Isolated Growth Hormone Deficiency and Idiopathic Short Stature: Comparative Efficiency after Growth Hormone Treatment up to Adult Height.

INTRODUCTION: Treatment with growth hormone (GH) is not approved for idiopathic short stature (ISS) in Europe. OBJECTIVES: To compare the growth of children treated with isolated GH deficiency (IGHD) vs. ISS-treated and untreated children. METHODS: A retrospective descriptive study of patients treated in the last 14 years for IGHD (Group A), in comparison with ISS-treated (Group B) and untreated (Group C) subjects. RESULTS: Group A had 67 males, who showed a height gain of 1.24 SD. Group B had 30 boys, who showed a height gain of 1.47 SD. Group C had 42 boys, who showed an improvement of 0.37 SD. The final heights were -1.52 SD, -1.31 SD, and -2.03 SD, respectively. Group A and C did not reach their target heights (with differences of 0.27 SD and 0.59 SD, respectively). Group B surpassed their target height by 0.29 SD. CONCLUSIONS: The final heights of the IGHD and treated ISS are similar. Treated groups were taller than untreated groups.

Differences between patients with isolated GH deficiency based on findings in brain magnetic resonance imaging / Diferencias entre pacientes con déficit aislado de GH según su resonancia cerebral

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

Introducción: El protocolo de prescripción de hormona sustitutiva en el déficit aislado de hormona del crecimiento (GH) incluye la realización de una resonancia cerebral. Hay controversia sobre la frecuencia de anomalías hipofisarias y la importancia de los hallazgos anormales de resonancia magnética en el pronóstico y la respuesta al tratamiento de GH. Métodos: Estudio descriptivo retrospectivo de niños de 0 a 14 años, de ambos sexos, con imágenes de resonancia magnética cerebral, que fueron diagnosticados de deficiencia aislada de GH en un hospital terciario en los últimos 14 años, para describir la frecuencia de las anomalías en la resonancia magnética y establecer si existen diferencias en el diagnóstico de talla y evolución de acuerdo con los hallazgos de la resonancia magnética. Además, comparamos los hallazgos en la resonancia con los hallazgos publicados en niños sanos, con el fin de establecer la incidencia. Resultados: Se estudiaron 96 pacientes, alcanzando 74/96 (77%) la edad adulta. El 11,5% tenía imágenes de resonancia magnética anormales (8/11 de origen hipofisario). En ningún caso se observó tumor cerebral o hipofisario. Los pacientes con imágenes anormales mostraron una edad media al inicio de tratamiento de 8 años, talla diana de -0,8 DE y una talla final de 1,04 DE; mientras que los pacientes con imágenes de resonancia magnética normal muestran una edad de inicio de tratamiento de 10 años, una talla diana de -1,44 DE y una talla final de -1,75 DE, con diferencias estadísticamente significativas. Conclusiones: Los pacientes con alteraciones en la resonancia magnética muestran una respuesta más favorable al tratamiento sustitutivo de GH

Differences between patients with isolated GH deficiency based on findings in brain magnetic resonance imaging.

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.

Mutación del gen INSR. Insulinorresistencia poco prevalente en edad pediátrica. A propósito de un caso / INSR gene mutation. Insulin resistance with low prevalence in pediatrics. A case review

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Eficacia y seguridad del tratamiento sustitutivo en el déficit aislado de hormona del crecimiento / Efficacy and safety of replacement treatment in isolated growth hormone deficiency

Introducción: El crecimiento en pacientes con déficit aislado de hormona del crecimiento (GH) es heterogéneo a pesar del tratamiento, debido a la baja especificidad de las pruebas diagnósticas, por lo que es necesario definir las variables de eficacia. Objetivos: Evaluar la eficacia de la terapia de reemplazo hormonal en niños con déficit aislado de GH. Métodos: Estudio observacional-ambispectivo de pacientes tratados en nuestro servicio en los últimos 14 años por déficit aislado de GH, definido como GH inferior a 7,4 mg/dl en 2 pruebas de estímulo, en pacientes con talla < -2DE y velocidad de crecimiento disminuida. Resultados: Se estudiaron 97 pacientes. El 69% eran varones. Con el tratamiento hubo una ganancia de talla de 1,17DE. El 79,31% alcanzaron la talla diana. El 71,13% fueron reevaluados en la edad adulta, de los cuales el 39,4% mantuvo el déficit. La talla diana, el pronóstico de talla adulta y la ganancia puberal total se correlacionaron positivamente con la talla adulta, mientras que la relación edad ósea/edad cronológica y factor de crecimiento insulínico tipo 1 inicial mostraron una correlación negativa. Ninguno tuvo efectos secundarios. Conclusiones: La mayoría de los pacientes alcanzaron la talla diana, aunque no todos mostraron permanencia del déficit en edad adulta. La talla diana, el pronóstico de talla adulta y las variables de pubertad están directamente relacionados con la talla adulta; mientras que la edad ósea/edad cronológica y factor de crecimiento insulínico tipo 1 están inversamente relacionadas, pudiendo utilizarse estas como variables de eficacia. No se han observado efectos adversos en la muestra con las dosis utilizadas

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 < 2SD and a decreased growth rate. Results: The study included a total 97 patients, of whom 69% were boys. The large majority (89.58%) achieved final height. None of them had side effects. The median dose of GH used was 0.028 mg/kg/day (0.03-0.025). There was a gain of 1.17 SD in final height. Around three-quarters (71.13%) of the patients were reassessed in adulthood, of whom 39.4% maintained the deficiency, and 79.31% achieved target range height. Target height, estimated height, and the total pubertal gain were positively correlated with final height, while the bone age/chronological age ratio and the initial insulin-like growth factor-1 showed a negative correlation. Conclusions: A majority of patients reached target size, although only a few of them maintained the deficiency in adulthood. Target size, estimated adult height, and pubertal variables are directly related to adult height, while bone age/chronological age and insulin-like growth factor-1 were inversely related, and these can be used as efficacy variables. No adverse effects were observed in the sample with the doses used for the treatment

[Efficacy and safety of replacement treatment in isolated growth hormone deficiency]. / Eficacia y seguridad del tratamiento sustitutivo en el déficit aislado de hormona del crecimiento.

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 7.4mg/dl in response to 2 stimulation tests in patients with height<2SD and a decreased growth rate. RESULTS: The study included a total 97 patients, of whom 69% were boys. The large majority (89.58%) achieved final height. None of them had side effects. The median dose of GH used was 0.028mg/kg/day (0.03-0.025). There was a gain of 1.17 SD in final height. Around three-quarters (71.13%) of the patients were reassessed in adulthood, of whom 39.4% maintained the deficiency, and 79.31% achieved target range height. Target height, estimated height, and the total pubertal gain were positively correlated with final height, while the bone age/chronological age ratio and the initial insulin-like growth factor-1 showed a negative correlation. CONCLUSIONS: A majority of patients reached target size, although only a few of them maintained the deficiency in adulthood. Target size, estimated adult height, and pubertal variables are directly related to adult height, while bone age/chronological age and insulin-like growth factor-1 were inversely related, and these can be used as efficacy variables. No adverse effects were observed in the sample with the doses used for the treatment.

Tratamiento con hormona de crecimiento en pequeños para la edad gestacional en España / Growth hormone treatment in small for gestational age children in Spain

INTRODUCCIÓN: Desde su aprobación por la Agencia Europea del Medicamento, el tratamiento con hormona de crecimiento recombinante ha sido empleado en un gran número de pacientes nacidos pequeños para la edad gestacional en España. El propósito de este estudio es conocer objetivamente los resultados del mismo en la práctica habitual. MÉTODOS: Se ha recogido información procedente de los registros existentes en los comités asesores que autorizan dichos tratamientos en los hospitales públicos de 6 comunidades autónomas. RESULTADOS: Se han obtenido datos válidos de 974 pacientes. Todos ellos cumplían los criterios exigidos por la Agencia Europea del Medicamento. Los pacientes que recibieron el tratamiento se caracterizaron por tener la longitud al nacer más afectada que el peso, talla diana inferior a -1 desviación estándar (DE) y un 23% con antecedentes de prematuridad. La talla al iniciar el tratamiento fue de − 3,1 ± 0,8 DE (media ± DE) y la edad de comienzo 7,2 ± 2,8 años. La ganancia de talla en el primer año fue de 0,7 ± 0,2 DE, y de 1,2 ± 0,8 DE hasta los 2 años. La talla final, alcanzada por un 8% de pacientes, fue de -1,4 ± 0,7 DE. CONCLUSIONES: Los resultados concuerdan con las series nacionales e internacionales publicadas y son representativos de la práctica habitual en nuestro país. Se constata un inicio tardío del tratamiento, observándose, sin embargo, un adecuado crecimiento, tanto a corto plazo como en la talla final. En el primer año se identifica un 24% de pacientes con respuesta deficiente

INTRODUCTION: Since its approval by the European Medicines Agency, a great number of patients born small for gestational date have received recombinant growth hormone treatment in Spain. The aim of this study is to analyse its outcome in the setting of ordinary clinical practice. METHODS: Information was gathered from the registers of the assessment boards that authorise all growth hormone treatments prescribed in public hospitals in six autonomic communities (regions). RESULTS: Valid data from 974 patients was obtained. All of them complied with criteria established by the European Medicines Agency. Patients in the sample were smaller in length than weight at birth, with their median target height being below 1 standard deviation (SD), and 23% of them had been delivered prematurely. Treatment was started at 7.2 ± 2.8 years (mean ± SD). The mean patient height at start was − 3.1 ± 0.8 SD. They gained 0.7 ± 0.2 SD in the first year, and 1.2 ± 0.8 SD after two years. Final height was attained by 8% of the sample, reaching -1.4±0.7 SD. CONCLUSIONS: These results are similar to other Spanish and international published studies, and are representative of the current practice in Spain. Despite treatment being started at a late age, adequate growth is observed in the short term and in the final height. Up to a 24% of patients show a poor response in the first year

[Growth hormone treatment in small for gestational age children in Spain]. / Tratamiento con hormona de crecimiento en pequeños para la edad gestacional en España.

INTRODUCTION: Since its approval by the European Medicines Agency, a great number of patients born small for gestational date have received recombinant growth hormone treatment in Spain. The aim of this study is to analyse its outcome in the setting of ordinary clinical practice. METHODS: Information was gathered from the registers of the assessment boards that authorise all growth hormone treatments prescribed in public hospitals in six autonomic communities (regions). RESULTS: Valid data from 974 patients was obtained. All of them complied with criteria established by the European Medicines Agency. Patients in the sample were smaller in length than weight at birth, with their median target height being below 1 standard deviation (SD), and 23% of them had been delivered prematurely. Treatment was started at 7.2±2.8 years (mean±SD). The mean patient height at start was -3.1±0.8 SD. They gained 0.7±0.2 SD in the first year, and 1.2±0.8 SD after two years. Final height was attained by 8% of the sample, reaching -1.4±0.7 SD. CONCLUSIONS: These results are similar to other Spanish and international published studies, and are representative of the current practice in Spain. Despite treatment being started at a late age, adequate growth is observed in the short term and in the final height. Up to a 24% of patients show a poor response in the first year.

[GHBP, IGF-1 and IGFBP-3 serum levels in familial short-statured and normal-statured children]. / Concentración sérica de GHBP, IGF-1 e IGFBP-3 en niños con talla baja familiar y con talla normal.

BACKGROUND AND OBJECTIVE: Growth hormone binding protein (GHBP), insuline-like growth factor 1 (IGF-1) and insuline-like growth factor binding protein 3 (IGFBP-3) serum concentrations were studied in familial short-statured patients (FSS) and age-matched normal-statured subjects. The aim of the study was to ascertain whether differences in growth factors concentrations between groups could be shown and whether they may contribute to explaining the different patterns of growth in both groups. SUBJECTS AND METHOD: Serum samples of 38 FSS patients (20 boys) and 31 normal-statured subjects (15 boys) in Tanner I stage (prepubertal), were analysed in a central laboratory. All auxological parameters (height, growth velocity, target height, body mass index (BMI) and biochemical parameters (IGF-1 and IGFBP-3) were standardised for age and sex-matched subjects. GHBP values were expressed as percentage of specific binding. RESULTS: The studied populations were similar and no statistically-significant differences in chronological age, bone age and BMI were found. Height, growth velocity and target height were significantly lower in FSS patients compared with normal subjects (p < 0.0001). IGF-1, IGFBP-3 and GHBP concentrations were significantly lower in the FSS group (p < 0.01). Correlations were found between IGF-1 and IGFBP-3 (r = 0.56; p = 0.0004) and between IGF-1 and GHBP (r = 0.34; p = 0.03) in the FSS group. However, in the normal-statured group only BMI and GHBP were correlated (r = 0.5; p = 0.02). CONCLUSIONS: These results strongly support the importance of the GH/IGF-1 functional axis in the pattern of growth and probably contribute to understanding of the pathophysiologic basis of the auxological differences found between groups.

Concentración sérica de GHBP, IGF-1 e IGFBP-3 en niños con talla baja familiar y con talla normal / GHBP, IGF-1 and IGFBP-3 serum levels in familial short-statured and normal-statured children

FUNDAMENTO Y OBJETIVO: Se estudiaron las concentraciones séricas de la porción extracelular del receptor de la hormona del crecimiento (GHBP), factor 1 de crecimiento insulínico (IGF-1) y proteína transportadora del crecimiento tipo 3 (IGFBP-3) en sujetos de talla baja familiar (TBF) y normales, con objeto de conocer la posible existencia de diferencias en las concentraciones de estas proteínas entre ambas poblaciones que pudieran contribuir a esclarecer algunas de las razones del diferente patrón de crecimiento de ambos grupos. SUJETOS Y MÉTODO: Las muestras pertenecientes a 38 pacientes (20 varones) con TBF y 31 sujetos (15 varones) de talla normal, en estadio I de Tanner, se estudiaron en un laboratorio central. Tanto los parámetros auxológicos -talla, velocidad de crecimiento, talla diana, índice de masa corporal (IMC)- como los bioquímicos (IGF-1 e IGFBP-3) se estandarizaron para sujetos de la misma edad y sexo. Los valores de GHBP se expresaron como porcentajes de unión específica. RESULTADOS: Las 2 poblaciones estudiadas tenían una edad cronológica, edad ósea e IMC similares. La talla, la velocidad de crecimiento y la talla diana eran significativamente inferiores en los pacientes con TBF respecto a los sujetos normales (p < 0,0001). En el grupo de TBF las concentraciones de IGF-1, IGFBP-3 y GHBP eran significativamente más bajas que en el grupo control (p < 0,01) y el análisis de correlaciones demostró que las concentraciones de IGF-1 e IGFBP-3 se correlacionaban significativamente entre sí (r = 0,56; p = 0,0004) al igual que las de IGF-1 y GHBP (r = 0,34; p = 0,03). Asimismo, el IMC se correlacionó significativamente con las concentraciones de IGFBP-3 y GHBP (r = 0,42; p = 0,009, y r = 0,40; p = 0,01, respectivamente). Por el contrario, en el grupo control sólo se encontró correlación significativa entre el IMC y las concentraciones de GHBP (r = 0,5; p = 0,02). CONCLUSIONES: Estos resultados parecen dar un evidente respaldo a la importancia funcional del eje GH/IGF-1 en el patrón de crecimiento. Dicho eje posiblemente constituiría el fundamento fisiopatológico de las diferencias mostradas por los parámetros auxológicos valorados en ambos grupos (AU)