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1.
Clin Endocrinol (Oxf) ; 79(3): 371-8, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23311724

RESUMO

OBJECTIVE: A high prevalence (60%) of central adrenal insufficiency (CAI) has been reported in Prader-Willi syndrome (PWS) using the metyrapone test. We have assessed CAI in adults with PWS using the low-dose short synacthen test (LDSST). DESIGN: Basal cortisol and ACTH, and 30-min cortisol after the administration of 1 µg synacthen, were determined in 53 PWS adults (33 females). A peak cortisol value of ≥500 nmol/l was taken as normal. Hormonal profiles were analysed in relation to gender, genotype and phenotype. Deficient patients were retested by high-dose short synachten test (HDSST) or a repeat LDSST. RESULTS: Mean ± SD basal cortisol and ACTH were 336·6 ± 140·7 nmol/l and 4·4 ± 3·7 pmol/l respectively. Cortisol rose to 615·4 ± 135·0 nmol/l after LDSST. Eight (15·1%) patients had a peak cortisol response <500 nmol/l, with a lower mean ± SD (range) basal cortisol of 184·9 ± 32·0 (138·0-231·7) compared with 364·1 ± 136·6 (149·0-744·5) in normal responders (P < 0·001). Seven of the eight patients underwent retesting, with 4 (7·5%) showing persistent suboptimal responses. Basal and peak cortisol correlated in females (r = 0·781, P < 0·001). Logistic regression revealed that only female gender and baseline cortisol were predictors of cortisol peaks (adjusted R square 0·505). CONCLUSIONS: Although CAI can be part of the adult PWS phenotype, it has a lower prevalence (7·5%) than previously reported. Clinicians are advised to test PWS patient for CAI. Our study also shows that basal cortisol is closely correlated with adrenal response to stimulation, indicating that its measurement may be helpful in selecting patients for LDSST.


Assuntos
Insuficiência Adrenal/complicações , Insuficiência Adrenal/diagnóstico , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/diagnóstico , Adolescente , Insuficiência Adrenal/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Feminino , Genótipo , Humanos , Hidrocortisona/sangue , Masculino , Pessoa de Meia-Idade , Fenótipo , Síndrome de Prader-Willi/sangue , Análise de Regressão , Resultado do Tratamento , Adulto Jovem
2.
Clin Endocrinol (Oxf) ; 76(6): 843-50, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22150958

RESUMO

OBJECTIVE: A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader-Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low-Dose Tetracosactrin Stimulation Test (LDTST), 1 µg] or standard-dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS. DESIGN: Cross-sectional evaluation of adrenal stress response to LDTST in a PWS cohort of a tertiary care referral centre. PATIENTS: Eighty-four children with PWS. MEASUREMENTS: Assessment of adrenal response by morning cortisol and ACTH dosage, and 1-µg tetracosactrin test. Response was considered appropriate when cortisol reached 500 nm; below this threshold, patients were submitted to a second test. Responses were correlated with the patients' clinical and molecular characteristics to assess genotype-phenotype correlation. RESULTS: Pathological cortisol peak responses to the LDTST were registered in 12 patients (14.3%) who had reduced basal (169.4 ± 83.3 nm) and stimulated (428.1 ± 69.6 nm) cortisol levels compared to patients with normal responses (367.1 ± 170.6 and 775.9 ± 191.3 nm, P < 0.001). Body mass index standard deviation score was negatively correlated with basal and peak cortisol levels (both P < 0.001), and the patients' ages (P < 0.001). In patients with deletion on chromosome 15, the cortisol peak was significantly lower than that in uniparental disomy (UPD) cases (P = 0.030). At multiple regression analysis, the predictors of peak response were basal cortisol, age, and UPD subclass (r(2) = 0.353, P < 0.001). Standard-dose (250 µg) tetracosactrin test confirmed CAI in 4/12 patients (4.8% of the cohort). CONCLUSIONS: Our results support the hypothesis that, albeit rare, CAI may be part of the PWS in childhood.


Assuntos
Insuficiência Adrenal/fisiopatologia , Síndrome de Prader-Willi/fisiopatologia , Adolescente , Insuficiência Adrenal/sangue , Hormônio Adrenocorticotrópico/sangue , Índice de Massa Corporal , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Hidrocortisona/sangue , Lactente , Recém-Nascido , Masculino , Síndrome de Prader-Willi/sangue , Análise de Regressão
3.
Arch Pediatr Adolesc Med ; 164(8): 714-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20679162

RESUMO

OBJECTIVE: To investigate a cohort of pediatric patients with thyroid nodules, defining histotype frequency and differences between subjects with hyperthyroidism and euthyroidism and benign and malignant nodules. DESIGN: Retrospective cohort. SETTING: Consecutive cases from 9 Italian pediatric endocrinology centers for the last 10 years. Patients One hundred twenty pediatric patients with thyroid nodules. Intervention Doppler ultrasonography was performed in 71 subjects; scintiscan, in 56; fine-needle aspiration biopsy in 104; and 63 underwent surgery. MAIN OUTCOME MEASURES: The differences in clinical, laboratory, and ultrasonographic data between patients with hyperthyroidism and euthyroidism and malignant and benign nodules were evaluated. RESULTS: One hundred fourteen patients had euthyroidism and 6, hyperthyroidism. The latter had more compressive signs (P=.003), greater nodule diameter (P=.02), intranodular vascularization pattern (P=.01), and increased scintiscan uptake (P<.001). Fine-needle aspiration biopsy disclosed benign lesions in 77 cases, malignant lesions in 19, and "suspicious" lesions in 8. Histologic examination disclosed 1 Hurthle cell and 5 follicular adenomas in patients with hyperthyroidism, whereas in patients with euthyroidism, 33 hyperplasic nodules, 19 carcinomas (14 papillary, 3 follicular, and 2 medullary), 3 follicular and 1 Hurthle cell adenoma, and 1 teratoma were detected. Nine patients had enhanced scintiscan uptake. Among the patients with euthyroidism, malignancies more frequently had palpable lymph nodes (P<.001), compressive signs (P=.004), microcalcifications (P<.001), intranodular vascularization (P=.01), and lymph node alterations (P<.001). CONCLUSIONS: The diagnosis of pediatric thyroid nodules should be based on a stepwise evaluation that includes clinical, laboratory, and radiographic modalities. While laboratory assessments establish thyroid function, ultrasonographic imaging identifies clinically unapparent nodules and provides detailed nodule characterization for suspected malignant lesions. Scintiscan in patients with hyperthyroidism and fine-needle aspiration biopsy in patients with euthyroidism represent the next logical step.


Assuntos
Nódulo da Glândula Tireoide/diagnóstico , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Masculino , Estudos Retrospectivos
4.
J Clin Invest ; 118(6): 2148-56, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18451997

RESUMO

Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.


Assuntos
Proteínas de Ligação a DNA/biossíntese , Diabetes Mellitus/genética , Proteínas de Choque Térmico/biossíntese , Insulina/genética , Insulina/fisiologia , Chaperonas Moleculares/biossíntese , Mutação , Proteínas Nucleares/biossíntese , Proinsulina/biossíntese , Sequência de Aminoácidos , Análise Mutacional de DNA , Chaperona BiP do Retículo Endoplasmático , Feminino , Heterozigoto , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Linhagem , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição , Proteína 1 de Ligação a X-Box
5.
Am J Med Genet A ; 146A(7): 861-72, 2008 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-18203198

RESUMO

Twenty-five medical centers and the Prader-Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4-46.7). Two hundred thirty-eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity-related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death.


Assuntos
Síndrome de Prader-Willi/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Cromossomos Humanos Par 15 , Feminino , Hormônio do Crescimento/uso terapêutico , Humanos , Hibridização in Situ Fluorescente , Lactente , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Síndrome de Prader-Willi/complicações , Síndrome de Prader-Willi/tratamento farmacológico , Síndrome de Prader-Willi/fisiopatologia
6.
Clin Dysmorphol ; 17(1): 35-39, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18049079

RESUMO

Silver-Russell syndrome (SRS) is clinically variable although most cases have several common signs. Different chromosomes and chromosomal regions have been associated with SRS. Maternal uniparental disomy (UPD) of chromosome 7 is responsible for 5-10% of cases, probably because of an imbalance between maternal and paternal imprinted genes and more recently maternal duplication or epimutations in the 11p15 imprinted region have been described. To date, only two patients with maternal UPD7 and a mosaic condition for a supernumerary ring 7 marker have been reported, and we here report a further case. Standard QFQ banding of lymphocytes as well as fluorescence in-situ hybridization analyses were performed to identify and characterize the supernumerary marker. UPD testing was performed on both the patient's and parents' DNA using chromosome 7 microsatellite markers. The patient demonstrated a ring in about 4% of the analysed cells. On the basis of cytogenetic and molecular results, break points were tentatively identified as 7p11.2 and 7q21. Maternal hetero-/iso-UPD and a paternal origin for the supernumerary ring were demonstrated. Clinical data comparison between our patient who has a SRS phenotype and cases with hetero-/iso-UPD7 mat and mosaicism for a paternally derived chromosome 7 ring and previously reported ring 7 cases suggest that the SRS phenotype is probably because of the UPD rather than to the partial trisomy.


Assuntos
Anormalidades Múltiplas/genética , Cromossomos Humanos Par 7 , Dissomia Uniparental , Criança , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , Síndrome
7.
Eur J Nucl Med Mol Imaging ; 34(9): 1498-503, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17318546

RESUMO

PURPOSE: Prompt initiation of L-thyroxine therapy in neonates with congenital hypothyroidism (CH) often prevents the performance of functional studies. Aetiological diagnosis is thus postponed until after infancy, when the required investigations are performed after L-thyroxine withdrawal. The aim of this study was to verify the efficacy and safety of new protocols for rhTSH (Thyrogen) testing during L-thyroxine replacement in the differential diagnosis of CH. METHODS: Ten CH patients (15-144 months old) were studied. Seven had neonatal evidence of gland in situ at the ultrasound examination performed at enrolment and received two rhTSH injections (4 microg/kg daily, i.m.) with 123I scintigraphy and perchlorate test on day 3. Three patients with an ultrasound diagnosis of thyroid dysgenesis received three rhTSH injections with 123I scintigraphy on days 3 and 4. TSH and thyroglobulin (Tg) determinations were performed on days 1, 3 and 4, and neck ultrasound on day 1. RESULTS: rhTSH stimulation caused Tg levels to increase in eight cases. Blunted Tg responses were seen in two patients with ectopia and hypoplasia. Interestingly, in two cases the association of different developmental defects was demonstrated. Perchlorate test revealed a total iodide organification defect in two patients, including one with a neonatal diagnosis of Pendred's syndrome, who were subsequently found to harbour TPO mutations. rhTSH did not cause notable side-effects. CONCLUSION: These new rhTSH protocols always resulted in accurate disease characterisation, allowing specific management and targeted genetic analyses. Thus, rhTSH represents a valid and safe alternative to L: -thyroxine withdrawal in the differential diagnosis of CH in paediatric patients.


Assuntos
Hipotireoidismo Congênito/diagnóstico , Cintilografia/métodos , Neoplasias da Glândula Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/metabolismo , Tireotropina/metabolismo , Criança , Pré-Escolar , Hipotireoidismo Congênito/sangue , Feminino , Humanos , Lactente , Iodetos/química , Radioisótopos do Iodo/farmacocinética , Masculino , Percloratos/farmacologia , Cintilografia/instrumentação , Proteínas Recombinantes/metabolismo , Tiroxina/farmacologia , Fatores de Tempo
8.
Am J Kidney Dis ; 49(1): 91-8, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17185149

RESUMO

BACKGROUND: Little information on the management and long-term follow-up of patients with biallelic mutations in the chloride channel gene CLCNKB is available. METHODS: Long-term follow-up was evaluated from 5.0 to 24 years (median, 14 years) after diagnosis in 13 patients with homozygous (n = 10) or compound heterozygous (n = 3) mutations. RESULTS: Medical treatment at last follow-up control included supplementation with potassium in 12 patients and sodium in 2 patients and medical treatment with indomethacin in 9 patients. At the end of follow-up, body height was 2.0 standard deviation score or less in 6 patients; 2 of these patients had growth hormone deficiency. Body weight (

Assuntos
Síndrome de Bartter/genética , Canais de Cloreto/genética , Mutação , Adolescente , Adulto , Alelos , Síndrome de Bartter/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Fatores de Tempo
9.
Arch Ital Urol Androl ; 76(3): 143-6, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15568308

RESUMO

Congenital adrenal hyperplasia (CAH) is an autosomal recessive condition characterized by an insufficient production of cortisol and mineraloactive hormones with a consequent hyperstimulation of hypothalamo-pituitary-adrenal feedback and an increase of androgens. Although the lack of different enzymes in adrenal steroidogenesis can be responsible for different forms of the disease, the deficiency of 21-hydroxylase is the more frequent defect. It is caused by mutations in CYP21 gene located on the short arm of chromosome 6 and it causes a heterogeneous phenotype characterized by a classical form (genitalia virilization in female, early onset acute adrenal insufficiency with salt wasting, precocious pseudopuberty, signs of hyperandrogenism), or by a simple virilizing form (presence of signs of hyperandrogenism without salt-loosing crises) or by a non-classic form evidenced only by mild to moderate signs of hyperandrogenism. The diagnosis can be made by 17-hydroxyprogesterone measurement in basal and after ACTH stimulation test. Glucocorticoid and mineraloactive therapy have been proved to reduce the risk of adrenal crisis reducing the levels of androgens and controlling the symptoms of the disease.


Assuntos
Hiperplasia Suprarrenal Congênita , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/terapia , Humanos
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