Avaliação do padrão de crescimento na síndrome de Noonan em pacientes com mutações identificadas nos genes PTPN11, SOS1, RAF1 e KRAS / Growth pattern of patients with Noonan syndrome with identified mutations in PTPN11, SOS1, RAF1 e KRAS genes

A Síndrome de Noonan (SN) é caracterizada por baixa estatura proporcionada de início pós-natal, dismorfismos faciais, cardiopatia congênita e deformidade torácica. A frequência da SN é estimada entre 1:1000 e 1:2500 nascidos vivos, com distribuição semelhante em ambos os sexos. A herança é autossômica dominante com penetrância completa, porém a maioria dos casos é esporádica. Até o momento, mutações em genes da via RAS-MAPK (PTPN11, KRAS, SOS1, RAF1, MEK1, NRAS e SHOC2) foram identificadas em aproximadamente 70% dos pacientes. Uma das principais características fenotípicas da SN é a baixa estatura pós-natal, embora o mecanismo fisiopatológico do déficit de crescimento nesta síndrome ainda não esteja totalmente esclarecido. Estudos que avaliaram o padrão de crescimento linear em crianças com SN foram realizados anteriormente ao conhecimento do diagnóstico molecular dessa síndrome. No presente estudo, avaliamos a frequência de mutação nos genes PTPN11, SOS1, RAF1 e KRAS em 152 pacientes com SN e o padrão de crescimento linear (altura) e ponderal [índice de massa corpórea (IMC)] dos pacientes com mutação identificada. No total, mutações nos genes relacionados foram encontradas em 99 pacientes (65%) do nosso estudo, com predominância do gene PTPN11 (47%), seguido do SOS1 (9%), RAF1 (7%) e KRAS (3%). Foram construídas curvas específicas para SN de Altura e IMC para idade e sexo utilizando o método LMS. Os pacientes com SN apresentaram crescimento pré-natal preservado, porém o comprometimento do crescimento pós-natal foi observado desde o primeiro ano de vida, atingindo uma altura final de -2,5 e -2,2 desvios-padrão da média para população brasileira em homens e mulheres, respectivamente. O prejuízo da altura foi maior nos pacientes com mutação no gene RAF1 em comparação com os genes PTPN11 e SOS1. O IMC dos pacientes com SN apresentou queda de 1 desvio-padrão em relação à média da população brasileira normal. O comprometimento do IMC foi menor...

Noonan Syndrome (NS) is characterized by distinctive facial features, short stature and congenital heart defects. The estimated prevalence is 1:1000 to 1:2500 live births, affecting equally both sexes. It is an autosomal dominant disorder with complete penetrance, but most cases are sporadic. To date, mutations in the RAS/MAPK pathway genes (PTPN11, KRAS, SOS1, RAF1, MEK1, NRAS and SHOC2) were identified in approximately 70% of patients. One of the cardinal signs of NS is proportional postnatal short stature although the physiopathological mechanism of growth impairment remains unclear. The current knowledge about the natural history of growth associated with NS was described before molecular diagnosis era. In this study, we performed PTPN11, SOS1, RAF1, and KRAS mutation analysis in a cohort of 152 NS patients and studied the natural linear (height) and ponderal growth [body mass index (BMI)] of NS patients with related mutations. Mutations in NS-causative genes were found in 99 patients (65%) of our cohort. The most common mutated gene was PTPN11 (47%), followed by SOS1 (9%), RAF1 (7%) and KRAS (3%). Sex-specific percentile curves for height and BMI were constructed using the LMS method. NS patients had birth weight and length within normal ranges but the postnatal growth impairment was observed during the first year of life, reaching a final height of -2.3 and -2.2 standard deviations from the mean for Brazilian healthy men and women, respectively. Postnatal growth impairment was higher in RAF1 mutation patients than in patients with SOS1 and PTPN11 mutations. BMI values in NS patients were lower in comparison with normal Brazilian population. BMI values were higher in patients with RAF1 mutations than in patients with other genotypes. Patients with mutations in PTPN11 and SOS1 genes were more likely to have pulmonary valve stenosis, whereas hypertrophic cardiomyopathy was more common in patients with mutations in the gene RAF1...

Growth impairment of primary chondrocyte cells by serum of rats with chronic renal failure

Insulin-like growth factor (IGF)/IGF binding protein (IGFBP) abnormalities may be important in the pathogenesis of growth failure in chronic renal failure (CRF). We induced experimental CRF by 5/6 nephrectomy in Sprague Dawley rats (100 g) and observed for 2 weeks comparing with sham-operated pair-fed control rats (Sham- C). CRF rats gained 30% less height than Sham- C rats (P10 kDa, containing IGFBPs) and low (<10 kDa, containing free IGF) molecular weight fractions using a gel filtration column. Both fractions obtained from CRF sera decreased the growth of control chondrocytes up to 40% compared with those from control sera. We suggest that the pathogenesis of growth failure in CRF may be involved in the increase of circulating IGFBP4 as well as the unidentified small molecular weight uremic serum factors which block the growth of chondrocytes in growth plate.

Insulin-like growth factors and their binding proteins in children with IDDM.

The structure of insulin-like growth factor (IGF), especially IGF-I, and its receptor is similar to that of insulin. Therefore, the changes of IGFs and IGF-binding proteins may be related to glucose homeostasis in children with insulin dependent diabetes mellitus (IDDM). Sixty-three fasting blood samples of 21 children with IDDM attending 3 consecutive diabetic clinics were studied. The HbA1c progressively decreased from the 1st to the 3rd visit. IGF-I levels, both total and free forms, were not significantly different from that of control. IGFBP-3 levels in 3 visits (3406+/-305, 3376+/-252, and 2406+/-247 ng/mL) were significantly lower than that of control (5020+/-415 ng/mL) with the p value of 0.007, 0.002, and < 0.001 respectively. IGFBP-1 levels in the 1st and 2nd visits (102.1+/-12.9 and 114.1+/-14.5 ng/mL) were significantly higher than that of control (60.1+/-15.2 ng/mL) with the p value of 0.03 and 0.01 respectively, but not in the 3rd visit. IGF-I level had a positive correlation with IGFBP-3 (R=0.56, p=0.01) and free IGF-I (R=0.53, p=0.01). Free IGF-I had a negative correlation with IGFBP-1 (R=-0.64, p=0.01). IGF-II at the 15 visit had a negative correlation with HbA1c (R=-0.49, p=0.047). The authors found no correlations between IGF-I, IGFBP-3, free IGF-I, IGFBP-1 and HbA1c in the study. The patients' height SDS followed the genetic height potential. It was, therefore, postulated that a near normal free IGF-I level in diabetic children resulted from a balance of interaction between IGFBP-1 and IGFBP-3 to total IGF-I in order to keep the normal metabolic status as much as possible.

Rol fisiológico del eje somatotrófico GH-IGF y otras hormonas en el crecimiento de los animales domésticos. Influencia del estado nutricional / Physiologic role of the somatotrophic GH-IGF and others hormones in the domestic animals growth. Influence of the nutritional status

En esta revisión se describen las principales hormonas invlolucradas en el desarrollo y crecimiento muscular, haciendo especial énfasis en la hormona de cricimiento (GH) y los factores del crecimiento semejante a insulina (IGF). Se recopila la composición química, el lugar de síntesis y los principales mecanismos de acción de estas hormonas. Se observó que la GH, IGF, las hormonas tiroideas, la insulina, los glucocorticoides y los esteroides sexuales actuán en una forma compleja y coordinada para producir una respuesta productiva a diferentes estrategias nutricionales.

Diagnostic value of insulin-like growth factor-I in short stature

For the present, to determine growth hormone(GH) deficiency in patients with short stature, many provocative tests using various pharmacological agents such as glucagon, insulin, clonidine, arginine, growth hormone releasing factor, etc. should be done. These are not only complicated but are also misleading in some patients. In search of a simple and accurate method of detecting GH deficiency that may replace the more complicated provocative tests, we measured basal plasma insulin-like growth factor-I (IGF-I) to see the correlation with the peak GH values in the GH stimulation test. But, in each group of patients with different types of short stature, IGF-I values were poorly correlated. In addition, IGF-I values of the patients with short stature compared to the age- and sex-matched normal ranges showed a significant overlap, and the difference between the proportion of patients with subnormal values in GH deficient patients and non-GH deficient patients was not prominent. Nevertheless, in response to human growth hormone (hGH) administration, both the yearly growth rate and IGF-I levels increased conspicuously. Therefore, even though it may not be feasible to use IGF-I as a single diagnostic measure of patients with short stature, the change in IGF-I values in the follow up of hGH therapy may well represent the response to hGH.

Diagnostic value of insulin-like growth factor-I in short stature

For the present, to determine growth hormone(GH) deficiency in patients with short stature, many provocative tests using various pharmacological agents such as glucagon, insulin, clonidine, arginine, growth hormone releasing factor, etc. should be done. These are not only complicated but are also misleading in some patients. In search of a simple and accurate method of detecting GH deficiency that may replace the more complicated provocative tests, we measured basal plasma insulin-like growth factor-I (IGF-I) to see the correlation with the peak GH values in the GH stimulation test. But, in each group of patients with different types of short stature, IGF-I values were poorly correlated. In addition, IGF-I values of the patients with short stature compared to the age- and sex-matched normal ranges showed a significant overlap, and the difference between the proportion of patients with subnormal values in GH deficient patients and non-GH deficient patients was not prominent. Nevertheless, in response to human growth hormone (hGH) administration, both the yearly growth rate and IGF-I levels increased conspicuously. Therefore, even though it may not be feasible to use IGF-I as a single diagnostic measure of patients with short stature, the change in IGF-I values in the follow up of hGH therapy may well represent the response to hGH.