Síndrome de interrupción del tallo pituitario: Relaciones clínicas, bioquímicas y neurorradiológicas / Pituitary stalk interruption syndrome: Clinical, biochemical and neuroradiological relationships

El síndrome de interrupción del tallo pituitario (PSIS) se caracteriza por la demostración neurorradiológica de un tallo pituitario ausente, interrumpido o hipoplásico, adenohipófisis aplásica/hipoplásica o neurohipófisis ectópica. Este síndrome se ha relacionado con formas severas de hipopituitarismo congénito (HPC), asociado a múltiples deficiencias de hormonas pituitarias (MPHD). Evaluamos a pacientes con HPC y PSIS, analizando los signos y los síntomas neonatales al diagnóstico, relacionándolos con las deficiencias hormonales pituitarias y signos neurorradiológicos presentes. Estudiamos retrospectivamente a 80 pacientes asistidos en el Hospital de Niños de Córdoba, con diagnóstico de HPC, de los cuales 42 (52%) presentaron PSIS; 22 mujeres y 20 varones, EC: 5 días-9,5 años. El 62% presentó MPHD y el 38% insuficiencia somatotrófica aislada (IGHD). El análisis de las variables perinatales demostró antecedentes de parto natural en el 52% (11/21) de las MPHD vs. 13% (2/15) de las IGHD. Cuatro pacientes, 2 con MPHD y 2 con IGHD presentaban antecedentes obstétricos consistentes en presentación podálica y transversa respectivamente, todos ellos resueltos mediante operación cesárea. Los signos y los síntomas perinatales fueron hipo- glucemia: 61% en MPHD vs. 19% en IGHD, p: 0,0105; ictericia: 38% en MPHD vs. 25% en IGHD; micropene: 77% en MPHD y colestasis: 19% en MPHD. Convulsiones neonatales se presentaron en el 75% de los niños con MPHD e hipoglucemia. EC media de consulta: 2,1 años en MPHD (30% en el período neonatal, 70% antes de 2 años) y 3,6 años en IGHD (44% en menores de 2 años). Los pacientes con MPHD presentaban: tallo no visible 81% (n: 21/26) vs. tallo hipoplásico: 19% (n: 5/26), p: 0,0001; en IGHD 56% (n: 9/16) vs. 44% (n: 7/16), p: 0,5067, respectivamente. El 100% de los neonatos con HPC tenían tallo pituitario ausente. Concluimos que la demostración de PSIS en niños con HPC proporciona información valiosa como predictor de la severidad fenotípica, la presencia de MPHD y de la respuesta al tratamiento. La baja frecuencia de antecedentes obstétricos posicionales potencialmente distócicos, como parte de los mecanismos fisiopatogénicos responsables de PSIS, indicaría la necesidad de analizar la importancia de posibles factores genéticos y epigenéticos involucrados. El diagnóstico precoz de HPC debe sospecharse en presencia de signos y síntomas clínicos, tales como hipoglucemia, colestasis, micropene y defectos asociados en la línea media facial. La resonancia magnética cerebral debe formar parte de los estudios complementarios en pacientes con esta presunción diagnóstica, especialmente a edades tempranas. El reconocimiento tardío de esta entidad puede aumentar la morbilidad y la mortalidad con efectos potenciales deletéreos y permanentes.

Pituitary stalk interruption syndrome (PSIS) is characterised by the combination of an interrupted or thin pituitary stalk, absent or ectopic posterior pituitary, and anterior pituitary hypoplasia. It is manifested as isolated (IGHD) or combined pituitary hormone deficiencies (CPHD) of variable degrees and timing of onset, with a wide spectrum of clinical phenotypes. PSIS may be an isolated morphological abnormality or be part of a syndrome. A retrospective evaluation is presented of clinical signs and symptoms present at early life stages, as well as an analysis of their relationship with hormone laboratory tests and diagnostic imaging in children with congenital hypopituitarism (CHP), and PSIS. This study was performed in a single centre on a sample of 42 children out of a total of 80 CHP patients, with a chronological age range between 5 days and 9.5 years from a database analysed over a period of 26 years. The study included 26/42 (62%) with CPHD and 16/42 (38%) with IGHD. The analysis of perinatal variables showed a natural delivery in 52% (11/21) of CPHD vs 13% (2/15) of IGHD. Four patients, two with CPHD and two IGHD had breech and transverse presentation respectively. All of them were resolved by caesarean section. The perinatal histories showed hypoglycaemia (61% CPHD vs 19% IGHD, P=.0105), jaundice (38% CPHDvs25% IGHD), micropenis (75%CPHD), hypoglycaemic seizures (75% CPHD), and cholestasis (19% CPHD). The mean CA of consulting for CPHD patients was 2.1 years, 30% in neonatal period and 70% before 2 years. The mean chronical age (CA) was 3.6 years in IGHD patients, with 44% of them less than 2 years. MRI showed that 81% of CPHD patients had absence of pituitary stalk vs 19% with thin pituitary stalk (P=.0001); Patients with IGHD presented 56% absence of pituitary stalk vs 44% with thin pituitary stalk (P=.5067). All (100%) of the patients diagnosed in the neonatal stage had absent pituitary stalk. The characterisation of GH deficient patients by presence and type of hypothalamic-pituitary imaging abnormality provides valuable information as a predictor of phenotypic severity, treatment response, and the potential to develop additional hormonal deficiencies. We conclude that demonstrating PSIS in children with HPC provides valuable information as a predictor of phenotypic severity, presence of MPHD, and response to treatment. The low frequency of potentially dysfunctional positional obstetric history, as part of the pathophysiological mechanisms responsible for PSIS, would indicate the need to analyse the importance of possible genetic and epigenetic factors involved. Early diagnosis of HPC should be suspected in the presence of clinical signs and symptoms, such as hypoglycaemia, cholestasis, micropenis, and associated facial midline defects. MRI should be part of complementary studies in patients with this diagnostic suspicion, especially at an early age. Late recognition of this entity may increase morbidity and mortality with potential permanent deleterious effects.

Clonidine-stimulated growth hormone concentrations (cut-off values) measured by immunochemiluminescent assay (ICMA) in children and adolescents with short stature

OBJECTIVES: To establish cut-off values for growth hormone concentrations using clonidine as a secretagogue and an immunochemiluminescent assay as the method of measurement and to analyze the response time as well as the influence of gender, nutritional status and pubertal stage. METHODS: A total of 225 tests were performed in 3 patient groups, categorized as group 1 (normal), group 2 (idiopathic short stature) and group 3 (growth hormone deficiency). Among the 199 disease-free individuals, 138 were prepubertal, and 61 were pubertal. Clonidine (0.1 mg/m2) was orally administered, and the growth hormone level was measured by immunochemiluminescent assay. The growth hormone peak and the difference between the growth hormone peak and the baseline level were then analyzed. Statistical analyses were performed using Student’s t-test or the Mann-Whitney test and Kruskal-Wallis test followed by Dunn’s post hoc test. Cut-off values were determined using a receiver operating characteristic curve. RESULTS: Group 1 and group 2 had no difference in growth hormone peak, gender, body mass index standard deviation score, or pubertal stage. Group 3 exhibited a significantly lower growth hormone peak than the other groups did. The receiver operating characteristic curve demonstrated that growth hormone concentrations ≥ 3.0 ng/mL defined responsiveness to clonidine. In total, 3.02% of individuals in group 1 and group 2 were considered false positive, i.e., these children lacked growth hormone deficiency and had a peak below 3.0 ng/mL. CONCLUSION: Clonidine-stimulated growth hormone concentrations ≥3 ng/mL, as measured by immunochemiluminescent assay, suggest responsiveness to the stimulus regardless of gender, body mass index standard deviation score or pubertal stage.

Análise molecular dos genes NEUROD4, FGFR1 e PROKR2 em pacientes com hipopituitarismo congênito / Comparison between Auditory Steady-State Responses and behavioral audiometry in pediatric cochlear implant candidates

INTRODUÇÃO: As Respostas Auditivas de Estado Estável permitem avaliação frequência específica em intensidades de até 120 dB NA e a detecção de audição residual em pacientes com perda auditiva severo-profunda. O objetivo deste estudo é comparar os limiares à RAEE e os resultados da avaliação comportamental em crianças com suspeita de surdez severo-profunda. MÉTODO: Estudo transversal para comparar respostas à RAEE e por audiometria com reforço visual (VRA) em 63 crianças candidatas ao implante coclear (126 orelhas) com idade entre 6 e 72 meses. Foram incluídas crianças com otomicroscopia normal, ausência de respostas ao PEATE clique a 90 dB NA e às emissões otoacústicas. Foram excluídas crianças com malformações de orelha interna, doenças do espectro da neuropatia auditiva, ou que não completaram a avaliação comportamental ou não atingiram ruído eletroencefalográfico < 30 nV durante a RAEE. Foram utilizados estímulos com tons contínuos sinusoidais (100% AM e 20% FM) nas frequências de 500, 1000, 2000 e 4000 Hz em intensidade máxima de 110 dB NA. Os limiares à VRA foram obtidos por tom warble nas frequências de 500, 1000, 2000 e 4000 Hz em cada orelha através de fones de inserção (ER-5A) ou tipo casco (TDH-39). A intensidade máxima de estimulação foi de 120 dB NA em cada frequência. RESULTADOS: Limiares comportamentais foram obtidos em 36,7% (185/504) de todas as frequências em todas as crianças, 9% em intensidade maior que 110 dB NA. Entre as 504 medidas da RAEE em 63 indivíduos, 53 limiares foram obtidos (10,5%). Ao todo, 89,5% das frequências testadas não apresentaram nenhuma resposta em 110 dB NA. A distribuição dos limiares à RAEE foi semelhante à da avaliação comportamental. A maioria das respostas foram em 500 Hz, diminuindo nas frequências agudas. A diferença média entre os limiares à VRA e à RAEE variou entre 0,09 e 8,94 dB. Foram realizadas 27 comparações entre RAEE e VRA: 12 em 500 Hz, 9 em 1000 Hz, 5 em 2000 Hz e 1 em 4000 Hz. Respostas...

Introduction and Objective: ASSR allows frequency-specific evaluation in intensities up to 120 dB HL and detection of residual hearing in patients with severe-toprofound hearing loss. The aim of this study was to compare ASSR thresholds and behavioral test results in children with suspected severe-to-profound hearing loss. Methods: A cross sectional study was carried out to compare ASSR and Visual Reinforcement Audiometry (VRA) responses in 63 pediatric cochlear implant candidates (126 ears) aged between 6 to 72 months. We included children with normal otomicroscopy findings, absent responses to click-ABR at 90 dB HL and otoaccoustic emissions. We excluded children with inner ear malformations, auditory neuropathy spectrum disorder or who did not complete VRA or achieve EEG noise < 30 nV during the ASSR test. Air-conduction ASSR stimuli were continuous sinusoidal tones (100% AM and 20% FM) presented at 0.5, 1, 2 and 4 kHz starting at the maximum presentation level of 110 dB HL. VRA thresholds were acquired with warble tones presented at 0.5, 1, 2 and 4 KHz in each ear through ER-tone 5A or TDH-39 phones. Maximum presentation level was 120 dB HL for each frequency. Results: Behavioral thresholds were obtained in 36.7% (185/504) of all frequencies in all subjects, 9% were in intensities > 110 dB HL. Among 504 ASSR measurements from 63 subjects, 53 thresholds were obtained (10.5%). Overall 89.5% of the tested frequencies did not show any response at 110 dB HL. The distribution of ASSR responses was similar to the behavioral test results. Most responses were at 500 Hz, decreasing among the higher frequencies. Mean differences between behavioral and ASSR thresholds varied from 0.09 to 8.94 dB. Overall, 27 comparisons of behavioral and ASSR thresholds were obtained: 12 at 0.5 KHz, 9 at 1 KHz, 5 at 2 KHz and 1 at 4 KHz. Absent responses were observed in both tests in 38.1% at 0.5 KHz, 52.4% at 1 KHz, 74.6% at 2 KHz and 81.0% at 4 KHz. The specificity was > 90% at 1,...

Efectividad y seguridad de la somatropina para el tratamiento de niños con déficit de la hormona del crecimiento / Effectiveness and safety of somatropin for the treatment of children with growth hormone deficiency

Introducción: la somatropina es una opción para el tratamiento del déficit de la hormona del crecimiento en niños. Esta evaluación tecnológica se desarrolló en el marco de la actualización integral del Plan Obligatorio de Salud para el año 2015. Objetivo: evaluar la efectividad y seguridad de la somatropina comparada con placebo o no tratamiento para el déficit de la hormona del crecimiento en niños. Metodología: la evaluación fue realizada de acuerdo con un protocolo definido a priori por el grupo desarrollador. Se realizó una búsqueda sistemática en MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects y LILACS, sin restricciones de idioma y limitada a revisiones sistemáticas publicadas en los últimos cinco años. Las búsquedas en bases de datos fueron hechas entre octubre y diciembre de 2014 y se complementaron mediante búsqueda manual en bola de nieve y una consulta con expertos temáticos. La tamización de referencias se realizó por dos revisores de forma independiente y los desacuerdos fueron resueltos por consenso. La selección de estudios fue realizada mediante la revisión en texto completo de las referencias preseleccionadas, verificando los criterios de elegibilidad. Se incluyeron revisiones sistemáticas de ensayos clínicos, su calidad fue valorada con la herramienta AMSTAR. Las características de las revisiones fueron extraídas a partir de las publicaciones originales. Se realizó una síntesis narrativa de las estimaciones del efecto para las comparaciones y desenlaces de interés a partir de los estudios de mejor calidad con AMSTAR. Resultados: se seleccionó una revisión sistemática que incluyó 28 ensayos clínicos (1830 pacientes), uno de estos ensayos (19 pacientes) fue de interés para la presente evaluación. La somatropina comparada con no tratamiento se asoció con un aumento estadísticamente significativo de la velocidad de crecimiento, la desviación estándar de la talla y los niveles de IGF-1 (somatomedina C). Conclusiones: el desempeño global de la somatropina para el tratamiento de niños con déficit de la hormona del crecimiento, muestra que la totalidad de los desenlaces de efectividad favorecen a la somatropina, en cuanto a su seguridad comparativa existe incertidumbre. Estas conclusiones se basan en los hallazgos de una revisión sistemática de alta calidad.(AU)

Children with isolated growth hormone deficiency: Empty sella versus normal sella.

BACKGROUND: Empty sella (ES) may be associated with variable clinical conditions ranging from the occasional discovery of a clinically asymptomatic pouch within the sella turcica to severe intracranial hypertension and rhinorrhea. The need for replacement hormone therapy in ES, as in other syndromes that may cause hypopituitarism, must be assessed for every single hormone, including growth hormone (GH). AIM: To determine whether or not the presence of ES could allow some changes in the GH responses of the isolated growth hormone deficiency (GHD) patients. MATERIALS AND METHODS: We included a cohort of 59 short stature children and adolescents with isolated GHD. According to computed tomography finding, they were classified into 2 groups: Group 1 included 40 children with normal sella and 19 children with ES in Group 2. All patients received recombinant human growth hormone (rhGH) with a standard dose of 20 IU/m2/week. RESULTS: The baseline results were not significantly different for all variables except weight standard deviation was smaller with statistical significant difference (P = 0.02). We identified no significant differences when comparing both groups, except for height standard deviation (HTSD) after the first year of therapy which revealed significant difference in favor of group 1. When comparing pre- and the two post-treatments HTSD results of the studied cases, all showed significant changes after GH therapy. The results of related variables pre-and post-treatment in both the groups showed significant improvement in all variables of the two groups of the study. CONCLUSION: Our study showed a similar stature outcome in the two treatment groups.

Effect of arginine infusion on ghrelin secretion in growth hormone-sufficient and gh-deficient children

The physiological link between ghrelin and growth hormone [GH] has not yet been fully clarified. Furthermore, the existence of a negative feedback mechanism between growth hormone-insulin-like growth factor [GH-IGF]-I axis and ghrelin and the influence of amino acids on ghrelin secretion in children remain matters of debate. To understand the regulation of ghrelin secretion and clarify the relationship between ghrelin and GH secretion in GH-deficient [GHD] and GH-sufficient [GHS] children. Ten GHD [male/female [M/F], 6/4; age [mean +/- SEM], 10.7 +/- 0.9 years] and 10 GHS prepubertal children [M/F, 6/4; age [mean +/- SEM], 10.3 +/- 0.6 years], underwent an arginine [ARG] test [infusion, 0.5 g/kg, iv]. Levels of GH, total ghrelin, and acylated ghrelin [AG] were assayed every 30 min from 0 to +120 min. Peak GH values were lower in GHD subjects than in GHS subjects [P < 0.0001]. The baseline levels, peak levels, or area under the curves [AUC] for total ghrelin and AG were similar between GHD and GHS children. ARG infusion was followed by a slight to significant decrease in total ghrelin levels, but not AG levels, both in GHD and GHS subjects with a nadir at +30 min. No correlation was seen between GH, total ghrelin, or AG response and ARG infusion. Total ghrelin and AG levels seemed unaffected by GH status in prepubertal children. ARG infusion was unable to blunt ghrelin secretion irrespective of GH status in childhood. Moreover, since ARG influences GH secretion via modulation of somatostatin release, ghrelin secretion seems to be partially refractory to somatostatin action

Growth hormone response to growth hormone-releasing peptide-2 in growth hormone-deficient Little mice

OBJECTIVE: To investigate a possible direct, growth hormone-releasing, hormone-independent action of a growth hormone secretagogue, GHRP-2, in pituitary somatotroph cells in the presence of inactive growth hormonereleasing hormone receptors. MATERIALS AND METHODS: The responses of serum growth hormone to acutely injected growth hormone-releasing P-2 in lit/litmice, which represent a model of GH deficiency arising frommutated growth hormone-releasing hormonereceptors, were compared to those observed in the heterozygous (lit/+) littermates and wild-type (+/+) C57BL/6J mice. RESULTS: After the administration of 10 mcg of growth hormone-releasing P-2 to lit/lit mice, a growth hormone release of 9.3±1.5 ng/ml was observed compared with 1.04±1.15 ng/ml in controls (p<0.001). In comparison, an intermediate growth hormone release of 34.5±9.7 ng/ml and a higher growth hormone release of 163±46 ng/ml were induced in the lit/+ mice and wild-type mice, respectively. Thus, GHRP-2 stimulated growth hormone in the lit/lit mice, and the release of growth hormone in vivo may be only partially dependent on growth hormone-releasing hormone. Additionally, the plasma leptin and ghrelin levels were evaluated in the lit/lit mice under basal and stimulated conditions. CONCLUSIONS: Here, we have demonstrated that lit/lit mice, which harbor a germline mutation in the Growth hormone-releasing hormone gene, maintain a limited but statistically significant growth hormone elevation after exogenous stimulation with GHRP-2. The present data probably reflect a direct, growth hormone-independent effect on Growth hormone S (ghrelin) stimulation in the remaining pituitary somatotrophs of little mice that is mediated by growth hormone S-R 1a.

Papel emergente do eixo GH/IGF-I no controle cardiometabólico / Emerging role of the GH/IGF-I on cardiometabolic control / Rol emergente del eje GH/IGF-I en el control cardiometabólico

O hormônio de crescimento (GH), principal regulador do crescimento pós-natal, tem importantes ações metabólicas em diferentes tecidos, sinérgicas ou até antagônicas às do fator de crescimento semelhante à insulina tipo I (IGF-I), produzido sobretudo no fígado após ligação do GH ao seu receptor. Experimentos em modelos animais indicam um papel importante do GH na resistência a insulina, enquanto o papel do IGF-I nessa condição ainda não está completamente elucidado. Em humanos, o GH promove aumento da lipólise e da oxidação lipídica, enquanto o IGF-I desencadeia o aumento da oxidação lipídica apenas cronicamente. Enquanto as ações sobre o crescimento são tempo limitado, as ações metabólicas e cardiovasculares do eixo GH/IGF-I perduram durante toda a vida. Os potenciais efeitos anabólicos do GH têm sido utilizados em condições crônicas e hipercatabólicas, embora as investigações sobre os desfechos clínicos ainda sejam escassas. Neste artigo, pretendemos revisar as ações metabólicas do GH oriundas de modelos animais, os estudos em humanos normais e indivíduos com deficiência de GH, diabete melito tipo 1, síndrome metabólica, estados hipercatabólicos e a relação do eixo GH/IGF-I com as adipocinas, disfunção endotelial e aterogênese.

Growth hormone (GH), the main regulator for post-natal growth, has important metabolic actions on different tissues, similar or opposite to insulin like growth factor I (IGF-I), mainly produced by the liver after the binding of GH to its receptor. Experiments with animal models indicate an important role of GH on insulin resistance although the IGF-I role is not yet completely established. In humans, GH promotes an increase on lypolisis and lipid oxidation, while IGF-I leads to an increase on lipid oxidation only in a chronic way. While growth actions are time-limited, metabolic and cardiovascular actions of the GH/IGF-I axis are throughout life. GH anabolic effects have been used on chronic and hypercatabolic conditions, although investigations on the clinical outcomes are still scarce. In this paper, we intend to review GH metabolic actions experienced by animal models, studies with normal humans and GH deficient individuals, individuals with diabetes mellitus type 1 and metabolic syndrome individuals, hypercatabolic states and the relationship between GH and adipokines, endothelial disfunction and atherogenesis.

la hormona de crecimiento (GH), principal regulador del crecimiento postnatal, tiene importantes acciones metabólicas en diversos tejidos, sinérgicas o incluso antagónicas a las del factor de crecimiento, a semejanza de la insulina tipo I (IGF-I) producido, principalmente, en el hígado y después del vínculo del GH con su receptor. Experimentos en modelos animales indican un papel importante del GH en la resistencia a la insulina, mientras que el papel del IGF-I en esa condición, todavía no está completamente elucidado. En los humanos, el GH genera el aumento de la lipólisis y de la oxidación lipídica, mientras que el IGF-I desencadena el aumento de la oxidación lipídica solamente desde el punto de vista crónico. Mientras las acciones sobre el crecimiento son de tiempo limitado, las acciones metabólicas y cardiovasculares del eje GH/IGF-I duran toda la vida. Los efectos potenciales anabólicos del GH han sido utilizados en condiciones crónicas e hipercatabólicas, aunque las investigaciones sobre los desenlaces clínicos todavía sean escasas. En este artículo, pretendemos revisar las acciones metabólicas del GH provenientes de modelos animales, los estudios en humanos normales y en individuos con deficiencia de GH, diabetes mellitus tipo 1, síndrome metabólico, estados hipercatabólicos y la relación del eje GH/IGF-I con las adipocinas, disfunción endotelial y aterogénesis.

Análise dos genes GHRH e GL12 em pacientes com deficiência de hormônio do crescimento congênita / GHRH and GLI2 genes analysis in patients with congenital growth hormone deficiency

Introdução: Alterações em genes relacionados com a secreção de GH ou a organogênese hipofisária foram identificadas em pacientes com deficiência de hormônio do crescimento (DGH) congênita. Entretanto, poucos casos de DGH têm sua etiologia esclarecida. O GHRH é um candidato óbvio para explicar a deficiência isolada de GH (DIGH). Na literatura, os estudos de análise do GHRH não conseguiram identificar mutações, porém são antigos e utilizaram uma metodologia com limitações. A maioria dos pacientes com deficiência hipotálamo-hipofisária múltipla (DHHM) apresenta neuroipófise ectópica sugerindo a importância do estudo de genes que atuam no início do desenvolvimento hipofisário, com expressão inclusive no infundíbulo. O GLI2 é um fator de transcrição na sinalização Sonic Hedgehog, envolvido com o início da embriogênese hipofisária, expresso na bolsa de Rathke primordial e no diencéfalo ventral. Previamente, mutações no GLI2 foram encontradas em pacientes com holoprosencefalia, e também alterações hipofisárias. Objetivos: Analisar o GHRH em 151 pacientes com DIGH (42 brasileiros e 109 encaminhados de centros internacionais) e analisar o GLI2 em 180 pacientes brasileiros com DIGH ou DHHM por PCR e sequenciamento automático dos genes; e descrever o fenótipo dos pacientes com mutações identificadas. Resultados: No GHRH foram identificadas seis variantes em heterozigose com previsão benigna pelas análises in silico. A análise do GLI2 identificou três mutações novas em heterozigose com códon de parada prematuro (p.L788fsX794, p.L694fsX722 e p.E380X), e geração de proteínas truncadas, com perda do domínio responsável pela ativação transcricional. A mutação p.L788fsX794 foi identificada numa paciente com baixa estatura, polidactilia, epilepsia e hipoglicemias. Apresentava deficiência de GH, TSH, ACTH, prolactina, LH e FSH. Na investigação familiar foi diagnosticada DIGH em dois tios e DHHM numa prima. Estes familiares, além de sua mãe e outros parentes maternos também...

Introduction: Alterations in genes related to GH secretion and pituitary organogenesis have been identified in patients with congenital GH deficiency (GHD). However, in only few cases of GHD the etiology has been established. GH-releasing hormone (GHRH) is an obvious candidate to explain isolated GH deficiency (IGHD). Previous reports in the literature did not identify mutations in GHRH, however, the methodology used was limited. Most patients with combined pituitary hormone deficiency (CPHD) have an ectopic posterior pituitary lobe (EPP) suggesting the study of genes involved in early pituitary development and also expressed in the infundibulum. GLI2 is a transcription factor in Sonic hedgehog signaling expressed in the primordial Rathkes pouch and ventral diencephalon during early pituitary development. Previously, GLI2 mutations were found in patients with holoprosencephaly and pituitary abnormalities. Aim: Analyse GHRH in 151 patients with IGHD (42 Brazilian and 101 from international centers) and GLI2 in 180 Brazilian patients with IGHD or CPHD by PCR and automatic sequencing, and describe the phenotype of patients with mutations. Results: In GHRH, six heterozygous variants that are benign according to in silico analysis were identified. GLI2 study revealed three novel heterozygous mutations leading to premature stop codons (p.L788fsX794, p.L694fsX722 e p.E380X) and truncated proteins, without the transcriptional activator domain. p.L788fsX794 was identified in a girl with short stature, polydactyly, epilepsy and hypoglycemia. She had GH, TSH, ACTH, prolactina, LH and FSH deficiencies. Two uncles had IGHD and one cousin CPHD. These relatives, the mother and other maternal relatives had polydactyly and carried the mutation. p.L694fsX722 was identified in a boy with short stature due to GHD who also had cleft lip and palate. His healthy father also carried the mutation. p.E380X was identified in an infant with delayed development, hypoglycemia, polyuria...

Evaluación de la talla final y sobrevida libre de eventos en pacientes sobrevivientes de meduloblastoma con deficiencia de hormona de crecimiento, tratados o no con hormona de crecimiento biosintética recombinante humana en la niñez. Comparación con pacientes con craneofaringioma tratados con rhGH / Evaluation of final height and event-free survival in medulloblastoma patients with growth hormone deficiency with and without biosynthetic recombinant human growth hormone treatment in childhood

Introduccion: La deficiencia de GH (DGH) y la radioterapia espinal (RE) han sido implicadas en la etiología de la talla adulta (TA) baja en los sobrevivientes de meduloblastoma en la niñez. Sin embargo la dinámica del crecimiento luego del diagnóstico tumoral y la efectividad de la Hormona de crecimiento biosintética recombinante humana (rhGH) sobre la TA en comparación con sobrevivientes no tratados con rhGH no han sido reportadas. Objetivo. Evaluación de la talla (T) SDS (SDST) desde el diagnóstico del meduloblastoma y el efecto de la rhGH en pacientes con DGH comparando con pacientes no tratados con rhGH y con pacientes con craniofaringioma y DGH, tratados con rhGH. Analizar si había alguna diferencia en la sobrevida libre de eventos en los pacientes con meduloblastoma al ser tratados con rhGH. Material Clínico y Métodos. Catorce pacientes con meduloblastoma recibieron rhGH hasta la TA, grupo meduloblastoma tratado con GH (GrMGH). Diecinueve pacientes rechazaron la terapia con rhGH, grupo meduloblastoma control (GrMC). Se midieron la talla parada (T) y la talla sentada (Tsent). Ocho pacientes con craneofaringioma recibieron rhGH hasta la TA (GrCra). Se realizó seguimiento de 72 pacientes con meduloblastoma, 20 con tratamiento con rhGH. Resultados. En GrMGH, la media±DS SDST disminuyó de 0.09±0.63 al diagnóstico del tumor a -1.38±0.91 al diagnóstico del DGH, y a -1.90±0.72 al comienzo de rhGH, p<0.01, pero se mantuvo sin cambios durante el tratamiento con rhGH (TA -2.12±0.55). En GrMC la SDST (-0.25±0.88) no fue diferente de GrMGH al diagnóstico del tumor, pero fue -3.40±0.88 a la TA, significativamente menor que en GrMGH, p=0.001. La Tsent SDS a la TA (-4.56±0.82) fue significativamente menor que al comienzo de rhGH (-2.86±0.75), p=0.003, y no fue diferente de GrMC (-4.85±1.77). El GrCra mostró la mayor ganancia de talla (GT = TA-SDSTinicial), p< 0.007, y la menor pérdida de talla (PT= Tblanco - TA), p < 0.0001. Conclusión. El tratamiento con rhGH mejora la TA en sobrevivientes de meduloblastoma en la niñez con DGH, pero no el crecimiento espinal. Las características del crecimiento y la respuesta a rhGH son diferentes en GrMGH y en GrCra, mientras que el primer grupo sólo pudo mantener la talla relativa, el segundo mostró una franca recuperación del crecimiento. Además no hubo diferencias en la sobrevida libre de eventos en los pacientes con meduloblastoma con y sin tratamiento con rhGH (AU)

Background. GH deficiency (GHD) and spine irradiation (SI) have been implicated in the mechanism of reduced adult height (AH) in childhood survivors of medulloblastoma. However, growth dynamics after tumor diagnosis and the effectiveness of (rhGH) Recombinant human Growth Hormone on AH in comparison with rhGH-untreated survivors has not been reported. Aim. Follow up of height (H) SDS (HSDS) after diagnosis of meduloblastoma, and the effect of rhGH in GHD meduloblastoma patients. Comparison with GH-untreated GHD meduloblastoma patients and with GHD craniopharyngioma patients treated with rhGH. To evaluate event free survival in medulloblastoma patiens treated with rhGH. Clinical Material and Methods. Fourteen survivors of medulloblastoma received rhGH treatment until AH, Medulloblastoma GH-treated group (MGHGr). Nineteen patients refused rhGH therapy, GH-untreated Control Medulloblastoma Group, (MCGr). Standing H and sitting H (SitH) were measured. Eight patients with craniopharyngioma received rhGH treatment until AH (CraGr). 72 patients with medulloblastoma were followed up, 20 with rhGH. Results. In MGHGr, mean±SD HSDS decreased from 0.09±0.63 at tumor diagnosis to -1.38±0.91 at diagnosis of GHD, and to -1.90±0.72 at the onset of rhGH, p<0.01, but it remained unchanged during rhGH (AH -2.12±0.55). MCGr HSDS (- 0.25±0.88) was not different from MGHGr at tumor diagnosis, but it was -3.40 ± 0.88 at AH, significantly lower than in MGHGr, p=0.001. SitH SDS at AH (-4.56±0.82) was significantly lower than at the onset of rhGH (-2.86±0.75), p=0.003, and it was not different from MCGr (-4.85 ± 1.77). CraGr showed the highest height SDS gain (HG = FH ­ startHSDS), p<0.007, and the lowest height lost (HL = targetH - AH), p< 0.0001. Conclusions. rhGH treatment improves AH in GH-deficient childhood medulloblastoma survivors but not spinal growth. Growth pattern and response to rhGH differed in MGHGr and CraGR, while the former just could maintain height SDS under treatment, the latter showed a clear catch up growth. There wasn't any difference in the event free survival in medulloblastoma patients with or without rhGH (AU)

Displasia septo-optica. Evaluación clínica, endocrinológica y neuro-radiológica. Seguimiento de 46 pacientes pediátricos / Septo-optic dysplasia. Clinical, endocrinological, and neuroradiological evaluation. Follow-up of 46 pediatric patients

La displasia septo-óptica (DSO) es una condición rara y altamente heterogénea, definida por la combinación de hipoplasia del nervio óptico (HNO), malformaciones cerebrales de la línea media, tales como aplasia/hipoplasia de septum pellucidum y cuerpo calloso, e insuficiencia hipotálamo-hipofisaria de grado variable. Se realizó un trabajo que tuvo como objetivo caracterizar la población de pacientes con diagnóstico de DSO seguidos en nuestro Hospital durante 7 años. Se incluyeron 46 pacientes (18 mujeres) que fueron divididos en 2 grupos, según tuviesen o no insuficiencia hipotálamo-hipofisaria (IHH). El 58.7% (n=27) presentó IHH de algún tipo, mientras que el 41.3% (n=19) no la presentó. En aquellos 19 pacientes con IHH se diagnosticaron deficiencia de GH y TSH (85.1%) y de ACTH (48.1%). La longitud corporal (mediana) del grupo con IHH fue más baja (p = 0,01) que la del grupo sin IHH, a pesar de que la edad fue menor a 2 años en todos los casos. Los pacientes fueron seguidos 1,3-8,3 años. Se observaron incidencias similares de agenesia del cuerpo calloso, del septum pellucidum, y ventriculomegalia, pero las alteraciones del desarrollo cortical se observaron con mayor frecuencia en los pacientes sin IHH. La ictericia neonatal, convulsiones y/o hipoglucemia, y micropene en neonatos y lactantes con DSO se presentaron en el subgrupo con IHH. El 58,7% de los pacientes con DSO presentaron algún grado de insuficiencia hipotálamo-hipofisaria. En la mayoría de los casos el diagnóstico de IHH no se realizó en el momento de aparición de los síntomas, sino más tardíamente en su seguimiento. En el 45% de los pacientes se evaluaron alteraciones radiológicas del SNC, específicamente en la región hipofisaria. Una fracción importante de las deficiencias de TSH/T4 (36,4%), GH (50%) y ACTH (23%) aparecieron mas tardíamente en el curso de la evolución. En 10 niños con déficit de hormona de crecimiento (2 tests farmacológicos sin respuesta) se realizó el tratamiento sustitutivo con rhGH (durante un periodo de 4±3 años), observándose una mejoría promedio de + 1,5 SDS en la talla de estos pacientes. En conclusión, la hipoplasia neonatal de nervios ópticos, asociada o no a ictericia e hipoglucemia, debe ser un signo de alarma para el diagnóstico de DSO, con riesgo de insuficiencia suprarrenal, shock y muerte, y puede requerir, por lo tanto, urgente tratamiento. Las deficiencias pueden aparecer en el curso de la evolución, a pesar del carácter congénito de la anomalía. Finalmente, se deben sustituir las deficiencias hormonales y tener presente que el tratamiento con rhGH puede mejorar la talla final en estos pacientes (AU)

Septo-optic dysplasia (SOD) is a rare and highly heterogeneous condition consisting of a combination of optic nerve hypoplasia (ONH), midline brain abnormalities, such as aplasia/hypoplasia of the septum pellucidum (ASP) and corpus callosum; and variable degree of hypoyalamo-pituitary insufficiency. The aim of this study was to characterize a population of SOD patients diagnosed and followed at the Garrahan Pediatric Hospital, from 1989 to 2006. We included 46 patients (18 females), that were divided into two groups according to the presence or absence of hypothalamic-pituitary insufficiency (IHH). Fifty nine% of SOD patients presented with IHH. GH and TSH deficiencies were diagnosed in 85.1% of IHH patients, while ACTH deficiency was found in 48.1%. Height (median) for the IHH group was shorter (p = 0,01) than for the group without IHH. Patients were followed for 1.3-8.3 years. Similar incidence of corpus callosum and/or septum pellucidum agenesis and ventriculomegaly were found in the two groups, but we observed more association with cortical developmental disorders in patients without IHH. In newborns, the association of ophthalmologic disorders and jaundice, seizures and/or hypoglycemia and micropene should frequently lead to the diagnosis of SOD and IHH. While 58,7% of DSO patients presented with hypothalamic-pituitary deficiency, only 45% of them showed sellar radiological abnormalities. Although SOD is a congenital disease, hormonal deficiencies may appear during follow-up. In 10 children with SOD and GH deficiency, rhGh treatment (for 4±3 years) improved height in 1.5 SDSs. In conclusion: in newborns with nerve optic hypoplasia, associated or not with jaundice, seizures and hypoglycaemia, the diagnosis of SOD and IHH should be considered. Treatment could be an emergency need because of risk of adrenal insufficiency and hypoglycemia (AU)

Farmacogenética do tratamento com hormônio de crescimento (GH) em crianças com deficiência de GH / Growth hormone pharmacogenetics in children with growth hormone deficiency

O hormônio de crescimento (GH) recombinante humano (rhGH) é o único tratamento disponível para crianças com deficiência de GH (DGH). Embora os resultados sejam em média satisfatórios, existe uma ampla variabilidade individual, de forma que alguns indivíduos ainda falham em atingir uma estatura normal ou dentro do seu potencial genético, mesmo quando diagnosticados e tratados sob as mesmas recomendações. Parte dessa variabilidade tem sido atribuída à falta de individualização da dose, uma vez que a terapia é baseada em doses fixas de rhGH ajustadas somente pelo peso. As variáveis clínicas preditivas de resposta ao tratamento com rhGH conhecidas até o momento explicam apenas 50% da variabilidade observada, sugerindo que outros parâmetros preditivos ainda estejam por ser reconhecidos. Apesar do intenso progresso de estudos moleculares, variáveis genéticas envolvidas na modulação da capacidade de resposta ao tratamento com rhGH permanecem amplamente desconhecidas. Sendo assim, o objetivo do presente estudo foi avaliar a influência de variantes gênicas comuns, presentes em genes envolvidos nos mecanismos de ação do GH, sobre a capacidade de resposta de crescimento de crianças com DGH tratadas com rhGH, de forma a fornecer ferramentas para a individualização do tratamento. Quatro polimorfismos de importância funcional presentes em três genes envolvidos nos mecanismos de ação do GH foram correlacionados à capacidade de resposta ao tratamento com rhGH em 84 crianças pré-púberes com DGH. Os achados moleculares foram correlacionados com a velocidade de crescimento no primeiro ano (n=84) e com a altura ao final (n=37) após tratamento com rhGH. As análises estatísticas foram ajustadas para as demais variáveis clínicas relacionadas à resposta ao tratamento com rhGH. Três desses polimorfismos a presença (GHRfl) ou ausência (GHRd3) do exon 3 do gene do receptor de GH (GHR); as repetições (CA)n, da região promotora do gene do fator de crescimento insulina-símile...

Recombinant human growth hormone (rhGH) is the standard treatment for children with growth hormone deficiency (GHD). Although growth outcomes are usually satisfactory, there is a wide range of individual variability, so that some children do not achieve normal adult height or fail to reach final heights near their genetic potential, even when diagnosed and treated according to the same recommendation. Part of this variability has been attributed to the lack of treatment individualization, since therapy is based on fixed rhGH doses adjusted only by body weight. Clinical variables which predict growth responses to rhGH so far explain only 50% of the variability observed, suggesting that other influential factors may be missing from current prediction models. Despite the striking progress of molecular studies, genetic variables which are involved in modulation of rhGH responsiveness remain largely unknown. Thus, the aim of the present study was to evaluate the influence of common genetic variants present in genes involved in GH actions on the rhGH responsiveness of children with GHD. We assessed the influence of four functional polymorphisms in three genes involved in GH actions on treatment outcomes after rhGH treatment in 84 prepubertal children with GHD. Genotypes were correlated to first year growth velocity (n = 84) and final height after treatment (n = 37). Statistical analyses were adjusted for other clinical influential factors. Our results demonstrated that three of these polymorphisms the presence (GHRd3) or absence (GHRfl) of GH receptor (GHR) gene exon 3; the (CA)n repeats, in the insulin-like growth factor-1 (IGF1) promoter region; and the -202 A/C polymorphism, in the promoter region of insulin-like growth factor binding protein -3 (IGFBP3) gene can independently and interactively influence the rhGH responsiveness of children with GHD...

Letrozole as a booster therapy in growth hormone deficiency.

A 13 year old boy presented to us with short stature. Evaluation revealed growth hormone (GH) deficiency. He was treated with GH replacement for 10 months and to further boost up the growth potential, an aromatase inhibitor Letrozole was added to GH therapy. After one year of combination therapy, patient had significant improvement in predicted adult height without a negative impact on pubertal progression.

Profile of hypopituitarism in a tertiary care hospital of eastern India--is quality of life different in patients with growth hormone deficiency?

Hypopituitarism is of diverse aetiology. Apart from pituitary adenoma and Sheehan's syndrome, snakebite is a common aetiology of hypopituitarism. A total of 82 patients of hypopituitarism were studied. Biochemical and radiological investigations were done in all the cases. A quality of life questionnaire was put among the patients. Scores were calculated from the answers of the questionnaire and they were assessed about quality of life. Though growth hormone deficiency is associated with poor quality of life there were no significant differences with patients with hypopituitarism without any growth hormone deficiency.

Deficiencia somatotrófica en niños: características clínicas y bioquímicas según la etiología en 75 casos / Somatotrophic deficiency in children: report of 75 cases

Somatotrophic deficiency (SDMT) can be due to a deficiency of growth hormone releasing hormone(GHRH), growth hormone (GH) or insulin like growth factor I (IGF-I). Although its clinical features have been thoroughly described, the diagnosis is still controversial. Now there is an effective treatment with GH or IGF-I for these patients. AIM: To analyze the main clinical, etiological and laboratory characteristics of 75 SD patients (44 males), aged 9.4 + 4.5 years, with severe growth retardation. The diagnosis was confirmed by the lack of response to two GH stimulation tests (Clonidine, Glugagon or Insulin) and low levels of IGF-I or insulin-like growth factor binding protein- 3 (IGFBP-3). RESULTS: In 34 patients (46 percent), the cause of DSMT was considered idiopathic (DSMT-I), in 31 (41 percent) there was an organic cause (DSMT-O), most commonly caused by malformations or pituitary tumors and in 10 (13 percent), it was genetic (DSMT-G) (three patients with Laron's Syndrome, five with mutations of GH gene and 2 with probable mutations of Prop-1 and Pit-1 genes). IGF-1 levels, were significantly lower in DSMT-O and DSMT-G thanin DSMT-I (21.2 +/- 46.1, 23.4 +/-30.3 ng/mL and 50.2 +/- 48.3 ng/mL, respectively). The lowest height score corresponded to DSMT-G, compared to DSMT-O and DSMT (­5.7 +/- 0.9, -4.0 +/- 1.6 and ­4.3 +/- 1.2 DS, respectively) CONCLUSIONS: The high percentage of organic and genetic etiologies in our patients can be due to the systematic search of these diseases. DSMT-G (Laron, mutations in GH and Pit-1 genes) had the most severe growth retardation.

Baixa estatura por insensibilidade ao hormônio de crescimento / Short stature caused by growth hormone insensitivity

Objetivo: crianças portadoras de baixa estatura apresentam um grande número de opções diagnósticas. Muitas vezes não se consegue estabelecer o diagnóstico preciso...

Introduction: Tasks for diagnosing short stature in children has been challenged by a broad array of pathways. Precise diagnosis has been often unconspicuous...