Novel SUZ12 mutations in Weaver‐like syndrome

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/146320/1/cge13415_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146320/2/cge13415-sup-0001-AppendixS1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/146320/3/cge13415.pd

Short children born small for gestational age: hormonal regulation of growth

It is generally recognized that children born small for gestational age (SGA) have a higher risk of short stature than children born at normal size. It has been suggested that the programming of the endocrine axes occurs during critical phases of fetal development and is affected by intrauterine growth retardation. The main objectives of this thesis were to study the hormonal regulation of growth in prepubertal children born SGA who did not show complete postnatal catch-up growth and to evaluate the efficacy and tolerability of growth hormone (GH) treatment.The study group included 177 children with a birth weight and/or birth length below -2 standard deviation score (SDS) compared with Swedish reference values corrected for gestational age. All of the children were still short at/or after 2 years of age, and were prepubertal and short at the time of the investigation. Fourteen children with dysmorphic features of Silver-Russell syndrome were included in the study group. Prepubertal healthy children born appropriate for gestational age (AGA) of both short or normal stature were used as reference groups.The mean estimated GH secretion rate was lower in the children born SGA compared with the reference groups born AGA, of either short or normal stature. Moreover, in the youngest children born SGA (2-6 years of age) a different pattern of GH secretion was found, with a high basal GH level, low peak amplitude, and high peak frequency. The majority of the children born SGA had pretreatment levels of GH-binding protein (GHBP) within the range previously reported for normal children. However, levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3) and leptin were significantly reduced compared with the reference values. In contrast, cortisol and insulin levels were not different to those in normal children born AGA of either normal or short stature.GH treatment for at least 2 years revealed a dose-dependent increase in the growth rate; mean height was normalized within 3 years of GH treatment. GH treatment was well tolerated and no side effects were observed. Up to 76% of the variability of the growth response could be explained by different prediction models: the best predictors were the dose of GH, the spontaneous GH secretion rate, chronological age at the start of treatment, maternal height SDS, basal leptin levels, and the short-term changes in the ratio of IGF-I/IGFBP-3 during treatment, in this order of importance. Mean GHBP levels increased by 27% after 1 year of therapy, despite the high degree of variability in the individual GHBP response to treatment. IGF-I levels increased significantly during the first year of treatment, whereas IGFBP-3 levels increased mainly during the first 10 days of therapy. A dose-dependent increase in insulin levels was observed after 2 years of treatment without negative consequences on glucose or glycosylated haemoglobin. In contrast, leptin levels decreased during the GH treatment period. In conclusion, the low spontaneous GH secretion rate and a disturbed GH secretion pattern, together with low serum levels of IGF-I, IGFBP-3 and leptin, might contribute to the reduced postnatal growth in the subgroup of children born SGA who remain short during childhood. These children may benefit from GH treatment. Finally, fasting insulin concentrations and cortisol levels were normal in short children born SGA.Key words: small for gestational age, intrauterine growth retardation, short stature, growth hormone, growth hormone-binding protein, insulin-like growth factor-I, insulin-like growth factor-binding protein-3, leptin, cortisol, insulin

Postnatal management of growth failure in children born small for gestational age

Objectives: To discuss the etiology and growth consequences of small size at birth and the indications, effects, and safety of biosynthetic growth hormone therapy in children born small for gestational age. Source of data: A comprehensive and non‐systematic search was carried out in the PubMed, LILACS, and SciELO databases from 1980 to the present day, using the terms “small for gestational age,” “intrauterine growth restriction,” and “growth hormone”. The publications were critically selected by the authors. Data synthesis: Although the majority of children born small for gestational age show spontaneous catch‐up growth during the first two years of life, some of them remain with short stature during childhood, with high risk of short stature in adult life. Treatment with growth hormone might be indicated, preferably after 2–4 years of age, in those small for gestational age children who remain short, without catch‐up growth. Treatment aims to increase growth velocity and to reach a normal height during childhood and an adult height within target height. Response to growth hormone treatment is variable, with better growth response during the pre‐pubertal period. Conclusions: Treatment with growth hormone in short children born small for gestational age is safe and effective to improve adult height. Efforts should be done to identify the etiology of small size at birth before treatment. Resumo: Objetivos: Discutir a etiologia e as consequências para o crescimento e as indicações, os efeitos e a segurança da terapia com hormônio de crescimento biossintético em crianças pequenas para idade gestacional. Fonte dos dados: Uma busca abrangente e não sistemática foi feita nas bases de dados PubMed, LILACS e SciELO de 1980 até a presente data, com os termos “small for gestational age” (pequeno para a idade gestacional), “intrauterine growth restriction” (restrição de crescimento intrauterino) e “growth hormone” (hormônio do crescimento). As publicações foram selecionadas criticamente pelos autores. Síntese dos dados: Embora a maioria das crianças nascidas pequenas para idade gestacional apresente recuperação espontânea do crescimento durante os dois primeiros anos de vida, algumas delas permanecem com baixa estatura durante a infância, com alto risco de baixa estatura na vida adulta. O tratamento com hormônio de crescimento pode ser indicado, preferencialmente após os dois aos quatro anos, naquelas crianças sem recuperação espontânea do crescimento e com baixa estatura. Seus objetivos são aumentar a velocidade de crescimento e atingir uma altura normal durante a infância e uma altura adulta dentro da altura‐alvo. A resposta ao tratamento com hormônio de crescimento é variável, com melhor resultado se iniciado durante o período pré‐puberal. Conclusões: O tratamento com hormônio de crescimento em crianças baixas nascidas pequenas para idade gestacional é seguro e eficaz para melhorar a estatura adulta. Esforços devem ser feitos para identificar a etiologia do nascimento pequenas para idade gestacional antes do tratamento. Keywords: Small for gestational age, Catch‐up, Growth hormone, Short stature, Adult height, Palavras‐chave: Pequeno para a idade gestacional, Catch‐up, Hormônio de crescimento, Baixa estatura, Estatura adult

Postnatal management of growth failure in children born small for gestational age

Objectives: To discuss the etiology and growth consequences of small size at birth and the indications, effects, and safety of biosynthetic growth hormone therapy in children born small for gestational age. Source of data: A comprehensive and non-systematic search was carried out in the PubMed, LILACS, and SciELO databases from 1980 to the present day, using the terms “small for gestational age,” “intrauterine growth restriction,” and “growth hormone”. The publications were critically selected by the authors. Data synthesis: Although the majority of children born small for gestational age show spontaneous catch-up growth during the first two years of life, some of them remain with short stature during childhood, with high risk of short stature in adult life. Treatment with growth hormone might be indicated, preferably after 2–4 years of age, in those small for gestational age children who remain short, without catch-up growth. Treatment aims to increase growth velocity and to reach a normal height during childhood and an adult height within target height. Response to growth hormone treatment is variable, with better growth response during the pre-pubertal period. Conclusions: Treatment with growth hormone in short children born small for gestational age is safe and effective to improve adult height. Efforts should be done to identify the etiology of small size at birth before treatment. Resumo: Objetivos: Discutir a etiologia e as consequências para o crescimento e as indicações, os efeitos e segurança da terapia com hormônio de crescimento biossintético em crianças pequenas para idade gestacional. Fonte dos dados: Uma busca abrangente e não sistemática foi feita nas bases de dados PubMed, LILACS e SciELO de 1980 até a presente data, com os termos “small for gestational age” (pequeno para a idade gestacional), “intrauterine growth restriction” (restrição de crescimento intrauterino) e “growth hormone” (hormônio do crescimento). As publicações foram selecionadas criticamente pelos autores. Síntese dos dados: Embora a maioria das crianças nascidas pequenas para idade gestacional apresente recuperação espontânea do crescimento durante os dois primeiros anos de vida, algumas delas permanecem com baixa estatura durante a infância, com alto risco de baixa estatura na vida adulta. O tratamento com hormônio de crescimento pode ser indicado, preferencialmente após os dois aos quatro anos, naquelas crianças sem recuperação espontânea do crescimento e com baixa estatura. Seus objetivos são aumentar a velocidade de crescimento e atingir uma altura normal durante a infância e uma altura adulta dentro da altura-alvo. A resposta ao tratamento com hormônio de crescimento é variável, com melhor resultado se iniciado durante o período pré-puberal. Conclusões: O tratamento com hormônio de crescimento em crianças baixas nascidas pequenas para idade gestacional é seguro e eficaz para melhorar a estatura adulta. Esforços devem ser feitos para identificar a etiologia do nascimento pequenas para idade gestacional antes do tratamento. Keywords: Small for gestational age, Catch-up, Growth hormone, Short stature, Adult height, Palavras-chave: Pequeno para a idade gestacional, Catch-up, Hormônio de crescimento, Baixa estatura, Estatura adult