Homozygous sickle cell disease in Uganda and Jamaica a comparison of Bantu and Benin haplotypes / La anemia de células falciformes homocigóticas en Uganda y Jamaica comparación de haplotipos Bantú y Benin

OBJECTIVE: To compare the haematological and clinical features of homozygous sickle cell (SS) disease in Bantu and Benin haplotypes in a cross-sectional study of 115 Ugandan patients attending the Sickle Cell Clinic at Mulago Hospital, Kampala, Uganda, with 311 patients in the Jamaican Cohort Study. METHODS: This involved comparison of clinical features and haematology with special reference to genetic determinants of severity including fetal haemoglobin levels, beta-globin haplotype and alpha thalassaemia status. RESULTS: The Bantu haplotype accounted for 94% of HbS chromosomes in Ugandan patients and the Benin haplotype for 76% of HbS chromosomes in Jamaica. Ugandan patients were marginally more likely to have alpha thalassaemia, had similar total haemoglobin and fetal haemoglobin levels but had higher reticulocyte counts and total bilirubin levels consistent with greater haemolysis. Ugandan patients had less leg ulceration and priapism, but the mode of clinical presentation, prevalence of dactylitis, features of bone pain and degree of delay in sexual development, assessed by menarche, were similar in the groups. In Ugandan patients, a history of anaemic episodes was common but these were poorly documented. CONCLUSION: The haematological and clinical features of the Bantu haplotype in Uganda were broadly similar to the Benin haplotype in Jamaica except for less leg ulceration and priapism and possibly greater haemolysis among Ugandan subjects. Anaemic episodes in Uganda were treated empirically by transfusion often without a clear diagnosis; better documentation including reticulocyte counts and observations on spleen size is necessary to evolve appropriate models of care.

OBJETIVO: Comparar los rasgos clínicos de la anemia de células falciformes homocigóticas (SS) en los haplotipos Bantú y Benin en un estudio transversal de 115 pacientes ugandeses que asisten a la Clínica de la anemia de células falciformes en el Hospital de Mulago, Kampala, Uganda, con 311 pacientes en un estudio de cohorte jamaicano. MÉTODOS: El estudio conllevó la comparación de los rasgos clínicos y hematológicos con referencia especial a los determinantes genéticos de la severidad, incluyendo los niveles de la hemoglobina fetal, haplotipos del gen de la globina beta, y el estado de la alfa talasemia. RESULTADOS: El haplotipo Bantú dio cuenta del 94% de los cromosomas HbS en los pacientes ugandeses, en tanto que los haplotipos Benin dieron cuenta del 76% de los cromosomas de HbS en Jamaica. Los pacientes de Uganda presentaron una probabilidad marginalmente mayor de alfa talasemia, tenían niveles similares de hemoglobina total y hemoglobina fetal, pero en cambio presentaban conteos más altos de reticulocitos así como niveles mayores de bilirrubina total, en correspondencia con una mayor hemólisis. Los pacientes ugandeses presentaban menor ulceración de las piernas y priapismo, pero el modo de presentación clínica, la prevalencia de dactilitis, los rasgos de dolor óseo, y el grado de retraso en el desarrollo sexual, evaluado por la menarquia, fueron similares en todos los grupos. Los pacientes de Uganda se caracterizaron comúnmente por una historia de episodios de anemia, pobremente documentados. CONCLUSIÓN: Los rasgos clínicos y hematológicos del haplotipo Bantú en Uganda fueron considerablemente similares al haplotipo Benin en Jamaica, salvo por una menor presencia de ulceración de las piernas y priapismo, así como posiblemente mayor hemólisis entre los sujetos de Uganda. Los episodios de anemia en Uganda fueron tratados empíricamente mediante transfusión, a menudo sin un diagnóstico claro. Se necesita una mejor documentación - incluyendo conteos de reticulocitos - así como observaciones del tamaño del bazo, a fin de desarrollar modelos de cuidado apropiados.

Pesquisa de mutações no gene do receptor do secretagogo de hormônio de crescimento (GHSR) em crianças com baixa estatura idiopática e deficiência isolada de hormônio de crescimento / Growth hormone secretatogue receptor gene (GHSR) analysis in patients with idiopathic short stature (ISS) and patients with isolated growth hormone deficiency

A ghrelina, hormônio secretado principalmente por células gástricas, liga-se ao seu receptor, o receptor de secretagogo de GH (GHSR - Growth hormone secretagogue receptor), localizado no hipotálamo e na hipófise, estimulando a síntese e secreção do GH. Recentemente foram identificadas mutações no gene GHSR em crianças com baixa estatura idiopática (BEI) e com deficiência isolada de GH (DGH). No presente estudo investigamos a presença de mutações no gene GHSR em crianças com DGH isolada de causa não identificada e crianças com BEI, incluindo um subgrupo de crianças com atraso constitucional de crescimento e desenvolvimento (ACCD). Foram selecionados 14 pacientes com deficiência isolada de GH sem alterações anatômicas da região hipotálamo-hipofisária e 96 pacientes com BEI, destes 31 (32%) apresentavam ACCD. Também foram estudados 150 controles adultos e 197 crianças controle com crescimento e puberdade normais. A região codificadora do GHSR foi amplificada utilizando-se oligonucleotídeos iniciadores específicos, seguida de purificação enzimática e seqüenciamento automático. Encontramos 6 variantes alélicas em heterozigose no GHSR: nenhuma delas presente nos controles estudados, e quatro destas variantes estão localizadas em regiões conservadas do gene. Uma variante foi encontrada em uma paciente do grupo DGH (p.Val249Leu) e as outras cinco (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) foram encontradas em pacientes do subgrupo ACCD do grupo BEI. As variantes missense foram submetidas a estudo funcional que evidenciou que as mutações p.Ser84Ile e p.Val182Ala possuem diminuição na atividade basal associadas à diminuição da expressão do receptor na superfície celular. Adicionalmente, a mutação p.Ser84Ile também apresenta redução na atividade do GHSR induzida pelo ligante. A variante p.Val249Leu foi encontrada em uma paciente do sexo feminino com diagnóstico de DGH isolado...

Ghrelin, hormone secreted by gastric cells, stimulates growth hormone secretion by acting on its receptor GHSR, located in the hypothalamus and pituitary. Recently, mutations in the GHSR gene were described in patients with growth hormone deficiency (GHD) and idiopathic short stature (ISS). In the present study we analyzed the GHSR gene in patients with isolated GHD and patients with ISS, including a subgroup of patients with constitutional delay of growth and puberty (CDGP). We studied 14 GHD patients with normal pituitary magnetic resonance imaging and 96 patients with ISS, 31 of them with CDGP. We also studied 150 adults and in 197 children with normal stature. The entire coding region as well as the exon-intron boundaries of GHSR were PCR amplified in all patients and control group and PCR products were bidirectionally sequenced. Six different heterozygous variants in GHSR were identified: none of them were found in the control group and four of these amino acid substitutions occurred at a conserved position within the GHSR. One variant (p.Val249Leu) was found in a GHD patient and the other five (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were found in patients with CDGP. The missense variants were submitted to functional studies. Two of these variants (p.Ser84Ile and p.Val182Ala) result in a decrease in basal activity that was in part explained by a reduction in cell surface expression. The p.Ser84Ile mutation was also associated with a defect in ghrelin potency. The p.Val249Leu variant, found in a female patient with isolated GHD, did not segregate with the phenotype in the family and had no functional impairment in vitro. This suggests that p.Val249Leu is not the cause of the GHD in the family and may be a rare allelic variant. The other variants (c.-6 G>C, p.Ser84Ile, p.Val182Ala, p.Ala169Thr e p.Ala358Thr) were identified only in patients with CDGP (3 male and 2 female)...

study of delayed puberty in females referred to pediatric endocrine clinic for 5 years [from 78/12/29 to 82/12/1]

The study of causes of delayed puberty in female referred to pediatric endocrine ward of university centers of Mashhad University of Medical Sciences from 1374 to 1382. This study was done both retrospectively and prospectively in a descriptive analytic manner. The studied population were 31 girls with delayed puberty referred to endocrinology pediatric clinic. The data was collected through history, physical examination, completing questionnaires, and was compared by T Test student Statistical analysis performed with SPSS-excel. On the whole, 31 girls with delayed puberty were studied. The mean age of the patients was 14.93 +/- 1.46 yr. Average bone age and weight was 10 +/- 1.5 and 31 +/- 8.3 gr respectively. Z score of Height and weight for Age was -3.83 an -2.68 respectively. Serum estradiol level in all patients was less than normal. Delayed puberty in 27% was constitutional, 23% had Turner syndrome. Major thalassemia was the cause in 13% of the cases. The prevalence of hypothyroidism in the population was 10% other systemic diseases such as, fancony syndrome etc were the less common causes of delayed puberty. Constitutional delayed puberty [27%] and Turner syndrome [23%] were the most common causes of hypogonadism and delayed puberty which concurs with other studies. The prevalence of major thalassemia [13%] is more than other studies which needs further studies. Attention to signs of puberty in the girls referring to physician at the time of puberty, leads to early diagnosis of delayed puberty in the patients. And also karyotype study is recommended in all girls with short stature and growth retardation

Delayed Puberty due to Pituitary Stalk Dysgenesis and Ectopic Neurohypophysis

Hypopituitarism is not a common cause of delayed puberty. A 22 year old man was referred to our clinic because of the absence of the development of secondary sexual characteristics. The patient had no complaints of physical discomfort. Random serum testosterone and luteinizing hormone level were obtained and found to be low. The combined pituitary function stimulation test revealed a partial hypopituitarism. A pituitary magnetic resonance imaging (MRI) was obtained and showed decreased pituitary stalk enhancement and ectopic neurohypophysis. Therefore, we conclude that the delayed puberty was a result of hypopituitarism due to pituitary stalk dysgenesis and ectopic neurohypophysis. The patient was started on hormone replacement therapy and gradually developed secondary sexual characteristics.

Crescimento puberal e altura final em 40 pacientes com diabetes mellitus tipo 1 / Pubertal growth and final height in 40 patients with type 1 diabetes mellitus

OBJETIVO: O diabetes mellitus tipo 1 (DM1) é a mais importante doença endócrino-metabólica crônica entre crianças e adolescentes, podendo ser causa de atraso do crescimento e da puberdade. Avaliamos a influência do DM1 no estirão de crescimento e na puberdade de indivíduos com doença iniciada antes ou no começo desta fase. CASUíSTICA E MÉTODOS: Foram avaliados retrospectivamente os prontuários de 40 pacientes (25 meninas), que apresentavam altura final, com coleta dos dados para o cálculo do tempo total de doença, os escores de DP da altura e do peso a cada consulta, a altura-alvo parental, as velocidades de crescimento (VC) anuais, o pico do estirão de crescimento, a duração da puberdade, o ganho total de crescimento durante o estirão puberal e a hemoglobina glicada (HbG). RESULTADOS: Em relação à adequação da altura final para a altura-alvo parental, 37 pacientes ficaram dentro da previsão e 3 ficaram abaixo do limite inferior. Não houve associação entre as variáveis analisadas com exceção da VC no pico do estirão, quando esta foi menor ou igual a 6cm/ano. A idade de início do DM1 e do pico do estirão puberal coincidiram com a faixa etária descrita na literatura; não foi observado atraso na idade de início da puberdade. No entanto, o ganho de altura durante a puberdade foi menor que o descrito na literatura, o mesmo ocorrendo em relação ao pico de VC puberal. De acordo com os valores da HbG, todos os pacientes avaliados apresentaram um controle crônico ruim do DM1. CONCLUSÕES: Neste grupo de DM1 com controle inadequado da doença, houve um prejuízo na altura final em relação à altura do início do DM1, provavelmente causado por uma baixa VC durante a puberdade, que, no entanto, não teve influência na altura final em relação ao alvo parental.

Short stature, body disproportion, and endocrine disorders in thalassemia major

short stature and endocrine disorders are common compications of beta thalassemia major [TM]. The aim of this study was to determine the prevalence and causes of short stature, body disproportion, delayed puberty, and skeletal changes among thalassemia patients in our area. Patients and a prospective study was done on 314 patients with TM, randomly chosen at the Thalassemic Treatment Center of Al Yarmook Teaching Hospital during the period from January 2, 2001 to April 30, 2001. Patients ranged from 2-20 years of age and were divided into 5 groups. The male to female ratio was 1.2:1. The study included measurements of standing height, ratio of upper body to lower segment, puberty staging according to Tanner staging. Estimation of the hormones for which assays were available including growth hormone, T4, TSH, LH, and FSH were performed. The liver enzymes AST and ALI, and serum calcium were measured. Radiographs of the head, long bones, vertebrae, and wrist joints were done. The abnormalities noted were correlated with the duration of the DFX chelation and serum ferritin levels. the study revealed that 28% of the patients exhibited short stature, predominantly in the age group 15-20 years, and 25% of the patients had short trunk but normal stature predominantly in the age group of 10-14. There was a significant relation to the duration of DFX chelation, p=0.0004. Delayed puberty was present in 33/63 patients [52.4%; 19 were females [57.5%] and 14 were males [42.5%]. Endocrine disorders were present in 25.9%. Hypogonadotropic hypogonadism and hypocalcemia were present in 8.4% and 12% of the patients respectively. There was a significant relation to the duration of the disease, p=0.00003 and 0.0004 respectively. Skeletal changes including platyspondylosis, maxillary overgrowth, hair-on-end appearance, rectangular metacarpals and metatarsals, and osteoporosis were found in 38.6% of the patients in the age group of 10-14 years and were significantly related to the duration of DFX chelation, p=0.0001. short stature, short trunk, skeletal changes and delayed puberty are significant problems in our thalassemic patients. The role of siderosis and DFX toxicity need further elucidation

Medicina deportiva pediátrica / Pediatric sport medicine

La máxima clásica dice: mens sana in corpore sano. Rousseau, más cerca de nuestros días escribe en su obra Emile: "¿Queréis cultivar la inteligencia de vuestro alumno?, cultivad las fuerzas que la han de gobernar. Ejercitad continuamente su cuerpo. Hacedlo fuerte y sano para que sea prudente y razonable; que trabaje, que actúe, que grite, que esté siempre en movimiento. Que sea hombre para la fuerza y así lo será para la razón"

Avaliaçäo de distúrbios do crescimento e da puberdade de origem idiopática ou após tratamento de neoplasias / Evaluation of growth and puberty disorders of idiopathic etiology or after neoplasms therapy

Em uma coletânea de artigos säo discutidos aspectos referentes aos distúrbios de crescimento e puberdade de origem idiopática ou decorrentes do tratamento de neoplasias. CAPÍTULO I: determinaçöes de IGF-1 e IGFBP-e além de desaceleraçäo precoce do crescimento (< 5 anos) säo marcadores diagnósticos de deficiência idiopática permanente de GH, enquanto que atraso de idade óssea, velocidade de crescimento diminuída e dois picos de GH < 10 ng/mL näo distinguem deficiência permanente de trasitória. Em adolescentes masculinos com retardo puberal a deficiência de GH é rara; a aceleraçäo do crescimento tem associaçäo positiva com a testosterona plasmática e o volume testicular, e näo com o pico de GH. Pequenas doses de testosterona näo reduzem a estatura final. CAPÍTULO II: O tratamento da puberdade precoce central com GnRHa baseado no cálculo da estatura projetada e da diferença entre esta e a estatura-alvo, pico LH/FSH, estradiol sérico e avanço de idade óssea possibilita uma estatura final adequada. Quando associam-se puberdade precoce e deficiência de GH, o tratamento combinado (GnRHa + GH) deve ser iniciado concomitantemente. Formas lentamente evolutivas de puberdade precoce sem tratamento näo apresentam reduçäo da estatura final. Em pacientes que receberam radioterapia craniana (24 Gy) por leucemia, a estatura final depende do pico de GH e da idade ao início da puberdade, e näo do protocolo quimioterápico. Nessa populaçäo, IGF-1 e IGFBP-3 näo säo bons marcadores de deficiência de GH, a qual é mais freqüente em pacientes irradiados antes de cinco anos. CAPÍTULO III: em pacientes com meduloblastoma que receberam radioterapia e quimioterapia, a reduçäo de GH-BP, IGF-1 e IGFBP-3 com secreçäo normal de GH sugere um mecanismo de resistência parcial ao GH, induzida pela quimioterapia. Entretanto, a longo prazo esta resistência trasitória näo impede a retomada de crescimento normal em pacientes submetidos a TMO. Em pacientes que receberam TBI, a näo-associaçäo entre pico de GH e perda estatural reflete o efeito associado da radioterapia sobre as cartilagens de crescimento. Níveis normais de IGF-1 e IGFBP-3 em pacientes com deficiência de GH sugerem um mecanismo de resistência parcial ao IGF-1. O tratamento da radioterapia näo reduz os efeitos deletérios desta sobre o crescimento.

Development of secondary sex characteristics in multitransfused thalassemic children.

Secondary sex characteristics were evaluated in thalassemic children (41, boys and 30 girls), who were on regular transfusion therapy and were above 11 years of age. The results of this study indicate that the development of secondary sex characteristics in thalassemic children is markedly delayed as compared to their non-thalassemic siblings and to the expected development criteria. Delay in development of secondary sex characteristics appears to be secondary to chronic hypoxia and iron overload.

Infusión de hormona liberadora de gonadotrofinas y prueba de clorpromazina: evaluación en hipogonadismo hipogonadotrófico y retraso puberal femenino / Gonadotropin releasing hormone infusion and chlorpromazine test: evaluation in hypogonadotropic hypogonadism and famele delayed puberty

El objetivo del presente trabajo fue evaluar la infusión de LH-RH y Test de Clorpromazina para mejorar la eficacia diagnóstica diferencial entre Hipogonadismo Hipogonadotrófico (HH) y Retraso Puberal Femenino (RP). Se estudiaron 10 pacientes, 5 HH y 5 RP mediante infusión intravenosa de LH-RH (0,83 µg/min) durante 120 min con dosaje de LH y FSH (IRMA) a los tiempos de 0, 15, 30, 45, 60 y 120 min. A los 7 días se realizó prueba de CPZ (0,33 mg/kg IM) midiendo PRL (IRMA) a los tiempos -15, 0, 30, 60, 90 y 120 min. Durante la infusión de LH-RH los HH mostraron una respuesta máxima de LH (15,56 ñ 4,57 m UI/ml) de menor magnitud que la de los RP (46,00 ñ 20,69 mUI/ml). Esta diferencia fue estadísticamente significativa (p < 0,01) según el test de Mann-Whitney. No se hallaron diferencias estadísticamente significativas en el basal de LH ni en ninguno de los valores de FSH ni de PRL en la prueba de CPZ entre ambos grupos. Conclusiones: * El aumento de LH en respuesta a la infusión de LH-RH permitió discriminar RP de HH. * Si bien no se encontró superposición de valores entre ambos grupos, esto debería confirmarse con un mayor número de casos. * La evaluación del eje prolactínico con CPZ no permitió discriminar los HH de los RP femeninos

Testosterone deficiency and extreme retardation of puberty in homozygous sickle-cell disease

Homozygous sickle-cell (SS) disease is associated with retardation of physical and sexual development but most Jamaican children commence their adolescent growth spurt before 16 years of age. Analysis of growth from children in the Jamaican Cohort Study noted extreme growth retardation , defined as an absence of the adolescent growth spurt and pre-pubertal sexual development (Tanner stage 1 or 2) at age 16 years, in 8/52(15 per cent) SS boys. These and two boys from the general sickle-cell clinic with a similar growth pattern provided a study group of 10 boys who were investigated for a possible endocrine explanation for their extreme retardation of physical maturation. A sub-optimal testosterone response (<10 nmol/l) to human chorionic gonadotrophin and an exaggerated gonadotrophin hormone releasing hormone was consistent with poor testicular function in 5 boys. Retardation of adolescent growth and development is common in boys wit SS disease but, when extreme, requires early investigation to identify potentially correctable mechanisms