Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders / Análise de mutações nos genes TAC3 e TACR3 em pacientes com distúrbios puberais centrais idiopáticos

OBJECTIVE: To investigate the presence of variants in the TAC3 and TACR3 genes, which encode NKB and its receptor (NK3R), respectively, in a large cohort of patients with idiopathic central pubertal disorders. SUBJECTS AND METHODS: Two hundred and thirty seven patients were studied: 114 with central precocious puberty (CPP), 73 with normosmic isolated hypogonadotropic hypogonadism (IHH), and 50 with constitutional delay of growth and puberty (CDGP). The control group consisted of 150 Brazilian individuals with normal pubertal development. Genomic DNA was extracted from peripheral blood and the entire coding region of both TAC3 and TACR3 genes were amplified and automatically sequenced. RESULTS: We identified one variant (p.A63P) in NKB and four variants, p.G18D, p.L58L (c.172C>T), p.W275* and p.A449S in NK3R, which were absent in the control group. The p.A63P variant was identified in a girl with CPP, and p.A449S in a girl with CDGP. The known p.G18D, p.L58L, and p.W275* variants were identified in three unrelated males with normosmic IHH. CONCLUSION: Rare variants in the TAC3 and TACR3 genes were identified in patients with central pubertal disorders. Loss-of-function variants of TACR3 were associated with the normosmic IHH phenotype. Arq Bras Endocrinol Metab. 2012;56(9):646-52.

OBJETIVO: Investigar a presença de variantes nos genes TAC3 e TACR3, os quais codificam a NKB e seu receptor (NK3R), respectivamente, em uma coorte de pacientes com distúrbios puberais centrais idiopáticos. SUJEITOS E MÉTODOS: Duzentos e trinta e sete pacientes foram estudados: 114 com puberdade precoce central (PPC), 73 com hipogonadismo hipogonadotrófico isolado normósmico (HHI) e 50 com retardo constitucional do crescimento e desenvolvimento (RCCD). O grupo controle consistiu de 150 indivíduos brasileiros que apresentaram desenvolvimento puberal normal. O DNA genômico foi extraído de sangue periférico, e as regiões codificadoras dos genes TAC3 e TACR3 foram amplificadas e sequenciadas automaticamente. RESULTADOS: Uma variante (p.A63P) foi identificada na NKB, e quatro variantes, p.G18D, p.L58L (c.172C>T), p.W275X e p.A449S, foram identificadas no NK3R, as quais foram ausentes no grupo controle. A variante p.A63P foi identificada em uma menina com PPC, e a variante p.A449S, em uma menina com RCCD. As variantes previamente descritas, p.G18D, p.L58L e p.W275X, foram identificadas em três indivíduos com HHI normósmico do sexo masculino não relacionados. CONCLUSÃO: Variantes raras nos genes TAC3 e TACR3 foram identificadas em pacientes com distúrbios puberais centrais idiopáticos. Mutações de perda de função no gene TACR3 foram associadas com o fenótipo de HHI normósmico. Arq Bras Endocrinol Metab. 2012;56(9):646-52.

Association between anthropometric hormonal measurements and bone mineral density in puberty and constitutional delay of growth and puberty / Asociación entre las mediciones hormonales antropométricas y la densidad mineral ósea en la pubertad y el retraso constitucional del crecimiento y la pubertad

The aim of this study is to evaluate the acquisition of bone mineral in healthy children throughout puberty and in children with constitutional delay of growth and puberty (CDGP), and to relate changes in bone mass to age, weight, height, sitting height, body mass index and sex hormones in healthy boys. A total of 90 boys: 15 boys with CDGP and 75 healthy boys in different pubertal stages were examined. The number of children assigned to each Tanner stages was 15. Although bone age, weight and Body Mass Index (BMI) were significantly higher in stages II, III, IV, V compared to stage I and CDGP, mean height and sitting height values were higher in stages III, IV, V compared to stage I and CDGP. Also, serum FSH, LH, oestradiol, total and free testosterone levels progressively increased, although serum sex hormone binding globulin (SHBG) levels decreased, in healthy children with progression of sexual development. Significant increase was observed for serum oestradiol levels at stage II and above (p < 0.001), for serum total and free testosterone levels at stage III and above (p < 0.001), for serum FSH and LH levels at stage IV and above (p < 0.01 and p < 0.001) respectively. Also, it was shown that bone mineral content (BMC) and bone mineral density (BMD) measurements were significantly higher for pubertal stage lll and above groups according to both the CDGP group and stage I group. When BMD and BMC measurements of children with CDGP (0.62 ± 0.05 gr/cm² and 23.4 ± 2.8 gr) were compared with bone age, age, BMI and height-matched controls, there was no significant difference between children with CDGP and controls, except for age. Bone mineral density and BMC measurements in children with CDGP were significantly lower than those of age-matched controls (for pubertal stage lll: p < 0.05, for pubertal stage IV: p < 0.01). The strongest correlation coefficients were found between BMD and height among auxological parameters (r = 0.63, p < 0.001) and serum oestradiol levels among hormones (r = 0.55, p < 0.001). The most important findings of this investigation was the determination of body composition and hormonal measurement changes during puberty in boys; oestradiol was the most potent determinant of BMD among pubertal boys. We suggested that there is a critical age period for accumulation of bone mass according to the results. Longitudinal studies will elucidate why sufficient mineralization does take place after puberty starts in CDGP.

El objetivo de este estudio es evaluar la adquisición de mineral óseo del hueso en niños saludables a través de la pubertad y en niños varones con retraso constitucional del crecimiento y la pubertad (RCCP), y relacionar los cambios de masa ósea a la edad, el peso, la altura, la altura sentado, el índice de masa corporal, y las hormonas del sexo en niños varones saludables. Examinamos un total de 90 niños, 15 niños con RCCP y 75 niños saludables en diferentes etapas de la pubertad. El número de niños asignados a cada etapa de Tanner fue 15. Aunque la edad ósea, el peso y el IMC fueron significativamente más altos en las etapas II, III, IV, V, comparados con la etapa I y el RCCP; la altura promedio y los valores de la altura sentado fueron más altos en las etapas III, IV, V, comparados con la etapa I y el RCCP. Por otra parte, los niveles séricos de HEF, HL, estradiol y testosterona total y libre, aumentaron progresivamente, aunque los niveles séricos de SHBG disminuyeron en los niños saludables con el avance del desarrollo sexual. Se observó un aumento significativo en los niveles de estradiol sérico en la etapa II y por encima (p <0.001), en los niveles séricos de testosterona libre y total en la etapa II y por encima (p < 0.001), y en los niveles séricos de HEF, HL en la etapa IV y por encima (p < 0.01 y p < 0.001). Además se observó que las mediciones del contenido mineral óseo (CMO) y la densidad mineral ósea (DMO) fueron significativamente mayores en la etapa III de la pubertad y grupos por encima, de acuerdo tanto con el grupo de RCCP cómo el grupo de la etapa I. Cuando las mediciones de DMO y CMO de niños con RCCP (0.62 ± 0.05 gr/cm² y 23.4 ± 2.8 gr) fueron comparadas con la edad ósea, la edad, IMC y los controles pareados por altura, no se halló ninguna diferencia significativa entre los niños con RCCP y los controles, excepto la edad. Las mediciones de DMO y CMO en niños con RCCP fueron significativamente más bajas que las de los controles pareados por edad (para la etapa III de la pubertad: p < 0.05; para la etapa IV de la pubertad: p < 0.01). Los coeficientes de correlación más fuertes se encontraron entre la DMO y la altura entre los parámetros auxológicos (r = 0.63, p < 0.001), los niveles séricos de estradiol entre las hormonas (r = 0.55, p < 0.001). Los hallazgos más importantes de esta investigación fueron la determinación de la composición corporal y los cambios en la medición hormonal durante la pubertad en los muchachos; el estradiol fue el determinante más potente de la DMO entre los niños en la pubertad. Sugerimos que hay un periodo de edad crítico para la acumulación de masa ósea de acuerdo con nuestros resultados. Los estudios longitudinales esclarecerán por qué se produce suficiente mineralización después de que la pubertad empieza en RCCP.

Uso de GH em pacientes com baixa estatura idiopática: [revisão] / GH treatment in patients with idiopathic short stature: [review]

Pacientes com baixa estatura idiopática podem ser tratados com GH. Os critérios clínicos e laboratoriais utilizados na decisão do uso do GH, bem como no reconhecimento da responsividade dos indivíduos ao tratamento, são discutidos. Não apenas os resultados antropométricos, mas também os aspectos éticos e psicossociais devem ser considerados na avaliação dos custos/benefícios envolvidos no tratamento com GH em pacientes com baixa estatura idiopática.

Growth hormone has been used in the treatment of patients with idiopathic short stature. Clinical and laboratorial criteria are discussed, taking into consideration the indication of GH and the evaluation of its efficacy and individual responsiveness. Anthropometric, psychosocial, ethical, and also cost/benefit aspects must be considered before GH prescription in idiopathic short stature patients.

Serum Peak Growth Hormone and Insulin like Growth Factor-I(IGF-I) Level After Insulin, L-dopa Provocation Test in Children with Constitutional Delay of Growth and Puberty / 대한소아내분비학회지

PURPOSE:There were many controversies whether constitutional delay of growth and puberty(CDGP) is simple varient of normal growth pattern, or one of the cause of growth disturbance induced by the disturbance of growth hormone secrtion or its function. So we studied about the difference in serum peak growth hormone level after insulin, L-dopa provocation test, and serum IGF-I leve between constitutional delay of growth and puberty(CDGP) and familial short stature(FSS). METHODS:Measurement of serum peak growth hormone and insulin like growth factor-I(IGF-I) level after insulin, L-dopa provocation test were performed in 33 children with costitutional delay of growth and puberty (CDGP). Two groups of children with familial short stature (FSS) whose height were below 10 percentile for chronologic age of Korean national height standards were included as control groups. RESULTS: 1)There were no significant difference of serum peak growth hormone level between children with CDGP and children with FSS and these results were similar in both sex. 2)The mean serum IGF-I level of children with CDGP were 125.69+/-4.06 ng/ml(71.53-189.34ng/ml) in male, 157.7+/-3.17ng/ml(81.9-279.2ng/ml) in female. Both results were significantly lower to those of FSS children by chronologic age group because the mean serum IGF-I level of FSS children were 190.19+/-7.97ng/ml (87.64-297.6ng/ml) in male, 205.47+/-15.87ng/ml(61.7-433.1ng/ml) in female. But compared to FSS children by bone age of 72-96 months, there were no significant difference noted because the mean serum IGF-I level of children with FSSwere130.47+/-0.27ng/ml(63.24-198.2ng/ml)inmale,162.35+/-9.43ng/ml(54.9-217.53 ng/ml) in female. CONCLUSIONS:The results of this study showed that the serum peak growth hormone level after insulin, L-dopa provocation test with children of CDGP revealed no significant difference with those of FSS children in both sex. Serum IGF-I level of CDGP children was lower significantly to those of FSS children by chronologic age group, but no much difference with FSS children of bone age group.