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Objective The aim was to determine the final adult height (FAH) achieved by recombinant human growth hormone (rhGH) treatment, the factors affecting FAH and the success of attaining the genetic potential. Methods Data of 133 patients treated with rhGH therapy were reviewed retrospectively. Patients were grouped according to diagnosis, either isolated GH deficiency (IGHD) or multiple pituitary hormone deficiency (MPHD), and by sex, and pubertal status at the beginning of treatment. Results The mean age of initiation of treatment was 12.3±2.18 years, and the mean duration of rhGH treatment was 3.65±1.5 years. The mean height standard deviation score (SDS) at diagnosis was -3.11±0.75 SD. All patients received a standardized GH dose of 0.033 mg/kg/day. Mean FAH-SDS was -1.8±0.77 and delta height-SDS (the change in height SDS between the beginning and end of treatment) was 1.28±0.94 SD. FAH-SDS was -1.79±0.86 SD in males; -1.82±0.64 in females (p=0.857); -1.94±0.71 at the beginning of treatment in pubertal patients and -1.68±0.81 in prepubertal patients (p=0.056); -1.84±0.89 in patients with IGHD and -0.47±0.2 in patients with MPHD (p˃0.05). In multiple regression analysis, First year delta height-SDS was the most predictive factor for both FAH-SDS and delta height-SDS. Conclusion The majority of our patients achieved a final height compatible with their genetic potential as well as population standards when treated with rhGH even having started at a relatively late age. First year delta height-SDS was a predictive factor for FAH.

We investigated whether growth hormone (GH) treatment could accelerate the onset of puberty in patients with isolated GH deficiency (GHD). Of the 135 boys and 89 girls who started GH treatment before the onset of puberty and were followed up at Tanaka Growth Clinic, 83 boys and 51 girls who started GH treatment sufficiently earlier than the average age at onset of puberty of GHD patients (

Introduction Protocol for prescribing hormone replacement therapy in isolated growth hormone (GH) deficiency includes magnetic resonance imaging of the brain. There is controversy on the frequency of structural pituitary abnormalities and on the importance of abnormal MRI findings on prognosis and response to GH replacement. Methods A descriptive, retrospective study of children of both sexes aged 0–14 years, who had undergone brain MRI, diagnosed with isolated GH deficiency at a tertiary hospital in the past 14 years, aimed at reporting the frequency of abnormal MRI findings in isolated GH deficiency, and to establish whether differences exist in height diagnosis and evolution according to MRI findings. MRI findings were also compared with the findings reported in healthy children in order to establish incidence. Results 96 patients were studied, of whom 74/96 (77%) reached adult age. Abnormal MRI findings were seen in 11.5% of them (8/11 of pituitary origin). No brain or pituitary tumor was seen in any case. Patients with abnormal images had a mean age at treatment start of 8 years, a target height of −0.8SD, and a final height of 1.04SD, while patients with normal MRI findings had an age at treatment start of 10 years old, a target height of −1.44SD, and a final height of −1.75SD, with statistically significant differences. Conclusions Patients with abnormal MRI findings show a more favorable response to GH replacement therapy.

Introduction: Growth in patients with isolated growth hormone (GH) deficiency is heterogeneous despite treatment due to the low specificity of diagnostic tests, making it necessary to define efficacy variables. Aims: To evaluate efficacy of hormone replacement therapy in children with isolated GH deficiency. Methods: Observational-ambispective study of patients treated in our department in the last 14 years for isolated GH deficiency. This was defined as a GH level less than 7.4 mg/dL in response to 2 stimulation tests in patients with height

Background: Hypothyroidism in children leads to growth retardation. However, there is some evidence that recombinant human growth hormone (rhGH) therapy could suppress thyroid function. The most common observation in rhGH-treated patients is a decrease in thyroxine levels, which is reported as transient, but the studies in the field are inconsistent. We aimed to evaluate thyroid function in initially euthyroid children with idiopathic isolated GH deficiency during long-term rhGH therapy and to determine who is at a higher risk of thyroid function alterations during the therapy. Methods: The study group consisted of 101 children treated with rhGH for at least three years. Serum TSH and fT4 levels were determined at baseline, after the first six months and after each full year of therapy. The associations between changes in thyroid hormone levels during rhGH therapy and GH deficit, insulin-like growth factor-1 levels and growth response were investigated. Results: A significant decrease in fT4 levels (p = 0.01) was found as early as after the first six months of rhGH therapy. This effect persisted in the subsequent years of treatment without any significant changes in TSH values and tended to be rhGH dose related. Children with a greater fT4 decrease after the initiation of rhGH therapy were older, had higher bone age and responded to that therapy worse than children with lower fT4 changes. Conclusions: Our study revealed a long-term decrease in fT4 levels during rhGH therapy in initially euthyroid GHD children. The decrease in fT4 levels was associated with a lower growth response to rhGH therapy.

Background and Objective: The current meta-analysis aims at evaluating whether the existing clinical evidence may ascertain the effects of growth hormone (GH) replacement therapy on cardiovascular risk, both in isolated GH deficien-cy (GHD) and in compensated panhypopituitarism including GH deficit. Methods: Original articles published from 1991 to 2015 were searched on Medline (Pubmed). Among an overall number of 181 potentially suitable studies, 24 fulfilled the selection criteria and were included in the analysis. Data aggregation was car-ried out through the calculation of the absolute risk reduction. The meta-analysis was then conducted by means of a fixed-effects model, according to the heteroge-neity test (Chi-square statistic). Results: Fat-free mass (FFM) increase and fat mass (FM) reduction were found, together with a C-LDL reduction, a wide variation in glycaemia and a neutral effect on glycated haemoglobin (HbA1c) and blood pressure. These effects were valid both for isolated GHD patients and for those with compensated panhypopituitarism. The global out-come D showed a nonsignificant reduction of the overall cardiovascular risk (0.53; 95% C.I. -1.23, 2.85). Conclusion: Our meta-analysis shows no signnificatly positive trend in cardiovascular risk after both short and long-term GH supplementation therapy in adult GHD patients. However, a reduction of LDL cholesterol levels has been found. No differences were found between isolated GHD participants and those affected by panhypopituitarism well compensated since at least 3 months.

Introduction: Enteroendocrine connections involve interactions between the alimentary system, energy balance, and several hormones, including insulin, GH, IGF-1, ghrelin, and GLP-1. While insulin and GLP-1 are crucial in the fed state, GH and ghrelin are more relevant during fasting or famine. Ghrelin, mostly produced by the neuroendocrine cells in the gastric mucosa, increases GH secretion, reduces insulin secretion, and stimulates hunger, peaking before meals. GLP-1, secreted by the entero endocrine L-cells in response to nutrient ingestion, potentiates insulin secretion, inhibits glucagon secretion, and contributes to satiety, peaking one hour after meal. Ghrelin enhances GLP-1 secretion in mice and probably in men. Conversely, somatostatin decreases GLP-1 secretion. Whether GH deficiency (GHD) affects the secretion of these hormones is unknown. We have studied this question in a cohort of subjects with isolated GHD (IGHD) due to a mutation in the GHRH receptor gene. These individuals exhibit severe dwarfism, visceral obesity, dyslipidemia, but delayed atherosclerosis, and normal longevity. We have previously shown that during OGTT the area under the curve (AUC) for glucose is higher, with similar AUC for insulin in comparison to controls, suggesting a combination of increased insulin sensitivity and reduced beta cell function. In addition, we have reported that these IGHD subjects eat proportionally more than matched controls. We hypothesized that these subjects may have higher ghrelin levels, resulting in reduced insulin secretion, partially compensated by an increase in GLP-1, contributing to the increased insulin sensitivity. Methods: We measured blood concentrations of glucose, insulin, total ghrelin, and GLP-1 in 20 IGHD adults (11 males, 49.4±13.4 yrs) and 20 gender- and age-matched controls (11 males, 48.9±13.6 yrs), during fasting and 30, 60, 120, 180 min after a standard test meal. HOMAir and HOMA-β were calculated. Sensations of hunger, fullness, and prospective food consumption were measured by a validated visual analogic scale questionnaire at each time point. Results: HOMAir and HOMA-β were lower in IGHD than controls (p=0.002 and p=0.023 respectively). AUC were higher for hunger (p

The GH/IGF axis plays an important role in the control of pre and postnatal growth. At least 48 monogenic defects have been described affecting the production, secretion, and action of GH and IGFs. Molecular defects of the GH/IGF axis resulting in short stature were arbitrarily classified into 4 groups: 1. Combined pituitary hormone deficiency (CPHD) (a. syndromic CPHD and b. non-syndromic CPHD), 2. Isolated GH deficiency (IGHD), 3. GH insensitivity, and 4. IGF-I insensitivity. Genetic diagnosis is obtained in about 30-40% of children with growth retardation, severe IGHD, CPHD, apparent GH or IGF-I insensitivity, and small for gestational age. Increased accessibility to next generation sequencing (NGS) techniques resulted in a significant number of likely pathogenic variants in genes previously associated with short stature as well as in completely novel genes. Functional in vitro assays and in vivo animal models are required to determine the real contribution of these findings. Fil: Domene, Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Domene, Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina

The GH/IGF-I axis has important interactions with the alimentary system and with the balance between energy intake (EI) and energy requirement (ER). Reduced EI has been described in adult-onset acquired GH deficiency (GHD). Individuals from the Brazilian Itabaianinha cohort, with isolated GHD (IGHD) due to a homozygous mutation (c.57+1G→A) in the GHRH receptor gene, are an ideal model to study the consequences of lifetime GHD. The purpose of this study is to evaluate EI and ER in this untreated IGHD cohort. Cross-sectional study of 24 adult IGHD patients and 23 controls from the same region, matched for age and gender. Estimated EI (EEI) was evaluated by dietary recall, and estimated ER (EER) by the equation of the Dietary Reference Intakes. Fat mass was assessed by DXA. Both EEI and EER were lower in IGHD than controls. However, when corrected by body weight, EEI was higher in IGHD (p = 0.005). IGHD individuals consume in percentage more proteins (p < 0.0001), less carbohydrates (p = 0.013), and equal amount of lipids in comparison to controls. The higher EEI per body weight suggests a possible increase of orexigenic mechanisms in untreated IGHD individuals, ensuring greater caloric intake, which would have adaptive advantages for small-sized individuals in environments with limited access to food. IGHD individuals seem to have a healthier dietary pattern than CO.

PubMedID: 29353264 The aim of the study was to assess the response to growth hormone (GH) treatment in very young patients with GH deficiency (GHD) through a national, multi-center study. Possible factors affecting growth response were assessed (especially mini-puberty). Medical reports of GHD patients in whom treatment was initiated between 0 and 3 years of age were retrospectively evaluated. The cohort numbered 67. The diagnosis age was 12.4±8.6 months, peak GH stimulation test response (at diagnosis) as 1.0±1.4 ng/mL. The first and second years length gain was 15.0±4.3 and 10.4±3.4 cm. Weight gain had the largest effect on first year growth response; whereas weight gain and GH dose were both important factors affecting second year growth response. In the multiple pituitary hormone deficiency (MPHD) group (n=50), first year GH response was significantly greater than in the isolated GH deficiency (IGHD) group (n=17) (p=0.030). In addition first year growth response of infants starting GH between 0 and 12 months of age (n=24) was significantly greater than those who started treatment between 12 and 36 months of age (n=43) (p

Nonalcoholic fatty liver disease (NAFLD) is known to be associated with insulin resistance, atherosclerosis, and low serum IGF1 levels. We have described a large cohort of patients with isolated GH deficiency (IGHD) due to the c.57+1G→A mutation in the GHRH receptor gene. These subjects have increased insulin sensitivity (IS), delayed atherosclerosis, and normal longevity. We hypothesized that, despite visceral obesity, NAFLD would be absent or mild due to the increased IS. To assess the prevalence and severity of NAFLD in adult subjects with lifetime, congenital, untreated IGHD, we studied 22 IGHD adults and 25 controls (COs) matched for age and sex. NAFLD was assessed by a comprehensive liver function panel, and ultrasonographic pattern (hyperechogenic pattern, HP) coded as follows: 0, absent; 1, mild; 2, moderate; and 3, severe. Compared with COs, IGHD individual had lower serum IGF1 (PP=0.027), lower prothrombin time (P=0.017), and similar activated partial thromboplastin time and fibrinogen values. Alanine transaminase (ALT) values were similar in the two groups, but aspartate transaminase was higher in IGHD (P=0.013). However, more IGHD subjects (7/22) than COs (3/23) had ALT above the upper limit of normal (P=0.044). The prevalence of NAFLD was higher in IGHD than COs (61 vs 29%, P=0.032), and the HP score was higher in IGHD than COs (P=0.041), but severe NAFLD was not observed in any IGHD (or CO) individual. Liver HP score is increased in lifetime, untreated, congenital IGHD, but the increase in transaminases is mild, suggesting a lack of advanced forms of NAFLD.

To ascertain the impact of pituitary size as judged by Magnetic Resonance Imaging (MRI), on response to Growth Hormone (GH) therapy in GH deficient children. Thirty nine children (9.1 ± 2.7 y, 22 boys) with non-acquired GH deficiency (21 Isolated GH deficiency and 18 Combined pituitary hormone deficiency) were consecutively recruited and followed up for one year. Clinical, radiological (bone age and MRI) and biochemical parameters were studied. Children with hypoplastic pituitary (pituitary height

Context and objective: Experimental models demonstrate an important role of growth hormone (GH) in retinal development. However, the interactions between GH/IGF-I axis and the neuro-vascularization of the human retina are still not clear. A model of untreated congenital isolated GH deficiency (IGHD) may clarify the action of GH on the retina. The purpose of this work was to assess the retinal neuro-vascularization in adults with congenital IGHD. Methods: In a cross sectional study, we performed fundus photographs (to assess the number of retinal vascular branching points and the optic disc and cup size), and optical coherence tomography (to assess the thickness of macula) in 25 adults IGHD subjects (13 males, 50,9 yr. [12,0]) homozygous for a null mutation (c.57+1 G>A) in the GH releasing hormone receptor gene and 28 controls (14 males, 46,4 yr. [14,7]). Results: Fisher's exact test revealed that IGHD subjects presented more reduction of vascular branching points in comparison to controls (91% vs. 53% [p=0.049]). Conversely, the percentage of moderate reduction in IGHD was higher than in control (p=0,01). The rates of individuals with increased optic disc and cup size were increased in IGHD in comparison to controls (92,9% vs. 57,1 for optic disc and 92,9% vs. 66,7% for cup [pA no gene do receptor do hormônio liberador do GH e 28 controles (14 homens, idade 46,4 anos [14,7]), pareados por idade e sexo. Ambos os grupos foram submetidos a retinografia (para avaliar o número de ramificações nos vasos retinianos, o tamanho do disco óptico e da escavação) e tomografia de coerência óptica (OCT) (para avaliar a espessura da mácula). Resultados: Os indivíduos com DIGH apresentaram maior redução no número de ramificações vasculares em relação aos controles (91% vs. 53% [p=0,049]), segundo teste exato de Fisher. A porcentagem de redução moderada foi maior na DIGH que nos controles (p=0,01). A taxa de indivíduos com aumento do disco óptico e da escavação foi maior na DIGH em relação aos controles (92,9% vs. 57,1% para o disco e 92,9% vs. 66,7% para a escavação [p

GH is important for the development and function of the immune system, but there is controversy on whether GH deficiency (GHD) is associated to immune disorders. A model of isolated GHD (IGHD), without others deficits or hormones replacement, may exclude if the lack of GH is associated with increased susceptibility to infections or with an altered responsiveness of the immune response. Our objective was to study the frequency of infectious diseases and the cellular and humoral immune response in adults with congenital, untreated IGHD. The study was performed in two steps: in the first, a cross-sectional study, 35 adults IGHD due to a homozygous mutation in the GHRH receptor gene and 31 controls were submitted to a clinical questionnaire to evaluate past and current history of infectious diseases, physical examination, and serology for tripanosomiasis, leishmaniasis, HIV, tetanus, hepatitis B and C. The only exclusion criterion for this first step was age less than 20 years old. In the second step, a study of cases with a control group for comparison of immune cellular and humoral response between the groups. The exclusion criteria were age less than 20 and more than 65 years old; diagnosis of HIV, infection or acute diseases; history of malignancies; autoimmune diseases; glucocorticoid and anti-allergic medications use; or current pregnancy. The immune response was evaluated in a subset of these subjects by serum total IgG, IgM, IgE and IgA measurement, skin tests (Protein Purified Derived (PPD), streptokinase and candidin), and response to vaccination for hepatitis B and tetanus (in individuals with negative serology), and to bacillus Calmette-Guérin (BCG) in subjects nonreactive to PPD. There was no difference between the groups in history of infectious diseases and baseline serologic data. IGHD subjects had lower total IgG, but within normal range, and a smaller induration diameter in streptokinase skin test, but no difference in the frequency of positivity to streptokinase (IGHD 2 in 21; controls 5 in 20). There was no difference in the positivity to PPD (IGHD 4 in 24; controls 10 in 28) and to candidin (IGHD 3 in 21; controls 1 in 19), or in the response to any of the vaccinations between the groups. The controls had a higher frequency of one positive skin test. In conclusion, adult untreated IGHD did not present an increased frequency of infections or significant alterations in the immunological tests, but we found lower total IgG levels and lower positivity to at least one skin test, without detectable clinical impact. O hormônio do crescimento (GH) é importante para o desenvolvimento e função do sistema imunológico, mas há controvérsias se a deficiência do GH (DGH) é associada a distúrbios imunes. Um modelo de deficiência isolada do GH (DIGH), sem outros déficits ou reposições hormonais, excluiria efeitos confundidores na análise das ações do GH na imunidade, podendo esclarecer se a ausência do GH é associada a uma maior susceptibilidade a infecções ou a uma alteração na resposta imunológica. Nosso objetivo foi estudar a frequência de doenças infecciosas e a resposta imune celular e humoral em adultos com DIGH congênita e não tratada. O estudo foi realizado em duas partes: na primeira, estudo transversal com 35 adultos DIGH devido à mutação homozigótica (C.57 + 1G > A) no gene do receptor do hormônio liberador do GH (GHRH) e 31 controles, que foram submetidos a um questionário clínico para avaliar a história prévia e atual de doenças infecciosas, exame físico e foram dosadas as sorologias para doença de Chagas, leishmaniose, HIV, tétano, hepatites B e C. O único critério de exclusão para esta primeira etapa foi ter menos de 20 anos de idade. Na segunda parte, foi feito um estudo de casos com grupo controle para comparação da resposta imunológica celular e humoral entre os grupos. Os critérios de exclusão foram ter menos do que 20 e mais do que 65 anos de idade, diagnóstico de HIV, infecções agudas, malignidades, doenças autoimunes como artrite reumatóide, lúpus eritematoso sistêmico, uso de medicações antialérgicas e glicocorticóides ou condições como gravidez. A resposta imune foi avaliada em um subgrupo destes indivíduos através das dosagens das imunoglobulinas séricas: IgG total, IgA, IgE e IgM, de testes cutâneos (Derivado Proteico Purificado (PPD), estreptoquinase e candidina), e da resposta à vacinação para hepatite B e tétano (nos indivíduos com sorologia negativa) e ao bacilo Calmette-Guérin (BCG), nos indivíduos que tivessem PPD negativo. Não houve diferença entre os grupos na história de doenças infecciosas e dados sorológicos basais. Indivíduos com DIGH apresentaram menores níveis de IgG total, mas dentro da variação normal e menor diâmetro da induração no teste cutâneo com estreptoquinase, embora sem diferença na positividade a este teste (DIGH 2 em 21; controles 5 em 20). Também não houve diferença na positividade ao PPD (DIGH 4 em 24; controles 10 em 28) e à candidina (DIGH 3 em 21; controles 1 em 19) nem na resposta às vacinações entre os grupos. Os controles tiveram uma maior frequência de um teste cutâneo positivo. Em conclusão, adultos com DIGH não tratada não apresentaram uma maior frequência de infecções ou alterações significantes nos testes imunológicos, mas apresentaram menores níveis de IgG total e menor positividade a pelo menos um teste cutâneo, embora sem impacto clínico.

The relation between nightly growth hormone (GH) secretion and sleep is poorly understood. To examine whether disturbances in GH secretion are reflected in abnormal sleep patterns 8 subjects with isolated GH deficiency and 9 subjects with excess of GH (acromegalics) underwent all night sleep studies, polysomnography. Moreover, the effect of correcting GH concentration on sleep patterns were examined in the same subjects. The results showed that all subjects with GH disturbances had abnormal REM and delta sleep and normalization of GH concentration was followed by correction of the sleep stages. By power spectrum analysis of the sleep EEG it was showed that during low GH concentration the sleep energy was low, and high GH concentration was associated with high sleep energy, and correction of abnormal plasma GH levels resulted in normalization of REM and delta sleep energy per time unit.

Summary Background Achalasia or idiopathic megaesophagus is rare in children, and an association with growth hormone (GH) deficiency has rarely been described. Case report This report is of a girl treated with recombinant GH (rGH) for isolated GH deficiency who simultaneously presented with idiopathic megaesophagus. Conclusion This case report highlights the fact that practitioners need to be aware of this possible morbid association.

Most children with idiopathic isolated GH deficiency (IGHD) normalize GH response to stimulation tests when retested at the completion of growth. The objective of this study was to test the effectiveness of early retesting in challenging the diagnosis of idiopathic IGHD and critically review the diagnostic workup leading to this diagnosis in children with short stature.We cross-sectionally retested 38 children with idiopathic IGHD and still on GH treatment. The initial diagnosis of idiopathic IGHD was based on subnormal GH responses to two stimulation tests and normal brain imaging or minor/nonspecific findings at magnetic resonance. The GH response normalization at retesting was considered as the main outcome measure. Clinical features of children who were falsely classified as idiopathic IGHD based on first GH testing were retrospectively analyzed.GH secretion was normal in 36/38 children (95%). Two children showed slightly reduced peak GH responses and normal IGF-I levels. Fourteen children underwent GH retesting before puberty, 24 children during puberty.The diagnostic process should be improved to minimize the rate of false positive at GH testing and, in case of unsatisfactory response to GH treatment, the diagnosis of isolated idiopathic GHD should be challenged with early retesting.

Growth hormone (GH) has been implicated as an important factor in the growth regulation of several visceral organs including the gastrointestinal tract. Our aim was to study the effects of GH administration on colonic growth in dwarf rats with an isolated GH deficiency. Dwarf rats were treated with recombinant human growth hormone (rhGH; 2.0 mg/kg/day) for four weeks and compared with saline treated dwarf rats and rats with normal pituitary function. The colonic wall composition was measured by means of stereological techniques. RhGH treatment of the dwarf rats increased body weight by 80% and proximal and distal colon weight by 63% and 90%, when compared with placebo treated dwarf rats (P0.01). The weight of the proximal colonic mucosa increased by 83% (P0.01), submucosa by 78% (P0.05), and the muscularis propria by 51% (P0.001) in rhGH treated dwarf rats compared with dwarf controls. The weight of the distal colonic mucosa increased by 88% (P0.01), submucosa by 88% (P0.05) and the muscularis propria by 58% (P0.05) compared with dwarf controls. The growth of mucosa involved all mucosal layers, with a 73 and 92% increase in the proximal and distal colon luminal surface area respectively (P0.001, P0.01). The food consumption, expressed as g/day/100 g BW was 13% higher in dwarf rats receiving rhGH than in placebo treated rats (P0.05) and normal control rats (P0.05). When weights of the GI tract compartments are corrected for the increase in body weight the effects of GH treatment were small or non-significant. RhGH administration in GH deficient dwarf rats induces visceral growth with a pronounced increase in colonic luminal surface area and growth of all layers of the colonic wall. These findings confirm the important role of GH in the regulation of intestinal growth.

OBJECTIVE Birth weight influences both postnatal growth and the initial response to GH therapy in GH-deficient subjects, but its relationship to final height is uncertain. Therefore, we examined final height results in a group of subjects treated for GH deficiency who were born small, appropriate or large for gestational age (GA). DESIGN Retrospective study. PATIENTS 108 GH-treated patients (age at diagnosis 11.1 ± 2.0 years) affected by idiopathic and isolated GH deficiency (peak

Objective: Isolated growth hormone deficiency (IGHD) is defined as a medical condition associated with growth failure due to insufficient production of GH or lack of GH action. Mutations in the gene encoding for GH-releasing hormone receptor (GHRHR) have been detected in patients with IGHD type IB. However, genetic defects on GHRHR causing IGHD in the Turkish population have not yet been reported. To identify mutations on GHRHR gene in a population of Turkish children with IGHD.Methods: Ninety-six Turkish children with IGHD were included in this study. Exon1-13 and exon/intron boundaries of GHRHR were amplified by suitable primers. The polymerase chain reaction products for GHRHR gene were sequenced with primers.Results: We analyzed the GHRHR gene for mutations in ninety-six patients with IGHD based on sequence results. We identified novel p.K264E, p.S317T, p.S330L, p.G369V, p.T257A and C base insertion on position 380 (c.380inserC) mutations. In 5 of the patients, the mutation was homozygote and in 1-heterozygote (p.S317T).Conclusion: Six new missense mutations and one first case of insertion mutations for the GHRHR gene are reported. © Journal of Clinical Research in Pediatric Endocrinology.

The aim of the present study was to evaluate retrospectively the influence of various auxological and laboratory parameters on final height in a group of GH-deficient children after replacement therapy and to compare their final height with that of a group of short children with normal GH secretion and hence not treated. The final height was evaluated of 83 patients (51 males and 32 females) affected by idiopathic isolated GH deficiency and treated with recombinant human GH (hGH) for 2-7 years. Inclusion criteria at the start of treatment were short stature (mean height for chronological age in standard deviation score (SDS) -2.21) due to idiopathic isolated GH deficiency (GH peak < 8 micrograms/l after two pharmacological tests and/or mean GH concentration < 3.3 micrograms/l during the night) and treatment with recombinant hGH for at least 2 years at a dose of 15-20 U/m2 per week by s.c. injection for 6 or 7 days/ week. Mean chronological age at diagnosis was 12.2 +/- 1.7 years; 35 were prepubertal and 48 pubertal. The final height of 51 untreated short stature (mean height for chronological age in SDS -2.13 at diagnosis) subjects (42 males and 9 females: 29 prepubertal and 22 pubertal at diagnosis with mean chronological age 11.6 +/- 2.4 years) with normal GH secretion was also evaluated. In the treated subjects final height SDS was higher than that of the untreated group (-1.3 vs -1.7 SDS; P = 0.01). Both treated and untreated subjects showed a final height lower than target height, but 39% of the treated subjects vs only 20% of the untreated group (P = 0.035) had a final height greater than target height. In the treated subjects this percentage was higher in the patients improving their height for bone age in the first years of therapy. While treated females showed a positive correlation only between target and final height (P = 0.0001), in treated males final height correlated with the Bayley-Pinneau prediction at diagnosis, height for chronological age and bone age at diagnosis and target height. Patients who started therapy before puberty also showed these correlations with data calculated at the onset of puberty, together with a correlation with chronological age at the onset of puberty. When considering the influence of GH response at tests on final height, the percentage of subjects exceeding target height increased progressively according to the severity of the GH deficiency. There was no difference in height gain between the patients starting therapy before or during puberty. The height gain, however modest, obtained by our treated patients, the number of patients with final height greater than target height and the favourable comparison with the untreated short-stature subjects represent a promising result, which could be improved by personalizing treatment.

The aim of the study was to assess the efficacy of GH therapy in GH-deficient children treated before the age of 3 yr. A noncomparative multicenter prospective study included 49 children (22 girls and 27 boys) with isolated GH deficiency (n = 19) or multiple pituitary hormone deficiency (n = 30) treated with daily sc injections (0.6 U/kg·week) for 3–5 yr. They were divided into two groups according to their height sd score for chronological age (CA) at the initiation of therapy: group A consisted of 8 patients presenting an initial height within the normal range (

Fil: Juanes, Matias Hernan. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatria "Juan P. Garrahan"; Argentina

Background: Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). Objective: To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. Methods: The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c.1146G>A (p.E382E) mutation. Results: A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. Conclusion: We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD.

For the first time, a broad study of the effectiveness of treatment with growth hormone (GH) in patients with varying degrees of impaired secretion of GH is undertaken. In this work, 885 patients of pre-pubertal age who received treatment for 1 year were examined. All children were given 2 standard tests with stimulation of the secretion of GH. The following diagnoses were established: idiopathic insufficiency of GH (classification number 1.1) or idiopathic stunting (3.1). Patients were divided into groups depending on the maximum release of GH during sampling: A - in both samples 5 ng/ml, B - in one sample 5 ng/ml, in another - 5-10 ng/ml, C - in both samples 5-10 ng/ml, D - in one sample 5-10 ng/ml, in another - 10 ng/ml, E - in both samples 10 ng/ml.anthropometric indicators, main parameters of therapy and results of treatment of GY were evaluated in all developed model (expected RESULTS). According to the study, patients with the most severe GH deficiency (group A) had better treatment outcomes, while the other groups were almost identical. The division of group A into a subgroup with isolated GH deficiency and a subgroup with deficiency of other tropic hormones (hypopituitarism) showed that in the first subgroup the growth of parents was significantly lower. Thus, despite the fact that standard samples with stimulation of GH can be used to diagnose the insufficiency of GH, the results of these samples do not always allow to predict the effectiveness of treatment of GH for 1 year. It should also be noted that the shortness of the parents, especially the growth of the mother, may indicate the presence of an additional hereditary factor in the Genesis of shortness in these patients.

Children with isolated GH deficiency have enlarged fat depots due to increased fat cell volume. The fat cell number is however decreased compared with appropriate controls. Treatment of patients with GH results in a relative loss of body fat and shifts both fat cell number and fat cell volume towards normal. These findings of adipose tissue cellularity in GH-deficient children before and after treatment can be explained by results from in vitro studies indicating that GH exerts a variety of effects on the metabolism of mature fat cells and on the proliferation and differentiation of cultured preadipocytes. Therefore, GH is one of the factors that determines adipose tissue development during childhood.

Comparing the growth promoting effect of IGF-I in children with Laron syndrome to that of hGH in children with isolated GH deficiency (IGHD) we found that hGH has a superior effect to that of IGF-I.

Both children with Laron syndrome (LS) and those with congenital isolated GH deficiency (IGHD) were found to have reduced muscle force and endurance. Replacement treatment with IGF-I of LS patients was less effective than that with hGH in IGHD patients in restoring muscle force.

Recent evidence suggests that GH and insulin growth factor-I (IGF-I) play a role in adrenal steroidogenesis. On the other hand, it has been shown that ACTH stimulates IGF-I secretion by cultured fasciculata adrenal cells. Aim of the present study was to investigate the influence of GH administration on adrenal steroids and IGF-I responsiveness to ACTH in children affected with isolated GH deficiency. Ten children (seven males and three females, 5-10 yr old) affected with isolated GH deficiency underwent a synthetic ACTH 1-17 test before and after administration of human recombinant GH at a dose of 4 IU/day sc for 10 days. After the therapy, no significant differences were detected in the responses of cortisol, dehydroepiandrosterone-sulfate, androstenedione, and 17-hydroxyprogesterone to ACTH 1-17, whereas an increased 11-deoxycortisol responsiveness to ACTH 1-17 was noted (P less than 0.005). Surprisingly, IGF-I significantly increased in response to ACTH 1-17 after short-term rGH administration (P less than 0.006). In conclusion, our data indicate that in isolated GH deficiency a short-term GH therapy does not substantially modify the adrenal responsiveness to exogenous ACTH, even if an increased 11-deoxycortisol and an induced IGF-I responsiveness to ACTH were observed.

In our previous studies we had demonstrated that, in children affected with isolated GH deficiency (IGHD), a short-term recombinant growth hormone (rGH) therapy increases the 11-deoxycortisol (S) secretion and induces an IGF-I responsiveness to the ACTH challenge. The aim of the present study was to further investigate the mechanisms by which IGF-I is secreted after ACTH challenge in children affected with IGHD by correlating IGF-I versus cortisol (F) time courses after ACTH administration. Ten children affected with IGHD were subjected to rGH therapy (4 IU/day subcutaneously) for 10 days. The responsiveness of IGF-I, F and S to the ACTH 1-17 test were evaluated before and at the end of the therapy. No IGF-I response to the ACTH test was recorded in the patients before the rGH treatment, whereas after rGH administration ACTH induced a significant IGF-I release (p < 0.001) which started at the 1st hour, reached a peak value between the 5th and 6th hours and disappeared at the 10th hour. In conclusion, our study confirms that a short-term rGH therapy induces an IGF-I responsiveness to ACTH and helps to better define the kinetics and the mechanism of this IGF-I response to ACTH.

Celiac disease (CD) is a prevalent, genetically determined, autoimmune, chronic inflammatory state caused by intolerance to gluten that results mainly in gastrointestinal manifestations. One of the most common extra-intestinal manifestations of CD is short stature, and in some patients, short stature may be the presenting and only symptom of the disease, making the diagnosis of CD challenging. Impaired growth in children with CD results mainly from nutritional deficits, and withdrawal of gluten from the diet is frequently associated with a marked improvement of linear growth. In some patients, CD may be characterized by growth hormone (GH) resistance, as suggested by normal or elevated GH levels and low insulin-like growth factor-I (IGF-I) levels. Rarely, it has been shown that poor catch-up growth and/or IGF-I response to gluten-free diet may be due to the coexistence of celiac disease and GH deficiency. We present two children with coexisting CD and GH deficiency. One patient had MRI findings suggesting congenital isolated GH deficiency, and a possibility of developing multiple pituitary hormone deficiencies later in life.

Consideration of GH re−testing should be performed in all adolescents reaching the transition period (if not at start of puberty) who had been previously diagnosed with idiopathic, isolated GH deficiency. In the presence of multiple hormone deficiencies and/or clear−cut evidence of organic disease, persistence of severe GH deficiency is much more likely. Thus, GH deficiency may be “confirmed” by a low serum IGF−I concentration. During the transition period, the optimal time to reassess the integrity of the GH−IGF−I axis after prior GH treatment, the specific testing protocol to use, and the definition of GH deficiency all remain unknown. During the transition period, patients should have their GH dose lowered with (upward) adjustments made on the basis of age−and gender−adjusted serum IGF−I concentrations. GH treatment during the transition period has been shown in most, but not all, studies to be beneficial in preventing development of the features of the adult GH deficiency syndrome. It is important to remember that, during the transition period in teenagers with GH deficiency, there must be initiation of a careful plan for transfer of care to an intermist−endocrinologist with expertise in management of hypothalamic−pituitary disease in young adults. Conflict of interest:None declared.

Aim: Validation of a preexisting mathematical model for predicting height velocity in the first year of growth hormone (GH) treatment, using an independent cohort of pediatric patients with confirmed GH deficiency (GHD). Design: 210 prepubertal and pubertal patients with isolated GHD were enrolled within the 'growth prediction module' of a prospective international postmarketing research program (GeNeSIS). Methods: The patients were grouped as 'prepubertal', at 'start of puberty' and 'pubertal', and the performance of the model was validated by comparing predicted and observed height velocity (HV) in the first treatment year for each group. The operational characteristics of the model, when used as a screening method to predict poor and good growth response to GH, were calculated using the first year change in height standard deviation score as a cut-off for treatment response. Results: Depending on pubertal stage, the growth prediction model explained 53-72% of the variability of the first year HV. The model fulfilled the statistical prerequisites to identify patients with poor and good responses to GH with sufficient reliability in individual patients. Conclusions: The growth prediction model was successfully validated in a large cohort of prepubertal and pubertal pediatric patients under field conditions.

The aim of this study is to estimate the annual incidence and prevalence rate of the GH treatment exposure in patients under the age of 18 treated for hypopituitarism or isolated GH deficiency (GHD) in Piedmont, during the period January 1, 2002 to December 31, 2004.The selection criteria for recombinant human GH (rhGH) treatment in childhood were approved by the Ministry of Health in Italy in the yr 1998. The present analysis is based on data from the Registry of subjects receiving GH therapy (GH Registry) made up of the 918 pediatric patients (age18 yr) with a diagnosis of GHD (excluding Prader-Willi and Turner syndromes and other conditions), diagnosed in the period January 1, 2002 - December 31, 2004. The case series has been described as regards the number of cases per year of diagnosis; the prevalence and incidence rates, calculated per 10,000 (per ten thousand) inhabitants, are given for each year of the study period.The prevalence rate increases slightly from 8.62 per thousand in 2002 to 9.44 per thousand in 2004 and the incidence rates estimated were 2.49 per ten thousand, 1.86 per ten thousand and 1.97 per ten thousand in the yr 2002, 2003 and 2004, respectively.The Piedmont GH Registry represents the first database available in Italy and could set an example for the other Italian regions as well.

TBI is one of the most important public health problems in the world. Although the relationship between TBI and hypopituitarism has been known for a long time, neuroendocrine changes were investigated in detail recently. The prevalence of neuroendocrine abnormalities in patients with TBI is very high. Gonadotropin and GH deficiencies appear to be the most common defects. Although combative sports are very popular around the world, trauma due to sports is not generally considered as a cause of TBI in most of the epidemiological studies. All the studies regarding TBI in sports published so far in the literature based on neuropshycological or radiological assessment and no neuroendocrine changes were investigated. In a recent study, pituitary functions in amateur boxers have been investigated and it has been reported that boxing is a cause of TBI and isolated GH deficiency is very common among amateur boxers. It seems that acute or chronic head trauma in sports is a possible cause of hypopituitarism. In this review, current data regarding TBI in sports are discussed.

The aim of the study was to investigate the influence of an acute administration of 22-kDa hGH (22-kDa GH) on 22-kDa GH and 20-kDa GH serum levels, biological activity of GH (Nb2-GH) and on 22-kDa/20-kDa GH ratio, in order to verify whether the assessment of the GH isoforms could be a potential tool for diagnosing GH abuse. Twenty-eight children (21 M, 7 F), age 10.4 +/- 0.8 y, affected by idiopathic isolated GH deficiency and 10 children (8 M, 2 F), age 9.2 +/- 2.3 y affected by constitutional growth delay, were evaluated. After an overnight fast, a basal blood sample was obtained between 8 a.m. and 9 a.m. and a dose of 22-kDa GH was then administered subcutaneously (0.1 U/Kg). Blood was drawn after 2, 4 and 6 h, for the evaluation of 22-kDa GH, Nb2-GH and 20-kDa GH serum levels. Similar results were obtained in patients and controls: a significant rise, although of variable amplitude, of 22-kDa GH and Nb2-GH was found (p < 0.001) and the maximum peak was detected after 4 h in the majority of subjects. No acute changes in 20-kDa GH serum levels were observed. The 22-kDa/20-kDa GH ratio increased progressively, due to the rising levels of 22-kDa GH. A positive correlation was seen between 22-kDa GH and Nb2-GH levels at baseline and at 2, 4 and 6 h (p < 0.014, r = 0.99). Since in normal subjects the ratio of endogenous 22-kDa GH and 20-kDa GH is constant, an altered ratio of 22-kDa/20-kDa GH is highly suggestive of GH abuse. The short period of time available for the evaluation however (within 3 h from GH injection), severely limits this investigational tool in athletes.

Clinical and laboratory investigations starting in 1958 of a group of dwarfed children resembling isolated GH deficiency but who had very high serum levels of GH led to the description of the syndrome of primary GH resistance or insensitivity (Laron syndrome) and subsequently to the discovery of its molecular defects residing in the GH receptor and leading to an inability of IGF-I generation. With the biosynthesis of IGF-I in 1986, therapeutic trials started. Continuously more and more patients are being diagnosed in many parts of the world with a variety of molecular defects. This syndrome proved to be a unique model that enables the study of the consequences of GH receptor defects, the physiopathology of GH-IGF-I disruption, and comparison of the GH-independent IGF-I effects. This review presents the personal experience gained from the study follow-up and treatment of the 60 patients followed up for many years in the Israeli cohort.

Amelogenesis imperfecta (AI) is a diverse group of hereditary disorders that are characterized by a defect in the formation of the tooth enamel and a high degree of clinical diversity. X-linked, autosomal dominant and recessive inheritance have been demonstrated. Growth hormone (GH) has an effect on bone and soft tissue development. Dental and facial abnormalities associated with pituitary dwarfism have been reported, but GH deficiency with AI is very rare. We describe a 12 year-old pre-pubertal boy who was referred to our hospital with teeth deformities and growth retardation. His teeth had brown-yellow pigmented surfaces, and dental examination showed extensive enamel deficiency in his permanent teeth. He also had severe growth retardation; height SDS was -3.6. Laboratory examinations showed reduced GH levels, and he was diagnosed as having idiopathic isolated GH deficiency and AI.

We present a boy diagnosed and treated with growth hormone (GH) for isolated GH deficiency. During 2 year follow up he did not catch up in both height and weight. Although there was no skeletal disproportionality, nor any other complaints, his walk began changing and lower limbs deformity appeared (genua vara). Extensive skeletal radiological survey found multiple enchondromatosis (knees, iliac bones) and Ollier disease was diagnosed. There is no specific treatment for this condition, but its presence questions future GH therapy. The poor response to growth hormone treatment and the risk of developing malignant transformation in the future raises the important questions of the real benefits and the possible harms of its maintenance.