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1.
Neuroendocrinology ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31671431

RESUMO

INTRODUCTION: Loss-of-function mutation of MKRN3 represents the most frequent genetic cause of familial central precocious puberty (CPP). The outcomes of gonadotropin-releasing hormone analog (GnRHa) treatment in CPP patients with MKRN3 defects are unknown. OBJECTIVE: To describe the clinical and hormonal features of patients with CPP with or without MKRN3 mutations after GnRHa treatment. Anthropometric, metabolic and reproductive parameters were evaluated. PATIENTS AND METHODS: Twenty-nine female patients with CPP due to loss-of-function mutations in the MKRN3 and 43 female patients with idiopathic CPP were included. Their medical records were retrospectively evaluated for clinical, laboratory, and imaging study, before, during, and after GnRHa treatment. All patients with idiopathic CPP and 11 patients with CPP due to MKRN3 defects reached final height (FH). RESULTS: At the diagnosis, there were no significant differences between clinical and laboratory features of patients with CPP with or without MKRN3 mutations. A high prevalence of overweight and obesity was observed in patients with CPP with or without MKRN3 mutations (47.3% and 50%, respectively), followed by a significant reduction after GnRHa treatment. No significant differences in the values of mean FH and target height were found between the two CPP groups after GnRHa treatment. Menarche occurred at the expected age in patients with or without CPP due to MKRN3 mutations (11.5 ± 1.3 yr and 12 ± 0.6 yr, respectively). The prevalence of polycystic ovarian syndrome was 9.1% in patients with CPP due to MKRN3 mutations and 5.9% in those with idiopathic CPP. CONCLUSION: Anthropometric, metabolic and reproductive outcomes after GnRHa treatment were comparable in CPP patients, with or without MKRN3 mutations, suggesting the absence of deleterious effects of MKRN3 defects in young female adults' life.

2.
Arch Endocrinol Metab ; 63(4): 438-444, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31460623

RESUMO

Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44.


Assuntos
Puberdade Precoce/genética , Proteínas de Ligação ao Cálcio , Inativação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Kisspeptinas/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Metilação , Mutação , Fenótipo , Puberdade Precoce/etiologia , Receptores de Kisspeptina-1/genética , Ribonucleoproteínas/genética
3.
Arch. endocrinol. metab. (Online) ; 63(4): 438-444, July-Aug. 2019. tab, graf
Artigo em Inglês | LILACS-Express | ID: biblio-1019366

RESUMO

ABSTRACT Pubertal timing in humans is determined by complex interactions including hormonal, metabolic, environmental, ethnic, and genetic factors. Central precocious puberty (CPP) is defined as the premature reactivation of the hypothalamic-pituitary-gonadal axis, starting before the ages of 8 and 9 years in girls and boys, respectively; familial CPP is defined by the occurrence of CPP in two or more family members. Pioneering studies have evidenced the participation of genetic factors in pubertal timing, mainly identifying genetic causes of CPP in sporadic and familial cases. In this context, rare activating mutations were identified in genes of the kisspeptin excitatory pathway (KISS1R and KISS1 mutations). More recently, loss-of-function mutations in two imprinted genes (MKRN3 and DLK1) have been identified as important causes of familial CPP, describing novel players in the modulation of the hypothalamic-pituitary-gonadal axis in physiological and pathological conditions. MKRN3 mutations are the most common cause of familial CPP, and patients with MKRN3 mutations present clinical features indistinguishable from idiopathic CPP. Meanwhile, adult patients with DLK1 mutations present high frequency of metabolic alterations (overweight/obesity, early onset type 2 diabetes and hyperlipidemia), indicating that DLK1 may be a novel link between reproduction and metabolism. Arch Endocrinol Metab. 2019;63(4):438-44

4.
J Clin Endocrinol Metab ; 104(6): 2112-2120, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30462238

RESUMO

BACKGROUND: Delta-like homolog 1 (DLK1), also called preadipocyte factor 1, prevents adipocyte differentiation and has been considered a molecular gatekeeper of adipogenesis. A DLK1 complex genomic defect was identified in five women from a single family with central precocious puberty (CPP) and increased body fat percentage. METHODS: We studied 60 female patients with a diagnosis of CPP or history of precocious menarche. Thirty-one of them reported a family history of precocious puberty. DLK1 DNA sequencing was performed in all patients. Serum DLK1 concentrations were measured using an ELISA assay in selected cases. Metabolic and reproductive profiles of adult women with CPP caused by DLK1 defects were compared with those of 20 women with idiopathic CPP. RESULTS: We identified three frameshift mutations of DLK1 (p.Gly199Alafs*11, p.Val271Cysfs*14, and p.Pro160Leufs*50) in five women from three families with CPP. Segregation analysis was consistent with the maternal imprinting of DLK1. Serum DLK1 concentrations were undetectable in three affected women. Metabolic abnormalities, such as overweight/obesity, early-onset glucose intolerance/type 2 diabetes mellitus, and hyperlipidemia, were more prevalent in women with the DLK1 mutation than in the idiopathic CPP group. Notably, the human metabolic alterations were similar to the previously described dlk1-null mice phenotype. Two sisters who carried the p.Gly199Alafs*11 mutation also exhibited polycystic ovary syndrome and infertility. CONCLUSIONS: Loss-of-function mutations of DLK1 are a definitive cause of familial CPP. The high prevalence of metabolic alterations in adult women who experienced CPP due to DLK1 defects suggests that this antiadipogenic factor represents a link between reproduction and metabolism.

5.
Clin Epigenetics ; 10(1): 146, 2018 11 22.
Artigo em Inglês | MEDLINE | ID: mdl-30466473

RESUMO

BACKGROUND: Recent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal. RESULTS: Analyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP. CONCLUSION: Methylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty.


Assuntos
Metilação de DNA , Proteínas de Ligação a DNA/genética , Estudo de Associação Genômica Ampla/métodos , Puberdade Precoce/genética , Fatores de Transcrição/genética , Animais , Estudos de Casos e Controles , Criança , Epigênese Genética , Feminino , Impressão Genômica , Humanos , Macaca mulatta , Linhagem , Regiões Promotoras Genéticas , Dedos de Zinco
6.
J Clin Endocrinol Metab ; 103(7): 2436-2446, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29659920

RESUMO

Context: Silver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap. Objective: To describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS. Patients: We retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis. Results: Seventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation. Conclusions: Most patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 14/genética , Síndrome de Silver-Russell/genética , Adolescente , Adulto , Proteínas de Ligação ao Cálcio , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Metilação de DNA/genética , Diagnóstico Diferencial , Feminino , Impressão Genômica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Proteínas de Membrana/genética , Fenótipo , Puberdade Precoce/genética , RNA Longo não Codificante/genética , Estudos Retrospectivos , Síndrome de Silver-Russell/diagnóstico , Síndrome , Dissomia Uniparental , Adulto Jovem
7.
Nutr Metab (Lond) ; 15: 18, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29467800

RESUMO

Background: The resting metabolic rate (RMR) decrease, observed after an obesity reduction therapy is a determinant of a short-time weight regain. Thus, the objective of this study was to evaluate changes in RMR, and the associated hormonal alterations in obese patients with a very low-calorie ketogenic (VLCK)-diet induced severe body weight (BW) loss. Method: From 20 obese patients who lost 20.2 kg of BW after a 4-months VLCK-diet, blood samples and body composition analysis, determined by DXA and MF-Bioimpedance, and RMR by indirect calorimetry, were obtained on four subsequent visits: visit C-1, basal, initial fat mass (FM) and free fat mass (FFM); visit C-2, - 7.2 kg in FM, - 4.3 kg in FFM, maximal ketosis; visit C-3, - 14.4 kg FM, - 4.5 kg FFM, low ketosis; visit C-4, - 16.5 kg FM, - 3.8 kg FFM, no ketosis. Each subject acted as his own control. Results: Despite the large BW reduction, measured RMR varied from basal visit C-1 to visit C-2, - 1.0%; visit C-3, - 2.4% and visit C-4, - 8.0%, without statistical significance. No metabolic adaptation was observed. The absent reduction in RMR was not due to increased sympathetic tone, as thyroid hormones, catecholamines, and leptin were reduced at any visit from baseline. Under regression analysis FFM, adjusted by levels of ketonic bodies, was the only predictor of the RMR changes (R2 = 0.36; p < 0.001). Conclusion: The rapid and sustained weight and FM loss induced by VLCK-diet in obese subjects did not induce the expected reduction in RMR, probably due to the preservation of lean mass. Trial registration: This is a follow up study on a published clinical trial.

8.
Clin Endocrinol (Oxf) ; 88(3): 425-431, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29265571

RESUMO

OBJECTIVES: The aetiology of congenital hypopituitarism (CH) is unknown in most patients. Rare copy number variants (CNVs) have been implicated as the cause of genetic syndromes with previously unknown aetiology. Our aim was to study the presence of CNVs and their pathogenicity in patients with idiopathic CH associated with complex phenotypes. DESIGN AND PATIENTS: We selected 39 patients with syndromic CH for array-based comparative genomic hybridization (aCGH). Patients with pathogenic CNVs were also evaluated by whole exome sequencing. RESULTS: Twenty rare CNVs were detected in 19 patients. Among the identified rare CNVs, six were classified as benign, eleven as variants of uncertain clinical significance (VUS) and four as pathogenic. The three patients with pathogenic CNVs had combined pituitary hormone deficiencies, and the associated complex phenotypes were intellectual disabilities: trichorhinophalangeal type I syndrome (TRPS1) and developmental delay/intellectual disability with cardiac malformation, respectively. Patient one has a de novo 1.6-Mb deletion located at chromosome 3q13.31q13.32, which overlaps with the region of the 3q13.31 deletion syndrome. Patient two has a 10.5-Mb de novo deletion at 8q23.1q24.11, encompassing the TRPS1 gene; his phenotype is compatible with TRPS1. Patient three carries a chromosome translocation t(2p24.3;4q35.1) resulting in two terminal alterations: a 2p25.3p24.3 duplication of 14.7 Mb and a 4-Mb deletion at 4q35.1q35.2. CONCLUSIONS: Copy number variants explained the phenotype in 8% of patients with hypopituitarism and additional complex phenotypes. This suggests that chromosomal alterations are an important contributor to syndromic hypopituitarism.


Assuntos
Variações do Número de Cópias de DNA , Hipopituitarismo/congênito , Hipopituitarismo/etiologia , Fenótipo , Aberrações Cromossômicas , Hibridização Genômica Comparativa , Hormônio do Crescimento Humano/deficiência , Humanos , Hipopituitarismo/genética , Deficiência Intelectual , Sequenciamento Completo do Exoma
9.
Horm Res Paediatr ; 89(1): 13-21, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29130988

RESUMO

BACKGROUND/AIMS: Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause. METHODS: We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array-based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature. RESULTS: We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause. CONCLUSION: CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause.


Assuntos
Cromossomos Humanos/genética , Deficiências do Desenvolvimento/genética , Nanismo/genética , Polimorfismo de Nucleotídeo Único , Pré-Escolar , Feminino , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos
10.
Nutr Hosp ; 34(1): 15-18, 2017 02 01.
Artigo em Espanhol | MEDLINE | ID: mdl-28244767

RESUMO

Objective: To present the results of the Spanish home enteral nutrition (HEN) registry of the NADYA-SENPE group for the years 2014 and 2015. Methods: From January 1st 2014 to December 31st 2015 the HEN registry was recorded and afterwards a further descriptive and analytical analysis was done. Results: In 2014, 3749 patients were recorded, and 4202 in 2015; prevalence was 80.58 patients/one million inhabitants in Spain in 2014 and 90.51 in 2015. There were 49.9% females in 2014 and 50.3% in 2015. Median age was 73 years (IQI 59-83) in 2014 as well as in 2015. 684 episodes finished in 2014 and 631 in 2015, with death as the main cause, in 54.9% and 50.4%, respectively. The ones who were fed through nasogastric tube had a mean age higher than the ones fed by any other route (p-value < 0.001). Sisty-seven paediatric patients were recorded in 2014 (56.7% females) and 77 in 2015 (55.8% females). Median age at the beginning of HEN among children was 5 months in 2014 and 5 months in 2015. The main route of administration was gastrostomy, in 52.5% in 2014 and nasogastric tube in 50.8% in 2015. 7 episodes finished in 2014 and 13 in 2015, having death as the main cause (57.1% in 2014 and 38.5% in 2015). It was found that were younger children the ones who were mainly fed by nasogastric tubes (p-value 0.004 vs. 0.002). Among paediatric patients as well as adults, the main diagnosis leading to HEN was neurological disease which gives aphagia or severe dysphagia. Conclusions: There has been an increase in the number of patients in the registry as well as the participating centers and the number of patients per center, without any significant change in the characteristics of the patients other than longer duration of the episodes.


Assuntos
Nutrição Parenteral no Domicílio/estatística & dados numéricos , Sistema de Registros , Adolescente , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Intubação Gastrointestinal/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Espanha , Adulto Jovem
11.
Nutr. hosp ; 34(1): 15-18, ene.-feb. 2017.
Artigo em Espanhol | IBECS | ID: ibc-161136

RESUMO

Objetivo: exponer los resultados del registro de nutrición enteral domiciliaria (NED) del año 2014 y 2015 del Grupo NADYA-SENPE. Métodos: se recopilaron los pacientes introducidos en el registro desde el 1 de enero al 31 de diciembre de 2014 y la mismas fechas de 2015, y se procedió al análisis descriptivo y analítico de los datos. Resultados: en el año 2014, se registraron 3.749 pacientes y en 2015, 4.202; la prevalencia fue de 80,58 pacientes/millón de habitantes en el año 2014 y de 90,51 en 2015. Por sexos, hubo un 49,9% de mujeres en 2014 y un 50,3% en 2015. La edad media fue de 73 años (IIQ 59-83) en ambos años. Finalizaron 684 episodios de NED en 2014 y 631 en 2015, la causa principal fue el fallecimiento en el 54,9% y 50,4% de los casos, respectivamente. Los portadores de sonda nasogástrica presentan una edad media superior a los pacientes con cualquier otra vía (p < 0,001). Se registraron 67 pacientes pediátricos en 2014 (56,7% niñas) y 77 en 2015 (55,8% niñas). La vía principal de administración fue la gastrostomía en el 52,0% de los casos de 2014 y sonda nasogástrica en el 50,8% de los casos de 2015. La causa principal de finalización de la nutrición fue el fallecimiento (57,1% en 2014 y 38,5% en 2015). Se observó que los niños más pequeños eran los que se alimentaban preferentemente por SNG (p 0,004 vs. 0,002).Tanto en pacientes pediátricos como en adultos el diagnóstico principal que motivó la necesidad de NED fue la enfermedad neurológica que cursa con afagia o disfagia severa. Conclusiones: se ha incrementado el número de pacientes del registro, así como el número de centros participantes y el número medio de pacientes comunicados por cada centro respecto a años anteriores, sin que se hayan modificado sustancialmente las características de los pacientes, salvo mayor duración de los episodios (AU)


Objective: To present the results of the Spanish home enteral nutrition (HEN) registry of the NADYA-SENPE group for the years 2014 and 2015. Methods: From January 1st 2014 to December 31st 2015 the HEN registry was recorded and afterwards a further descriptive and analytical analysis was done. Results: In 2014, 3749 patients were recorded, and 4202 in 2015; prevalence was 80.58 patients/one million inhabitants in Spain in 2014 and 90.51 in 2015. There were 49.9% females in 2014 and 50.3% in 2015. Median age was 73 years (IQI 59-83) in 2014 as well as in 2015. 684 episodes finished in 2014 and 631 in 2015, with death as the main cause, in 54.9% and 50.4%, respectively. The ones who were fed through nasogastric tube had a mean age higher than the ones fed by any other route (p-value < 0.001). Sixty-seven paediatric patients were recorded in 2014 (56.7% females) and 77 in 2015 (55.8% females). Median age at the beginning of HEN among children was 5 months in 2014 and 5 months in 2015. The main route of administration was gastrostomy, in 52.5% in 2014 and nasogastric tube in 50.8% in 2015. 7 episodes finished in 2014 and 13 in 2015, having death as the main cause (57.1% in 2014 and 38.5% in 2015). It was found that were younger children the ones who were mainly fed by nasogastric tubes (p-value 0.004 vs. 0.002). Among paediatric patients as well as adults, the main diagnosis leading to HEN was neurological disease which gives aphagia or severe dysphagia. Conclusions: There has been an increase in the number of patients in the registry as well as the participating centers and the number of patients per center, without any significant change in the characteristics of the patients other than longer duration of the episodes (AU)


Assuntos
Humanos , Nutrição Enteral/estatística & dados numéricos , Intubação Gastrointestinal/estatística & dados numéricos , Gastrostomia/estatística & dados numéricos , Transtornos de Deglutição/terapia , Registros de Doenças/estatística & dados numéricos , Serviços Hospitalares de Assistência Domiciliar/estatística & dados numéricos , Distribuição por Idade e Sexo
12.
Nat Rev Endocrinol ; 13(2): 105-124, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27585961

RESUMO

This Consensus Statement summarizes recommendations for clinical diagnosis, investigation and management of patients with Silver-Russell syndrome (SRS), an imprinting disorder that causes prenatal and postnatal growth retardation. Considerable overlap exists between the care of individuals born small for gestational age and those with SRS. However, many specific management issues exist and evidence from controlled trials remains limited. SRS is primarily a clinical diagnosis; however, molecular testing enables confirmation of the clinical diagnosis and defines the subtype. A 'normal' result from a molecular test does not exclude the diagnosis of SRS. The management of children with SRS requires an experienced, multidisciplinary approach. Specific issues include growth failure, severe feeding difficulties, gastrointestinal problems, hypoglycaemia, body asymmetry, scoliosis, motor and speech delay and psychosocial challenges. An early emphasis on adequate nutritional status is important, with awareness that rapid postnatal weight gain might lead to subsequent increased risk of metabolic disorders. The benefits of treating patients with SRS with growth hormone include improved body composition, motor development and appetite, reduced risk of hypoglycaemia and increased height. Clinicians should be aware of possible premature adrenarche, fairly early and rapid central puberty and insulin resistance. Treatment with gonadotropin-releasing hormone analogues can delay progression of central puberty and preserve adult height potential. Long-term follow up is essential to determine the natural history and optimal management in adulthood.


Assuntos
Gerenciamento Clínico , Internacionalidade , Síndrome de Silver-Russell/diagnóstico , Síndrome de Silver-Russell/terapia , Hormônio Liberador de Gonadotropina/uso terapêutico , Hormônio do Crescimento Humano/uso terapêutico , Humanos , Síndrome de Silver-Russell/metabolismo
13.
Am J Med Genet A ; 170A(4): 1046-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26689153

RESUMO

The 9p trisomy syndrome is a rare condition, clinically characterized by a wide range of dysmorphic features, intellectual disability, and, in most patients, by short stature. Recombinant human growth hormone (rhGH) therapy is still controversial in syndromic disorders, the reason for which it is not currently indicated. Here we report a 7-year-old boy with 9p trisomy syndrome and marked short stature. Results of routine laboratory assessments were normal. IGF1 and IGFBP3 levels were both in the normal range (-1.6 and -0.7 SDS, respectively). GH peak in response to oral clonidine stimulation test was 3.5 µg/L, which is considered a normal response. Chromosomal analysis revealed the karyotype 47,XY, + del(9)(pter-q11:) dn. SNP array data indicated absence of mosaicism [arr 9p24.3-p13.1 (203,861-38,787,480) x3]. By the age of 8.3 years, the patient had persistent short stature (-2.9 SDS) with normal growth velocity (4.9 cm/y; -0.7 SDS), not showing spontaneous catch-up. After 5.6 years of rhGH therapy (50 µg/kg/d), height SDS improved from -2.9 to -1.0. This result suggests that rhGH therapy could be considered for patients with 9p trisomy syndrome who present with short stature. The degree of intellectual disability and the potential for social inclusion should be taken into account when recommending this treatment. Additional studies are needed to establish the benefits of height gain in these patients.


Assuntos
Transtornos Cromossômicos/tratamento farmacológico , Transtornos Cromossômicos/genética , Hormônio do Crescimento Humano/uso terapêutico , Proteínas Recombinantes/uso terapêutico , Trissomia , Criança , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 9 , Nanismo/tratamento farmacológico , Nanismo/genética , Facies , Gráficos de Crescimento , Humanos , Cariotipagem , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único , Resultado do Tratamento , Trissomia/diagnóstico
14.
São Paulo; s.n; 2015. [129] p. ilus, graf, tab.
Tese em Português | LILACS | ID: biblio-870752

RESUMO

A pesquisa de variações no número de cópias (CNVs; copy number variants) cromossômicas tem revelado o importante papel destas alterações genômicas na diversidade populacional e na etiologia de doenças humanas. O modelo de associação de CNVs a doenças envolve deleções e/ou duplicações individualmente raras, mas com segmentos cromossômicos de tamanhos relevantes. Os pacientes com baixa estatura de início pré-natal constituem um grupo heterogêneo com quadros clínicos complexos frequentemente resultantes de alterações genéticas, que, desde o período intrauterino, perturbam os mecanismos e vias de desenvolvimento e crescimento fetais. Assim sendo, aventamos a hipótese de que CNVs raras possam estar entre as causas genéticas de baixa estatura de início prénatal. Para tanto, nosso estudo visou avaliar a presença de deleções ou duplicações submicroscópicas em um grupo selecionado de pacientes nascidos pequenos para idade gestacional (PIG) com baixa estatura persistente sem causa definida. Foram avaliados 51 pacientes nascidos PIG com baixa estatura persistente após o 4º ano de vida que apresentavam dismorfismos, atraso de desenvolvimento neuropsicomotor (DNPM) ou deficiência intelectual, porém sem caracterizar síndromes conhecidas e com cariótipo normal. Amostras de DNA dos pacientes foram submetidas à hibridização genômica comparativa por microarray (aCGH; array comparative genomic hybridization) baseada em oligonucleotídeos na plataforma 60K. Os achados foram comparados com CNVs descritas em bancos de dados de controles normais. Foram identificadas 18 CNVs, ausentes em controles saudáveis, em 17 dos 51 pacientes (33%). As alterações foram avaliadas para classificação de sua patogenicidade de acordo com os seguintes critérios: 1) padrão de herança e segregação familiar; 2) sobreposição a coordenadas genômicas de síndromes conhecidas; 3) sobreposição a CNVs patogênicas descritas em banco de dados; 4) e conteúdo gênico. Quatro CNVs, encontradas em 3 pacientes, foram...


Analysis of chromosomic copy number variants (CNVs) have demonstrated the important role of these genomic imbalances in population diversity and human disease. The model of CNV disease association involves deletions and/or duplications that are individually rare but encompass chromosomal segments of relevant size. Prenatal onset short stature patients constitute a complex group characterized by clinical heterogeneity. The causes of prenatal growth impairment frequently involve genetic changes that disturb the mechanisms and the pathways of fetal growth and development. Thus, we hipothesized that rare CNVs might contribute to the genetic etiology of prenatal onset short stature. In order to evaluate this assumption, our study analyzed the presence of submicroscopic deletions and/or duplications in a selected group of patients born small for gestational age with persistent short stature but without a recognized cause. A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features, developmental delay and/or intellectual disability, but without criteria for known syndromes, were selected. All patients had normal G-banded karyotyping. Array-based comparative genomic hybridization (aCGH) in a whole-genome 60K platform was performed using DNA obtained from all patients. Detected CNVs were compared with CNV data from healthy controls individuals, excluding common copy number polymorphisms. In 17 of the 51 patients screened (33%), 18 rare CNVs were identified. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance and familial segregation; overlap with genomic coordinates for a known genomic imbalance syndrome; overlap with CNVs previously identified in other patients with prenatal onset short stature; and gene content. Four distinct CNVs, found in three patients, were classified as pathogenic: 1) del 22q11.21; 2) dup 10q26.2-26.3 and del 10q26.3; and 3) del 4q28.2-q31.21. Five CNVs, found...


Assuntos
Humanos , Masculino , Feminino , Deleção Cromossômica , Duplicação Cromossômica , Hibridização Genômica Comparativa , Retardo do Crescimento Fetal/genética , Transtornos do Crescimento/diagnóstico , Transtornos do Crescimento/genética
15.
Eur J Endocrinol ; 171(2): 253-62, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24878679

RESUMO

BACKGROUND: The etiology of prenatal-onset short stature with postnatal persistence is heterogeneous. Submicroscopic chromosomal imbalances, known as copy number variants (CNVs), may play a role in growth disorders. OBJECTIVE: To analyze the CNVs present in a group of patients born small for gestational age (SGA) without a known cause. PATIENTS AND METHODS: A total of 51 patients with prenatal and postnatal growth retardation associated with dysmorphic features and/or developmental delay, but without criteria for the diagnosis of known syndromes, were selected. Array-based comparative genomic hybridization was performed using DNA obtained from all patients. The pathogenicity of CNVs was assessed by considering the following criteria: inheritance; gene content; overlap with genomic coordinates for a known genomic imbalance syndrome; and overlap with CNVs previously identified in other patients with prenatal-onset short stature. RESULTS: In 17 of the 51 patients, 18 CNVs were identified. None of these imbalances has been reported in healthy individuals. Nine CNVs, found in eight patients (16%), were categorized as pathogenic or probably pathogenic. Deletions found in three patients overlapped with known microdeletion syndromes (4q, 10q26, and 22q11.2). These imbalances are de novo, gene rich and affect several candidate genes or genomic regions that may be involved in the mechanisms of growth regulation. CONCLUSION: Pathogenic CNVs in the selected patients born SGA were common (at least 16%), showing that rare CNVs are probably among the genetic causes of short stature in SGA patients and revealing genomic regions possibly implicated in this condition.


Assuntos
Variações do Número de Cópias de DNA/genética , Transtornos do Crescimento/genética , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Peso ao Nascer , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/genética , Feminino , Deleção de Genes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Anotação de Sequência Molecular
16.
Arq. bras. endocrinol. metab ; 55(8): 541-549, nov. 2011. ilus, tab
Artigo em Português | LILACS | ID: lil-610454

RESUMO

Aproximadamente 10 por cento das crianças nascidas pequenas para a idade gestacional (PIGs) não apresentam recuperação espontânea do crescimento. As causas desse déficit de crescimento pré-natal e sua manutenção após o nascimento ainda não são completamente conhecidas na maioria dos casos. Nos últimos oito anos, diversas mutações inativadoras e deleções do gene IGF1R em heterozigose foram relatadas, indicando o papel de defeitos no eixo IGFs/IGF1R como causa do déficit de crescimento. Postula-se que pelo menos 2,5 por cento das crianças nascidas PIGs possam apresentar defeitos no gene IGF1R. O quadro clínico desses pacientes apresenta grande variabilidade quanto à gravidade do retardo de crescimento e aos parâmetros hormonais. Nos casos mais evidentes, os pacientes apresentam microcefalia, déficit cognitivo leve e valores elevados de IGF-1, associados à baixa estatura de início pré-natal. Esta revisão abordará os aspectos clínicos, moleculares e do tratamento da baixa estatura com hrGH de crianças com mutações no IGF1R.


Approximately 10 percent of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5 percent of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.


Assuntos
Humanos , Recém-Nascido , Retardo do Crescimento Fetal/genética , Mutação/genética , Receptor IGF Tipo 1/genética , Retardo do Crescimento Fetal/tratamento farmacológico , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento
17.
Arq Bras Endocrinol Metabol ; 55(8): 541-9, 2011 Nov.
Artigo em Português | MEDLINE | ID: mdl-22218435

RESUMO

Approximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene.


Assuntos
Retardo do Crescimento Fetal/genética , Mutação/genética , Receptor IGF Tipo 1/genética , Retardo do Crescimento Fetal/tratamento farmacológico , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento
18.
Endocrine ; 38(3): 391-6, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20972723

RESUMO

The prevalence of thyroid dysfunction varies in different populations. The aim of this cross-sectional study was to analyze the prevalence of undiagnosed thyroid dysfunction and thyroid antibodies and their relationship with urine iodine excretion in a representative sample of 1,124 (55.5% women; mean age: 44.8 ± 15.2 years) non-hospitalized Mediterranean adults, in Catalonia (Spain). Free thyroxine, thyroid-stimulating hormone, thyroperoxidase and thyroglobulin antibodies, and urine iodine were measured. Undiagnosed thyroid dysfunction was 5.3% (hypothyroidism 3.8%; 56.66% of these subjects were women). The total (diagnosed + undiagnosed) thyroid dysfunction was 8.9% (71.15% women). Thyroperoxidase antibodies were positive in 2.4% of men and 9.4% of women and thyroglobulin antibodies, in 1.3% of men and 3.8% of women. No differences were observed in urine iodine between groups with thyroid dysfunction and euthyroidism, or between subjects with positive or negative antibodies. In subjects over 60, undiagnosed thyroid dysfunction was 9.8% (hypothyroidism 6.9%, hyperthyroidism 3.3%; 36.36% women) and total thyroid dysfunction 13.61% (53.12% women). Women and men over 60 had similar thyroid dysfunction prevalence. Thus, aggressive case-finding should be recommended in both, over 60.


Assuntos
Anticorpos/sangue , Iodo/urina , Doenças da Glândula Tireoide/epidemiologia , Glândula Tireoide/imunologia , Adulto , Doenças Assintomáticas/epidemiologia , Diagnóstico Tardio/estatística & dados numéricos , Feminino , Humanos , Iodo/metabolismo , Masculino , Região do Mediterrâneo/epidemiologia , Pessoa de Meia-Idade , População , Prevalência , Espanha/epidemiologia , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/urina , Testes de Função Tireóidea
19.
Endocrine ; 35(3): 420-8, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19291424

RESUMO

Type A chronic atrophic gastritis (CAG) is increased in type 1 diabetic patients (DM1). To address this issue, we determined and analyzed the number of peripheral blood regulatory T cells (Tregs) in 15 DM1-CAG patients, 15 DM1 patients without associated autoantibodies (DM1) and 15 healthy controls by flow cytometry and compared gastric Tregs expression (CD4+Foxp3+/CD4+) in DM1-CAG patients with that observed in 10 control Helicobacter pylori CAG-infected biopsies. The percentage of peripheral Tregs was higher in DM1-CAG patients compared to DM1 and controls (CD4+Foxp3+: 7.67 +/- 1.91% vs. 5.38 +/- 1.57% and 5.65 +/- 1.76%, P < 0.001, respectively), with no differences between DM1 and controls. Gastric mucosal Tregs were higher in H. pylori CAG than in DM1-CAG patients (31.31 +/- 5.52% vs. 7.68 +/- 3.70%; P < 0.001). Data suggest that Tregs are stimulated in patients with more than one autoimmune disease (DM1 + CAG) in an ineffectual attempt to control autoimmune response and that the number of Tregs in gastric mucosa implicated in the chronification of gastritis differs according to the etiology.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/imunologia , Gastrite Atrófica/complicações , Linfócitos T Reguladores/patologia , Adulto , Idoso , Doenças Autoimunes/complicações , Doenças Autoimunes/imunologia , Doenças Autoimunes/patologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 1/patologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Gastrite Atrófica/imunologia , Gastrite Atrófica/metabolismo , Gastrite Atrófica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Best Pract Res Clin Gastroenterol ; 18(6): 1125-46, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15561643

RESUMO

At the beginning of the 21st Century, obesity has become the leading metabolic disease in the World. So much so, that the World Health Organisation refers to obesity as the global epidemic. In fact, obesity is a common disease affecting not only affluent societies but also developing countries. Currently 300 million people can be considered as obese and, due to the rising trend in obesity prevalence, this figure could double by year 2025 if no action is taken against this threat. In terms of health impairment, the importance of obesity lies in the fact that, besides being a disease in itself, it is a risk for many other diseases, mainly from the metabolic and cardiovascular area. Among these, type 2 diabetes, dyslipemia, hyperuricemia, arterial hypertension and cardiovascular disease are the most frequent. Also, respiratory diseases such as obesity hypoventilation syndrome and obstructive sleep apnoea syndrome are strongly associated with obesity.


Assuntos
Obesidade/complicações , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/etiologia , Doenças da Vesícula Biliar/etiologia , Humanos , Hiperlipidemias/etiologia , Hiperuricemia/etiologia , Hipoventilação/etiologia , Resistência à Insulina/fisiologia , Nefropatias/etiologia , Locomoção/fisiologia , Neoplasias/etiologia , Obesidade/diagnóstico , Obesidade/epidemiologia , Obesidade/fisiopatologia , Osteoartrite/etiologia , Apneia Obstrutiva do Sono/etiologia , Síndrome
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