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1.
BMC Public Health ; 19(1): 1627, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796007

RESUMO

BACKGROUND: Recommendations on preventive lipid screening among children and adolescents remain controversial. The aim of the study was to assess age and puberty-related changes in serum lipids, including total cholesterol (TC), and high-density (HDL-C) and non-high-density lipoprotein cholesterol (Non-HDL-C). METHODS: Using cross-sectional data from the National Health Interview and Examination Survey for Children and Adolescents in Germany (KiGGS 2003-2006; N = 13,676; 1-17 years), changes in distributions of serum lipids were visualized according to sex, age and maturation. Youth aged 10-17 years were classified as prepubescent, early/mid-puberty, and mature/advanced puberty. Multiple linear regressions were used to quantify the impact of pubertal stage on serum lipid levels, adjusted for potential confounding factors. RESULTS: Among children 1-9 years mean serum lipid measures increased with age, with higher mean TC and Non-HDL-C among girls than boys. Among children 10-17 years, advanced pubertal stage was independently related to lower lipid measures. Adjusted mean TC, HDL-C and Non-HDL-C was 19.4, 5.9 and 13.6 mg/dL lower among mature/advanced puberty compared to prepubescent boys and 11.0, 4.0 and 7.0 mg/dL lower in mature/advanced puberty compared to prepubescent girls. CONCLUSIONS: Lipid concentrations undergo considerable and sex-specific changes during physical growth and sexual maturation and significantly differ between pubertal stages. Screening recommendations need to consider the fluctuations of serum lipids during growth and sexual maturation.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31698478

RESUMO

OBJECTIVE: We investigated direct effects of a therapeutic growth hormone dose on lipolysis, glucose and amino acid metabolism. METHODS: This crossover microdialysis trial involved six healthy male volunteers receiving single subcutaneous injections of both growth hormone (0.035 mg/kg) and placebo (0.9% sodium chloride). The investigation comprised three test days with standard diet. The first day served for adaptation, the second and third one for determining study data during 9 night hours with or without growth hormone. Abdominal subcutaneous microdialysate and blood were continuously collected and forwarded to a separate room next door where hourly taken samples were centrifuged and frozen until analysed. RESULTS: Growth hormone achieved the peak serum level after 3 h followed by a plateau-like course for the next 6 h. Glycerol in microdialysate started to rise 2 h following growth hormone injection achieving significance compared to placebo after 9 h (P<0.05). Serum glycerol increased 4 h after growth hormone administration achieving significance after 6 h (P<0.05). Glucose and amino acid concentrations showed neither in microdialysate nor in serum significant differences between growth hormone and placebo. Serum values of insulin and C-peptide revealed no significant difference between growth hormone and placebo. SUMMARY AND CONCLUSION: As the result of a high single subcutaneous dose of GH, persistent lipolysis can be shown in continuously collected microdialysate and blood, but no indication for gluconeogenesis or protein anabolism.

3.
J Pediatr Endocrinol Metab ; 32(9): 969-977, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31323004

RESUMO

Background Prolactin-secreting pituitary adenomas in childhood and adolescence are rare. First-line therapy consists of dopamine agonists (DAs) like cabergoline. Experience in treating prolactinomas in paediatric and adolescent patients is limited. Methods This study was a retrospective analysis of clinical data, laboratory data, radiological findings and medical treatment of paediatric and adolescent patients with prolactinomas between 2009 and 2018. Results Our cohort of nine patients had a median age at diagnosis of 13 years (range 5-17). Main presenting symptoms were weight gain, disorders of the pituitary-gonadal axis and headache. Treatment with cabergoline resulted in a marked reduction in prolactin concentration in all nine patients. Tumour mass reduction was confirmed by magnetic resonance imaging (MRI) scan in seven patients. Noteworthy is that cabergoline therapy triggered frequent adverse effects in a total of eight patients - seven of whom suffered from mental disorders, five of whom had neurological symptoms and five of whom had gastrointestinal problems. The adverse effects occurred at a median dose of only 0.5 mg/week (range 0.25-2.0). Most symptoms were alleviated after the cabergoline dose was lowered. Therapy discontinuation was not necessary in any patient. Conclusions Cabergoline effectively lowers prolactin levels and may reduce tumour mass in paediatric and adolescent patients with prolactinomas. Potential adverse effects may include mental disorders and behavioural problems even at low cabergoline doses. Low starting doses and careful individual dose adjustments are required to enable therapy adherence.


Assuntos
Cabergolina/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Transtornos Mentais/epidemiologia , Neoplasias Hipofisárias/tratamento farmacológico , Prolactinoma/tratamento farmacológico , Adolescente , Cabergolina/efeitos adversos , Criança , Pré-Escolar , Agonistas de Dopamina/efeitos adversos , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Transtornos Mentais/induzido quimicamente , Neoplasias Hipofisárias/patologia , Prognóstico , Prolactinoma/patologia , Estudos Retrospectivos
4.
Pediatr Diabetes ; 20(5): 622-628, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30993848

RESUMO

BACKGROUND/OBJECTIVE: Microvascular alterations play a key role in the development of diabetes complications. Retinal vessel analysis is a unique method to examine microvascular changes in brain-derived vessels. METHODS: Sixty-seven pediatric and adolescent type 1 diabetes patients and 58 healthy control persons (mean age 12.4 ± 2.9 years) underwent non-mydriatic retinal photography of both eyes. Central retinal arteriolar and central retinal venular (CRVE) diameter equivalents as well as the arteriolar-to-venular ratio were calculated using a semiautomated software. All anthropometric and laboratory parameters were measured according to standardized procedures for children. RESULTS: Retinal vessel diameter did not differ between type 1 diabetic children and healthy controls. However, there was an independent association of higher hemoglobin A1c (HbA1c) levels with arteriolar narrowing. Arteriolar narrowing of 5.4 µm was observed with each percent increase in HbA1c. Longer duration of diabetes was associated with wider retinal arterioles. CRVE was not associated with diabetes duration or HbA1c. CONCLUSIONS: Microvascular arteriolar alterations are already present in childhood and may indicate subclinical atherosclerosis and increased risk of diabetes complications later in life. Future research will have to investigate the potential use of retinal vessel diameters for treatment monitoring and guidance of therapy in children.

5.
J Pediatr Endocrinol Metab ; 32(3): 287-294, 2019 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-30811345

RESUMO

Background During pubertal development in healthy boys, increased levels of different sex steroids occur which are responsible for sexual maturation and physical changes. However, relationships between various sex hormones and pubertal development stages have not been sufficiently studied. Methods The investigation included 165 normal boys (mean age 12.7±2.8 years, mean body mass index [BMI] 19.6±4.2 kg/m2). Pubic hair (PH) stages were stratified by Tanner and testicular volume (TV) by means of the Prader orchidometer and assigned to the prepubertal, pubertal and postpubertal development phase. Four different sex steroids (testosterone [TE], dehydroepiandrosterone [DHEA]/dehydroepiandrosterone-sulfate [DHEAS], androstenedione (AE), 17-hydroxyprogesterone [17-OHP]) were measured in saliva by enzyme-linked immunosorbent assay (ELISA) and as serum total steroids by different assays (radioimmunoassay [RIA], chemiluminescence immunoassay [CLIA], electrochemiluminescence immunoassay [ECLIA]). Validation of saliva-based ELISA tests included data related to inter- and intra-assay coefficients of variation (CVs), recovery and linearity. Results Using Spearman rank correlation, salivary steroids significantly correlated (p<0.001) with pubertal development: TE (TV r=0.74 and PH stages r=0.72), DHEA (r=0.58 and 0.62), AE (r=0.38 and 0.45) and 17-OHP (r=0.42 and 0.43). Correlations between salivary and serum concentrations of steroids were also statistically significant (p<0.001). Binomial logistic regression analysis revealed significant correlations between salivary TE and pubertal maturation during the development phases of prepuberty-puberty and puberty-postpuberty. Inclusion of further salivary steroids did not improve analysis results. Conclusions Salivary TE permits a good non-invasive characterization of pubertal maturation stages. The consideration of further salivary sex steroids did not improve diagnostic accuracy.


Assuntos
17-alfa-Hidroxiprogesterona/análise , Androstenodiona/análise , Sulfato de Desidroepiandrosterona/análise , Desidroepiandrosterona/análise , Puberdade/metabolismo , Saliva/química , Testosterona/análise , Adolescente , Criança , Humanos , Masculino
6.
J Perinat Med ; 47(4): 448-454, 2019 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-30759068

RESUMO

Background A legitimate indication for growth hormone (GH) therapy in children born too light or short at birth [small-for-gestational age (SGA)] exists in Germany and the European Union only if special criteria are met. Methods We conducted a longitudinal, multi-centered study on full-term appropriate-for-gestational age (AGA, n=1496) and pre-term born SGA (n=173) and full-term SGA children (n=891) in Germany from 2006 to 2010. We analyzed height, weight, body mass index (BMI) and head circumference. Results Pre-term or full-term born SGA children were shorter, lighter and had a lower BMI from birth until 3 years of age than full-term AGA children. The growth velocity of the analyzed anthropometric measurements was significantly higher in pre-term and full-term SGA children exclusively in the first 2 years of life than in AGA children. The criteria for GH treatment were fulfilled by 12.1% of pre-term SGA children compared to only 1.3% of full-term SGA children. Conclusion For children that do not catch up growth within the first 2 years of life, an earlier start of GH treatment should be considered, because a catch-up growth later than 2 years of life does not exist. Pre-term SGA-born children more frequently fulfill the criteria for GH treatment than full-term SGA children.


Assuntos
Desenvolvimento Infantil , Hormônio do Crescimento Humano/administração & dosagem , Recém-Nascido Prematuro/crescimento & desenvolvimento , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estudos Longitudinais , Masculino
7.
Z Geburtshilfe Neonatol ; 223(2): 85-91, 2019 Apr.
Artigo em Alemão | MEDLINE | ID: mdl-30273936

RESUMO

A significant influence of maternal body height and weight on neonatal birth outcome has been confirmed before, whereas the influence of paternal traits is rather unknown. In order to analyze the correlation between parental body measurements and the birth weight of newborns, data of 1312 eutrophic term newborns and their parents were collected based on a multicenter study in 10 participating German maternity clinics. The collected data included the birth weight of the infants and the body height and weight of their parents. The results show a significant correlation between infant birth weight and maternal body height. Even with a constant body height and body weight of fathers in a range between 176-184 cm and 76-84 kg, taller mothers gave birth to children with a higher birth weight than shorter mothers. Furthermore, higher maternal body weight is also correlated with increased birth weights, although this correlation is attenuated in higher maternal weight groups. Data regarding body weight and body height of fathers showed similar results with regard to birth weight of the newborns. At a constant maternal body height (164-172 cm) and weight (56-64 kg), the body weight of newborns significantly correlates with the body height of fathers but not with their body weight. The multivariable regression analysis resulted in the following ranking of influence factors on the birth weight of newborns: 1) body height of mother, 2) body weight of mother, 3) body height of father. The results gave support to the assumption of a certain genetic influence of parental body stature on their neonates but argue for an even stronger impact of maternal environmental conditions on the developmental status of neonates.


Assuntos
Antropometria , Peso ao Nascer , Pais , Estatura , Peso Corporal , Pai , Feminino , Humanos , Recém-Nascido , Masculino , Mães
8.
Exp Clin Endocrinol Diabetes ; 127(5): 289-294, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30089321

RESUMO

OBJECTIVE: We evaluated percutaneous penetration of topical testosterone and subsequent transfer to subcutaneous tissue, blood and saliva. METHODS: This microdialysis trial involved eight healthy male volunteers. Five participants received a single dose of 50 mg testosterone gel on the abdominal skin and three untreated participants served as controls. Two microdialysis probes were inserted percutaneously into the abdominal subcutaneous adipose tissue. On the skin above one probe, testosterone gel was applied (ipsilateral side). A second control probe was inserted on the contralateral side. For the determination of total and free testosterone, samples of subcutaneous microdialysate, serum, and saliva were collected over six hours, frozen, and analysed using ELISA procedures. RESULTS: Testosterone values in the ipsilateral microdialysate of treated subjects increased significantly within 6 h after gel application compared to controls. Salivary testosterone levels showed a rapid increase within 20 min after transdermal application followed by a plateau phase with tenfold increased testosterone levels. Microdialysate testosterone of the contralateral site started to rise moderately within the normal range 1 h after administration of testosterone gel whereas total and free testosterone serum concentrations increased within 2 h in each case followed by a plateau phase. SUMMARY AND CONCLUSION: Single topical administration of testosterone gel leads to a continuous increase of testosterone in the subcutaneous ipsilateral microdialysate. Rapid salivary testosterone increase happens after gel administration followed by tenfold increased testosterone plateau values. Despite continuous influx, testosterone concentrations in serum, saliva, and contralateral microdialysate show a plateau formation thus avoiding testosterone excess.


Assuntos
Sangue , Saliva , Gordura Subcutânea , Testosterona/farmacocinética , Administração Cutânea , Adulto , Humanos , Masculino , Microdiálise , Testosterona/administração & dosagem , Adulto Jovem
10.
Nutr J ; 17(1): 51, 2018 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-29753318

RESUMO

BACKGROUND: Maple syrup urine disease (MSUD) is an autosomal recessive disorder of branched-chain amino acid metabolism. Patients with MSUD are at risk of life-threatening metabolic decompensations with ketoacidosis and encephalopathy. These episodes are often triggered by physiological stress. Only few cases of pregnancies in MSUD mothers have been reported so far. CASE PRESENTATION: We present the favorable outcome of a pregnancy in a woman with classical MSUD. She presented in the metabolic outpatient clinic in week 7 of gestation. Branched-chain amino acid concentrations were measured at least weekly to adjust dietary leucine intake. Despite excellent compliance, leucine concentrations frequently exceeded the target value of < 300 µmol/L during the first trimester. From the second trimester until delivery, protein and leucine intake increased continuously to about threefold compared to pre-pregnancy values. To maximize patient safety during delivery and the postpartum period, a detailed plan including peripartal infusion therapy, dietary recommendations and monitoring parameters was developed. Primary Caesarean section was performed in week 38 of gestation, and the patient gave birth to a healthy girl. Lactation was successfully implemented. Leucine levels were maintained within the target range throughout the complete postpartum period. In addition to our case, we give an overview about all cases of pregnancies in MSUD mothers published so far. CONCLUSIONS: Management of pregnancy, delivery, postpartum period and lactation may be challenging in patients with MSUD. Careful monitoring and interdisciplinary collaboration is essential to minimize the risk of metabolic crisis, especially after delivery.


Assuntos
Doença da Urina de Xarope de Bordo/complicações , Complicações na Gravidez/terapia , Resultado da Gravidez , Adulto , Aminoácidos de Cadeia Ramificada/sangue , Cesárea , Dieta , Dieta com Restrição de Proteínas , Feminino , Humanos , Lactação , Leucina/administração & dosagem , Leucina/sangue , Doença da Urina de Xarope de Bordo/sangue , Doença da Urina de Xarope de Bordo/terapia , Período Pós-Parto , Gravidez
11.
Pediatr Diabetes ; 19(5): 937-944, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29411927

RESUMO

OBJECTIVE: To investigate differences in cardiovascular risk factors and metabolic control in girls with type 1 diabetes with or without use of oral contraceptives (OC) from the multicenter "diabetes prospective follow-up" (DPV) registry. METHODS: Twenty-four thousand eleven adolescent girls (13 to < 18 years of age) from Germany, Austria or Luxembourg with type 1 diabetes from the DPV registry were included in this cross-sectional study. Multivariable regression models were applied to compare clinical characteristics (hemoglobin A1c [HbA1C ], blood pressure, serum lipids, body mass index) and lifestyle factors (smoking, physical inactivity, alcohol consumption) between girls with or without OC use. Confounders: age, diabetes duration and migration background. STATISTICAL ANALYSIS: SAS 9.4. RESULTS: In girls with type 1 diabetes and OC use, clinical characteristics and lifestyle factors were less favorable compared to non-users. Differences were most pronounced for the prevalence of dyslipidemia (OC-users: 40.0% vs non-users: 29.4; P < .0001) and the number of smokers (OC-users: 25.9% vs non-users: 12.5%; P < .0001). OC use, sociodemographic characteristics and lifestyle factors explained between 1 and 7% of the population variance in serum lipids and blood pressure. The use of OC explained a small additional proportion in all variables considered (<1%). CONCLUSIONS: OC use in adolescent girls with type 1 diabetes was associated with a poorer cardiovascular risk profile. Biological risk factors were partly explained by a clustering of sociodemographic and lifestyle factors with a small additional contribution of OC use. Prescription of OC should therefore be combined with a screening for cardiovascular risk factors and targeted education.


Assuntos
Doenças Cardiovasculares/etiologia , Anticoncepcionais Orais , Diabetes Mellitus Tipo 1/complicações , Sistema de Registros , Adolescente , Estudos Transversais , Feminino , Comportamentos de Risco à Saúde , Humanos , Estilo de Vida
12.
J Diabetes Sci Technol ; 12(2): 341-348, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28931321

RESUMO

BACKGROUND: Continuously measured glucose and lactate levels in interstitial fluid (ISF) may markedly differ from their respective blood levels. METHODS: Combining microdialysis with a bioanalytical microsystem, the interstitial glucose and lactate concentrations of eight male volunteers with different body mass index (BMI) were monitored during a 2-fold glucose tolerance test over the period of three hours. RESULTS: Significant correlations were found between abdominally measured sensor results and reference measurements ( R2 = .967 for glucose and R2 = .936 for lactate, P < .05). The physiological delay of the abdominally observed glucose appearance in the ISF correlated positively with the BMI ( R2 = .787, P < .05). The relative in vivo recovery of glucose and lactate was inversely proportional to the BMI of the volunteers ( R2 = .540 for glucose, R2 = .609 for lactate, P < .05). One subject with a BMI of > 34 kg/m2 showed abdominally as well as the antebrachially significantly reduced tissue glucose values compared to blood glucose values ( P < .001). CONCLUSIONS: A very good correlation between abdominally measured sensor results and the results of the reference method verified the reliability of the BioMEMS. The abdominally measured glucose level in ISF decreased significantly with increasing BMI. Therefore, an in vivo calibration of glucose levels in ISF with blood levels seems to be necessary especially in markedly obese subjects.


Assuntos
Líquido Extracelular/química , Glucose/análise , Ácido Láctico/análise , Obesidade/metabolismo , Adulto , Índice de Massa Corporal , Teste de Tolerância a Glucose , Voluntários Saudáveis , Humanos , Masculino , Adulto Jovem
13.
Mol Genet Metab ; 122(1-2): 67-75, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28689740

RESUMO

2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union. 63% of the study participants presented with a metabolic decompensation while most others were identified via newborn screening or family studies. In symptomatic patients, age at manifestation ranged between 5months and 6.8years. Only 7% developed a major mental disability while the vast majority was cognitively normal. More than one third of the identified mutations in ACAT1 are intronic mutations which are expected to disturb splicing. We identified several novel mutations but, in agreement with previous reports, no clear genotype-phenotype correlation could be found. Our study underlines that the prognosis in MAT deficiency is good and MAT deficient individuals may remain asymptomatic, if diagnosed early and preventive measures are applied.


Assuntos
Acetil-CoA C-Aciltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Ácidos Graxos/metabolismo , Isoleucina/metabolismo , Corpos Cetônicos/metabolismo , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Aciltransferase/genética , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Criança , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Prognóstico , Estudos Retrospectivos , Adulto Jovem
14.
Mol Genet Metab ; 121(3): 206-215, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28583327

RESUMO

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important.


Assuntos
Acetil-CoA C-Acetiltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Bélgica , Criança , Pré-Escolar , Ácidos Graxos/metabolismo , Feminino , Estudos de Associação Genética , Alemanha , Humanos , Lactente , Corpos Cetônicos/metabolismo , Leucina/metabolismo , Masculino , Mutação , Países Baixos , Oxo-Ácido-Liases/genética , Avaliação de Resultados da Assistência ao Paciente , Suíça , Turquia , Adulto Jovem
15.
PLoS One ; 12(5): e0176720, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28459839

RESUMO

Mutations in NR5A1 have been reported as a frequent cause of 46,XY disorders of sex development (DSD) associated to a broad phenotypic spectrum ranging from infertility, ambiguous genitalia, anorchia to gonadal dygenesis and female genitalia. Here we present the clinical follow up of four 46,XY DSD patients with three novel heterozygous mutations in the NR5A1 gene leading to a p.T40P missense mutation and a p.18DKVSG22del nonframeshift deletion in the DNA-binding domain and a familiar p.Y211Tfs*83 frameshift mutation. Functional analysis of the missense and nonframeshift mutation revealed a deleterious character with loss of DNA-binding and transactivation capacity. Both, the mutations in the DNA-binding domain, as well as the familiar frameshift mutation are associated with highly variable endocrine values and phenotypic appearance. Phenotypes vary from males with spontaneous puberty, substantial testosterone production and possible fertility to females with and without Müllerian structures and primary amenorrhea. Exome sequencing of the sibling's family revealed TBX2 as a possible modifier of gonadal development in patients with NR5A1 mutations.


Assuntos
Disgenesia Gonadal/genética , Disgenesia Gonadal/fisiopatologia , Mutação , Fator Esteroidogênico 1/genética , Adolescente , Criança , Feminino , Seguimentos , Disgenesia Gonadal/terapia , Células HeLa , Humanos , Masculino , Fenótipo , Fator Esteroidogênico 1/metabolismo , Proteínas com Domínio T/genética
16.
J Pediatr Endocrinol Metab ; 29(10): 1181-1186, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27710915

RESUMO

BACKGROUND: The objective of the study was to assess the effect of atorvastatin on inflammation markers and low-density lipoprotein (LDL) subfractions. METHODS: In a prospective, randomized, double-blind pilot study involving 28 adolescents with type 1 diabetes (T1D), lipoprotein-associated phospholipase A2 (Lp-PLA2) activity, high-sensitivity C-reactive protein (hsCRP), and subfractions of LDL were measured at baseline, after 1 year and 2 years of treatment with atorvastatin (10 mg/day) vs. placebo. RESULTS: For the atorvastatin group, we found posttreatment reductions of Lp-PLA2 activity (p<0.001), LDL cholesterol (p=0.001), non-small dense LDL cholesterol (p<0.001), total cholesterol (p<0.001), and apolipoprotein B (apo B) (p<0.001), whereas small dense LDL cholesterol and hsCRP did not change significantly. CONCLUSIONS: In adolescents with T1D, long-term treatment with atorvastatin is safe and may reduce cardiovascular risk by significant decreases of Lp-PLA2 activity and LDL cholesterol.


Assuntos
1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , Atorvastatina/farmacologia , Biomarcadores/análise , LDL-Colesterol/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Adolescente , Anticolesterolemiantes/farmacologia , Proteína C-Reativa/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Método Duplo-Cego , Feminino , Humanos , Técnicas Imunoenzimáticas , Masculino , Prognóstico , Estudos Prospectivos
17.
Eur J Hum Genet ; 24(9): 1274-9, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26813946

RESUMO

Whole-exome sequencing allows for an unbiased and comprehensive mutation screening. Although successfully used to facilitate the diagnosis of single-gene disorders, the genetic cause(s) of a substantial proportion of presumed monogenic diseases remain to be identified. We used whole-exome sequencing to examine offspring from a consanguineous marriage featuring a novel combination of congenital hypothyroidism, hypomagnesemia and hypercholesterolemia. Rather than identifying one causative variant, we report the first instance in which three independent autosomal-recessive single-gene disorders were identified in one patient. Together, the causal variants give rise to a blended and seemingly novel phenotype: we experimentally characterized a novel splice variant in the thyroglobulin gene (c.638+5G>A), resulting in skipping of exon 5, and detected a pathogenic splice variant in the magnesium transporter gene TRPM6 (c.2667+1G>A), causing familial hypomagnesemia. Based on the third variant, a stop variant in ABCG5 (p.(Arg446*)), we established a diagnosis of sitosterolemia, confirmed by elevated blood plant sterol levels and successfully initiated targeted lipid-lowering treatment. We propose that blended phenotypes resulting from several concomitant single-gene disorders in the same patient likely account for a proportion of presumed monogenic disorders of currently unknown cause and contribute to variable genotype-phenotype correlations.


Assuntos
Hipercolesterolemia/genética , Hipotireoidismo/genética , Enteropatias/genética , Erros Inatos do Metabolismo Lipídico/genética , Deficiência de Magnésio/genética , Mutação , Fenótipo , Fitosteróis/efeitos adversos , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adolescente , Consanguinidade , Feminino , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/diagnóstico , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico , Enteropatias/complicações , Enteropatias/diagnóstico , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/diagnóstico , Lipoproteínas/genética , Deficiência de Magnésio/complicações , Deficiência de Magnésio/diagnóstico , Masculino , Linhagem , Fitosteróis/genética , Processamento de RNA , Canais de Cátion TRPM/genética , Tireoglobulina/genética , Adulto Jovem
18.
J Pediatr Endocrinol Metab ; 29(2): 203-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26501158

RESUMO

BACKGROUND: Growth hormone deficiency (GHD) and small for gestational age (SGA) status are associated with cardiovascular risks. We therefore, investigated antiatherogenic effects of growth hormone (GH). METHODS: Subfractions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), lipoprotein-associated phospholipase A2 (Lp-PLA2), and high-sensitivity C-reactive protein (hsCRP) were measured at baseline, after 8 and 52 weeks of GH treatment in 51 short children born SGA (n=33) or with GHD (n=18). RESULTS: The overall group showed post-treatment reductions of LDL cholesterol (LDL-C) (p=0.016), small-dense LDL cholesterol (sdLDL-C, p<0.001), Lp-PLA2 (p<0.001), and hsCRP (p=0.005), but increase of HDL2a cholesterol (HDL2a-C, p=0.025). SGA children revealed significant correlations between Lp-PLA2 and LDL-C and sdLDL-C both before and after GH, significant reductions of sdLDL-C, Lp-PLA2, hsCRP, and an increase of HDL2a-C. GHD children showed the same lipid responses, though not significantly. CONCLUSIONS: Children with GHD or born SGA may benefit from GH by growth acceleration and reduction of cardiovascular long-term risks.


Assuntos
Estatura , LDL-Colesterol/sangue , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/uso terapêutico , Recém-Nascido Pequeno para a Idade Gestacional , Fosfolipases A2/metabolismo , Criança , Feminino , Humanos , Recém-Nascido , Masculino
19.
J Pediatr ; 167(3): 627-32.e1-4, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26164381

RESUMO

OBJECTIVE: To examine the current extent of the obesity problem in 2 large pediatric clinical registries in the US and Europe and to examine the hypotheses that increased body mass index (BMI) z-scores (BMIz) are associated with greater hemoglobin A1c (HbA1c) and increased frequency of severe hypoglycemia in youth with type 1 diabetes (T1D). STUDY DESIGN: International (World Health Organization) and national (Centers for Disease Control and Prevention/German Health Interview and Examination Survey for Children and Adolescents) BMI references were used to calculate BMIz in participants (age 2-<18 years and ≥ 1 year duration of T1D) enrolled in the T1D Exchange (n = 11,435) and the Diabetes Prospective Follow-up (n = 21,501). Associations between BMIz and HbA1c and severe hypoglycemia were assessed. RESULTS: Participants in both registries had median BMI values that were greater than international and their respective national reference values. BMIz was significantly greater in the T1D Exchange vs the Diabetes Prospective Follow-up (P < .001). After stratification by age-group, no differences in BMI between registries existed for children 2-5 years, but differences were confirmed for 6- to 9-, 10- to 13-, and 14- to 17-year age groups (all P < .001). Greater BMIz were significantly related to greater HbA1c levels and more frequent occurrence of severe hypoglycemia across the registries, although these associations may not be clinically relevant. CONCLUSIONS: Excessive weight is a common problem in children with T1D in Germany and Austria and, especially, in the US. Our data suggest that obesity contributes to the challenges in achieving optimal glycemic control in children and adolescents with T1D.


Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Obesidade/epidemiologia , Adolescente , Áustria/epidemiologia , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Alemanha/epidemiologia , Hemoglobina A Glicada/análise , Humanos , Hipoglicemia/epidemiologia , Masculino , Sistema de Registros , Estados Unidos/epidemiologia
20.
J Inherit Metab Dis ; 38(5): 873-9, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25860818

RESUMO

Alpha-aminoadipic and alpha-ketoadipic aciduria is an autosomal recessive inborn error of lysine, hydroxylysine, and tryptophan degradation. To date, DHTKD1 mutations have been reported in two alpha-aminoadipic and alpha-ketoadipic aciduria patients. We have now sequenced DHTKD1 in nine patients diagnosed with alpha-aminoadipic and alpha-ketoadipic aciduria as well as one patient with isolated alpha-aminoadipic aciduria, and identified causal mutations in eight. We report nine novel mutations, including three missense mutations, two nonsense mutations, two splice donor mutations, one duplication, and one deletion and insertion. Two missense mutations, one of which was reported before, were observed in the majority of cases. The clinical presentation of this group of patients was inhomogeneous. Our results confirm that alpha-aminoadipic and alpha-ketoadipic aciduria is caused by mutations in DHTKD1, and further establish that DHTKD1 encodes the E1 subunit of the alpha-ketoadipic acid dehydrogenase complex.


Assuntos
Ácido 2-Aminoadípico/metabolismo , Adipatos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/genética , Cetona Oxirredutases/genética , Ácido 2-Aminoadípico/urina , Adipatos/urina , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Pré-Escolar , Feminino , Humanos , Recém-Nascido , Cetona Oxirredutases/deficiência , Cetona Oxirredutases/metabolismo , Masculino , Adulto Jovem
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