RESUMO
CONTEXT: Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. OBJECTIVE: To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. PATIENTS: 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. METHODS: SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). RESULTS: Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. CONCLUSIONS: Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Metabolismo Energético/fisiologia , Mutação , Fator Esteroidogênico 1/genética , Esteroides/biossíntese , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Masculino , LinhagemRESUMO
BACKGROUND: FSH-secreting pituitary adenomas are extremely rare in children and are seldom associated with clinical manifestations of high serum gonadotrophin levels. Thus, most patients have a late presentation, usually as macroadenomas. CASE REPORTS: Two different clinical forms of presentation of FSH-secreting pituitary adenomas are reported: one in a 12-year-old boy with macroorchidism due to a pituitary microadenoma, probably FSH-secreting, and the other in a 15-year-old boy with panhypopituitarism due to an FSH-producing macroadenoma. Both patients presented slightly high or high FSH with low LH and high inhibin B levels. In the first case, the microadenoma was treated medically with cabergoline, which failed to reduce FSH and inhibin B levels. No radiological progression has been observed despite increasing testicular volume. In the second case, surgery was performed on the macroadenoma, leading to a decrease in FSH and inhibin B levels. The patient developed severe hypothalamic obesity and is currently under treatment with somatostatin. CONCLUSIONS: FSH-secreting pituitary tumors have an extremely variable clinical expression. The discrepancy between normal or slightly increased FSH and low LH values, together with high inhibin B levels, strongly suggests FSH hypersecretion which should be studied.
Assuntos
Adenoma/diagnóstico , Hormônio Foliculoestimulante/metabolismo , Hipopituitarismo/etiologia , Neoplasias Hipofisárias/diagnóstico , Doenças Testiculares/etiologia , Adenoma/sangue , Adenoma/patologia , Adenoma/fisiopatologia , Adolescente , Criança , Hormônio Foliculoestimulante/sangue , Humanos , Hiperplasia/etiologia , Hiperplasia/patologia , Subunidades beta de Inibinas/sangue , Hormônio Luteinizante/sangue , Masculino , Neoplasias Hipofisárias/sangue , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/fisiopatologia , Doenças Testiculares/patologia , Testículo/patologiaRESUMO
A rare case of glycogen storage disease type III with unusually absent ketone body production during hypoglycemia is presented. A 10-month-old boy presented with asymptomatic hepatomegaly. GOT/GPT 2555/1160 IU/L, CK 302 IU/L, triglycerides 1223 mg/dL, cholesterol 702 mg/dL and uric acid 7.9 mg/dL. After a 9-hour fast, glucose was 27 mg/dL and adequate lipolysis without ketogenesis was observed (total/free carnitine 34.5/20 micromol/L, free fatty acids 1620 micromol/L and beta-hydroxybutyrate 172 micromol/L). Result of MCT (medium-chain triglycerides) load test: basal hydroxybutyrate 29 micromol/L rose to 5748 micromol/L. Treatment with a fat-restricted diet supplemented with formula containing MCT was initiated and the patient presented a satisfactory initial evolution. Three months later, CK were 3000 IU/L. Muscle biopsy was diagnostic of glycogenosis. Enzymatic activity in skin fibroblasts was 0% for amylo-1,6-glucosidase. The diagnosis of glycogenosis type III was established. Echocardiography performed at that time showed non-obstructive ventricular hypertrophy. Until now hypoketosis during hypoglycemia has only been described in glycogenosis type I.
Assuntos
Doença de Depósito de Glicogênio Tipo III/diagnóstico , Cetose/diagnóstico , Doenças Assintomáticas , Testes de Química Clínica , Dietoterapia , Doença de Depósito de Glicogênio Tipo III/complicações , Doença de Depósito de Glicogênio Tipo III/metabolismo , Hepatomegalia/etiologia , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Humanos , Hipoglicemia/etiologia , Hipoglicemia/metabolismo , Hipoglicemia/patologia , Lactente , Cetose/etiologia , Cetose/metabolismo , Masculino , Músculo Esquelético/enzimologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologiaRESUMO
BACKGROUND AND OBJECTIVE: "Niñ@s en movimiento" is an interventional programme (11 weekly sessions of 90 minutes' duration) designed to modify psychological aspects and nutritional and life style habits in obese children aged 6-12 and in their families. PATIENTS AND METHOD: Eighty-one obese children (46 girls, 35 boys), 6-12 years of age were included. Body mass index (BMI), Mediterranean diet (KIDMED), anxiety (CMAS-R) and depression tests (CDS) were evaluated in at the start and end of the programme. RESULTS: In 72 patients (88.9%) BMI decreased from a mean (standard deviation) 27.8 (3.8) to 26.5 (3.6) kg/m(2) (p < 0.001) and from 3.3 (1,4) to 2.6 (1.2) kg/m(2) (p < 0.001). Diary fruit intake increased from 63.3% to 82.7% of patients (p < 0.001) and greens from 45.6% to 88,2% of patients (p < 0.001). Breakfast intake of industrial cakes decreased from 17.7% to 1.3% of patients (p < 0.001) and the number of patients who skipped breakfast changed from 36.7% to 11.7% (p < 0.001). Anxiety and depression scores fell from 53.46 (27.69) to 47.22 (26.3) (p < 0.03) and from 29.68 to 16.88 (p < 0.001), respectively. The relative risks of suffering a depressive or anxiety disorder dropped from 38.8% to 22.5% (p < 0.001) and from 15% to 8.2% (p = 0.01) of the patients respectively. CONCLUSIONS: Application of the "Niñ@s en movimiento" programme leads to a decrease in BMI and in anxiety and depression scores and an increase in Mediterranean diet score.
Assuntos
Pesos e Medidas Corporais , Dieta Mediterrânea , Estilo de Vida , Obesidade/psicologia , Obesidade/terapia , Ansiedade/etiologia , Criança , Depressão/etiologia , Feminino , Humanos , Masculino , Obesidade/complicações , Sobrepeso/psicologia , Sobrepeso/terapiaRESUMO
OBJECTIVE: To report the long-term follow-up of three nonpancreatectomized patients with persistent hyperinsulinemic hypoglycemia of infancy due to mutations in the ABCC8 gene. RESEARCH DESIGN AND METHODS: Oral glucose tolerance test (OGTT) and venous 24-h glucose-insulin profile were performed yearly from adolescence. RESULTS: Patient 1 (now aged 31 years) developed insulin-dependent diabetes at the age of 25 years. In patient 2 (now aged 17 years), impaired fasting glucose and a diabetic OGTT response with normal A1C values have been observed since the age of 10 years. In patient 3 (now aged 24 years), intolerant OGTT response and hyperglycemic episodes with normal A1C have been observed since the age of 16 years. All patients presented relatively low insulin levels during hyperglycemia, normal BMI, and negative autoantibodies (GAD antibody, insulinoma-associated protein 2, and islet cell antibody). CONCLUSIONS: Development of glucose metabolism impairment ranging from glucose intolerance to insulin-dependent diabetes is observed in the evolution of these patients.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Hiperinsulinismo Congênito/genética , Intolerância à Glucose/genética , Mutação , Canais de Potássio Corretores do Fluxo de Internalização/genética , Receptores de Droga/genética , Adolescente , Adulto , Criança , Seguimentos , Teste de Tolerância a Glucose , Humanos , Lactente , Insulina/sangue , Masculino , Receptores de SulfonilureiasRESUMO
OBJECTIVE: GH1 gene presents a complex map of single nucleotide polymorphisms (SNPs) in the entire promoter, coding and noncoding regions. The aim of the study was to establish the complete map of GH1 gene SNPs in our control normal population and to analyse its association with adult height. DESIGN, SUBJECTS AND MEASUREMENTS: A systematic GH1 gene analysis was designed in a control population of 307 adults of both sexes with height normally distributed within normal range for the same population: -2 standard deviation scores (SDS) to +2 SDS. An analysis was performed on individual and combined genotype associations with adult height. RESULTS: Twenty-five SNPs presented a frequency over 1%: 11 in the promoter (P1 to P11), three in the 5'UTR region (P12 to P14), one in exon 1 (P15), three in intron 1 (P16 to P18), two in intron 2 (P19 and P20), two in exon 4 (P21 and P22) and three in intron 4 (P23 to P25). Twenty-nine additional changes with frequencies under 1% were found in 29 subjects. P8, P19, P20 and P25 had not been previously described. P6, P12, P17 and P25 accounted for 6.2% of the variation in adult height (P = 0.0007) in this population with genotypes A/G at P6, G/G at P6 and A/G at P12 decreasing height SDS (-0.063 +/- 0.031, -0.693 +/- 0.350 and -0.489 +/- 0.265, Mean +/- SE) and genotypes A/T at P17 and T/G at P25 increasing height SDS (+1.094 +/- 0.456 and +1.184 +/- 0.432). CONCLUSIONS: This study established the GH1 gene sequence variation map in a normal adult height control population confirming the high density of SNPs in a relatively small gene. Our study shows that the more frequent SNPs did not significantly contribute to height determination, while only one promoter and two intronic SNPs contributed significantly to it. Studies in larger populations will have to confirm the associations and in vitro functional studies will elucidate the mechanisms involved. Systematic GH1 gene analysis in patients with growth delay and suspected GH deficiency/insufficiency will clarify whether different SNP frequencies and/or the presence of different sequence changes may be associated with phenotypes in them.