Background: Most congenital adrenal hyperplasia (CAH) patients carry CYP21A2 mutations derived from conversion events involving the pseudogene, and the remaining carry new mutations. Objective: To review causal mutations and genotype-phenotype correlation in 480 Brazilian patients. Methods: DNA was extracted from 158 salt-wasters (SWs), 116 simple virilizing (SV), and 206 nonclassical (NC) patients. Fourteen point mutations were screened by allele-specific PCR, large rearrangements by Southern blotting/ MLPA, and sequencing was performed in those with incomplete genotype. The gene founder effect was analyzed by microsatellite studies. Patients were divided into six genotypes (Null; A: <2%; B: 3-7%; C: >20% of residual enzymatic activity (EA); D: unknown EA; E: incomplete genotype). Results: Targeted methodologies defined genotype in 87.6% of classical and in 80% of NC patients and the addition of sequencing in 100 and 83.5%, respectively. The most frequent mutations were p.V281L (26.6% of alleles), IVS2-13A/C>G (21.1%), and p.I172N (7.5%); seven rare mutations and one novel mutation (p.E351V) were identified. Gene founder effect was observed in all but one (p.W19X) mutation. Null, A, B, and C genotypes correlated with SW (88%), SW (70%), SV (98%), and NC forms (100%), respectively. In group D, the p.E351V mutation correlated with classical form and group E comprised exclusively NC-patients. ACTH-stimulated 17OHP level of 44.3 ng/mL was the best cutoff to identify NC-patients carrying severe mutations. Conclusions: We identified a good genotype-phenotype correlation in CAH, providing useful data regarding prediction of disease´s severity; moreover, we suggest that ACTH-stimulated 17OHP levels could predict carrier status for severe mutations. Sequencing is essential to optimize molecular diagnosis in Brazilian CAH patients.

OBJECTIVE—To look for technical simplification and economic efficiency in the treatment of pediatric diabetic ketoacidosis (DKA) with subcutaneous use of the fast-acting insulin analog (lispro) and compare its use with regular intravenous insulin treatment. RESEARCH DESIGN AND METHODS—In this controlled clinical trial from June 2001 to June 2003, we randomized 60 episodes of DKA with a blood glucose level ≥16.6 mmol/l (300 mg/dl), venous pH &lt;7.3 and/or bicarbonate &lt;15 mmol/l, or ketonuria greater than ++. Of the 60 episodes, 30 were treated with subcutaneous lispro (0.15 units/kg) given every 2 h (lispro group) and the other 30 cases received continuous intravenous regular insulin (0.1 unit · kg−1 · h−1; CIRI group). Volume deficit was repaired with 10-ml/kg aliquots of 0.9% sodium chloride. Laboratory monitoring included hourly bedside capillary glucose, venous blood gas, β-hydroxybutyrate, and electrolytes. Plasma blood glucose levels were measured on admission, 2 h after admission, when capillary blood glucose reached ≤13.8 mmol/l (250 mg/dl), and 6, 12, and 24 h thereafter. RESULTS—Capillary glucose levels decreased by 2.9 and 2.6 mmol · l−1 · h−1 in the lispro and CIRI groups, respectively, but blood glucose fluctuated at different time intervals. In the CIRI group, metabolic acidosis and ketosis resolved in the first 6-h period after capillary glucose reached 13.8 mmol/l, whereas in the lispro group, they resolved in the next 6-h interval; however, both groups met DKA recovery criteria without complications. CONCLUSIONS—DKA treatment with a subcutaneous fast-acting insulin analog represents a cost-effective and technically simplified procedure that precludes intensive care unit admission.

To recognize patients with 21- and/or 11betaOHD, we recommend evaluation of 17OHP or 21DF and S. Also, 21DF may be useful to follow up pubertal patients with 21OHD. Because 1% of patients with alleged 21OHD may have 11betaOHD, its frequency seems underestimated, as per our experience in a Brazilian population.

Among the adverse effects arising from chronic high-dose glucocorticoid treatment, adrenal insufficiency secondary to suppression of the hypothalamic-pituitary-adrenal (HPA) axis is a cause for concern. Glucocorticoid-induced adrenal suppression is related to the duration of therapy, type of steroid used and dosage, and schedule of glucocorticoid administration. To evaluate the suppression and recovery time of the HPA axis in children with acute leukemia, we performed the ovine CRH (oCRH) stimulation test in 15 patients, who were given high doses of dexamethasone as part of their induction chemotherapy for 42 days. The oCRH tests were performed before, and 7 and 14 days after, discontinuation of the glucocorticoid. The ACTH levels were not significantly different among the 3 tests. The cortisol levels, however, were significantly (albeit mildly) lower, both basally and after oCRH, 1 and 2 weeks post treatment than before therapy. Six patients had cortisol values that remained suppressed 2 weeks after discontinuation of therapy. One of these patients had manifestations of mild adrenal insufficiency, 6-8 days after discontinuation of therapy, but required no glucocorticoid coverage. We conclude that up to 2 weeks after discontinuation of 6 weeks of high-dose dexamethasone administration, the HPA axis of patients with acute leukemia is mildly suppressed but infrequently associated with clinical manifestations of adrenal insufficiency. This may indicate that major stress, when concurrent with glucocorticoid treatment, may prevent clinically significant adrenal suppression.

SUMÁRIOO MCT8 é um transportador celular de hormônios tireoidianos, importante para sua ação e metabolização. Relatamos o caso de um menino com a nova mutação inativadora 630insG no éxon 1 do MCT8. O paciente caracterizou-se por grave comprometimento neurológico (inicialmente com hipotonia global, evoluindo com hipertonia generalizada), crescimento normal nos dois primeiros anos de vida, reduzido ganho ponderal e ausência dos sinais e sintomas típicos de hipotireoidismo. A sua avaliação sérica revelou elevação do T3, redução do T4 total e livre e TSH levemente aumentado. O tratamento com levotiroxina melhorou o perfil hormonal tireoidiano, mas não modificou o quadro clínico do paciente. Esses dados reforçam o conceito de que o papel do MCT8 é tecido-dependente: enquanto os neurônios são altamente dependentes do MCT8, o osso, o tecido adiposo, o músculo e o fígado são menos dependentes do MCT8 e, portanto, podem sofrer as consequências da exposição a níveis séricos elevados de T3. Arq Bras Endocrinol Metab. 2011;55(1):60-6 SUMMARY MCT8 is a cellular transporter of thyroid hormones important in their action and metabolization. We report a male patient with the novel inactivating mutation 630insG in the coding region in exon 1 of MCT8. He was characterized clinically by severe neurologic impairment (initially with global hypotonia, later evolving with generalized hypertonia), normal growth during infancy, reduced weight gain, and absence of typical signs and symptoms of hypothyroidism, while the laboratory evaluation disclosed elevated T3, low total and free T4, and mildly elevated TSH serum levels. Treatment with levothyroxine improved thyroid hormone profile but was not able to alter the clinical picture of the patient. These data reinforce the concept that the role of MCT8 is tissue-dependent: while neurons are highly dependent on MCT8, bone tissue, adipose tissue, muscle, and liver are less dependent on MCT8 and, therefore, may suffer the consequences of the exposition to high serum T3 levels. Arq Bras Endocrinol Metab. 2011;55(1):60-6

RESUMOObjetivos: Avaliar as alterações metabólicas de crianças e adolescentes portadores da Síndrome de Prader-Willi tratadas com hormônio de crescimento recombinante humano (rhGH). Casuística e métodos: Foram estudados sete pacientes: quatro meninos e três meninas, com idades de seis anos e seis meses a 14 anos e 11 meses. Receberam rhGH, 0,1 U/Kg/dia subcutâneo, seis vezes por semana, durante dois anos. Avaliamos dados antropométricos, lípides séricos, glicemia, IGF-I e composição corpórea, no início e após 12 e 24 meses de tratamento com rhGH. Resultados: Todos os pacientes tiveram elevação do IGF-I. Houve diminuição das pregas cutâneas, sendo que a média de perda de massa adiposa foi de 5,0% e a massa magra aumentou em média 7,6 kg nos pré-púberes, e a paciente púbere ganhou 4,8 kg e teve um decréscimo de 5,6% de massa adiposa. Houve ganho de massa óssea de 0,07 g/cm 2 (7,3%) nos pré-púberes e de 0,02 g/cm 2 (2,0%) na menina púbere. Conclusão: Em nosso estudo, o uso do hormônio de crescimento na Síndrome de PraderWilli melhorou a composição corpórea e demonstrou aumento da massa muscular e massa óssea com melhora dos níveis lipídicos. Aim: The focus of this study was to evaluate the metabolic profile of Prader-Willi Syndrome (PWS) patients treated with growth hormone. Patients and methods: Seven patients (four boys and three girls) with ages between six years and six months and 14 years and 11 months were treated with GH 0.1 U/kg/day subcutaneous by six times a week, for two years. Anthropometric data, lipids, glucose, IGF-I and body composition were evaluated at baseline and after 12 and 24 months. Results: IGF-I levels increased in all cases. Skin folds decreased. The mean reduction in body fat was 5.0% and the mean increased in lean mass was 7.6 kg in the prepubertal patients. The pubescent girl increased 4.8 kg and showed a 5.6% decrease in fat mass. A mean gain in the bone mass was 0.07 g/cm 2 (7.3%) in prepubescent cases, and 0.02 g/cm 2 (2.0%) in the pubescent girl. Conclusion: In our study GH treatment improved lean body and bone masses and had beneficial effect on lipid values.

Background: McCune-Albright syndrome (MAS) is a genetic disorder characterized by the triad of fibrous dysplasia, skin hyperpigmentation, and autonomous hyperfunction of various endocrine organs. MAS frequently presents in females as precocious puberty (PP). Although many treatments have been proposed, the preservation of final height (FH) in these patients remains a challenge. Objectives: To evaluate the efficacy of tamoxifen in improving the FH prediction (FHP) in patients with MAS. Method: We retrospectively analyzed 8 female patients with MAS who presented with café-au-lait spots and gonadotropin-independent PP. The patients were followed for a mean period of 8.3 years (range: 3-16). Results: All patients were treated with tamoxifen (10-20 mg/day) for 3-8 years (mean ± SD: 5.75 ± 2.05), which resulted in the cessation of vaginal bleeding and the stabilization of bone age maturation. There was a significant difference between the FHP at the beginning of treatment and at the end of treatment (145.1 ± 8.6 cm; Z score -2.84 ± 1.44 cm) and at the last evaluation (157.0 ± 9.2 cm; Z score -0.85 ± 0.54 cm; p < 0.001). Conclusion: Our results support a role for tamoxifen in improving the FHP in patients with MAS.

We analyzed the clinical and molecular data of 205 patients with the three different clinical forms of 21-hydroxylase deficiency, in whom the clinical and molecular diagnosis were already defined. The most frequent mutations were I2 splice in the salt wasting form, I172N in the simple virilizing and V281L in the nonclassical form, presenting similar frequencies as those observed in other populations. We found a lower frequency of 21-hydroxylase gene deletion, similar to that previously identified in Argentinean and Mexican populations. Five new mutations were described in our population: G424S, H28+C, Ins 1003 1004 A, R408C and IVS2-2A>G. The genotype was classified in three groups according to the impairment of enzymatic activity observed in vitro, Group A: 0-2%, Group B: 3-7% and Group C: >20%. Group A mutations correlated with the salt wasting form, the Group B with simple virilizing form and Group C with the non classical form. The severity of genotype showed a positive correlation with higher 17OH-progesterone and testosterone levels. The I2 splice mutation in homo or hemizygosis confers classical form phenotype with both salt wasting and simple virilizing forms, precluding the prediction of the clinical form through genotype in pre and neonatal diagnosis. The good genotype-phenotype correlation in patients with 21-hydroxylase deficiency shows the usefulness of genotype to predict the clinical form for genetic counseling, prenatal diagnosis and to confirm neonatal screening diagnosis, except in cases with I2 splice mutation.