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Objectives: To improve adult height in pubertal girls with a poor height prediction, treatment with growth hormone (GH) can be used in combination with a gonadotropin releasing hormone agonist (GnRHa), to delay closure of the growth plates. However, there are few studies to support this practice, and they show conflicting results. The objective of this trial is to assess the safety and efficacy of this combination treatment in early pubertal girls with a short predicted height, in comparison with matched controls. Design patients and methods: We designed an open-label, multicenter, interventional case-control study. Early pubertal girls with predicted adult height (PAH) below -2.5 SDS, were recruited in tertiary care centers in Belgium. They were treated for four years with GH and GnRHa. The girls were followed until adult height (AH) was reached. AH vs PAH, AH vs Height at start, and AH vs Target Height (TH) were evaluated, as well as safety parameters. Control data were assembled from historical patient files or from patients who preferred not to participate in the study. Results: Sixteen girls with mean age ( ± SD) at start of 11.0 years (± 1.3) completed the study protocol and follow-up. Their mean height ( ± SD) increased from 131.3 ± 4.1 cm (-2.3 ± 0.7 SDS) at start of treatment to 159.8 ± 4.7 cm (-1.1 ± 0.7 SDS) at AH. In matched controls, height increased from 132.3 ± 4.2 cm (-2.4 ± 0.5 SDS) to 153.2 ± 3.4 cm (-2.1 ± 0.6 SDS) (p<0.001). AH surpassed initial PAH by 12.0 ± 2.6 cm in treated girls; and by 4.2 ± 3.6 cm in the controls (p<0.001). Most treated girls reached normal adult height (>-2SD) (87.5%) and 68.7% reached or superseded the target height (TH), which was the case in only a minority of the controls (37.5% and 6.2%, respectively) (p= 0.003 and 0.001). A serious adverse event possibly related to the treatment, was a fracture of the metatarsals. Conclusion: A four-year GH/GnRHa treatment in early pubertal girls with a poor PAH seems safe and results in a clinically relevant and statistically significant increase in AH compared with matched historical controls. Clinical trial registration: ClinicalTrials.gov, identifier NCT00840944.
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Hormônio do Crescimento Humano , Puberdade Precoce , Feminino , Humanos , Adulto , Criança , Hormônio do Crescimento , Hormônio Liberador de Gonadotropina , Estudos de Casos e Controles , Estatura , Hormônio do Crescimento Humano/uso terapêutico , Puberdade Precoce/tratamento farmacológicoRESUMO
The HLA region is the major genetic risk determinant of Type 1 diabetes. How non-HLA loci contribute to the genetic risk is incompletely understood, but there are indications that at least some impact progression of asymptomatic autoimmunity. We examined whether SNPs in 7 susceptibility loci (INS, SH2B3, PTPN2, PTPN22, CTLA4, CLEC16A, and IL2RA) could improve prediction of the progression from single to multiple autoantibody positivity, and from there on to diagnosis. SNPs were genotyped in persistently autoantibody positive relatives by allelic discrimination qPCR and disease progression was studied by multivariate Cox regression analysis. In our cohort, only the CTLA4 GA genotype (rs3087243, P = 0.002) and the CLEC16A AA genotype (rs12708716, P = 0.021) were associated with accelerated progression from single to multiple autoantibody positivity, but their effects were restricted to presence of HLA-DQ2/DQ8, and IAA as first autoantibody, respectively. The interaction of CTLA4 and HLA-DQ2/DQ8 overruled the effect of DQ2/DQ8 alone. The HLA-DQ2/DQ8-mediated risk of progression to multiple autoantibodies nearly entirely depended on heterozygosity for CTLA4. The SH2B3 TT genotype (rs3184504) was protective for HLA-DQ8 positive subjects (P = 0.003). At the stage of multiple autoantibodies, only the CTLA4 GA genotype was a minor independent risk factor for progression towards clinical diabetes (P = 0.034). Our study shows that non-HLA polymorphisms impact progression of islet autoimmunity in a subgroup-, stage- and SNP-specific way, suggesting distinct mechanisms. If confirmed, these findings may help refine risk assessment, follow-up, and prevention trials in risk groups.
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Diabetes Mellitus Tipo 1 , Humanos , Autoanticorpos , Autoimunidade/genética , Antígeno CTLA-4/genética , Diabetes Mellitus Tipo 1/genética , Predisposição Genética para Doença , Genótipo , Lectinas Tipo C/genética , Proteínas de Transporte de Monossacarídeos/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genéticaRESUMO
Context: Idiopathic central precocious puberty (iCPP) is defined by the premature reactivation of the hypothalamic-pituitary-gonadal axis with normal magnetic resonance imaging scan of the central nervous system, causing the development of secondary sexual characteristics before age 8 years in girls and 9 years in boys. MKRN3 loss of function variants now represent the most common genetic cause of iCPP. Objective: This work aims to document the clinical course of puberty in 8 families harboring pathogenic MKRN3 variants. Methods: This is an observational case series study of patients with CPP due to MKRN3 variants followed in a single center. Results: Genetic analysis of MKRN3 was carried out in 28 unrelated patients with iCPP and a family history of paternal inheritance or no/unavailable maternal inheritance, particularly in case of very early and rapidly evolving CPP. We identified 6 novel and 2 recently described variants in the MKRN3 gene in 9 girls, 1 boy, and their family members. These mutations were all predicted to be deleterious by in silico prediction programs. Conclusion: We have identified 6 novel MKRN3 mutations in children with CPP. An MKRN3 loss of function should be considered after careful history pinpointing paternally inherited CPP. A family segregation study allowed the detection of an MKRN3 variant in 2 young brothers still prepubertal, raising the question of screening and management of asymptomatic prepubertal family members.
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INTRODUCTION: To assess the impact of real-time continuous glucose monitoring (RT-CGM) instead of first-generation flash glucose monitoring (FGM) on hypoglycaemia in children and adolescents with type 1 diabetes. METHODS: In this randomized controlled interventional study, young individuals with type 1 diabetes used RT-CGM or FGM for 8 weeks. We evaluated changes in time below range (TBR), severe hypoglycaemia (SH), HbA1c, glycaemic variability, and impaired awareness of hypoglycaemia with RT-CGM (intervention group) in comparison with FGM. RESULTS: We randomly assigned 37 participants to either the intervention group (n = 19) or the control group (n = 18). At 8 weeks, we did not find a decrease in TBR in either group, but there was a significant reduction in SH in the intervention group. For participants with TBR ≥ 5% at baseline, we observed significant reductions in 24-h TBR, wake TBR, sleep TBR, and glucose variability at 8 weeks in the intervention group. CONCLUSIONS: The use of RT-CGM versus FGM decreased SH in young individuals with type 1 diabetes, and TBR and glucose variability in patients with a higher TBR at baseline. The patient's history should be taken into account when advising on the method of blood glucose monitoring, as RT-CGM could be more effective in younger patients at high risk for SH. TRIAL REGISTRATION: ClinicalTrials.gov NCT04249102.
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Objective: Experimental evidence suggests that the clinical manifestations of Triple A syndrome result from oxidative stress. Several conditions caused by oxidative stress display retinal involvement. Our objective was to assess the retina and optic nerve involvement in children with Triple A syndrome. Methods: Eleven patients with genetically proven Triple A syndrome followed-up in our centre were approached for study participation. The main outcome was the measurement of the thicknesses of the different retinal layers by Optical Coherence Tomography (OCT). Results: 9 patients with triple A syndrome had OCT measurements. 7 patients were children and 2 were adults; 4 were females and 5 were males. The 7 paediatric patients had at least two OCT measured at a mean interval of 7.9 months after the first one. The average Retinal Nerve Fibre Layer thickness was 74 ± 10 µm in patients compared to the paediatric reference range of 100 ± 2 µm (p<0.05). Conclusions and Relevance: This is the first study to document retinal layer thicknesses in a series of patients with Triple A syndrome. Nearly all retinal thickness and peripapillary RNFL measurements were very significantly inferior to the reference range in Triple A patients, whatever their age. RNFL thinning was more marked at the temporal part of the optic nerve. OCT being non-invasive, it represents a promising tool to assess the severity of neurodegeneration in patients with Triple A syndrome.
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Insuficiência Adrenal/complicações , Acalasia Esofágica/complicações , Doenças Neurodegenerativas/patologia , Retina/patologia , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Doenças Neurodegenerativas/etiologia , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
AIMS/HYPOTHESIS: We examined whether the non-HLA susceptibility locus ERBB3/IKZF4 influences progression of type 1 diabetes stage specifically according to sex. METHODS: SNPs of ERBB3 (rs2292239 T/G) and IKZF4 (rs1701704 G/T) were screened by allelic discrimination quantitative PCR assay in first-degree relatives of type 1 diabetes patients who had developed at least one circulating autoantibody. The effect of ERBB3/IKZF4 genotypes and sex, on the progression of single autoantibody positivity to multiple autoantibody positivity and from multiple autoantibody positivity to diabetes, was studied by Kaplan-Meier analysis and multivariate Cox regression. RESULTS: In the cohort of autoantibody-positive first-degree relatives, the risk allele frequencies for ERBB3 rs2292239 (T) and IKZF4 rs1701704 (G) were increased. There was a significant male excess at the stage of multiple autoantibody positivity (p = 0.021). In Kaplan-Meier survival analysis, progression from single to multiple antibody positivity was delayed in female participants with genotype ERBB3 GG (p = 0.018, vs ERBB3 TG+TT) or IKZF4 TT (p = 0.023, vs IKZF4 GT+GG), but not in male participants. In multivariate Cox regression models, the interaction effects between female sex and ERBB3 GG (p = 0.012; HR = 0.305 [95% CI 0.120, 0.773]) or between female sex and IKZF4 TT (p = 0.011; HR = 0.329 [95% CI 0.140, 0.777]) emerged as potential determinants of delayed progression to multiple autoantibodies. The progression from multiple autoantibody positivity to type 1 diabetes appeared not to be influenced by ERBB3/IKZF4. CONCLUSIONS/INTERPRETATION: In siblings and offspring of type 1 diabetes patients, polymorphism in region ERBB3/IKZF4 may affect disease progression at the level of epitope spreading in female individuals. Our findings suggest that interaction between sex and ERBB3/IKZF4 may contribute to the post-pubertal male excess in type 1 diabetes.
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Autoanticorpos/sangue , Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Epitopos/imunologia , Fator de Transcrição Ikaros/genética , Receptor ErbB-3/genética , Caracteres Sexuais , Adolescente , Adulto , Criança , Diabetes Mellitus Tipo 1/genética , Progressão da Doença , Feminino , Predisposição Genética para Doença , Humanos , Insulina/imunologia , Masculino , Polimorfismo de Nucleotídeo Único/genética , Modelos de Riscos Proporcionais , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Transportador 8 de Zinco/imunologiaRESUMO
OBJECTIVES: Questions are emerging concerning the long-term consequences of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, as a possible increase in type 1 diabetes. This study aims to describe the prevalence of anti-SARS-CoV-2 antibodies in children developing type 1 diabetes during this pandemic in Belgium. METHODS: This observational study included children and adolescents (under 16 years) admitted with new-onset type 1 diabetes. SARS-CoV-2 serology was taken within the first month of diabetes. RESULTS: Of the 75 participants, anti-SARS-CoV-2 antibodies were positive in 20% of patients. They had an increased bicarbonate and base excess at diagnosis. Overall 29% of patients presented diabetic ketoacidosis at diagnosis and 9% of them were positive for anti-SARS-CoV-2 antibodies. Insulinoma-associated protein 2 antibodies positivity had significantly higher frequencies in children without anti-SARS-CoV-2 antibodies (49 (81%) vs. 5 (33%), p=0.038). Nine (15%) patients, initially seronegative, have developed anti-SARS-CoV-2 antibodies between the two samples (mean time 8 ± 4 weeks). CONCLUSIONS: The prevalence of anti-SARS-CoV-2 antibodies in children with newly diagnosed type 1 diabetes (20%) is similar to that found in children without diabetes in Belgium, a country severely affected by this pandemic.
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Anticorpos Antivirais/sangue , COVID-19/epidemiologia , Diabetes Mellitus Tipo 1/imunologia , SARS-CoV-2/imunologia , Adolescente , Bélgica/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , MasculinoRESUMO
Objective: Several criteria for first-year growth response (FYGR) to growth hormone (GH) treatment have been proposed. We explored which FYGR criteria predicted best the final height outcome after GH treatment in prepubertal children with GH deficiency (GHD). Design and methods: Height data of 129 GHD children (83 boys) who attained adult height and had been treated with GH for at least 4 consecutive years with at least 1 year before pubertal onset, were retrieved from the Belgian GH Registry. The FYGR parameters were: (1) increase in height (ΔHt) SDS, (2) height velocity (HV) SDS, (3) ΔHV (cm/year), (4) index of responsiveness (IoR) in KIGS prediction models, (5) first-year HV SDS based on the KIGS expected HV curve (HV KIGS SDS), (6) near final adult height (nFAH) prediction after first-year GH treatment. Poor final height outcome (PFHO) criteria were: (1) total ΔHt SDS <1.0, (2) nFAH SDS <-2.0, (3) nFAH minus midparental height SDS <-1.3. ROC curve analyses were performed to define the optimal cut-off for FYGR parameters to predict PFHO. Only ROC curves with an area under the curve (AUC) of more than 70% were further analyzed. Results: Twelve, 22 and 10% of the children had respectively a total ΔHt SDS <1, nFAH SDS <-2, and nFAH minus midparental height SDS <-1.3. The AUC's ranged between 73 and 85%. The highest AUC was found for first-year ΔHt SDS to predict total ΔHt SDS <1, and predicted nFAH SDS to predict nFAH SDS <-2. The currently used FYGR criteria had low specificities and sensitivities to detect PFHO. To obtain a 95% specificity, the cut-off value (and sensitivity) of FYGR parameters were: ΔHt SDS <0.35 (40%), HV SDS <-0.85 (43%), ΔHV <1.3 cm/year (36%), IoR <-1.57 (17%), HV KIGS SDS <-0.83 (40%) to predict total ΔHt SDS <1; predicted nFAH SDS (with GH peak) <-1.94 (25%), predicted nFAH SDS (without GH peak) <-2.02 (25%) to predict nFAH SDS <-2. At these cut-offs, the amount of correctly diagnosed poor final responders equals the amount of false positives. Conclusion: First-year growth response criteria perform poorly as predictors of poor final height outcome after long-term GH treatment in prepubertal GHD children.
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BACKGROUND: Diabetic ketoacidosis (DKA) is the leading cause of morbidity and mortality in children with type 1 diabetes (T1D). Little is known about the association between genetic and immunological markers and the risk for DKA at onset of T1D. The aim of this study was to create a model foreseeing the onset of DKA in newly diagnosed patients. METHODS: This retrospective study included 532 T1D children (aged <18 years at diagnosis) recruited in our hospital, from 1995 to 2014. DKA and its severity were defined according to the criteria of ISPAD. Genetic risk categories for developing T1D were defined according to the Belgian Diabetes Registry. Multivariate statistical analyses were applied to investigate risk factors related to DKA at diagnosis. RESULTS: Overall 42% of patients presented DKA at diagnosis. This study outlined the major risk of DKA at diagnosis for younger children (<3 years) and for those belonging to ethnic minorities. Children carrying neutral genotypes had a 1.5-fold increased risk of DKA at diagnosis than those with susceptible or protective genotypes, a paradoxical observation not previously reported. Only solitary positive IA-2A increased the risk of DKA at diagnosis. The proposed model could help to predict the probability of DKA in 70% of newly diagnosed cases. CONCLUSIONS: This was the first reported implication of IA-2A positivity and neutral genotypes predisposing to DKA at diagnosis regardless of its severity. Earlier diagnosis through genetic and immunological screening of high-risk children could decrease DKA incidence at diabetes onset.
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Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/epidemiologia , Bélgica/epidemiologia , Criança , Pré-Escolar , Cetoacidose Diabética/genética , Cetoacidose Diabética/imunologia , Feminino , Humanos , Lactente , Modelos Logísticos , Masculino , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção Terciária/estatística & dados numéricosRESUMO
Background: Flash glucose monitoring (FGM) is covered by the Belgian public health insurance for type 1 diabetes since 2016. The objective of this study was to describe the use of FGM and diabetes outcomes in type 1 diabetic children and adolescents 1 year after reimbursement. Methods: All patients had the choice to convert to FGM or to continue with self-monitoring of blood glucose (SMBG). Clinical data were collected at baseline, at the next visit, and after 12 months; glucose profiles at next visit and after 12 months. Regression analyses were performed to identify predictors of FGM acceptance and changes in metabolic control. Results: A total of 334 subjects were included, of whom 278 (83.2%) switched to FGM. They were younger (13.6 vs. 15.2 years; P = 0.012) and performed more SMBG testing at baseline than patients who did not switch (4.3 vs. 4.1 tests daily; P = 0.008). At the end of follow-up, the rate of severe hypoglycemia decreased by 53% in the group of FGM users (P = 0.012) while it remained stable in SMBG users. Median glycated hemoglobin did not change significantly in both groups. Among subjects who switched to FGM, 15.8% reverted to SMBG after a median use of 5.3 months. Adverse events, diabetes duration, and FGM utilization were independent predictors of the risk for reverting. FGM-related adverse events were associated with a fivefold increased risk to revert to SMBG (hazard ratio = 5.12; P < 0.0001). Conclusions: FGM is relatively well accepted and decreases the risk of severe hypoglycemic events in our pediatric population. FGM is more often discontinued in patients experiencing adverse events and with longer diabetes duration.
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Automonitorização da Glicemia/instrumentação , Automonitorização da Glicemia/estatística & dados numéricos , Diabetes Mellitus Tipo 1/terapia , Hipoglicemia/prevenção & controle , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Automonitorização da Glicemia/economia , Criança , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/psicologia , Feminino , Humanos , Hipoglicemia/etiologia , Reembolso de Seguro de Saúde , Masculino , Estudos ProspectivosRESUMO
OBJECTIVE: We investigated the effect of HLA class I risk alleles on disease progression in various phases of subclinical islet autoimmunity in first-degree relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: A registry-based group of siblings/offspring (aged 0-39 years) was monitored from single- to multiple-autoantibody positivity (n = 267) and from multiple-autoantibody positivity to clinical onset (n = 252) according to HLA-DQ, -A*24, -B*18, and -B*39 status. Genetic markers were determined by PCR sequence-specific oligotyping. RESULTS: Unlike HLA-B*18 or -B*39, HLA-A*24 was associated with delayed progression from single- to multiple-autoantibody positivity (P = 0.009) but not to type 1 diabetes. This occurred independently from older age (P < 0.001) and absence of HLA-DQ2/DQ8 or -DQ8 (P < 0.001 and P = 0.003, respectively), and only in the presence of GAD autoantibodies. In contrast, HLA-A*24 was associated with accelerated progression from multiple-autoantibody positivity to clinical onset (P = 0.006), but its effects were restricted to HLA-DQ8+ relatives with IA-2 or zinc transporter 8 autoantibodies (P = 0.002). HLA-B*18, but not -B*39, was also associated with more rapid progression, but only in HLA-DQ2 carriers with double positivity for GAD and insulin autoantibodies (P = 0.004). CONCLUSIONS: HLA-A*24 predisposes to a delayed antigen spreading of humoral autoimmunity, whereas HLA-A*24 and -B*18 are associated with accelerated progression of advanced subclinical autoimmunity in distinct risk groups. The relation of these alleles to the underlying disease process requires further investigation. Their typing should be relevant for the preparation and interpretation of observational and interventional studies in asymptomatic type 1 diabetes.
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Autoanticorpos/sangue , Autoimunidade/genética , Diabetes Mellitus Tipo 1/patologia , Antígeno HLA-A24/genética , Antígeno HLA-B18/genética , Antígenos HLA-DQ/genética , Ilhotas Pancreáticas/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Progressão da Doença , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Recém-Nascido , Anticorpos Anti-Insulina/sangue , Masculino , Sistema de Registros , Fatores de Risco , Adulto JovemRESUMO
AIM: To assess the management and outcome of the congenital hypothyroidism (CH) patients followed at our institution since the introduction of systemic neonatal screening for CH. STUDY DESIGN: The records of 139 CH patients referred to our center between 1978 and 2014 were retrospectively reviewed. Biochemical and imaging data at diagnosis, initial treatment and growth were analyzed. RESULTS: 111 patients had thyroid dysgenesis (64 ectopy, 46 athyreosis and 1 hypoplasia) and 28 patients had a gland in situ (17 dyshormonogenesis/goiter and 11 normal-sized gland). Levothyroxine treatment was initiated at a median age of 11 days with a mean dose of 11.4 µg/kg/day. Compared to those with ectopy, patients with athyreosis had higher thyroid-stimulating hormone (TSH) and lower thyroxine at diagnosis as well as more delayed bone maturation. Between 1978 and 2014, we observed earlier treatment and earlier TSH normalization. Birth auxology was slightly above the mean of the reference population. Growth at 1 and 6 years and school progression at 11 years were similar to those of the reference population. CONCLUSION: Ectopy is the commonest cause of CH. Children with CH treated early with a mean levothyroxine dose of 11.4 µg/kg/day had a median TSH of 3.07 mU/l at 1 month of age and normal growth.
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Hipotireoidismo Congênito/tratamento farmacológico , Tiroxina/administração & dosagem , Hipotireoidismo Congênito/diagnóstico , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos RetrospectivosRESUMO
AIM: To study the relationship between insulin sensitivity and growth response in short children born small for gestational age (SGA) treated with growth hormone (GH). METHODS: Randomized, open-label, 24-month intervention study in 40 short prepubertal SGA children [age (mean ± SD) 5.3 ± 1.5 years], who either remained untreated (n = 20) or were treated with GH (66 µg/kg/day; n = 20). Changes in fasting glucose, insulin, quantitative insulin sensitivity check index (QUICKI), IGF-1 and leptin after 1 and 2 years were studied. RESULTS: Mean height SDS increased from -3.3 ± 0.7 to -2.3 ± 0.7 after 1 year, and to -1.9 ± 0.7 after 2 years of treatment. QUICKI decreased significantly (p = 0.008) in the first year of GH treatment and stabilized in the second year. Baseline QUICKI was positively associated (r = 0.40; p < 0.05) with the change in height SDS in the first year. CONCLUSION: Higher insulin sensitivity at the start of GH therapy is associated with greater first-year growth response to GH, and could be a promising parameter in selecting prepubertal short SGA children for GH treatment. However, this finding needs to be confirmed in larger studies.
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Desenvolvimento Infantil/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Recém-Nascido Pequeno para a Idade Gestacional/crescimento & desenvolvimento , Resistência à Insulina/fisiologia , Fatores Etários , Estatura/efeitos dos fármacos , Estatura/fisiologia , Criança , Desenvolvimento Infantil/fisiologia , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Transtornos do Crescimento/metabolismo , Humanos , Recém-Nascido , Recém-Nascido Pequeno para a Idade Gestacional/metabolismo , Masculino , Puberdade/metabolismo , Puberdade/fisiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.
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Fosfatase Ácida/deficiência , Fosfatase Ácida/genética , Autoimunidade , Doenças do Desenvolvimento Ósseo/metabolismo , Encéfalo/metabolismo , Cálcio/química , Predisposição Genética para Doença , Isoenzimas/deficiência , Isoenzimas/genética , Doenças Autoimunes/enzimologia , Doenças Autoimunes/genética , Osso e Ossos/diagnóstico por imagem , Criança , Homozigoto , Humanos , Masculino , Mutação , Osteocondrodisplasias/enzimologia , Osteocondrodisplasias/genética , Osteopontina/metabolismo , Fosforilação , Radiografia , Fosfatase Ácida Resistente a TartaratoRESUMO
CONTEXT: In 46,XY disorders of sex development, 5α-reductase deficiency is rare and is not usually the first-intention diagnosis in newborn ambiguous genitalia, contrary to partial androgen insensitivity syndrome. Yet the cause of ambiguous genitalia may guide sex assignment, and rapid, precise diagnosis of 5α-reductase deficiency is essential. OBJECTIVE: The aim of the study was to describe relevant data for clinical diagnosis, biological investigation, and molecular determination from 55 patients with srd5A2 mutations identified in our laboratory over 20 yr to improve early diagnosis. SETTING: The study was performed at Montpellier University Hospital. PATIENTS: We studied a cohort of 55 patients with srd5A2 gene mutations. MAIN OUTCOME MEASURE(S): Genetic analysis of srd5A2 was conducted. RESULTS: Clitoromegaly (49.1%) and microphallus with various degrees of hypospadias (32.7%) were frequent phenotypes. Female external genitalia (7.3%) and isolated micropenis (3.6%) were rare. Seventy-two percent of patients were initially assigned to female gender; five of them (12.5%) switched to male sex in peripuberty. Over 72% of patients were considered for 5α-reductase deficiency diagnosis when the testosterone/dihydrotestosterone cutoff was 10. In 55 patients (with 20 having a history of consanguinity), we identified 33 different mutations. Five have never been reported: p.G32S, p.Y91H, p.G104E, p.F223S, and c.461delT. Homozygous mutations were present in 69.1% of cases, compound heterozygous mutations in 25.5%, and compound heterozygous mutations alone with the V89L polymorphism in 5.4%. Exons 1 and 4 were most affected, with 35.8 and 21.7% mutant alleles per exon, respectively. CONCLUSIONS: In the largest cohort to date, we demonstrate a wide spectrum of phenotypes and biological profiles in patients with 5α-reductase deficiency, whatever their geographical or ethnic origins.
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3-Oxo-5-alfa-Esteroide 4-Desidrogenase/deficiência , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Transtornos do Desenvolvimento Sexual/genética , Proteínas de Membrana/genética , Adolescente , Alelos , Substituição de Aminoácidos/genética , Síndrome de Resistência a Andrógenos/diagnóstico , Síndrome de Resistência a Andrógenos/genética , Criança , Pré-Escolar , Estudos de Coortes , DNA/genética , Di-Hidrotestosterona/sangue , Éxons/genética , Feminino , Genitália Feminina/anormalidades , Genitália Masculina/anormalidades , Genótipo , Heterozigoto , Humanos , Lactente , Masculino , Mutação , Fenótipo , Polimorfismo Genético/genética , Testosterona/sangue , Adulto JovemRESUMO
OBJECTIVE: Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI), a disorder caused by mutations in the vasopressin (AVP)-neurophysin II (NPII) gene, manifests gradually during early childhood with progressive polyuria and polydipsia. Patients are usually treated with synthetic AVP analog. If unlimited access to water is provided, prognosis is usually good even in the absence of specific treatment. In this study, we describe three families with adFNDI, in which growth failure was a prominent complaint, on the clinical and molecular level. DESIGN/METHODS: Histories from affected and unaffected family members were taken. Height and weight of index patients were recorded longitudinally. Patients underwent water deprivation tests, magnetic resonance imaging, and genetic analysis. One mutant was studied by heterologous expression in cell culture. RESULTS: A total of ten affected individuals were studied. In two of the three pedigrees, a novel mutation in the AVP-NPII gene was found. The index children in each pedigree showed growth retardation, which was the reason for referral in two. In these cases, water intake was tightly restricted by the parents in an attempt to overcome suspected psychogenic polydipsia and to improve appetite. Once the children were treated by hormone replacement, they rapidly caught up to normal weight and height. CONCLUSIONS: Genetic testing and appropriate parent counseling should be enforced in adFNDI families to ensure adequate treatment and avoid chronic water deprivation, which causes failure to thrive.
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Diabetes Insípido Neurogênico/genética , Transtornos do Crescimento/genética , Neurofisinas/genética , Vasopressinas/genética , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mutação , Linhagem , Poliúria/genética , Privação de ÁguaRESUMO
Hypoglycemia is one of the most common acute complications in the treatment of type 1 diabetes. It is the result of a mismatch between insulin dose, food consumed, and recent exercise. Hypoglycemia occurs more frequently in younger children and with lower HbA1c levels. Symptoms of hypoglycemia result from autonomic (adrenergic) activation and/or neurological dysfunction (neuroglycopenia). Severe hypoglycemia means that the child is having altered mental status and cannot assist in his care, is semiconscious or unconscious, or in coma--convulsions and may require parenteral therapy (glucagon or i.v. glucose). The blood glucose threshold for symptoms may be affected by antecedent hypoglycemia, duration of diabetes with decrease in neurohormonal counterregulatory responses. This phenomenon is termed hypoglycemia unawareness and is an important cause of severe hypoglycemia. Fortunately, there is absence of adverse effects of severe hypoglycemia on cognitive function in children with diabetes over 18 months, even if some controversies exist. Severe hypoglycemia is rapidly reversed by injection of glucagon 0.5 mg if < 25 kg, 1.0 mg if > 25 kg. In the hospital, intravenous infusion of glucose should be administered, e.g. glucose 10%, 2-5 mg/kg/min (1.2-3.0 ml/kg).
Assuntos
Diabetes Mellitus Tipo 1/complicações , Hipoglicemia/etiologia , Hipoglicemia/prevenção & controle , Adolescente , Criança , Diabetes Mellitus Tipo 1/sangue , Humanos , Hipoglicemia/complicações , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
Diabetic ketoacidosis results from relative or absolute deficiency of insulin and is a frequent metabolic emergency. It occurs in previously undiagnosed diabetes, in half of the cases in Europe, or is the consequence of a severe unbalance in a well-known diabetic patient, who, deliberately or not, does not take enough or not at all insulin. In population studies, the mortality rate in children ranges from 0,15% to 0,30%, cerebral edema accounts for 60% to 90%. Three stages are described: ketosis, ketoacidosis, ketoacidotic coma. This paper summarizes the physiopathology as well as the clinical and biological signs. It opens up an algorithm for the management of diabetic ketoacidosis and its complications and indicates prevention methods.
Assuntos
Cetoacidose Diabética/diagnóstico , Cetoacidose Diabética/terapia , Criança , Árvores de Decisões , Cetoacidose Diabética/fisiopatologia , HumanosRESUMO
Neonatal diabetes, transient (TND) or permanent (PND) is a rare disease, with a reported frequency of 1/300,000. If establishing a diagnosis is quite easy, treatment remains challenging during childhood. Understanding of physiopathology increased this last decade, as many mutations in genes playing critical roles in the development of pancreas, have been described: the most common are chromosome 6q anomalies in the case of TND, and mutations in KCNJ11 and ABCC8 genes encoding the subunit of the insulin cell potassium channel in the case of PND. We report on 2 peculiar stories: the first one is the unique case of a newborn with isodisomy of chromosome 6, methylmalonic acidemia and pancreatic beta cell agenesis, who died on the 16th day of life. The second one is the longest follow-up ever described, 38-year, of a permanent neonatal diabetes mellitus without complications, except for rare micro-aneurysms, in spite of insufficient metabolic control.
Assuntos
Diabetes Mellitus/congênito , Ilhotas Pancreáticas/anormalidades , Adulto , Aberrações Cromossômicas , Cromossomos Humanos Par 6 , Diabetes Mellitus/tratamento farmacológico , Seguimentos , Humanos , Hipoglicemiantes/uso terapêutico , Recém-Nascido , Insulina/uso terapêutico , MasculinoRESUMO
We describe the natural history of the RTSII phenotype in a 7-year-old boy who developed intrauterine and postnatal growth retardation, failure to thrive and persisting diarrhoea. The growth hormone stimulation test identified an isolated growth hormone deficiency. Since infancy, the patient manifested skin lesions characterized by a very mild poikilodermic-like appearance on the cheeks only, widespread café-au-lait spots and the absence of eyebrows and eyelashes. There was no cataract. Orthopaedic and radiologic work-up identified the absence of thumb anomaly and radial head luxation and patellar hypoplasia. Neurologic, cognitive milestones and intelligence were normal. The cytogenetic work-up did not show any anomaly. Based on this clinical presentation, we carried out a sequencing analysis of the RECQL4 gene, which is responsible for Rothmund-Thomson, RAPADILINO and Baller-Gerold syndromes and found a splice site mutation (IVS10-1G>A) and a nucleotide substitution in exon 12 (L638P). The mother was identified as a carrier for the substitution in exon 12 and the father for the splice site mutation, respectively. An analysis of the transcripts focused on the RECQL4 helicase domain: in the proband only those generated from the maternal L638 allele were present. This case report emphasizes the clinical overlap between RAPADILINO and Rothmund-Thomson syndromes within a continuum phenotypic spectrum. The distinctive set of clinical signs displayed by the patient may be accounted for by his unique combination of two different RECQL4 mutations. The molecular findings provide information that enhances our comprehension of genotype-phenotype correlations in RECQL4 diseases, enables a more precise genetic counseling to the parents and facilitates a more appropriate long-term follow-up to the affected child.