Diagnostic value of pituitary MRI in differentiation of children with normal growth hormone secretion, isolated growth hormone deficiency and multiple pituitary hormone deficiency

Pituitary height, volume and morphology were investigated by MRI in patients aged 3.5-24.9 years with growth hormone deficiency (GHD) in relation to birth history and hormonal findings. Three groups with comparable age, sex and pubertal stage were studied: group I (n=42)--patients with isolated growth hormone deficiency (IGHD); group II (n=22)-- patients with multiple pituitary hormone deficiency (MPHD); and group III (n=30)--healthy controls. Pituitary height and volume differed significantly between the three groups, with the smallest in group II and largest in group III (p <0.001 for both). Both variables correlated significantly with peak GH value in the patient groups (p <0.001). The specificity of pituitary dysmorphology in the determination of GHD was 100% and its sensitivity in differentiation of IGHD and MPHD was 95%. Ectopic neurohypophysis was present in 75% of breech births and 27% of head-presenting patients (p <0.01). This study emphasizes the differential diagnostic value of pituitary MRI and its contribution to the understanding of the pathogenesis and prognosis in GHD.     

Responses of bone turnover markers and bone mineral density to growth hormone therapy in children with isolated growth hormone deficiency and multiple pituitary hormone deficiencies

Growth hormone deficiency (GHD) is an important cause of decreased bone mass in childhood and adolescence. The role of other pituitary hormone deficiencies on bone mass is still a query in children. Thirty-nine children (28 with isolated GHD [IGHD] and 11 with multiple pituitary hormone deficiency [MPHD]) were investigated to show the effects of IGHD vs MPHD on bone status. Bone turnover markers (calcium, phosphate, alkaline phosphatase [ALP] Bone ALP [BALP], osteocalcin [OSC], carboxyterminal propeptide of type-1 collagen [CPP-I], parathyroid hormone [PTH]) were measured before and every four months during growth hormone (GH) therapy; bone mineral density (BMD) of the lumbar spine was measured before and every six months during therapy. All bone turnover markers except calcium and PTH increased significantly during 1 year of GH therapy. There were no differences in the levels of bone turnover markers between children with IGHD and MPHD at baseline, and after 4, 8 and 12 months of therapy. Lumbar spine BMD SDS of all patients increased significantly during 1 year of therapy (p = 0.035 after 6 months and p <0.001 after 12 months compared with baseline). BMD SDS of both IGHD and MPHD groups were similar at baseline and after 6 and 12 months of therapy (p = 0.235, p = 0.295 and p = 0.384). Height SDS (HtSDS) at baseline was the most important predictor of baseline BMD SDS in children with GHD (t = 4.166, p <0.001). DeltaHtSDS was also positively related to deltaBMD SDS after 1 year of GH therapy. In conclusion, there was no difference in bone status of the patients with IGHD and MPHD at baseline. GH therapy yielded similar increases in bone mass in both groups. Increase in height contributed to increase in BMD during 1 year of GH therapy.     

Posterior pituitary ectopy in children with idiopathic growth hormone deficiency

AIMS: To evaluate the underlying pathogenesis in children with pituitary hormone deficiency by means of high resolution MRI of the brain. PATIENTS/METHODS: Thirty-seven children with short stature and isolated GH deficiency (IGHD, n = 17) or multiple pituitary hormone deficiency (MPHD, n = 20) were subjected to an MRI of the brain at the age of 1.0-17.3 years. The anatomic condition of the hypothalamo-pituitary area was analyzed and the height of the pituitary gland was measured and compared to the data of age-matched healthy subjects. RESULTS: Seventy percent of the patients had a characteristic anomaly: the adenohypophysis was hypoplastic, the infundibulum was absent and the posterior pituitary lobe was ectopic at the bottom of the median eminence. The height of the anterior pituitary was significantly reduced in these patients (1.9 +/- 0.1 mm; mean +/- SD) when compared to age-matched healthy controls (4.1 +/- 0.8 mm, p<0.001) or hypopituitary patients with a normal MRI (4.3 +/- 0.8 mm). MPHD was found in 62% of patients with the pituitary anomaly whereas only 27% of children with a normal MRI had MPHD (p<0.05). CONCLUSIONS: The pathogenesis of the pituitary anomaly is unknown; a disorder during embryonal development or perinatal events have been discussed as causal factors. MRI should have a prominent position in the work-up of hypopituitary children. When an anatomical malformation is visualized by MRI, the diagnostic terminology should be adapted accordingly.     

Long-term response to human growth hormone in 36 children with idiopathic growth hormone deficiency

The results of long term treatment with human growth hormone (Crescormon^®, 12.4 IU/m²/week) in 36 patients with idiopathic growth hormone deficiency are given. Birth trauma—in particular assisted breech delivery (30%)—is the major aetiological cause. Twelve patients had isolated growth hormone deficiency (IGHD), 24 had multiple pituitary hormone deficiencies (MPHD) of which 19 were treated with additional thyroid hormones. The results were judged by the criteria of height velocity, total height gain and change of height prediction (TW₂, age based).It is concluded that the growth hormone dose chosen in many cases is insufficient to maintain high growth rates after the first year of treatment, when catch-up no longer takes place. The tendency of patients supplemented with thyroid hormone to grow better—without additional bone-age advancement—calls for careful search for hypothyroidism and suggests the use of thyroxin in cases of doubt.     

Growth response to human growth hormone treatment in children with partial and total growth hormone deficiency

The growth response during the first and second years of human growth hormone (hGH) treatment was studied in 14 prepubertal children with so-called "partial" GH deficiency (peak GH between 8 and 15 mU/l) and compared to 28 prepubertal children with "total" GH deficiency (peak GH less than 8 mU/l). There was no difference in growth acceleration between children with partial and total GH deficiency, when initial covariables were taken into account. In a stepwise multiple regression analysis initial stature, pre-treatment growth velocity and skinfold thickness were shown to be most related to growth response, but after exclusion of 3 children with a genetic form of total GH deficiency and partial TSH deficiency this relationship was lost. GH levels during provocation tests and auxological criteria have a poor predictive value for growth response to hGH therapy.     

伴有促肾上腺皮质激素缺乏的儿童多种垂体激素缺乏症临床分析

多种垂体激素缺乏症(MPHD)是一类以生长激素分泌减少伴一种或多种垂体前叶激素缺乏的疾病.由于临床症状缺乏特异性,常有误诊.尤其是伴有促肾上腺皮质激素(ACTH)缺乏的MPHD,在感染、创伤、手术等应激状态下可出现肾上腺危象和低血糖抽搐,是严重的儿科急诊疾病之一.通过对我院1996年6月至2007年8月收治的25例伴有ACTH缺乏的MPHD患儿的临床特征和诊断、治疗进行分析,旨在提高临床医生对该病的早期诊治.现将结果报告如下.     

Optic nerve size evaluated by magnetic resonance imaging in children with optic nerve hypoplasia, multiple pituitary hormone deficiency, isolated growth hormone deficiency, and idiopathic short stature

OBJECTIVE: To objectively define criteria for intracranial optic nerve (ON) size in ON hypoplasia (ONH) on magnetic resonance imaging (MRI) scans. STUDY DESIGN: Intracranial ON sizes from MRI were compared between 46 children with ONH diagnosed by ophthalmoscopy (group 1, isolated ONH, 8 children; and group 2, ONH associated with abnormalities of the hypothalamic-pituitary axis and septum pellucidum, 38 children) and children with multiple pituitary hormone deficiency (group 3, multiple pituitary hormone deficiency, 14 children), isolated growth hormone deficiency (group 4, isolated growth hormone deficiency, 15 children), and idiopathic short stature (group 5, idiopathic short stature, 10 children). Intracranial ON size was determined by the cross-sectional area, calculated as [pi x (1/2) height x (1/2) width]. RESULTS: Groups 1 and 2 had lower intracranial ON size than did groups 3, 4, and 5 (P < .001). No patients in groups 3 through 5 who had MRI after 12 months of age (when 95% adult size of ONs is attained) had ONs <2.9 mm 2 . Visual acuity correlated significantly with ON size (P < .01). CONCLUSIONS: Magnetic resonance imaging of the ONs with cross-sectional area <2.9 mm 2 in a short child more than 12 months of age, with or without hypothalamic-pituitary axis abnormalities, confirms the clinical diagnosis of ONH.     

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.     

Borjeson-Forssman-Lehmann syndrome and multiple pituitary hormone deficiency

We describe two brothers with Borjeson-Forssman-Lehmann syndrome and the 22A-->T (Lys8X) PHF6 mutation, who presented with the symptoms and signs of multiple pituitary hormone deficiency. Biochemical investigations and radiology confirmed growth hormone (GH), thyroid stimulating hormone (TSH) and adrenocorticotrophic hormone (ACTH) as well as gonadotrophin deficiency. They were also found to have optic nerve hypoplasia. This family suggests that the BFL gene product may play an important role in midline neuro-development including the hypothalamo-pituitary axis.     

Elevation of serum creatine phosphokinase during growth hormone treatment in patients with multiple pituitary hormone deficiency

Serum creatine phosphokinase (s-CPK) increased to more than 500 U/l in 5 out of 21 patients with growth hormone (GH) deficiency during the 2 years of treatment with biosynthetic GH. In three of these five patients, s-CPK had elevated gradually after the start of GH treatment and remained high in one patient except in the period when GH injection was interrupted, and gradually decreased in the other two patients during treatment. These three patients had complete GH deficiency associated with multiple pituitary hormone deficiency due to pituitary stalk transection. One of the remaining two patients had Noonan syndrome and his s-CPK levels before therapy were relatively high. The fifth patient was a baseball athlete and the elevation of s-CPK seemed to be attributable to the strenous exercise.Conclusion s-CPK increases significantly in a certain group of patients with GH deficiency during GH replacement therapy. Measurement of s-CPK is to be included in the follow up laboratory tests at least in the 1st treatment year to evaluate the potential hazardous effects of GH on muscle.     

Foot length before and during insulin-like growth factor-I treatment of children with laron syndrome compared to human growth hormone treatment of children with isolated growth hormone deficiency

OBJECTIVE: To compare foot length deficits between patients with Laron syndrome (LS) (primary growth hormone [GH] insensitivity) and congenital isolated GH deficiency (IGHD) and their response to replacement therapy with insulin-like growth factor-I (IGF-I) and hGH, respectively. DESIGN: Data for the study were collected from the records of nine children with LS (3 M, 6 F) 7.8 +/- 4.8 years old (mean +/- SD), and nine children with IGHD (3 M, 6 F), 3.8 +/- 3.3 years old. Fifteen non-treated adult patients with LS were also included in the study. METHODS: Measurements of foot length were recorded without treatment and monitored during 9 years of treatment in the children and in the untreated adult patients. For statistical analysis the non-parametric Mann-Whitney U test was used. RESULTS: With almost similar basal values in growth deficit and pre-treatment growth velocities, the achievements towards norms after 9 years of treatment were greater in the patients with IGHD than in the patients with LS: foot length reached -1.4 +/- 0.8 vs. -3.3 +/- 1.0 SDS (mean +/- SD), and body height -2.2 +/- 1.0 vs. -3.9 +/- 0.5 SDS. The difference between the two groups could be due to the initiation of replacement therapy in the patients with IGHD at a younger age. Adult foot size of untreated patients with LS is small but less retarded than the height deficit. CONCLUSIONS: Both IGF-I and hGH are potent growth stimulating hormones of linear growth and acrae as exemplified by foot growth.     

High prevalence of pituitary magnetic resonance abnormalities and gene mutations in a cohort of Brazilian children with growth hormone deficiency and response to treatment

Data were retrospectively collected from 69 Brazilian patients (45 boys) with growth hormone deficiency (GHD) who received exogenous growth hormone (GH) for a median duration of 4 years (range 1-13 years). Forty-two patients had multiple pituitary hormone deficiencies and 27 had isolated GHD. Peak GH was < 7 ng/ml (IRMA) or < 3.2 ng/ml (IFMA) after two stimulation tests. Therapy was started at median age of 10.0 years (range 2.2-21.6 years), bone age of 5.8 years (0.5-13.5 years) and height standard deviation score -4.4 (range -9.3 to -1.6). MRI revealed pituitary abnormalities in 87% of patients. Homozygous mutations in PROP-1, GHRH-R, GH-1 or HESX-1 genes were found in 12 patients. Mean height velocities were 3.3 pretreatment and 10.3, 7.8, 7.4 and 6.4 cm/yr, respectively, during 1-4 years of treatment with GH. In conclusion, the high prevalence (96%) of genetic and/or pituitary abnormalities probably reflects the stringent diagnostic criteria used, and GH replacement resulted in significant catch-up growth.     

生长激素缺乏症患儿垂体MRI检查的临床应用价值

目的 研究特发性生长激素缺乏症(GHD)儿童垂体MRI检查的临床应用价值,为进一步探索GHD病理机制提供临床依据.方法 选取100例2005-2007年内分泌专科就诊的GHD儿童乖体MRI资料,其中男74例,女26例;平均年龄为(8.82±3.68)岁.于SE序列T1WI头颅正中矢状及冠状面上观测垂体大小形态及信号特征,并比较其与临床的联系.结果 在10～15岁GHD患儿头颅MRI检查垂体矢状高径明显优于其他各径线(P<0.01);在联合垂体功能缺陷(MPHD)中垂体后叶异位(EPP)的发生率(92.3%)显著高于CHD(7.7%,P<0.01).结论 对GHD儿童应重视头颅MRI检查,其垂体形态、结构的阳性发现可有助于临床疾病的诊断及鉴别诊断,必要时应随访MRI,结合临床综合判断诊治及其预后.