RESUMO
INTRODUCTION: Treatment with recombinant human growth hormone (rhGH) has been shown to improve adult height in pediatric patients with GH deficiency (GHD). However, reassessment of patients after they reach their final height shows some of them have permanent GH deficiency (PGHD), while others had a transient deficiency (TGHD). The study objective was to assess, in a cohort of pediatric patients with GHD, potential differences in response to treatment with rhGH depending on whether deficiency is permanent or transient. MATERIALS AND METHODS: A retrospective study of 89 patients with GHD, who were monitored from diagnosis to adult height. Clinical, auxological, radiographic and laboratory variables were collected at diagnosis, after the first year of treatment, and when they had reached their adult height. RESULTS: PGHD was found in 28% of patients. Initial height was -2.46 ± 0.86 SD and -2.24 ± 0.68 SD in subjects with PGHD and TGHD respectively. Peak GH level at diagnosis was 4.26 ± 2.78 and 6.20 ± 2.01 ng/mL (p < 0.01) in the PGHD and TGHD groups respectively. After the first year of treatment, increase in growth velocity was greater in the PGHD group: 4.33 ± 3.53 SD vs. 2.95 ± 2.54 SD in the PGHD group (p = 0.043). Final height was -0.81 ± 0.87 SD in the PGHD and -0.95 ± 0.83 SD in the TGHD group (p = 0.47). CONCLUSIONS: Patients with PGHD had a better short- and long-term response to rhGH. They also showed lower GH levels in stimulation tests at diagnosis, as previously reported.
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Nanismo Hipofisário/tratamento farmacológico , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Adolescente , Adulto , Estatura , Criança , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: To assess metabolic control in a paediatric T1D population in Spain and analyse the rate of severe acute decompensations and chronic complications. METHODS: Data from patients treated at eight paediatric diabetes units with experienced diabetes teams between June and December 2014 were analysed in an observational prospective study. Variables included: age, sex, diabetes duration, number of follow-up visits/year, anthropometrical data, insulin treatment modalities, mean annual HbA1c and the prevalence of acute and chronic complications. SPSS statistics 21.0 was used. RESULTS: A total of 853 patients (49.7% female) with a mean age of 12.1 ± 3.7 years were included. Anthropometric data were normal. Mean diabetes duration was 8 ± 3.4 years. Mean outpatient follow-up was 4.7 ± 0.04 visits/year. Twenty-five per cent were on continuous subcutaneous insulin infusion (CSII). Mean HbA1c was 7.3 ± 1% (56 ± 8 mmol/mol) and 66.6% had HbA1c < 7.5% (58 mmol/mol). HbA1c value correlated negatively with age at onset and positively with years of diabetes, number of visits/year and current age (F = 7.06; p = 0.01). Patients on CSII (n = 213) were younger, attended the outpatient clinic more frequently, were diagnosed earlier, had better metabolic control and had presented more severe hypoglycaemic episodes the previous year. The rate of severe decompensation (episodes/100 patients/year) was ketoacidosis 1.5 and severe hypoglycaemia 4.5. The prevalence of chronic complications was very low. CONCLUSIONS: Our data describe the good compliance of paediatric T1D patients treated at eight paediatric units in Spain following international standards of metabolic control.
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Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/terapia , Adolescente , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/epidemiologia , Cetoacidose Diabética/epidemiologia , Feminino , Humanos , Hipoglicemia/epidemiologia , Hipoglicemiantes/uso terapêutico , Lactente , Recém-Nascido , Insulina/administração & dosagem , Sistemas de Infusão de Insulina , Masculino , Espanha/epidemiologiaRESUMO
INTRODUCTION: The onset of obesity at young ages is strongly associated with the early development of type 2diabetes (T2D). The shape of the curves of glucose and insulin curves during an oral glucose tolerance test (OGTT) could predict the risk of developing T2D. OBJECTIVE: To analyse the morphology of the OGTT and determine T2D risk factors in a mainly Caucasian population of children and adolescents. METHODS: Observational retrospective study including 588 patients (309 males, 279 females) with a mean age of 11.1±2years, and of whom 90.3% were Caucasian. Risk factors for T2D were compared in patients with a monophasic or biphasic pattern during the performance of an OGTT, as well as anthropometric and biochemical variables, insulin resistance, and beta-cell function. RESULTS: The shape of the glucose curve was monophasic in 50.2% of patients (50.8% male), biphasic in 48.5% (47.6% males), and indeterminate in 1.3%. The monophasic pattern showed lower insulin-sensitivity and worse beta-cell function. Patients with a biphasic pattern had a higher BMI, waist circumference, and blood pressure, although the results were not significant. Latin-American patients had significantly lower serum glucose levels with higher insulin levels during the OGTT. CONCLUSIONS: The pattern of response to an OGTT reflects different metabolic phenotypes. Paediatric patients with a biphasic pattern have lower risk-profiling for T2D. The performing of an OGTT could be useful to implement early intervention strategies in children and adolescents with obesity, in order to prevent the development of pre-diabetes or T2D.
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Diabetes Mellitus Tipo 2/diagnóstico , Obesidade Infantil/metabolismo , Adolescente , Criança , Pré-Escolar , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Obesidade Infantil/complicações , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de RiscoRESUMO
We describe the case of a 7-year-old girl referred to our diabetes unit for hyperglycemia associated with facial dysmorphic features, intellectual disability, and cerebral cavernomas. Based on presence of anti islet antigen-2 (IA2) antibodies and a human leukocyte antigen of DR3/DR4/DQ2, the patient was initially diagnosed to be a case of type 1 diabetes mellitus. At follow-up, the very good metabolic control on a low insulin dose and negative IA2 antibodies led to a suspicion of glucokinase (GCK)-related maturity-onset diabetes of the young (MODY 2). This suspicion was substantiated in multiplex ligation-dependent probe amplification (MLPA) which showed a heterozygous GCK deletion (exons 1 to 12). However, the patient's parents did not have such a deletion and were clinically euglycemic. Given the clinical picture and the MLPA findings, array based comparative genomic hybridization was performed showing a monoallelic deletion of 7.23 Mb in the short arm of chromosome 7 (7p13-p12.1). The deleted intervals contain 39 genes listed in the Online Mendelian Inheritance in Man list, including GCK associated with MODY 2, CCM2 associated with type 2 cerebral cavernous malformations, IGFBP-3 associated with decrease in postnatal growth, and OGD associated with alpha-ketoglutarate dehydrogenase deficiency, with cognitive impairment and movement abnormalities. This previously unreported deletion was considered to explain the clinical picture of the patient. Also, the findings suggest that 7p13-p12.1 contains genes involved in intellectual disability and craniofacial development.
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Deleção Cromossômica , Cromossomos Humanos Par 7 , Anormalidades Craniofaciais/genética , Hiperglicemia/genética , Deficiência Intelectual/genética , Micrognatismo/genética , Costelas/anormalidades , Criança , Anormalidades Craniofaciais/complicações , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Hiperglicemia/complicações , Deficiência Intelectual/complicações , Micrognatismo/complicaçõesRESUMO
IGSF1 (Immunoglobulin Superfamily 1) gene defects cause central hypothyroidism and macroorchidism. However, the pathogenic mechanisms of the disease remain unclear. Based on a patient with a full deletion of IGSF1 clinically followed from neonate to adulthood, we investigated a common pituitary origin for hypothyroidism and macroorchidism, and the role of IGSF1 as regulator of pituitary hormone secretion. The patient showed congenital central hypothyroidism with reduced TSH biopotency, over-secretion of FSH at neonatal minipuberty and macroorchidism from 3 years of age. His markedly elevated inhibin B was unable to inhibit FSH secretion, indicating a status of pituitary inhibin B resistance. We show here that IGSF1 is expressed both in thyrotropes and gonadotropes of the pituitary and in Leydig and germ cells in the testes, but at very low levels in Sertoli cells. Furthermore, IGSF1 stimulates transcription of the thyrotropin-releasing hormone receptor (TRHR) by negative modulation of the TGFß1-Smad signaling pathway, and enhances the synthesis and biopotency of TSH, the hormone secreted by thyrotropes. By contrast, IGSF1 strongly down-regulates the activin-Smad pathway, leading to reduced expression of FSHB, the hormone secreted by gonadotropes. In conclusion, two relevant molecular mechanisms linked to central hypothyroidism and macroorchidism in IGSF1 deficiency are identified, revealing IGSF1 as an important regulator of TGFß/Activin pathways in the pituitary.
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Ativinas/metabolismo , Subunidade beta do Hormônio Folículoestimulante/metabolismo , Hipotireoidismo/patologia , Imunoglobulinas/genética , Proteínas de Membrana/genética , Receptores do Hormônio Liberador da Tireotropina/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Análise Mutacional de DNA , Subunidade beta do Hormônio Folículoestimulante/genética , Seguimentos , Deleção de Genes , Humanos , Hipotireoidismo/genética , Recém-Nascido , Masculino , Camundongos , Hipófise/metabolismo , Hipófise/patologia , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Receptores do Hormônio Liberador da Tireotropina/genética , Proteínas Smad/metabolismo , Testículo/metabolismo , Testículo/patologiaRESUMO
OBJECTIVE: The aims of the study are to evaluate the efficacy and safety of continuous subcutaneous insulin infusion (CSII) treatment in pre-school children with type I diabetes, and to assess whether the criteria of good metabolic control are achieved. METHOD: A review was performed on the medical charts of patient's<6 years of age who started CSII treatment between 2003 and 2014. The cohort consisted of 27 patients (mean age 4 (2.9-4.7) years, 56% males). An analysis was made including the age at onset, type I diabetes duration, HbA1c (HPLC, Menarini, normal value 5.1±0.31%), insulin dose (u/kg/day), number of capillary blood glucose measurements, number of baseline processes per day, % baseline/total insulin (B/TI), insulin ratios (I/HC) at different meals, severe hypoglycaemia (HS episodes/100 patients years), DKA events, percentages of normal blood glucose (70-180mg/dl), hyperglycaemia (>180mg/dl), and hypoglycaemia (<70mg/dl), mean blood glucose, standard deviation and coefficient of variation (SD/mean glucose ×100). Statistical analysis was performed using SPSS. RESULTS: HbA1c decreased from 6.9% (6.7-7.5) to 6.8% (6.4-7.1) after one year of CSII. Afterwards, it remained under 6.8% during the follow-up (median 5 years [3-6]). Prior to CSII, 74% of children had HbA1c levels < 7.5%. It increased to 96% after one year of CSII. Median blood glucose measurements /day was 10 (9-11). Total insulin dose did not change significantly. During the follow-up, there was one episode of DKA and one episode of HS. I/HC at breakfast were higher than at other meals (0.92 vs. 0.55, 0.6 and 0.5, respectively). CONCLUSIONS: CSII is effective and safe in pre-school children. It allows good metabolic control (based on Society for Paediatric and Adolescent Diabetes / American Diabetes Association criteria) to be achieved and maintained for long periods of time without an increase in adverse events.
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Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Criança , Pré-Escolar , Feminino , Fidelidade a Diretrizes , Humanos , Infusões Subcutâneas , Masculino , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
Neonatal diabetes mellitus (NDM) is a rare form of diabetes diagnosed within the first 6 months of life. Genetic studies have allowed the identification of several genes linked to the development of NDM; however, genetic causes for â¼20% of the cases remain to be clarified. Most cases of NDM involve isolated diabetes, but sometimes NDM appears in association with other pathological conditions, including autoimmune diseases. Recent reports have linked activating mutations in STAT3 with early-onset autoimmune disorders that include diabetes of autoimmune origin, but the functional impact of STAT3-activating mutations have not been characterized at the pancreatic ß-cell level. By using whole-exome sequencing, we identified a novel missense mutation in the binding domain of the STAT3 protein in a patient with NDM. The functional analyses showed that the mutation results in an aberrant activation of STAT3, leading to deleterious downstream effects in pancreatic ß-cells. The identified mutation leads to hyperinhibition of the transcription factor Isl-1 and, consequently, to a decrease in insulin expression. These findings represent the first functional indication of a direct link between an NDM-linked activating mutation in STAT3 and pancreatic ß-cell dysfunction.
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Hipotireoidismo Congênito/genética , Diabetes Mellitus/genética , Células Secretoras de Insulina/metabolismo , Insulina/biossíntese , Fator de Transcrição STAT3/genética , Animais , Western Blotting , Linhagem Celular , Imunoprecipitação da Cromatina , Colite Colagenosa/complicações , Hipotireoidismo Congênito/complicações , Feminino , Humanos , Recém-Nascido , Proteínas com Homeodomínio LIM/metabolismo , Mutação , Mutação de Sentido Incorreto , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de DNA , Fatores de Transcrição/metabolismo , TransfecçãoRESUMO
AIMS: To evaluate the efficacy and safety of Continuous Subcutaneous Insulin Infusion (CSII) in a pediatric cohort and to determine if the ISPAD/IDF/ADA criteria for good metabolic control are achieved during long periods of time. METHODS: Retrospective longitudinal study including ninety patients [10.5 (6.5-13.9) years of age, 58% males]. Age at debut, type 1 diabetes mellitus duration, pubertal stage, HbA1c, insulin dose, mean number of glycemic controls, number of basal rates, % basal/total insulin, severe hypoglycemia and diabetic ketoacidosis events were analyzed. Subgroup analysis based on age and pubertal stage was performed. RESULTS: HbA1c decreased from 6.9% [52 mmol/mol] to 6.7% [50 mmol/mol] after one year of CSII. Afterwards, it remained less than 7% during the follow-up period (median 3.5 ± 1.8 years (range 1-8). Prior to CSII, 76% of the subjects met ISPAD/ADA criteria. One year after initiating CSII, 96% of children had HbA1c<7.5%. Improvement in glycohemoglobin levels was most prominent in those patients with the highest HbA1c initial levels. Total insulin dose decreased from 0.89 to 0.73 UI/kg/day (p<0.001). Proportion of basal/total insulin changed significantly (47 to 42% (p<0.05)). Number of fractions of the basal rate increased from 5.6 ± 1.8 at one year of CSII to 6.7 ± 2.1 five years later. Incidence of severe hypoglycemic events decreased from 19 to 6.9 episodes/100 patient-year. Only 2 episodes of diabetic ketoacidosis occurred. CONCLUSIONS: CSII allows reaching ISPAD/IDF/ADA goals safely during an extended follow-up period in a diabetic pediatric cohort.
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Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Sistemas de Infusão de Insulina/estatística & dados numéricos , Insulina/administração & dosagem , Adolescente , Glicemia/metabolismo , Índice de Massa Corporal , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Cetoacidose Diabética/epidemiologia , Cetoacidose Diabética/etiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Incidência , Estudos Longitudinais , Masculino , Estudos Retrospectivos , Espanha/epidemiologiaRESUMO
AIM: The "T1D Exchange Clinic Registry" of 13.316 pediatric patients with type 1 diabetes (T1D) in U.S. recently revealed that most children have HbA1c values above target levels established by the American Diabetes Association (ADA) and the International Society for Pediatric and Adolescent Diabetes (ISPAD). The aim of this study is to assess the proportion of youngsters with T1D who meet the internationally accepted targets for good metabolic control of diabetes at a single, referral Pediatric Diabetes Center in Spain. PATIENTS AND METHODS: Cross-sectional study of 236 children and adolescents with T1D controlled at our Pediatric Diabetes Unit. We analyzed the compliance to metabolic goals set by ADA and ISPAD and the differences between patients treated with continuous subcutaneous insulin infusion and multiple daily injections. STATISTICS: SPSS™ version 21.0. RESULTS: Mean age: 12.6 ± 4.6 years old, mean age at diagnosis: 6.1 ± 4.3 years old and mean diabetes duration: 6.4 ± 4.3 years; 47% female. HbA1c average: 6.7 ± 0.7% (49.7 ± 7.6 mmol/mol). The age-specific ADA and ISPAD HbA1c targets were achieved by 93% and 91% of patients, respectively. Among pump users, 97%/97% met ADA/ISPAD HbA1c targets compared to 87%/88% of MDI users (p = 0.04/p = 0.03), without significant differences in the analysis by groups of age. Among participants, 95%, 62%, 95%, 98% and 89% met HDLc, LDLc, triglycerides, BP and BMI targets. CONCLUSIONS: Most patients in our children and adolescent cohort of T1D patients correctly achieve metabolic goals established by ADA and ISPAD with low incidence of hypoglycemia.
Assuntos
Logro , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/metabolismo , Objetivos , Insulina/administração & dosagem , Insulina/uso terapêutico , Sociedades Médicas/normas , Adolescente , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Criança , Estudos Transversais , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/epidemiologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Incidência , Injeções , Sistemas de Infusão de Insulina , Metabolismo dos Lipídeos/fisiologia , Masculino , Espanha/epidemiologiaRESUMO
AIM: To assess lung function in children and adolescents with type 1 diabetes mellitus (T1DM). PATIENTS AND METHODS: We conducted a case-control study of 100 patients with T1DM [median age 13 (10.6-14.7), 44% men, 23% prepubertal, and all nonsmokers] and 77 controls. None had evidence of lung disease or any other comorbidity. We performed pulmonary function tests, including spirometry [forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and FEV1/FVC ratio], plethysmography [total lung capacity (TLC), residual volume (RV), RV/TLC ratio, and airway resistance (Raw)], and diffusing capacity of carbon monoxide in the lung (TLCO), alveolar volume (AV), and TLCO/AV ratio. The duration of diabetes, degree of metabolic control, insulin dose, and presence of diabetic complications were registered. The χ²-test and analysis of variance were used to compare categorical and quantitative variables, respectively. RESULTS: The duration of diabetes was 6.2±3.8 years with a median HbA1c of 7.08±0.4%. FEV1/FVC ratio was found to be significantly higher in patients with TIDM than in controls. Patients with diabetes also had a nonsignificant trend towards lower FVC, FEV1, Raw, and TLCO, and higher RV, TLC, and RV/TLC than controls. There were no differences in pulmonary function based on duration of disease or metabolic control. We found differences in pulmonary evaluation when pubertal stage was analyzed. CONCLUSIONS: The lung is functionally involved in children with T1DM. Pubertal development stage influences the evaluation of lung function.
Assuntos
Diabetes Mellitus Tipo 1/fisiopatologia , Pulmão/fisiopatologia , Adolescente , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Feminino , Humanos , Pneumopatias/epidemiologia , Pneumopatias/etiologia , Pneumopatias/fisiopatologia , Masculino , Puberdade , Testes de Função RespiratóriaRESUMO
Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in the CF transmembrane conductance regulator (CFTR). CFTR is primarily present in epithelial cells of the airways, intestine and in cells with exocrine and endocrine functions. Mutations in the gene encoding the channel protein complex (CFTR) cause alterations in the ionic composition of secretions from the lung, gastrointestinal tract, liver, and also the pancreas. CF-related diabetes (CFRD), the most common complication of CF, has a major detrimental impact on pulmonary function, nutrition and survival. Glucose derangements in CF seem to start from early infancy and, even when the pathophysiology is multifactorial, insulin insufficiency is clearly a major component. Consistently, recent evidence has confirmed that CFTR is an important regulator of insulin secretion by islet ß-cells. In addition, several other mechanisms were also recognized from cellular and animals models also contributing to either ß-cell mass reduction or ß-cell malfunction. Understanding such mechanisms is crucial for the development of the so-called 'transformational' therapies in CF, including the preservation of insulin secretion. Innovative therapeutic approaches aim to modify specific CFTR mutant proteins or positively modulate their function. CFTR modulators have recently shown in vitro capacity to enhance insulin secretion and thereby potential clinical utility in CFDR, including synergistic effects between corrector and potentiator drugs. The introduction of incretins and the optimization of exocrine pancreatic replacement complete the number of therapeutic options of CFRD besides early diagnosis and implementation of insulin therapy. This review focuses on the recently identified pathogenic mechanisms leading to CFRD relevant for the development of novel pharmacological avenues in CFRD therapy.
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Fibrose Cística/complicações , Fibrose Cística/terapia , Diabetes Mellitus/etiologia , Diabetes Mellitus/terapia , Fibrose Cística/diagnóstico , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Diabetes Mellitus/diagnóstico , Diagnóstico Precoce , Estudos de Associação Genética , Humanos , Células Secretoras de Insulina/patologia , Mutação de Sentido IncorretoRESUMO
Cystic fibrosis related diabetes (CFRD) is a strong determinant for lung function decline and increased mortality. Insulin treatment of CFRD is reportedly beneficial for this situation. We report on the long-term impact of insulin treatment of CFRD on pulmonary function and nutritional status in a CF male patient since diagnosis of diabetes. We report the case of a patient diagnosed with CF at the age of 16. Two years later, he experienced a rapidly evolving decrease in pulmonary function, some months later criteria were met warranting lung transplantation. Concomitantly, he was diagnosed with CFRD and insulin therapy was started. Lung function (spirometry), nutritional status (body mass index) and metabolic control (HbA(1c)) were determined every 3 months. After the introduction of insulin treatment, pulmonary function and nutritional status progressively improved and good glycemic control was achieved. The significant and sustained improvement in pulmonary function allowed for the patient's withdrawal from the lung transplantation program within 4 months, a situation which has been maintained until now, 8 years later. The long follow-up of our patient documents the rapid and prolonged beneficial effect of proper metabolic control of CFRD on the respiratory deterioration in CF.
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Fibrose Cística/complicações , Fibrose Cística/tratamento farmacológico , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Estado Nutricional , Adolescente , Fibrose Cística/sangue , Fibrose Cística/fisiopatologia , Complicações do Diabetes/sangue , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/sangue , Diabetes Mellitus/fisiopatologia , Hemoglobinas Glicadas/análise , Humanos , Masculino , Espirometria , Fatores de TempoRESUMO
Noonan syndrome (NS) and neurofibromatosis type 1 (NF1) are well-defined entities. The association of both disorders is called neurofibromatosis-Noonan syndrome (NFNS), a disorder that has been related to mutations in the NF1 gene. Both NS and NFNS display phenotypic overlapping with LEOPARD syndrome (LS), and differential diagnosis between these two entities often represents a challenge for clinicians. We report on three patients (two brothers and a not-related patient) diagnosed as having NFNS. They fulfilled NF1 diagnostic criteria and had some features of NS. The three of them had hypertophic cardiomyopathy while neurofibromas, Lisch nodules, and unidentified bright objects on MRI were absent. PTPN11 gene assays revealed a T468M mutation, typical of LS. Thorough clinical examinations of the patients revealed multiple lentigines, which were considered to be freckling in the initial evaluation. We conclude that NF1 clinical criteria should be used with caution in patients with features of NS. Patients with hyperpigmented cutaneous spots associated with cardiac anomalies, even if fulfilling the minimal NF1 criteria for diagnosis, should be strongly considered for LS diagnosis.
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Síndrome LEOPARD/diagnóstico , Neurofibromatose 1/diagnóstico , Síndrome de Noonan/diagnóstico , Adolescente , Criança , Análise Mutacional de DNA , Diagnóstico Diferencial , Humanos , Lactente , Síndrome LEOPARD/genética , Masculino , Linhagem , Proteína Tirosina Fosfatase não Receptora Tipo 11/genéticaRESUMO
OBJECTIVE: Couples at risk of severe congenital adrenal hyperplasia (CAH) may be offered prenatal treatment or preimplantation diagnosis. However, proper genetic counselling requires the accurate identification of apparently 'mild alleles' in partners of CAH-carriers/patients. METHODS: CYP21A2 gene analyses were performed in 255 patients with severe 21-hydroxylase deficiency (21-OHD), 94 with mild 21-OHD, 752 parental samples, 233 clinically unaffected partners and 253 historic DNA samples. GENSCAN and ClustalX2.0 software were used for in silico analyses, and Epidat 3.1 software for statistical calculations. RESULTS: Twenty-seven partners were carriers of p.Val282Leu (alias p.Val281Leu, allele frequency 11.7%, 7.4-16.1). 'Val282Leu alleles' were detected in 30 patients with salt-wasting (SW) disease, 21 with other pseudogene-derived and rare coding cis severe mutations, and 9 without. These CYP21A2 genes were compared to those of 94 fully characterized patients with mild deficiency carrying p.Val282Leu in compound heterozygosity with a severe allele. A rare intronic variant, c.292+5G>A, was detected in the nine 'severe Val282Leu alleles' and that was not seen in mild p.Val282Leu alleles, in other deficient alleles or in normal chromosomes. The in silico documented effect on splicing and the clinical association (p < 0.0001) confirmed p.Val282Leu; c.292+5G>A as a severe allele. CONCLUSION: As only severe alleles require clinical intervention, CAH-carrier detection of p.Val282Leu should be followed by the analysis of c.292+5G>A.
Assuntos
Hiperplasia Suprarrenal Congênita/enzimologia , Heterozigoto , Diagnóstico Pré-Natal/métodos , Esteroide 21-Hidroxilase/genética , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/genética , Alelos , DNA/química , DNA/genética , Feminino , Aconselhamento Genético , Variação Genética , Humanos , Recém-Nascido , Masculino , Repetições de Microssatélites , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo ÚnicoRESUMO
The aim of this study is to determine the proper initial dose adjustment when switching from multiple daily injections to continuous subcutaneous insulin infusion for type-1 diabetic pediatric patients. Our hypothesis is that the insulin adjustment varies depending on the pubertal status and the previous long-acting insulin used. Charts of 60 patients were reviewed. Data regarding insulin dose, type of insulin administrated, HbA1c, BMI, severe hypoglycemia and DKA events were collected during the previous year and after 6 weeks of pump therapy. In the prepubertal patients the reduction was 19% (26% if the previous insulin used was detemir). Pubertal patients experienced a decrease of 26%, and the detemir group 33%. The ratio long acting-basal/short acting-bolus insulin changed from 1.26 ± 0.84 to 0.93 ± 0.46 (P < 0.05). The total daily insulin dose needs to be decreased. Basal insulin constitutes 40-45% in prepubertal and 45-50% in pubertal patients. The reduction is different depending on the previous long-acting insulin used; being greater if the insulin is detemir.
Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Cálculos da Dosagem de Medicamento , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/metabolismo , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Lactente , Injeções Subcutâneas , Sistemas de Infusão de Insulina , Insulina de Ação Prolongada/administração & dosagem , Masculino , Estudos RetrospectivosAssuntos
Puberdade Precoce/etiologia , Síndrome de Turner/complicações , Criança , Feminino , HumanosRESUMO
OBJECTIVE: To report a case of a 46,XX male with an intratubular undifferentiated germ cell neoplasia within an extra-abdominal gonad. DESIGN: Case report. SETTING: Molecular, cytogenetic, pathologic, and clinical units of three tertiary hospitals. PATIENT(S): A male with ambiguous genitalia at birth and descended testes observed in a pediatric endocrinology setting. INTERVENTION(S): Physical examination, hormonal assays, cytogenetic investigation, molecular analysis, surgical intervention for biopsies and bilateral orchiectomy, and pathologic evaluation. MAIN OUTCOME MEASURE(S): Pathologic evaluation with immunostaining for placental alkaline phosphatase and C-kit. RESULT(S): Conventional chromosome analysis revealed a 46,XXq- karyotype, and fluorescence in situ hybridization experiments with the SRY probe found a signal at the short arm of the deleted X chromosome. Molecular analysis indicated the presence of a portion of the short arm of the Y chromosome including the proto-oncogene TSPY. Pathologic evaluation of the gonads revealed an intratubular undifferentiated germ cell neoplasia. CONCLUSION(S): This is the first case of a 46,XX male with descended testes in whom an intratubular undifferentiated germ cell neoplasia developed. When proposals of management in this subgroup of disorders of sexual differentiation are formulated, the risk of germ cell malignancy must be taken into account.
Assuntos
Diferenciação Celular , Disgenesia Gonadal 46 XX/genética , Neoplasias Embrionárias de Células Germinativas/patologia , Neoplasias Testiculares/patologia , Testículo/patologia , Adolescente , Fosfatase Alcalina , Proteínas de Ciclo Celular/genética , Proteínas Ligadas por GPI , Humanos , Isoenzimas/análise , Masculino , Neoplasias Embrionárias de Células Germinativas/química , Neoplasias Embrionárias de Células Germinativas/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-kit/análise , Proteína da Região Y Determinante do Sexo/genética , Neoplasias Testiculares/química , Neoplasias Testiculares/genética , Testículo/químicaRESUMO
CONTEXT: The GNAS gene encodes the alpha-subunit of the stimulatory G proteins, which play a crucial role in intracellular signal transduction of peptide and neurotransmitter receptors. Heterozygous inactivating maternally inherited mutations of GNAS (including translation initiation mutations, amino acid substitutions, nonsense mutations, splice site mutations and small insertions or deletions) lead to a phenotype in which Albright hereditary osteodystrophy is associated with pseudohypoparathyroidism type Ia. OBJECTIVE: We sought to identify the molecular defect in a patient who was thought to have PHP-Ia. METHODS AND RESULTS: The GNAS gene of a 5-year-old boy with brachydactily, mental retardation, pseudohypoparathyroidism and congenital hypothyroidism was investigated. We found a heterozygous inversion of exon 2 and part of intron 1 of de novo origin. Molecular studies of cDNA from blood RNA demonstrated that both the normal and the mutant variants were stable and that new splice-sites were generated. CONCLUSION: This report demonstrates the first evidence for an inversion at the GNAS gene responsible of pseudohypoparathyroidism type Ia.
Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Pseudo-Hipoparatireoidismo/genética , Sequência de Bases , Pré-Escolar , Cromograninas , Hipotireoidismo Congênito/complicações , Hipotireoidismo Congênito/genética , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Masculino , Modelos Biológicos , Dados de Sequência Molecular , Mutação/fisiologia , Conformação de Ácido Nucleico , Linhagem , Polidactilia/complicações , Polidactilia/genética , Pseudo-Hipoparatireoidismo/congênitoRESUMO
BACKGROUND AND OBJECTIVE: Hypogonadotropic hypogonadism and anosmia characterize Kallmann's syndrome, whose X-linked form is due to mutations in the KAL1 gene. We studied a family with 6 affected members. PATIENTS AND METHOD: We compare their clinical (chryptorchidism, micropenis, puberty, associated malformations), analytical (gonadotrophin releasing hormone test, and human chorionic gonadotropin test), genetic (cariotype), and radiological data of the described familiar cases with other reported sporadic cases. RESULTS: The described cases carried the R191X mutation. We found phenotypic heterogeneity between the patients. CONCLUSIONS: We report the first familiar cases of Kallmann's syndrome due to the R191X mutation. Probably other genes and/or epigenetic factors determine the phenotype.