Introduction. Information on insulin reference values and insulin sensitivity indices in the field of pediatrics is scarce. Objective. To describe insulin range and insulin sensitivity surrogate indices during childhood. Population and methods. Fasting insulin level range and surrogate indices, such as the homeostasis model assessment of insulin resistance (HOMA-IR), among healthy children and adolescents by age, body mass index, pubertal stage (PS), insulin-like growth factor-1 (IGF-1), total cholesterol, and triglycerides. Results. Two hundred and twenty-six healthy children and adolescents (1-18 years old) were included. Insulin increased with age, body mass index, pubertal stage, IGF-1 and triglyceride levels (r²= 0.38, p 7.5 years old had higher insulin levels [median (P3 and P97) pIU/mL: 5.0 (1.7-9.6)] than prepubertal children < 7.5 years old [2.9 pIU/ mL (1.3-10.9), p < 0.01]. During puberty (from PS II to PS V), insulin was higher in girls than in boys [7.4 (1.8-16.9) versus 5.8 (1.8-12.9), p 7.5 years old: 1.1 (0.32.0) versus children < 7.5 years old: 0.6 (0.3-1.4, p < 0.01). The insulin level and HOMA-IR results were higher in pubertal children compared to the prepubertal group (p 2.0 and > 2.6 in prepubertal and pubertal children, respectively, may be considered a warning sign for pediatricians to further investigate insulin resistance.

Introducción. Existe escasa información acerca de los valores de referencia de la insulina y de los índices de insulinosensibilidad en pediatría. Objetivo. Describir la variación de insulina e índices subrogantes de insulinosensibilidad en la etapa pediátrica. Población y métodos. Variación de la concentración de insulina en ayuno y de los índices subrogantes, como el modelo de evaluación homeostática de resistencia a la insulina (homeostasis model assessment of insulin resistance; HOMA-IR, por sus siglas en inglés), en niños sanos con la edad, el índice de masa corporal, estadio puberal (EP), la concentración de IGF-I, colesterol total y triglicéridos. Resultados. Se incluyeron 226 niños sanos (1-18 años). La insulina aumentó con la edad, el índice de masa corporal, el EP, los niveles de IGF-I y triglicéridos (r²= 0,38; p 7,5 años presentaron mayores valores de insulina [mediana (Pc3 y Pc97) pUI/ mL: 5,0 (1,7-9,6)] que los prepuberales < 7,5 años [2,9 pUI/mL (1,3-10,9); p < 0,01]. En la pubertad (del EP II al EP V), la insulina fue mayor en las niñas que en los varones [(7,4 (1,8-16,9) versus 5,8 (1,8-12,9); p 7,5 años: 1,1 (0,3-2,0) versus niños < 7,5 años: 0,6 (0,3-1,4; p < 0,01). Los grupos puberales presentaron niveles más elevados de insulina y de HOMA-IR respecto de los niños prepuberales (p 2,0 y > 2,6 en prepúberes y púberes, respectivamente, podrían alertar a los pediatras sobre un posible estado de insulinorresistencia.

Mutações ativadoras no gene receptor de TSH (TSHR) foram identificadas como a base molecular do hipertireoidismo congênito não autoimune. Descrevemos os achados clínicos e a caracterização molecular de uma menina que apresentou hipertireoidismo autoimune grave desde o nascimento, nascida de uma mãe com desordem tiroidiana autoimune. Tratada com metilmercaptoimidazol e β-bloqueadores, ela permaneceu com hipertiroidismo e necessitou de tiroidectomia total. A fim de caracterizar a presença da mutação ativadora, foram analisados toda a sequência codificadora assim como os extremos dos íntrons e éxons do gene TSHR. A paciente era heterozigota para a mutação p.Ser281Asn e para o polimorfismo p.Asp727Glu. Essa mutação recorrente, p.Ser281Asn, caracterizada in vitro pelo aumento da produção basal de cAMP, é a única variante genética ativadora da linhagem germinativa descrita até hoje no domínio extracelular do receptor de TSH. Interessantemente, a mãe da paciente apresentou hipertireoidismo sem qualquer mutação ativadora do gene TSHR. Embora o hipertireoidismo congênito não autoimune seja uma condição rara, ele deve ser investigado quando há persistência da doença grave, mesmo em um recém-nascido de uma mãe com hipertireoidismo autoimune, a fim de se diferenciar o caso da forma mais comum da doença autoimune congênita. Arq Bras Endocrinol Metab. 2012;56(8):513-8

Activating mutations in the TSH Receptor (TSHR) gene have been identified as the molecular basis for congenital non-autoimmune hyperthyroidism. We describe the clinical findings and molecular characterization in a girl who presented severe non-autoimmune hyperthyroidism since birth, born to a mother with autoimmune thyroid disease. She was treated with methylmercaptoimidazol and β-blockers, but remained hyperthyroid and required total thyroidectomy. To characterize the presence of an activating mutation, the whole coding sequence and intron-exon boundaries of TSHR gene were analyzed. The patient was heterozygous for p.Ser281Asn mutation and p.Asp727Glu polymorphism. This recurrent mutation, p.Ser281Asn, characterized in vitro by increased basal production of cAMP, is the unique germline activating gene variant described so far in the extracellular domain of TSH receptor. Interestingly, the patient's mother presented hyperthyroidism but without any TSHR gene activating mutation. Although congenital non-autoimmune hyperthyroidism is a rare condition, it should be investigated when severe disease persists, even in a newborn from an autoimmune hyperthyroid mother, in order to differentiate it from the more common congenital autoimmune disease. Arq Bras Endocrinol Metab. 2012;56(8):513-8

A deficiência isolada do hormônio do crescimento (DIGH) pode ser resultado de deleções/mutações no gene GH1 ou no gene GHRHR. O objetivo deste estudo foi caracterizar o defeito molecular em uma menina que apresenta DIGH. A paciente nasceu às 41 semanas de gestação de pais não consanguíneos. As avaliações clínica e bioquímica incluíram medidas antropométricas, avaliação da função pituitária e concentrações de IGF-I e IGFBP-3. A caracterização molecular foi feita por meio de amplificação do GH1 por PCR e digestão com SmaI de dois fragmentos homólogos flanqueando o gene, usando-se DNA genômico da paciente e de seus pais como padrões. Com 1,8 ano de idade, a paciente apresentou atraso grave no crescimento (altura 61,2 cm, -7.4 DP), obesidade central, protuberância frontal, face de boneca e acromicria. A RM mostrou hipoplasia pituitária. Os achados laboratoriais confirmaram a DIGH. O gene GH1 não pôde ser amplificado nas amostras da paciente, enquanto as amostras de seus pais produziram um fragmento do tamanho esperado. A digestão com SmaI foi consistente com a paciente ser heterozigota composta para deleções para 6,7 e 7,6 Kb, enquanto seus pais parecem ser carreadores heterozigotos para deleções de 6,7 ou 7,6 Kb. Caracterizamos a DIGH tipo IA causada por duas deleções diferentes no gene GH1, sugerindo que essa condição pode ser considerada na DIGH grave, mesmo em famílias não consanguíneas. Arq Bras Endocrinol Metab. 2012;56(8):558-63

Isolated growth hormone deficiency (IGHD) may result from deletions/mutations in either GH1 or GHRHR genes. The objective of this study was to characterize the molecular defect in a girl presenting IGHD. The patient was born at 41 weeks of gestation from non-consanguineous parents. Clinical and biochemical evaluation included anthropometric measurements, evaluation of pituitary function, IGF-I and IGFBP-3 levels. Molecular characterization was performed by PCR amplification of GH1 gene and SmaI digestion of two homologous fragments flanking the gene, using genomic DNA from the patient and her parents as templates. At 1.8 years of age the patient presented severe growth retardation (height 61.2 cm, -7.4 SDS), truncal obesity, frontal bossing, doll face, and acromicria. MRI showed pituitary hypoplasia. Laboratory findings confirmed IGHD. GH1 gene could not be amplified in samples from the patient while her parents yielded one fragment of the expected size. SmaI digestion was consistent with the patient being compound heterozygous for 6.7 and 7.6 Kb deletions, while her parents appear to be heterozygous carriers for either the 6.7 or the 7.6 Kb deletions. We have characterized type IA IGHD caused by two different GH1 gene deletions, suggesting that this condition should be considered in severe IGHD, even in non-consanguineous families. Arq Bras Endocrinol Metab. 2012;56(8):558-63

Idiopathic Short Stature (ISS) includes a heterogeneous group of children with growth failure. One possible explanation for the growth failure is a reduced responsiveness to growth hormone (GH). Human circulating GH is partially bound to a highaffinity binding protein (GHBP) which is derived from proteolytical cleavage of the extracellular domain of the GH receptor. Many reports have demonstrated a close relationship between GHBP and liver GH receptor status in physiological conditions and diseases. Moreover, serum GHBP measurement has been proposed as an useful peripheral index of GH receptor abundance. Our objective was the evaluation of serum GHBP levels and its probable association with serum growth factors (IGF-I, IGFBP-3 and ALS) and the exon 3 polymorphism of the extracellular domain of the GHR gene in ISS children. Children with ISS presented significantly lower height SDS, BMI SDS, serum components of the IGFs system and GHBP concentration as compared to an age-matched control group of normal children (p<0.001). Interestingly, exon 3 genotype did not influence the differences observed in these parameters. The maximal GH response obtained after two GH provocative tests inversely and significantly correlated to GHBP serum levels (r= -0.28, p= 0.012). A frequency study showed a deviation to low SDS values of serum GHBP, IGF-I, IGFBP-3 and ALS. Conclusion: 1- in children with ISS the exon 3 genotype of the GHR gene is not a factor that could explain the lower levels observed in circulating GHBP concentration and components of the IGFs system; 2- low serum GHBP together with low IGF-I, IGFBP-3 or ALS levels would help pointing to GH insensitivity due to GH receptor gene abnormalities in ISS.

La talla baja idiopática (TBI) incluye a un grupo heterogéneo de pacientes con fallas en su crecimiento. Una causa probable de TBI puede ser la insensibilidad a la GH (IGH). La proteína de unión de GH de alta afinidad (GHBP) se genera por el clivaje proteolítico de la porción extracelular del receptor de GH (GHR) y su determinación se propone como un marcador periférico del nivel de GHR en los tejidos. El objetivo de este trabajo fue evaluar los niveles de GHBP circulantes y su asociación con factores de crecimiento y el polimorfismo del exón 3 del gen GHR en niños con TBI. Los niños con TBI presentaron talla, IMC, IGF-I, IGFBP-3, ALS y niveles de GHBP significativamente más bajos que un grupo de niños de edad comparable (p<0.001). El genotipo del exón 3 del GHR no fue un factor determinante de las diferencias observadas. La máxima respuesta de GH de los tests de estímulo de secreción correlacionó negativa y significativamente con los niveles de GHBP (r= -0.28, p= 0.012). Los perfiles de distribución de la concentración de GHBP, IGF-I, ALS y BP3 expresadas en score de desvío estándar (SDE) en la TBI, mostraron un sesgo hacia niveles bajos. En conclusión, los marcadores de acción de GH y los niveles de GHBP fueron bajos en la TBI, independientemente del genotipo del exón 3 del gen GHR. En un subgrupo de niños con TBI, niveles disminuidos de GHBP y de componentes del sistema de los IGFs, colaborarían en la evaluación de la IGH sugiriendo la búsqueda de defectos en el GHR.

Introduction. Approximately 10% of children born small for gestational age (SGA) do not show spontaneous catch-up growth. Objective. Our objective was to assess the efficacy and safety of 2 years growth hormone treatment in children younger than 6 years of age, born SGA. Material and methods. Fourteen patients, mean age 4.2 ± 1.1 years were treated with growth hormone at 1.0 UI/kg/wk for two years. Results. Growth velocity increased from a mean ± SD of 5.4 ± 1.7 cm/yr to 9.8 ± 1.50 cm/yr and 7.6 ± 1.5 cm/yr during the first year and second year, respectively (p 0.00058). Serum IGF-I and its binding protein BP3 increased significantly throughout treatment. Basal glucose and insulin levels increased significantly during treatment, p= 0.0006 and p= 0.036, respectively, without significant changes in postprandial glucose or insulin levels. A mild change in insulin sensitivity was observed along treatment. Conclusion. Two years growth hormone treatment induced a significant growth acceleration in children born small for gestational age, allowing them to attain a normal height. No serious adverse events were reported.

Introducción. Un 10% de los niños nacidos pequeños para la edad gestacional no presentan un crecimiento compensador y permanecen bajos. El tratamiento con hormona de crecimiento, aprobado en los países desarrollados, ha demostrado su eficacia en estos niños. Objetivo. Determinar la eficacia y la seguridad del tratamiento con hormona de crecimiento durante dos años en niños nacidos pequeños para la edad gestacional sin deficiencia de hormona de crecimiento. Material y métodos. Se trataron 14 niños menores de 6 años con hormona de crecimiento a 1,0 UI/kg/semana. Resultados. Se observó un aumento significativo en la velocidad de crecimiento (media ± DE) de 5,4 ± 1,7 cm/año a 9,8 ± 1,5 cm/año y 7,6± 1,5 cm/año durante el primer y segundo años, respectivamente, (p= 0,00058). Ello resultó en una mejoría significativa en el puntaje z de talla (media ± DE) de -2,79 ± 0,3 a -1,27 ± 0,5 en 2 años (p < 0,0001). Se observó un incremento significativo en las concentraciones de IGF-I y su proteína transportadora BP3 a los 12 y 24 meses del tratamiento. Las concentraciones de glucosa e insulina aumentaron significativamente durante el estudio (ANOVA, p = 0,0006 y p = 0,036, respectivamente). Dos de los índices de sensibilidad a la insulina utilizados revelaron una leve alteración en la sensibilidad a la insulina. Conclusiones. El tratamiento durante 2 años con hormona del crecimiento produjo un aumento significativo de la talla de los pacientes nacidos pequeños para la edad gestacional y permitió alcanzar una talla dentro de los límites normales. No se informaron episodios adversos mayores durante el tratamiento.