Hilton Kuperman

Estudo multicêntrico de pacientes brasileiros com deficiência da 21-hidroxilase: correlação do genótipo com o fenótipo

ABSTRACT Multicentric Study of Brazilian Patients With 21-Hydroxylase Defi-ciency: A Genotype-Phenotype Correlation. We analyzed the clinical and molecular data of 205 patients with thethree different clinical forms of 21-hydroxylase deficiency, in whom theclinical and molecular diagnosis were already defined. The most fre-quent mutations were I2 splice in the salt wasting form, I172N in the sim-ple virilizing and V281L in the nonclassical form, presenting similar fre-quencies as those observed in other populations. We found a lower fre-quency of 21-hydroxylase gene deletion, similar to that previously iden-tified in Argentinean and Mexican populations. Five new mutations weredescribed in our population: G424S, H28+C, Ins 1003^1004 A, R408C andIVS2-2A>G. The genotype was classified in three groups according to theimpairment of enzymatic activity observed in vitro , Group A: 0-2%, GroupB: 3-7% and Group C: >20%. Group A mutations correlated with the saltwasting form, the Group B with simple virilizing form and Group C withthe non classical form. The severity of genotype showed a positive cor-

Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities

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.

Home blood glucose monitoring in type 1 diabetes mellitus

OBJETIVO: Identificar cual de los dos esquemas de monitorizacion propuestos posibilita realizar un mejor control metabolico, en diabeticos del tipo1, durante los 12 meses de participacion en grupos educativos. METODO: Ensayo clinico cruzado con 21 pacientes divididos en dos grupos y sometidos a dos diferentes esquemas de monitorizacion. La efectividad de los esquemas fue evaluada por medio de la HbA1c. La variacion de los promedios de HbA1c fue analizada con la prueba de Friedman. RESULTADOS: Durante todo el estudio la variacion de los promedios de HbA1c, para el grupo A, fue de 8,48(±1,00) la 7,37(±0,99) y de 9,89(±0,86) la 8,34(±1,06) para el grupo B. Los analisis de la variacion de la HbA1c colocaron en evidencia una reduccion significativa (p<0,05) en los dos grupos, en los 3 periodos evaluados: primeros y ultimos 6 meses y durante los 12 meses de estudio. CONCLUSIONES: Los dos esquemas mejoraron el control metabolico y el esquema antes de las comidas fue mas efectivo.OBJECTIVE To determine which of two simplified blood glucose monitoring schemes promotes better metabolic control in type 1 diabetic patients during 12 months of participation in educational groups. METHODS A crossover clinical trial involving 21 patients divided into two groups was conducted. They were submitted to a two monitoring schemes: 2 alternate daily preprandial measurements and 2 alternate daily pre-and postprandial measurements. The effectiveness of the schemes was evaluated based on HbA1c. Variations in mean HbA1c were analyzed by Friedman test. RESULTS The groups were homogenous in terms of sociodemographic and clinical variables (p>0.05). Mean HbA1c levels ranged from 8.48 (+/-1.00) to 7.37 (+/-0.99) over time in Group A and from 9.89 (+/-0.86) to 8.34 (+/-1.06) in Group B. The analysis of the HbA1c showed a significant reduction in the first and last 6 months and over the 12 months of the study in two groups (p<0.05). The preprandial scheme demonstrated the largest number and highest percentage of significant drops in HbA1c. CONCLUSIONS The two monitoring improved the metabolic control and the preprandial scheme was more effective.

Precocious puberty: an endocrine manifestation in congenital toxoplasmosis.

We reviewed retrospectively seven children with congenital toxoplasmosis and precocious puberty. All seven showed very high levels of LH (25.2-155.0 IU/ml) and FSH (7.1-38.2) upon stimulation with GnRH. Three of them showed low GH response to an insulin tolerance test. All the children had severe mental retardation. We emphasize that children with congenital toxoplasmosis should have their hypothalamopituitary function evaluated even in subclinical situations that could be responsible for endocrinological disturbances such as precocious puberty.

Molecular CYP21A2 Diagnosis in 480 Brazilian Patients with Congenital Adrenal Hyperplasia Before Newborn Screening Introduction

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 44.3ng/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 diseases 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.

Growth and puberty after treatment for acute lymphoblastic leukemia

UNLABELLED Over the last 20 years, after combining treatment of chemotherapy and radiotherapy, there has been an improvement in the survival rate of acute lymphoblastic leukemia patients, with a current cure rate of around 70%. Children with the disease have been enrolled into international treatment protocols designed to improve survival and minimize the serious irreversible late effects. Our oncology unit uses the international protocol: GBTLI LLA-85 and 90, with the drugs methotrexate, cytosine, arabinoside, dexamethasone, and radiotherapy. However, these treatments can cause gonadal damage and growth impairment. PATIENTS AND METHOD The authors analyzed 20 children off therapy in order to determine the role of the various doses of radiotherapy regarding endocrinological alterations. They were divided into 3 groups according to central nervous system prophylaxis: Group A underwent chemotherapy, group B underwent chemotherapy plus radiotherapy (18 Gy), and group C underwent chemotherapy plus radiotherapy (24 Gy). Serum concentrations of LH, FSH, GH, and testosterone were determined. Imaging studies included bone age, pelvic ultrasound and scrotum, and skull magnetic resonance imaging. RESULTS Nine of the patients who received radiotherapy had decreased pituitary volume. There was a significant difference in the response to GH and loss of predicted final stature (Bayley-Pinneau) between the 2 irradiated groups and the group that was not irradiated, but there was no difference regarding the radiation doses used (18 or 24 Gy). The final predicted height (Bayley-Pinneau) was significantly less (P = 0.0071) in both groups treated with radiotherapy. Two girls had precocious puberty, and 1 boy with delayed puberty presented calcification of the epididymis. CONCLUSION Radiotherapy was been responsible for late side effects, especially related to growth and puberty.

Tireoidite de Hashimoto na Infância e na Adolescência: Estudo Retrospectivo de 43 Casos

Hashimotos thyroiditis (HT) is the autoimmune disorder considered the main etiology of goiter and acquired hypothyroidism among children and adolescents in non-endemic areas. This study evaluated retrospectively 43 patients aged 1.1 to 17.6 years with HT, 36 female and 7 male (proportion 5:1). Goiter was present in 81% of these patients. At the first appointment 37% of the patients were in euthyroid state (n=16), 28% in subclinical hypothyroid state (n=12), 26% in clinical hypothyroid state (n=11) and 9% in hyperthyroid state (n=4). Anti-thyroperoxidase antibody was positive in 75% of these patients and anti-thyroglobulin antibody in 68%. All hypothyroid patients were treated with thyroid hormone replacement. Only 3 patients entered in remission after puberty suggesting the importance of a periodic evaluation.

Thyroid carcinoma in children and adolescents - review of six cases

Objective: Thyroid carcinoma occurs rarely in children, and there are controversial aspects about its management. This study was carried out to evaluate diagnostic and follow-up aspects of these patients. Methods: The clinical courses of six patients with thyroid cancer followed in a Pediatric Endocrinology Unit for 17 years were retrospectively reviewed. Results: There were six females ranging in age from 4.5 to 12 years. At initial examination thyroid nodules were present in all cases. The ultrasonography and 131 I scan showed solid and cold nodules in four patients. Histologically, four were papillary and two were follicular carcinomas. All of them underwent total thyroidectomy, four also had to do radioiodine therapy because of the presence of metastasis and/or thyroid remnants. Conclusions: Our findings support the clinical impression that children and adolescents with thyroid carcinoma have a good prognosis: there were no deaths in this follow-up of 17 years. These data are similar to those in the literature, that reveals low mortality in these cases.

Genitália ambígua: diagnóstico diferencial e conduta

Genital ambiguity is considered a pediatric emergency and the patients successful bio-psycho-social follow-up depends on the adequate and timely intervention early in life. The authors review the pathophysiology of gonadal determination and sexual differentiation, allowing the possibility of differential diagnosis and proper conduct.

A novel DAX1/NR0B1 mutation in a patient with adrenal hypoplasia congenita and hypogonadotropic hypogonadism

We report a case of adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH) due to a novel DAX1 mutation. A 19-month-old boy with hyperpigmentation and failure to thrive came to our service for investigation. Three brothers of the patient had died due to adrenal failure, and a maternal cousin had adrenal insufficiency. Adrenoleukodystrophy was excluded. MRI showed normal pituitary and hypothalamus. Plasma hormone evaluation revealed high ACTH (up to 2,790 pg/mL), and low levels of androstenedione, DHEA-S, 11-deoxycortisol, and cortisol. At 14 years of age the patient was still prepubescent, his weight was 43.6 kg (SDS: -0.87) and his height was 161 cm (SDS: -0.36), with normal body proportions. In the GnRH test, basal and maximum values of LH and FSH were respectively 0.6/2.1 and < 1.0/< 1.0 U/L. Molecular investigation identified a novel mutation that consists of a deletion of codon 372 (AAC; asparagine) in exon 1 of DAX1. This mutation was not found in a study of 200 alleles from normal individuals. Prediction site analysis indicated that this alteration, located in the DAX1 ligand-binding domain, may damage DAX1 protein. We hypothesize that the novel (p.Asp372del) DAX1 mutation might be able to cause a disruption of DAX1 function, and is probably involved in the development of AHC and HH in this patient.