic alkalosis that is often associated with failure to thrive and recurrent episodes of dehydration. The combination of BS and cholelithiasis in an infant is very rare. Herein, we report a premature male infant with NBS who developed cholelithiasis and hydrocephalus on clinical follow up. We recommend that periodic routine hepatobiliary ultrasonograpic screening for cholelithiasis should be performed in patients with NBS.     

A review of growth hormone deficiency

Growth hormone deficiency (GHD) is a rare but important cause of short stature in children. It is treatable. However, diagnosis is challenging and often requires referral to a specialist paediatric endocrinologist to facilitate testing and the interpretation of results. Careful history and examination with meticulous auxology data are critical components of the initial evaluation in clinic. Thereafter, further investigations are required to exclude other causes of short stature, and to establish the diagnosis. It is a highly variable condition and to an extent the clinical features depend upon the severity of GHD itself. GH stimulation tests may be indicated in the short child who is growing slowly and who has low growth factor concentrations. There is, however, no consensus with respect to a diagnostic gold standard test for GHD, and this is usually based upon a combination of clinical, biochemical, and neuroradiological data, although molecular diagnosis may aid in years to come. This short article gives an overview of the importance of GHD and offers advice on how to take a history, conduct and examination and begin investigation for a child with suspected GHD. It discusses the known benefits and potential risks of treatment and offers practical advice for the generalist.     

Screening for growth hormone deficiency using urinary growth hormone measurement

The diagnostic approach in growth hormone deficiency (GHD) is complicated. Two or more provocative tests are essential for definitive diagnosis of GHD. However, such testing cannot be carried out routinely on all subjects with short stature because of the need for hospitalization and blood sampling. A simple screening method for GHD would be of great value. Human growth hormone (hGH) levels were measured in the early morning urine of 192 children aged 7–15 years with height 2.0 s.d. below the mean for their ages. Sixty-eight subjects were selected because they showed a urinary hGH level < 10 ng/g creatinine. They were further examined in terms of bone age and plasma insulin-like growth factor (IGF-I) levels. In 30 subjects, the ratio of bone age: chronological age was < 0.8 and/or plasma IGF-I level was < 0.7 U/mL. Finally 24 of these subjects were examined with provocative tests and other endocrinological tests. Eleven subjects proved to have poor growth hormone secretion and one subject was diagnosed as having Turner syndrome. In conclusion, 11 patients with GHD were diagnosed from 192 children with short stature using urinary hGH measurement as the first screening method. These findings suggests that urinary hGH measurement could be a useful and simple method for detecting GHD.     

生长激素缺乏症患儿重组人生长激素治疗前、后肾上腺皮质功能的变化

目的观察生长激素缺乏症(GHD)患儿重组人生长激素(rh GH)治疗前、后肾上腺皮质功能的变化。方法选取72例确诊GHD并接受rh GH治疗6个月以上的患儿,其中32例伴促肾上腺皮质激素(ACTH)缺乏,回顾性分析其在接受rh GH治疗前及治疗后3、6个月时清晨空腹血皮质醇(COR)、ACTH水平的变化。结果 32例伴ACTH缺乏患儿通过外源性补充氢化可的松(HC)使COR达正常水平后,再开始rh GH治疗,治疗前COR水平和使COR达正常下限时的HC剂量呈显著负相关(r=-0.899,P0.01)。单纯HC治疗1个月后COR水平较治疗前明显增高,ACTH水平明显下降,差异均有统计学意义(P0.001);经rh GH和HC替代治疗后3、6个月后COR及ACTH水平与单纯HC治疗1个月差异无统计学意义(P0.05)。40例无ACTH缺乏患儿在rh GH治疗后COR水平显著降低,与治疗前比较差异有统计学意义(P0.01),其中10例MRI显示下丘脑-垂体异常患儿表现为COR水平低下。结论 GHD患儿在rh GH治疗过程中可出现肾上腺皮质功能减低,特别是MRI显示垂体异常的患儿,应注意监测肾上腺皮质功能,及早干预。     

Excessive growth in a child with craniopharyngioma and growth hormone deficiency

In a 5-year-old boy presenting with clumsiness and excessive growth, a large craniopharngioma was diagnosed. Biochemically, there was a deficiency of growth hormone, a hypothalamic hypothyroidism and hypocorticalism, a thyroxine binding globulin elevation, an abnormal gonadotropin secretion and a mild hyperprolactinaemia. After removal of the tumour growth stopped almost completely. Plasma insulin-like growth factor (IGF)-I was in the lower normal range. Plasma IGF-II decreased after tumour removal. It is speculated that the tumour produced a growth factor causing excessive growth.Abbreviations GH growth hormone - IGF insulin-like growth factor - TSH thyroid-stimulating hormone - SDS standard deviation score - TBG thyroxine binding globulin - LH luteinizing hormone     

Occurrence of acute megakaryoblastic leukemia in a patient with idiopathic growth hormone deficiency

We describe a case of a 15 year old boy who developed acute megakaryoblastic leukemia (AMKL) while receiving treatment with human growth hormone (hGH) for idiopathic growth hormone deficiency (GHD). He was diagnosed as having idiopathic GHD and given hGH from December 1991. The examination of his peripheral blood showed mild pancytopenia 2 months before the start of the hGH therapy. Since January 1992, paleness of the skin, general fatigue and fervescence progressed gradually. In February 1992, because of the occurrence of acute leukemia, administration of hGH was discontinued. Judging from the results of surface marker analysis of the blast cells, the patient was diagnosed as having AMKL. He was treated with chemotherapy for acute non-lymphoblastic leukemia from March 1992. A complete remission was obtained after 4 weeks of treatment. The chemotherapy was completed in July 1993. He remains in complete remission 26 months after diagnosis. This case suggests the importance of hematological examination and, when there is any abnormality which is not caused by GHD, such as pancytopenia, more detailed medical examinations (for example bone marrow examination) are necessary.     

Chemotherapy-induced growth hormone deficiency in children with cancer

Background. Chemotherapy (CT) may produce growth impairment, however, the pathogenesis is still unclear. Methods. A series of 25 patients mean age 13.3 years (6.3–19.8), previously treated for malignant solid tumours with only CT and surgery were studied. Growth hormone (GH) reserve was assessed by two different provocative stimuli (Clonidine and L-Dopa). Mean time between completion of treatment and GH evaluation was 18.5 months (2–74 months). At that time, all patients were in complete remission. Results. GH deficiency (GHD), defined by an impaired GH response to both provocative tests was observed in 11 out of 25 patients (44%). At diagnosis, mean standing height was +0.23 ± 1.42 SDS in the GHD group (GHD-g) and +0.18 ± 1.23 SDS in the non-GHD group (n-GHD-g). At the end of therapy, the mean standing height in the GHD-g was ?0.31 ± 1.22 SDS and ?0.17 ± 1.41 in the n-GHD-g, differing from the former group (P = 0.05). For a mean follow-up of 30 months from the end of treatment, the mean standing height was ?0.48 ± 1.23 SDS in the GHD-g and ?0.24 ± 1.51 SDS for the n-GHD-g (P = 0.03). Growth rate at the end of treatment was +0.13 ± 1.54 in the GHD-g and +0.21 ± 1.75 in the n-GHD-g. For a mean follow-up of 30 months from the end of treatment, the growth rate was different between GHD-g and n-GHD-g (?0.31 ±2.72 vs. ?0.21 ± 1.93, P < 0.05). Conclusions. 1) Growth impairment in children treated because of malignant diseases has a multifactorial etiology, but CT-induced GH deficiency is one potential adverse factor. 2) An endocrine follow-up should be introduced in order to detect and treat hormonal deficiencies as early as possible. © 1995 Wiley-Liss, Inc.     

Heart rate increases in patients with growth hormone receptor deficiency treated with insulin-like growth factor I

Cardiac function was measured in 16 prepubertal Ecuadorean patients with growth hormone receptor deficiency given insulin-like growth factor I (IGF-I) during part of a clinical trial. The IGF-I was given subcutaneously twice daily at a dose of 40 μg/kg on days 1 and 2, 80 μg/kg on days 3 and 4, and 120 μg/kg thereafter. Heart rate was determined at baseline (pretreatment) and on days 1–7 by repeated palpation of the radial artery and at baseline and on days 2, 4 and 7 by continuous portable Holter monitoring. Heart rate measured by both methods rose progressively with increasing doses of IGF-I. The mean palpated pulse exceeded baseline on each treatment day and was significantly higher on day 5 than day 4 and significantly higher on day 3 than day 2. The mean Holter heart rate was significantly higher on day 4 than on day 2 and significantly higher on day 2 than at baseline. Non-significant glucose and electrolyte changes did not appear to be associated with the cardiac events.     

生长激素治疗生长激素缺乏症时心脏结构和功能变化

目的评价用人重组生长激素（r－hGH）治疗原发性生长激素缺乏症患者时心脏结构和功能变化。方法对9例确诊为原发性生长激素缺乏患者用r－hGH治疗前后及对20例年龄、性别相匹配的正常青少年通过一维和二维心超检查。结果治疗后患儿的空间隔厚度、左室后壁厚度及心肌重量指数明显上升,与正常相比,仍有一定差异,但差异比治疗前明显缩小。结论生长激素缺乏患者心脏的结构已经受累,但功能尚未有影响,经r-hGH治疗后,心肌重量指数明显上升,提示r-hGH对改善生长激素缺乏患者心脏结构有一定作用。     

Prediction of growth response in prepubertal children treated with growth hormone for idiopathic growth hormone deficiency

Several multiple regression models have been developed to predict the first-year growth response to human growth hormone (hGH) in children with growth hormone deficiency (GHD). It was the aim of this study to analyse the significance of various growth parameters for a height prediction model. Data from 148 prepubertal children with idiopathic GHD were evaluated. The prediction model was developed by means of univariate and stepwise linear regression analysis and an “all possible” regression approach using Mallow's C(p) statistics. Six out of eight selected variables had a significant influence on the first-year growth rate. The most important parameter was the difference between target height SDS and height SDS at the start of therapy (THSDS - HSDSC0), accounting for 23.95% and 25.74% of the variability. No other single variable or combination of variables was more informative than the variable THSDS - HSDSC0 alone. From these data, growth velocity for the first year of hGH treatment was estimated as 1.106 (THSDS - HSDSC0) + 6.8 cm/y ± 2.2 cm (SE), allowing a prediction for different intervals between THSDS and HSDSC0. This equation was validated in a small group of 18 GHD patients demonstrating a predicted vs. observed first-year growth rate of 9.4 ± 1.1 vs. 9.5 ± 2.6 cm/y. We conclude that the difference between THSDS and height SDS at the start of therapy is an important predictor of the first-year growth response in children treated with hGH for idiopathic GHD. Unlike in previous studies, additional parameters did not increase predictability.     

Changes with growth hormone treatment in growth hormone deficient children

A total of 54 previously untreated patients (15 girls, 39 boys) with poor growth due to idiopathic growth hormone deficiency (IGHD) were treated with human growth hormone (hGH), continuously up to 4 years. All of the patients had a peak hGH level which was below 10 ng/mL after at least two pharmacological tests and/or blunted physiologic hGH secretion, and their height was below ?2.5 s.d. for age and gender. After the 1st year of therapy, height velocity (HV) increased significantly when compared with baseline (from 3.18 ±0.76 cm/year to 9.17±1.03 cm/year; P <0.001), declined during the 2nd year and then remained significantly higher than pretreatment HV. When considering improvement in height expressed by height standard deviation score (SDS), during the therapy all of the patients showed a significant gain ± 1.72±1.09 (from ?4.11±0.61 to ?2.21±0.48). The height values were significantly higher than pretreatment, but remained below ?2 s.d. after 4 years of hGH therapy in our patients. Increased height velocity has been sustained, but height improvement after therapy was inversely correlated to height SDS for chronological age of patients at the start of therapy. In conclusion post-treatment height has been shown to be related to height deficit at the beginning of therapy. Therapy was well tolerated with no local or systemic adverse effects or acceleration of bone age.     

Congenital nephrotic syndrome with a novel NPHS1 mutation

Congenital nephrotic syndrome of the Finnish type (CNF) is a rare autosomal recessive disorder. The incidence of CNF is relatively high in Finland but considerably lower in other countries. We encountered a male newborn with CNF, associated with compound heterozygous mutations in nephrosis 1, congenital, Finnish type (NPHS1). The patient was admitted to hospital as a preterm infant. Physical and laboratory findings fulfilled the diagnostic criteria of nephrotic syndrome, and were compatible with a diagnosis of CNF, but there was no family history of the disease. On genetic analysis of NPHS1 a paternally derived heterozygous frame‐shift mutation caused by an 8 bp deletion, resulting in a stop codon in exon 16 (c.2156‐2163 delTGCACTGC causing p.L719DfsX4), and a novel, maternally derived nonsense mutation in exon 15 (c.1978G>T causing p.E660X) were identified. Early genetic diagnosis of CNF is important for proper clinical management and appropriate genetic counseling.