Advances in the pathogenesis and treatment of short stature in Noonan syndrome / 国际儿科学杂志

Noonan syndrome(NS)is an inherited disease involving multiple systems.The main clinical manifestations include distinctive facial features, short stature, heart defects, developmental delay and chest deformity.Short stature, reported in up to 70% of NS patients, is one of the main reasons NS patients seek medical treatment.The pathogenesis is associated with the up-regulation of RAS-mitogen activated protein kinase(RAS-MAPK)signal pathway.Further study is needed for some further specific mechanisms.Recombinant human growth hormone(rhGH)therapy has been approved for NS patients with short stature and has achieved a good therapeutic effect.However, the knowledge of drug dosage, influencing factors, long-term efficacy and risk of rhGH treatment is still insufficient.This paper reviews the pathogenesis and treatment of short stature in NS, providing help for the treatment and management of the disease.

Male-female differences in 6-sulfatoxymelatonin excretion in hypopituitary patients

ABSTRACT Objective To evaluate melatonin secretion in adult hypopituitary patients with Growth Hormone deficiency (AGHD) on and off replacement therapy. Subjects and methods We studied 48 subjects: 12 (6 males) untreated AGHD (AGHDnt), 20 (10 males) treated AGHD (AGHDt) and 16 healthy subjects (8 males) as control group (CG). We measured urinary 6-sulfatoxymelatonin (6-SM) in total (24 h samples), nocturnal (6-SMn): 1800-0800 and diurnal samples (6-SMd): 0800-1800. Results Significant differences were observed among the 3 groups of male subjects, in total 6-SM (p < 0.05), nocturnal 6-SM (p < 0.02) and nighttime-daytime delta values (p < 0.003). CG had significantly higher values than the AGHDnt in total 6-SM (p < 0.01), nocturnal 6-SM (p < 0.05) and nighttime-daytime delta values (p < 0.01). AGHDt patients showed significantly higher levels in nighttime-daytime delta values than AGHDnt patients (p < 0.05). In females, no significant differences were found among the 3 groups studied in total, nocturnal, diurnal or nighttime-daytime delta values. In males, significant correlations were found among total 6-SM (r = 0.58; p = 0.029), nocturnal 6-SM (r = 0.70; p = 0.006) and nighttime-daytime delta values (r = 0.71; p = 0.004) vs. serum IGF-1 levels in subjects evaluated. In females, significant correlations were found among total 6-SM (r = 0.57; p = 0.02) vs. serum IGF-1 levels in subjects evaluated. A tendency towards a significant correlation was found in diurnal 6-SM (r = 0.48; p = 0.07). Conclusions Our findings show a sexual dimorphism in 6-SM excretion in AGHD patients and provide an interesting approach to a further understanding of some chronobiological disorders involved in GH deficiency.

Controversias en el manejo de la talla baja idiopática

La talla baja idiopática (TBI) es un diagnóstico de exclusión que abarca un amplio y heterogéneo grupo de niños aparentemente sanos pero con talla inferior a -2 desviaciones estándar. En los Estados Unidos está aprobado el uso de hormona de crecimiento (HC) en niños con TBI, a diferencia de la mayoría de países Europeos. La respuesta terapéutica de los niños con TBI tratados con HC es muy variable y dependiente de múltiples factores al inicio y durante el tratamiento, por lo cual el beneficio de su uso no ha podido establecerse de forma consensual. Esta revisión recoge información actualizada sobre los más recientes estudios publicados en pacientes con TBI tratados con HC hasta alcanzar talla final, los diferentes factores asociados a la respuesta terapéutica, los efectos metabólicos, psicosociales y efectos adversos de la HC, y sobre otras opciones terapéuticas a considerar tales como HC con análogos de la GnRH, inhibidores de aromatasa e IGF1 humana recombinante.

Idiopathic short stature (ISS) is an exclusion diagnostic which includes a broad and heterogeneous group of supposedly healthy children with height below -2 standard deviations. In the United States, treatment with growth hormone (GH) is approved for children with ISS, as opposed to the majority of European countries. The final height of children with ISS whom are treated with GH is highly variable and dependent on multiples factors at the beginning and during the treatment. For this reason, the indication of GH therapy in ISS children is not consensual. This revision contains actual data about the most recently published studies in patients with ISS treated with GH until final height, associated factors to height gaining, metabolic, psychosocial and adverse events, and finally, other therapeutic options such as GH combined with GnRH analogues, aromatase inhibitors and recombinant human IGF1.

Systematic review of the clinical and genetic aspects of Prader-Willi syndrome / 소아과

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that is caused by the lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. This syndrome has a characteristic phenotype including severe neonatal hypotonia, early-onset hyperphagia, development of morbid obesity, short stature, hypogonadism, learning disabilities, behavioral problems, and psychiatric problems. PWS is an example of a genetic condition caused by genomic imprinting. It can occur via 3 main mechanisms that lead to the absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and an imprinting defect. Over 99% of PWS cases can be diagnosed using DNA methylation analysis. Early diagnosis of PWS is important for effective long-term management. Growth hormone (GH) treatment improves the growth, physical phenotype, and body composition of patients with PWS. In recent years, GH treatment in infants has been shown to have beneficial effects on the growth and neurological development of patients diagnosed during infancy. There is a clear need for an integrated multidisciplinary approach to facilitate early diagnosis and optimize management to improve quality of life, prevent complications, and prolong life expectancy in patients with PWS.

Changes of amino-terminal propeptide of C-type natriuretic peptide and growth velocity in patients with idiopathic short stature or isolated growth hormone deficiency after recombinant human growth hormone treatment / 中华内分泌代谢杂志

Objective To explore the value of amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) in evaluating the efficacy of therapy with recombinant human growth hormone ( rhGH ) in patients with idiopathic short stature (ISS) and isolated growth hormone deficiency ( IGHD ).Methods Forty-eight prepubertal children( IGHD n=25,ISS n=23 ) treated for at least 1 year with rhGH were included.Serum insulin-like growth factor- Ⅰ ( IGF- Ⅰ ) and NTproCNP levels were measured before starting treatment and 6 months later.Twelve months after starting treatment,all patients were assessed and annual growth velocity ( GV ),height standard deviation score ( HTSDS),and gained HTSDS (△HTSDS) were recorded.Results In GHD group,positive relationships between GV and change of IGF- ISDS( △IGF- ISDS ),GV and change of NTproCNP concentrations(△NTproCNP) were found( r=0.407,P=0.044 ;r=0.490,P=0.013 ).GH peak value was also positively associated with IGF- ISDS and NTproCNP before therapy ( r =0.558,P =0.004; r =0.630,P =0.001 ).△IGF- ISDS and △NTproCNP were positively associated after therapy ( r =0.466,P =0.019 ).In ISS group,GV was associated with △NTproCNP ( r=0.845,P＜ 0.01 ).Conclusions NTproCNP is a novel biomarker of growth as its level increases during growth-promoting treatment.Furthermore,IGF- Ⅰ is also valuable in evaluating the efficacy of rhGH therapy in short stature patients.

Analysis of cytosine adenine repeat polymorphism of the IGF-I promoter gene in children with idiopathic short stature / 소아과

PURPOSE: A polymorphism in the IGF-I gene promoter region is known to be associated with serum IGF-I levels, birth weight, and body length, suggesting that IGF-I gene polymorphism might influence postnatal growth. The present study aimed to investigate the role of this polymorphic cytosine-adenine (CA) repeat of the IGF-I gene in children with idiopathic short stature. METHODS: The study involved 131 children (72 boys and 59 girls) diagnosed with idiopathic short stature, aged 7-15 years. Genomic DNA was extracted from anticoagulated peripheral whole blood. The primers were designed to cover the promoter region containing the polymorphic CA repeat. Data were analyzed using GeneMapper software. The correlations between age and serum IGF-I levels were analyzed using Spearmans correlation coefficient. RESULTS: The CA repeat sequences ranged from 15 to 22 , with 19 CA repeats the most common with an allele frequency of 40.6%. Homozygous for 19 CA repeat was 13.0%, heterozygous for 19 CA repeat was 56.5%, and 19 CA non-carrier was 30.5%. The three different genotype groups showed no significant differences in height, body weight and body mass index, and serum IGF-I levels. The serum IGF-I level and age according to the IGF-I genotypes were significantly correlated in the entire group, 19 CA repeat carrier group, and the non-carrier group. The three groups also showed no significant differences in the first year responsiveness to GH treatment. CONCLUSION: There were no significant different correlations between 19 CA repeat polymorphism and serum IGF-I levels according to genotype. Our results suggest that the IGF-I 19 CA repeat gene polymorphism is not functional in children with idiopathic short stature.

Novas opções e preparações na terapia com hormônio de crescimento / News options and preparations in growth hormone therapy

Nos últimos 20 anos, o hormônio de crescimento recombinante humano (GHhr) vem sendo utilizado para tratar a deficiência do hormônio de crescimento (GH) em crianças e, mais recentemente, em adultos. Porém, a necessidade de injeções diárias compromete a aderência ao tratamento. Esforços de melhorar esta aderência incluem o uso de canetas e dispositivos desprovidos de agulha, haja vista que as bombas de infusão, nem sempre são fisiológicas e são de uso restrito. Quando a finalidade do tratamento for o crescimento, a terapêutica diária com GHhr continua a mais recomendada. Contudo, a expansão da terapêutica com GH, especialmente nos usos mais recentes e em adultos, necessitará de outras preparações. No momento atual, os secretagogos orais não têm eficácia comprovada para a utilização clínica, e as formulações de depósito de GHRH e de GH, que melhorariam a aderência dos pacientes, ainda requerem mais estudos de eficácia em longo prazo e segurança.

In the last twenty years, recombinant human Growth hormone (hrGH) has been available for the treatment of Growth Hormone Deficiency (GHD) in children and more recently in adults. However, the necessity of daily injections compromises the patient's compliance. Attempts to improve this compliance includes the use of pens and needle free devices, once the infusion pumps, not always physiologic, are of restricted use. When growth is the purpose of treatment, daily subcutaneous hrGH is still the most indicated. Nevertheless the expansion of GH replacement to new uses and especially in adults will need new preparations. Nowadays, the oral secretagogues have not proved efficacy to be used in clinical practice and the slow- release preparations of GH and GH releasing hormone that could improve the patient's compliance will need to be studied considering long term efficacy and safety.

The Effect of Growth Hormone and the Factors Influencing Growth in Pediatric Chronic Peritoneal Dialysis Patients

PURPOSE: Growth failure is a common problem in chronic renal failure(CRF). We studied the effect of growth hormone(GH) treatment and the factors influencing growth on chronic peritoneal dialysis patients. METHODS: Seventeen patients who were treated with peritoneal dialysis and GH for more than one year were enrolled. Factors influencing growth such as age, height at start of GH treatment, total Kt/Vurea, residual renal Kt/Vurea, hemoglobin, albumin, BUN, creatinine, total CO2, calcium, phosphate and iPTH during GH treatment were compared between the growth group(increase in height-standard deviation score(Ht-SDS) after one year of GH treatment, n=11) and poor growth group(no increase in Ht-SDS after one year of GH treatment, n=6). RESULTS: The mean age at the start of dialysis was 7.7+/-5.2 years and the mean age at the start of GH treatment was 8.5+/-4.8 years. In the growth group, Ht-SDS at start of GH treatment was smaller(-1.72+/-1.00 vs. -0.77+/-0.88, P=0.048) and residual renal Kt/Vurea was better (1.54+/-0.51 vs. 0.15+/-0.26, P=0.02) than the poor growth group. After three years of GH treatment, Ht-SDS of the growth group was better than the poor growth group. CONCLUSIONS: GH treatment in children with peritoneal dialysis was more effective on patients who had more severe growth retardation. The reservation of residual renal function was important for improvement of effect of GH treatment. And the growth response during the first year of GH treatment may be predicted as the indicator for long-term response.

The Effect of Growth Hormone on Patients with Growth Hormone Deficiency and Idiopathic Short Stature / 소아과

PURPOSE: This study was designed to evaluate the effect of growth hormones on children with growth hormone deficiency(GHD) or idiopathic short stature(ISS). METHODS: Between January 1988 to July 2003, 45 patients(M26, F19) with GHD and 24 patients (M13, F11) with ISS were enrolled in this study. Height standard deviation score(Ht SDS) for chronological age(CA) and Ht SDS for bone age(BA) were obtained for each patient upon diagnosis and after growth hormone(0.1-0.15 IU/kg) was injected subcutaneously daily. RESULTS: Ht SDS for CA was -2.06+/-0.23 before treatment, -1.60+/-0.21 at one year, -1.52+/-0.23 at two years, -1.61+/-0.28 at three years, -1.60+/-0.31 at four years, and -1.54+/-0.32 at five years, showing a statistically significant increase for five years(P or =0.05). CONCLUSION: Both groups exhibited significant increase in Ht SDS through growth hormone treatment, proving its efficacy. As for the evaluation of growth-related factors, the 1st year increase of Ht SDS was the most important factor in evaluation of growth effect in both groups. However, further study is required to investigate the effect of GH therapy on ISS.

Factors Affecting on Final Adult Height and Total Height Gain in Children with Idiopathic and Organic Growth Hormone Deficiency after Growth Hormone Treatment

PURPOSE: The purpose of this study was to evaluate the factors affecting the final adult height and total height gain in idiopathic and organic growth hormone deficient(GHD) children after growth hormone(GH) treatment. METHODS: Thirteen patients with idiopathic GHD and 22 patients with organic GHD who had been treated with GH and attained adult final height were included in this study. Factors which could affect the final adult height(FAH) and total height gain, were evaluated. RESULTS: Height SDS(standard deviation score) at initial GH treatment in idiopathic GHD was significantly shorter than that in organic GHD(-4.13+/-1.28 vs -1.66+/-1.06, P<0.001). Growth velocity during the first year of GH treatment was 9.69+/-3.19 cm(idiopathic GHD) and 7.87+/-3.65 cm(organic GHD). Height(SDS) at puberty in organic GHD was significantly greater than in idiopathic GHD (-0.55+/-1.25 vs -2.28+/-0.95, P<0.001). Final adult height(SDS) was significantly greater in organic GHD than in idiopathic GHD(0.22+/-1.06 vs -1.44+/-0.84, P<0.001). In idiopathic GHD, total height gain (SDS) was most significantly correlated with midparental height minus initial height(MPH-IH)(SDS) (r=0.886, P<0.001). Total height gain(SDS) was more significantly correlated with MPH-IH(SDS) and prepubertal height gain(SDS) in idiopathic GHD(r=0.640, P=0.01, r=0.801, P<0.001). CONCLUSION: Final adult height was greater in organic GHD than in idiopathic GHD patients. While total height gain(SDS) was more pronounced in children with lower initial height compared to MPH, absolute final adult height was influenced by height at puberty. To improve the final adult height in children with GHD, height at onset of puberty must be increased by early diagnosis and continuous treatment with optimal doses of GH. There results should be evaluated with more patients.

Lipid Profiles after Discontinuation of Growth Hormone Treatment in Adults with Childhood-onset Hypopituitarism / 대한소아내분비학회지

PURPOSE: The need for continuing Growth Hormone(GH) replacement after adolescence in patients with childhood-onset GH deficiency has been recognized. The purpose of this study was to evaluate the abnormalities of lipid profiles in young adults with childhood-onset hypopituitarism who discontinued GH therapy after the completion of height growth. METHODS: Nine male patients(mean age:22.4+/-3.3 years) with childhood-onset hypopituiatarism in whom GH treatment had been discontinued after final height was achieved were included. Their body mass index(BMI) and serum levels of total cholesterol, triglyceride(TG), high-density lipoprotein(HDL) cholesterol, and low-density lipoprotein(LDL) cholesterol were measured. The relationships of duration after GH discontinuation, age, and BMI to lipid profiles were anaylzed. RESULTS: BMI increased significantly from 21.8+/-1.9 kg/m2 before GH discontinuation to 23.0+/-3.0 kg/m2 after GH discontinuation(P or = 200 mg/dL, TG > or = 150 mg/ dL, LDL cholesterol > or = 140 mg/dL, and HDL cholesterol < or = 40 mg/dL were 77.8%, 88.9%, 44.4%, and 33.3%, respectively. All subjects had some abnormalities of lipid profiles. A significant positive correlation was found between duration after GH discontinuation and serum levels of total cholesterol and TG(r=0.84, P<0.01; r=0.83, P<0.01). A significant positive correlation was also found between age and serum levels of total cholesterol and TG(r=0.86, P<0.01; r=0.81, P<0.01). There were no correlations between BMI and serum lipid levels. CONCLUSION: Most of young adult patients with childhood-onset hypopituitarism had abnormal lipid profiles by 1-5 years after discontinuation of GH treatment. These data suggest that continuous GH treatment after completion of height growth is necessary.

The Effect of Growth Hormone on Carbohydrate Metabolism in Turner Syndrome / 대한소아내분비학회지

PURPOSE:The incidence of glucose intolerance is increased in patients with Turner syndrome. Both noninsulin dependent diabetes mellitus and insulin dependent diabetes mellitus are increased. The purpose of this study was to investigate the impaired rate of carbohydrate metabolism in Turner syndrome after growth hormone treatment. METHODS:We investigated the incidence of carbohydrate intolerance and diabetes mellitus in 94 patients with Turner syndrome with NDDG and WHO criteria. The oral glucose tolerance test was performed in 78 patients. In 12 patients treated with growth hormone, the glucose tolerance test was performed before and after treatment. The insulin tolerance test was done in 20 patients. RESULTS:Only one patient had random plasma glucose level of more than 200 mg/dl. In results of the glucose tolerance test(n=78), 2 patients had glucose tolerance by NDDG criteria and 7 patients had it by WHO criteria. There was no change in glucose tolerance test results during growth hormone treatment. According to the results of the insulin tolerance test, we couldn't find any difference in insulin resistance between the growth hormone treatment group and the other treatments(oxandrolone, estrogen) group. CONCLUSION: The impaired rate of carbohydrate metabolism in Turner syndrome was much lower than in other reports. We observed that the impaired rate of carbohydrate metabolism did not increase after growth hormone treatment. However, the long-term effects in patients treated with growth hormone will be elucidated.

Final Adult Height in Patients with Turner Syndrome / 대한소아내분비학회지

PURPOSE: Short stature is the most constant finding in Turner syndrome. Short stature in Turner syndrome has lately received considerable attention, mostly because of recent attemp to improve growth by hormonal treatments; growth hormone, oxandrolone, estrogen. The aim of this study was to find out whether growth promoting treatment would improve final height in girls with Turner syndrome. METHODS:Seventy-one girls with the clinical chracteristics Turner syndrome verified by karyotype analysis were entered into this study. The following selection criteria for final adult height were used; Chronological age of more than 14years old, bone age of more than 15years old and growth velocity of less than 0.5cm per 6months. Analysis was performed by means of multiple regression analysis between descriptive data; modality of treatment with oxandrolone and/or estrigen, parental height, karyotype and final adult height. RESULTS: 1) The final adult height of untreated Turner syndrome was 138.9+/-3.9cm. 2)The final adult height in 29 GH treated Turner girls was 143.9+/-6.5cm, significant higher value than 42 GH untreated Turner girls height, 139.8+/-5.2cm(p<0.01). 3) The final height in GH only group and combined group were 141.2+/-6.0cm, 146.2+/-6.2cm, respectively. The combined therapy was more effective than GH therapy(p<0.01). 4) The final height in 32 patients with karyotype of 45,X was 141.6+/-5.6cm, and that of 31 structural aberration group was 140.3+/-6.2cm. There was no significant difference between two groups. But in mosaicism, only numeric abnormalities, the final height 145.9+/-6.1cm was much more higher than other two groups(p<0.05). 5) The final adult height in Turner syndrome was in good correlation with target height. Final adult height(cm)= 1.01*Target height(cm)- 4.97 r=0.51, p<0.05. 6) There was positive correlation between final adult height and height SDS at start GH treatment and negative correlation with age at start GH treatment. The delta height (final height - height at start treatment) correlate with GH treatment duration. CONCLUSIONS:The final adult height in Turner syndrome in a given ethinic or national population varies in the same way as adult height in normal women. Growth hormone therapy may increase final height in Turner syndrome irrespective of ethinic or national difference. Further growth was observed in GH combined with estrogen or oxandrolone.

The Changes of the Bone Mineral Density by Treatment Modality in Patients with Turner Syndrome / 대한소아내분비학회지

PURPOSE:Decreased bone mineral density(BMD) has been reported in girls with Turner syndrome. Estrogen therapy is recommanded to improve sexual infantilism and decreased BMD. Short stature is also characteristic finding in patients with Turner syndrome. Treatment modality for short stature has included estrogen, anabolic steroids and growth hormone(GH). Recently GH therapy in GH deficient children could increase BMD in addition to improve short stature. We observed the treatment effects on bone mineral density in patients with Turner syndrome. METHODS: Bone Mineral Density in second to fourth lumbar spine area were measured by dual energy X-ray absorptiometry in 56 girls with Turner syndrome, before and after growth hormone and/or estrogen. All Turner girl was confirmed by clinical and chromosomal examination. RESULTS: 1) There was no significant difference in BMD according to karyotype. 2) The mean BMD of untreated Turner syndrome was 0.752+/-0.122g/cm2. 3) The mean BMD before and after GH treatment were 0.620+/-0.028g/cm2, 0.793+/-0.093g/cm2 respectively. The mean BMD before and after estrogen treatment were 0.761+/-0.125g/cm2, 0.918+/-0.141g/cm2 respectively. In combined group, the BMD were 0.752+/-0.087g/cm2 and 0.939+/-0.134g/cm2. Growth hormone was also effective to improve BMD as well as estrogen. But the changes of BMD were more significant in estrogen and combined group(p<0.05). 4) A significant positive correlation was found between age and BMD(p<0.05). CONCLUSIONS:Estrogen therapy can accelerate epiphysial maturation and compromise final height. Growth hormone therapy in Turner girls was effective for improvement bone mineral density as well as growth improvement. But growth hormone and estrogen combined therapy or Estrogen therapy is more effective to improve bone mineral density in Turner syndrome. Estrogen replacement can be delayed for a while on growth hormone treatment and the appropriated time of estrogen therapy should be elucidated.

The Effect of Recombinant Human Growth Hormone on the Growth in the Children with Chronic Renal Failure

PURPOSE: We observed the effect of three year-administration of recombinant human growth hormone(rhGH) on the growth in the children with chronic renal failure(CRF). METHODS: Five prepubertal children(three boys and two girls) with CRF, who had been managed by conservative methods, were given rhGH(1 U/kg/week) for three years. Growth parameters, such as growth velocity, height standard deviation score(SDS), and predicted final adult height, obtained by TW, BP, and RWT methods, were monitored during rhGH treatment periods. RESULTS: 1) The GV increased significantly with rhGH therapy from 3.8+/-1.2cm/year to 8.4+/-1.3cm/year(1st year), 7.1+/-3.8cm/year(2nd year), and 6.3+/-0.9cm/year(3rd year) and GV tended to decrease over years with rhGH therapy(Fig. 1, p<0.05). 2) The height SDS increased signficantly with rhGH from -3.2+/-1.3 to -2.6+/-1.1(1st year), -2.2+/-1.2(2nd year) and -2.2+/-1.5(3rd year) and height SDS also tended to decrease over years with rhGH therapy(Fig. 2, p=0.05). 3) FAHs, obtained by TW and BP methods, seemed to increase at 1st and 2nd year of rhGH therapy(p=0.05, and p<0.05, respectively), but did not show any significant increase at 3rd year of therapy, compared to those of pretreatment. FAH, obtained by RWT method, did not show any significant change with rhGH therapy. 4) There was no significant correlation between the GV and chronological or bone age at the start of rhGH therapy, but there was a significant correlation between the chronological age and the height SDS at 2nd year(p<0.05, r=-0.93) and at 3rd year (p<0.05, r=-0.97) of rhGH therapy(Fig. 4), but there was no relationship between the height SDS and bone age. 5) There had been no noticeable side effect, especially deterioration of renal function. CONCLUSIONS: The long-term administration of rhGH in the children with CRF can result in the improvement of growth parameters, such as growth velocity, height SDS, and predicted final adult height, but these parameters seems to be weakened over years with rhGH therapy, which could be overcome by the increase of rhGH dose. It seems to be better to start rhGH treatment at an early stage of CRF and early chronological age to achieve better growth.