生长激素在矮身材儿童中的临床应用

人生长激素(hGH)是脑神经垂体嗜酸性细胞分泌的一种蛋白质激素,它是体内最重要的促进生长的激素.儿童身高的增长主要是通过长骨骨干与骨骺之间的软骨板中的细胞分裂增殖实现的,生长激素(GH)正是对这种软骨细胞的分裂增殖具有显著的促进作用.     

Nocturnal urinary growth hormone excretion in children with short stature

Nocturnal urinary growth hormone levels in children with short and normal stature were measured by a sensitive enzyme immunoassay. Urinary GH excretion during sleep correlated positively with peak plasma GH values during pharmacological (r = 0.74, P less than 0.001) and sleep (r = 0.85, P less than 0.001) tests. The amounts of urinary GH excretion during sleep differed significantly from each other in the following groups: complete GH deficiency (mean +/- SEM: 0.1 +/- 0.1 ng/m2 of body surface area; range: less than 0.1-0.4), partial GH deficiency (1.6 +/- 0.3 ng/m2; 0.2-3.1), and short stature without GH deficiency (3.7 +/- 0.6 ng/m2; 0.7-11.5). No significant difference was found between short stature without GH deficiency and normal stature (5.0 +/- 0.5 ng/m2; 2.1-10.5). Measurement of nocturnal urinary GH excretion is a simple method for screening of GH excretion and may be helpful in the differentiation of the various etiologies of short stature in children.     

The GH-IGF-I axis in children with idiopathic short stature.

Idiopathic short stature (ISS) is a term used for children in whom the etiology of the short stature is undefined. Investigations of the growth hormone (GH)-insulin-like growth factor I axis have revealed several molecular and endocrinological defects in ISS patients. Abnormalities of GH secretion and action, although not frequent, will help to categorize some children with ISS. Because most diagnostic methods remain crude, however, their modification might be necessary to identify more subtle and yet functionally significant abnormalities of this endocrine axis.     

Leptin responses to insulin administration in children with short stature

Abstract The aim of the study was to investigate the effect of standard insulin tolerance test on plasma leptin levels in children with idiopathic short stature (ISS) and in children with growth hormone deficiency (GHD). Furthermore, plasma leptin levels were analyzed with regard to age, body mass index (BMI), and plasma levels of human growth hormone and of insulin-like growth factor-1 (IGF-1). Sixty-three patients with a height below the third percentile, an age of 10.24 +/- 0.40 years and a BMI standard deviation score (SDS) of -0.78 +/- 0.13 (weight SDS -0.07 +/- 0.12; height SDS -2.39 +/- 0.10) were investigated (mean +/- SD). Based on responses to insulin tolerance test, the patients were classified as ISS (n = 49) or GHD (n = 14). Plasma leptin levels were significantly lower in all patients 60 minutes ( P < .001) and 120 minutes ( P < .001) after insulin administration. This effect was independent of GHD, and no difference in leptin decrease was found when comparing patients with ISS to those with GHD. A correlation was found when comparing plasma leptin levels of all patients to BMI SDS (r = 0.43; P < .001) and plasma IGF-1 levels (r = 0.31; P < .01). Furthermore, positive correlation was found when BMI SDS was compared to IGF-1 (r = 0.25; P < .05). In summary, we found that insulin administration in children with short stature decreases plasma leptin levels, equally in those with and without GHD.     

Abnormal GH receptor signaling in children with idiopathic short stature

Peripheral GH insensitivity may underlie idiopathic short stature in children. As the clinical and biochemical hallmarks of partial GH insensitivity have not yet been clearly elucidated, the identification of such patients is still difficult. We integrated functional, biochemical, and molecular studies to define the more reliable marker(s) of GH insensitivity. In particular, we measured GH receptor transducing properties through GH-induced protein tyrosine phosphorylation in patients' peripheral blood mononuclear cells and performed direct sequencing analysis of GH receptor-coding exons. Five of 14 idiopathic short stature patients with low basal IGF-I levels showed low or absent IGF-I increment after 4 d of GH administration. However, a prolonged GH stimulation induced in 3 of them an increase in IGF-I 40% above the baseline value. The IGF-binding protein-3 behavior paralleled that of IGF-I. The 2 GH-unresponsive subjects showed an abnormal tyrosine phosphorylation pattern after GH challenge. Sequence analysis of the GH receptor gene revealed a heterozygous mutation resulting in an Arg to Cys change (R161C) in exon 6 in only 1 patient, who had normal GH receptor responsiveness. Our findings indicate that abnormal GH receptor signaling may underlie idiopathic short stature even in the absence of GH receptor mutations. Thus, combining the 4-d IGF-I generation test and the analysis of GH-induced protein tyrosine phosphorylation is a useful tool to help identify idiopathic short stature patients with partial GH insensitivity.     

Psychological criteria for treating children with idiopathic short stature

The role of psychological criteria in guiding treatment decisions about growth hormone (GH) replacement in idiopathic short stature (ISS) is a current topic of debate. This summary discusses findings about the impact of short stature in terms of observer-rated and patient-reported psychological outcomes. Although a literature review did not provide conclusive evidence for differences in psychological status between short children and children of normal height in the general population, patients and parents, when probed, reported issues, especially in the social domain. Studies do not clearly suggest that the diagnosis of ISS or GH deficiency is related to impaired psychological functioning; they also do not imply that height is the only determinant of psychological status. Similarly, results on treatment-related changes in psychological status are equivocal. Assessment of psychological status should be included in future research and in the current clinical care of patients with ISS. Accumulating evidence suggests that assessment of psychological criteria may become a factor in guiding treatment decisions in patients with ISS.     

Auxological criteria for treating children with idiopathic short stature

Children with idiopathic short stature (ISS) may not reach an adult height within their genetic target. In 2003, the United States Food and Drug Administration approved biosynthetic growth hormone (GH) for the treatment of children with ISS whose heights exceeded 2.25 standard deviation scores below the mean and who were considered unlikely to reach a normal adult height. Results of controlled studies have shown that, although GH treatment leads to a substantial increase in adult height, the individual response to therapy is difficult to predict. A number of auxological variables (i.e., age and height at start of treatment, bone age delay, mean predicted height, height velocity and first-year responsiveness) are used in multivariate analyses to predict outcomes. Estimation of target height, predicted adult height and pattern of growth should guide the decision to treat a child with ISS.     

hrGH treatment of glucocorticoid-induced short stature in children

The treatment of systemic diseases with glucocorticoids is often associated with decreased height velocity (HV), and can result in shorter final height. Interactions between adrenal and GH-IGF axis have been described and can occur at hypothalamic-pituitary level or at the regulation of IGF system, including the IGF1R signaling. The clinical state of these patients may be considered as an absolute and/or functional IGF-1 deficiency. Interventions aiming to restore the normal function of GH-IGF axis might reduce the glucocorticoids-induced growth suppression in these children. It has been shown that recombinant human GH (hrGH) induces an increase in HV and a decrease in protein loss in patients with juvenile idiopathic arthritis treated with glucocorticoids. Significant increment in HV was also described after hrGH treatment in children under glucocorticoid therapy due to inflammatory bowel disease or renal transplantation. There is a positive correlation between HV and the dose of hrGH. The results support that the IGF-1 deficiency in these children may be counteract by hrGH therapy. The effect of hrGH is observed only during the treatment period and depends on the replacement strategy, nutritional status and disease control.     

Antipituitary antibodies recognizing growth hormone (GH)-producing cells in children with idiopathic GH deficiency and in children with idiopathic short stature

CONTEXT: Antipituitary antibodies (APA) recognizing GH-secreting cells may indicate an autoimmune pituitary involvement in adults with idiopathic GH deficiency (IGHD). OBJECTIVE: We aimed 1) to investigate the presence of APA in prepubertal children with IGHD or idiopathic short stature (ISS), identifying the pituitary hormone-producing cells targeted by APA; and 2) to verify whether in patients with ISS the presence of APA could predict the development of GHD. DESIGN: We performed a cross-sectional and partially longitudinal cohort study. SETTING: The study was performed at the Endocrinology Unit and Pediatric Unit of the Second University and University Federico II of Naples, respectively. PATIENTS: Twenty-six children with IGHD (group 1), 60 children with ISS (group 2), 33 children with GHD caused by lesions/abnormalities of the hypothalamus or pituitary (group 3), and 40 controls participated in the study. Nineteen children of group 2 were reevaluated after 2 yr. MAIN OUTCOME MEASURES: IGF-I levels, GH secretion, and APA (by indirect immunofluorescence) were evaluated in all participants. RESULTS: At study entry, APA recognizing GH-producing cells were detected in seven of 26 children in group 1 and in 14 of 60 in group 2. Two years later, all eight initially APA-positive and all 11 APA-negative of the 19 reevaluated patients persisted positive and negative, respectively. The reevaluation of GH secretion in these patients revealed the development of GHD in all but one of the APA-positive children but in none of the APA-negative ones. CONCLUSIONS: IGHD in children can be frequently associated with APA targeting GH-secreting cells; thus, the detection of APA in children with ISS could identify those prone to develop GHD.     

Prevalence of celiac disease in Iranian children with idiopathic short stature

AIM： To determine the prevalence of celiac disease （CD） in children with idiopathic short stature （ISS） and the diagnostic value of immunoglobulin （Ig） A G antigliadin antibodies （AGA） and transglutaminase （TTG） antibodies for CD.METHODS： A total of 104 children （49 male, 55 female） with ISS without a specific etiology were studied. Extensive endocrine investigations had shown no abnormalities in any subject. Anthropometric parameters and IgA AGA and IgA TTG antibodies were evaluated in this study group. These antibodies were measured by enzyme-linked immunosorbent assay. All patients were referred for an endoscopic intestinal biopsy. The biopsy samples were classified according to revised Marsh criteria （UEGW 2001）.RESULTS： We detected positive IgA TTG antibodies in 36 and IgA AGA in 35 of these patients. Thirty one IgA TTG antibody positive and 28 IgA AGA positive subjects showed histological abnormalities compatible with celiac disease （33.6%）. Sensitivity, specificity, positive predictive value （PPV） and negative predictive value for IgA AGA were found to be 80%, 88.4%, 77.8% and 89.7%, respectively. Sensitivity, specificity and PPV for IgA TTG antibodies were 88.6%, 94.2% and 88.6%, espectively.CONCLUSION： We conclude that the prevalence of celiac disease is high in patients with ISS and it is important to test all children with ISS for celiac disease by measuring serologic markers and performing an intestinal biopsy.     

Growth hormone treatment in children with short stature due to IUGR

Most of the children with intrauterine growth retardation show fair catch-up growth by two years of age, while approximately 10% of them fails the catch-up and remains short as adult. Growth hormone has been applied to those who stay short (height<-2SD of mean) in relatively high dose, and favorable results come out in terms of not only height but also psychosocial positiveness. The long-term out come, however, should be carefully monitored, especially the effect of early pubertal onset for height and pubertal height gain on the final height, and metabolic effect of long-term pharmacological dose of GH exposure from early childhood, such as glucose intolerance.     

Lupus cystitis in association with severe gastrointestinal manifestations in an adolescent

Lupus cystitis is a rare interstitial inflammatory disease of the bladder seen in systemic lupus erythematosus that usually occurs in association with gastrointestinal manifestations, and occasionally with central nervous system involvement. There are few reported pediatric cases. We describe this entity as the presenting manifestations of lupus in an adolescent female.     

Circadian variation of plasma cortisol in prepubertal children with normal stature, short stature and growth hormone deficiency

OBJECTIVES: When studying the relationship between spontaneous secretion of growth hormone (GH) and cortisol in children, most studies show no correlation in mean levels of these two hormones, while others found positive or even strongly negative correlations. These contradictory results could be partly due to the inability to properly compare hormones that are characterized by circadian and ultradian variations in their secretory profiles. We aim here to study possible differences in rhythm characteristics of plasma cortisol with stature and to compare the circadian secretory patients of cortisol and GH. PATIENTS: We analysed data from 135 prepubertal children: (1) 14 GH-deficient children; (2) 36 children with short stature (2-3 SD below their peer group mean); (3) 57 children with very short stature (3-4 SD below their peer group mean); and (4) a reference group of 28 children with normal stature (+/- 2 SD). Subjects were living in a hospital setting on a diurnal waking (07.30-22.30 h), nocturnal resting routine during sampling, consuming the usual hospital diet at fixed times. MEASUREMENTS: Cortisol and GH concentrations were determined by radioimmunoassay in plasma obtained at about 2-3 h intervals during most of the day and at half-hour intervals between 22.00 and 02.00 h. Circadian rhythm characteristics obtained by least-squares estimation were compared between groups divided according to gender and stature with a parameter test. RESULTS: Show a statistically significant circadian rhythm in cortisol secretion for all groups studied (P < 0.001 in all cases). A comparison of circadian parameters indicated similar characteristics between subjects of short, very short and normal stature. Despite a borderline statistically significant difference in rhythm-adjusted mean and amplitude of GH between nondeficient and GH-deficient children, there was no difference in the circadian pattern of cortisol secretion between these two groups. No correlation was found in circadian mean, amplitude, average, standard deviation, standard error, minimum or maximum between GH and cortisol for any of the groups of children. CONCLUSIONS: Any possible relation between GH and cortisol remains unclear. Moreover, GH-deficient children are not necessarily characterized by either hyper- or hypocortisolaemia.     

Deletions of the homeobox gene SHOX (short stature homeobox) are an important cause of growth failure in children with short stature

Short stature, with an incidence of 3 in 100, is a fairly frequent disorder in children. Idiopathic short stature refers to patients who are short due to various unknown reasons. Mutations of a human homeobox gene, SHOX (short stature homeobox), have recently been shown to be associated with the short stature phenotype in patients with Turner syndrome and most patients with Léri-Weill dyschondrosteosis. This study addresses the question of the incidence and type of SHOX mutations in patients with short stature. We analyzed the SHOX gene for intragenic mutations by single strand conformation polymorphism, followed by sequencing, in 750 patients and for complete gene deletions by fluorescence in situ hybridization in 150 patients (total, 900 patients). This is the largest group of patients with short stature studied to date for SHOX mutations. All patients had a normal karyotype, and their height for chronological age were below the third percentile or minus 2 SD of national height standards. All were without obvious skeletal features reminiscent of the Leri-Weill syndrome at the time of diagnosis. Silent, missense, and nonsense mutations and a small deletion in the coding region of SHOX were identified in 9 of the 750 patients analyzed for intragenic mutations. Complete gene deletions were detected in 3 of the 150 patients studied for gene deletions. At least 3 of the 9 intragenic mutations were judged to be functional based upon the genotype- phenotype relationship for the parents and normal control individuals. We conclude that SHOX mutations have been detected in 2.4% of children with short stature. The spectrum of SHOX mutations is biased, with the vast majority leading to complete gene deletions. The prevalence of short stature due to SHOX gene mutations among children with short stature appears to be similar to that of GH deficiency or Turner syndrome. Family studies of the children with SHOX mutations often reveal older family members with same mutation who exhibit mild skeletal features reminiscent of the Turner syndrome, such as high-arched palate, short neck, abnormal auricular development, cubitus valgus, genu valgum, short fourth metacarpals, and Madelung deformity.     

Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo

The influence of short stature on psychological adaptation in childhood and adolescence is controversial. GH is currently used to treat children with idiopathic short stature (ISS, also known as non-GH-deficient short stature). This study represents the first double-blind, placebo-controlled trial of the effects of GH on the psychological adaptation of children and adolescents with ISS, treated with GH until adult height was attained.Sixty-eight children (53 males, 15 females), 9-16 yr old, with marked ISS (measured height or predicted adult height -2.5 sd or less) received either GH 0.074 mg/kg or placebo sc three times per week until height velocity decreased to less than 1.5 cm/yr. Parents completed the Child Behavior Checklist (CBCL) and children the Self-Perception Profile (SPP) and Silhouette Apperception Technique at baseline and annually thereafter.Baseline behavioral/emotional adjustment (CBCL) and self-concept (SPP) scores for children with ISS were within the normative range. The two study groups exhibited similar behavioral and self-concept profiles (CBCL) during the first 2 yr of the study. However, CBCL behavior problems (internalizing, externalizing, and total problems) appeared to decline, in yr 3 and 4, in the GH-treated group relative to the placebo-treated group. Group differences in CBCL competency domains and the SPP were not observed at any point during the study.Short stature among children with ISS enrolled in this long-term, placebo-controlled study was not associated with problems in psychological adaptation or self-concept with the psychological instruments employed. GH treatment was associated with a trend toward improvement in problem behaviors, as measured by questionnaires (CBCL) completed by study participants' parents. It remains to be determined whether GH treatment significantly impacts adaptation, psychosocial function, or quality of life in children with ISS.