Rosana Marques Pereira

Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation

Background: An inherited germline P53 mutation has been identified in cases of childhood adrenocortical carcinoma (ACT), a neoplasm with a high incidence in southern Brazil. The penetrance of ACT in carriers of the point mutation, which encodes an arginine-to-histidine substitution at codon 337 of TP53 (R337H), has not been determined. Objective: To investigate the penetrance of childhood ACT in carriers of the R337H TP53 mutation. Methods: The family histories of 30 kindreds of 41 southern Brazilian children with ACT were obtained. A PCR based assay was used to detect this P53 mutation in a large number of relatives of children with ACT. In all, 927 individuals were tested for the mutation, 232 from the non-carrier and 695 (including the 40 probands) from the carrier parental lines. Results: 40 children with ACT carried the TP53 R337H mutation; the remaining child with ACT was not tested. There was no evidence of Li-Fraumeni syndrome in any of the kindreds; however, seven met the criteria for Li-Fraumeni-like syndrome. The carrier parental line was identified in each kindred. Of the 695 individuals tested in the carrier parental line, 240 (34.5%) were positive for the mutation, while none of the 232 individuals in the other parental line carried the mutation. The penetrance of ACT was 9.9% (95% confidence interval, 8.7% to 11.1%). Conclusions: The TP53 R337H mutation dramatically increases predisposition to childhood ACT but not to other cancers, and explains the increased frequency of ACT observed in this geographic region.

Clinical and Molecular Analysis of Thyroid Hypoplasia: A Population-Based Approach in Southern Brazil

BACKGROUND Congenital hypothyroidism (CH) is mainly due to developmental abnormalities leading to thyroid dysgenesis (TD). TD encompasses very distinct morphologic subtypes of disease. This study examined and compared the phenotype in TD variants and searched for genetic alterations in sporadic thyroid hypoplasia (TH), the most misdiagnosed form of CH. This was a longitudinal study over a 14-year period (1990-2004). METHODS A continuous series of 353 children with TD was identified using thyroid function tests [thyroxine (T4) and TSH], scintigraphy, and ultrasound as diagnostic tools. Individual phenotypes were analyzed in 253 children with TD. Mutations in the most likely candidate genes were studied in 35 cases of TH. RESULTS The overall birth prevalence of permanent CH was 1:4795. Ectopy represented 37% of all cases of permanent primary CH, dyshormonogenesis 28%, agenesis 24%, hypoplasia 10%, and hemiagenesis 1%. The lowest screening T4 level and the highest TSH level were in the agenetic group, followed by TH. The TH group had an improvement in the thyroid function showing less-severe phenotype with aging. In the molecular analysis, one patient was identified with a mutation in the PAX8 gene (155G>C; R52P); four patients had a heterozygous G>C substitution in position -569; two patients showed a (234C>A; P52T) or (2181C>G; D727E) polymorphic variants of the TSH-R gene; and one patient presented a novel heterozygous nonsynonymous substitution, 293G>A; S98N, in the NKX2.5 gene. CONCLUSIONS The prevalence of CH was within the previously reported range of 1:3000-4000. Ectopy was the most common etiology. Clinical analysis revealed distinct hormonal patterns in TH subgroup when compared with other variants of TD, with genetic abnormalities identified only in few cases in the TSH-R, PAX8, and NKX2.5 genes.

Amplification of 9q34 in childhood adrenocortical tumors: a specific feature unrelated to ethnic origin or living conditions

Adrenocortical tumors (ACT) in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72). Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

Tumores do córtex adrenal na infância

Adrenocortical tumors (ACT) in children are uncommon. However, the incidence of these tumors in Parana, Brazil, is 15 times higher than that worldwide. We describe the clinical, laboratory and treatment characteristics and outcome of 125 patients treated in a single institution in the State of Parana. The median age at diagnosis was 4.3 years, with a female:male ratio of 2.6:1. The most common forms of presentation were isolated virilization (51.2%) and virilization and Cushings syndrome (42%). Nonfunctioning tumors comprised 4.8% of the cases. Two patients (1.6%) had isolated Cushings syndrome and 1 (0.8%) had Conns syndrome. Fifty-six percent presented hypertension. Surgery is the only curative treatment. Our data show that disease stage 1, absence of spillage during surgery and absence of intravenous thrombus were associated with better survival rates.

Muscle strength and body composition during the transition phase in patients treated with recombinant GH to final height

Abstract We assessed body composition and muscle strength during the transition phase in 18 growth hormone (GH) deficient males treated with recombinant GH to final height and 18 controls. According to peak-stimulated GH and basal insulin-like growth factor-1 (IGF-1) during the transition phase, patients were subdivided into GH deficient (GHD-TP, n=9) and GH sufficient (GHS-TP, n=9) groups. Assessments included lean and fat body mass and bone mineral density (BMD), all measured by dual-energy X-ray absorptiometry, and dynamic knee muscle strength, assessed by isokinetic dynamometer. Total body and lumbar spine BMD and muscle strength were lower in GHD-TP patients when compared with GHS-TP and controls (all p<0.05), whereas lean and fat body mass were lower in both GHD-TP and GHS-TP patients when compared with controls (p<0.05). These findings suggest that administration of recombinant GH to final height is not sufficient to provide normal body composition and muscle strength in young male patients with GH deficiency.

Câncer de tireóide na infância e adolescência: relato de 15 casos

Thyroid tumors are rare in childhood and adolescence. A retrospective analysis was done of fifteen patients (8 female) with thyroid carcinoma attended in the Pediatric Endocrinology Unit of the HC-UFPR, from February 1988 to March 2003. The most frequent initial complaint was an anterior cervical nodule. Ten patients were papillary carcinoma (PTC) bearers, four had medullary carcinoma (MTC; three of them with MEN-2B) and one had follicular carcinoma. Two patients with MEN-2B have de novo proto-oncogene RET mutation (Met918Thr). Fine needle aspiration (FNA) was performed in ten patients and was malignancy positive in only five of them. All patients underwent total thyroidectomy. Adjuvant radioiodine (131I) therapy was made in ten patients. Two patients died from unrelated diseases. Nine patients presented no clinical or laboratorial evidence of disease; one (PTC) developed recurrence 5 years after initial treatment and three (1 PTC, 2 MTC) have disease evidence yet. Our prognosis and clinical manifestations data are according to the literature. However, MTC prevalence (27%), sex distribution and FNA results differ from the majority of published casuistics, that can be atributed to the number of cases reported here.

Hipotireoidismo neonatal transitório causado pelo uso de amiodarona durante a gestação: relato de dois casos e revisão da literatura

INTRODUCTION Amiodarone (AMD) is an antiarrhythmic agent which contains 37% of iodine. It can reach the fetus by transplacental passage and induce transient congenital hypothyroidism (TCH). We report two cases of TCH caused by gestational exposure to AMD, detected by the Newborn Screening Program for Congenital Hypothyroidism of the State of Paraná-Brazil. CLINICAL CASE 1 (C1): Neonatal TSH value was 78.2 mU/L (normal<15 mU/L). AMD had been given to the mother during pregnancy to treat maternal arrhythmia. The screening results were confirmed by serum thyroid function tests. Levothyroxin (L-T4) (50 microg/day) was started on the first visit, on the 14th day of life (dl). CLINICAL CASE 2 (C2): Neonatal TSH value was 134.0 mU/L. AMD had been given to the mother in the third trimester of pregnancy to treat maternal arrhythmia. The screening results were confirmed by serum thyroid function tests: L-T4 (50 microg/day) was started on the first visit, with 13 dl. FOLLOW-UP TSH and T4 normalized on 51 dl (C1) and 36 dl (C2); L-T4 could be diminished gradually and stopped within 16 months (C1) and 10 months (C2). They were followed-up until 22 months (C1) and 16 months (C2) with normal thyroid function tests. Their growth and mental development, evaluated by the Cognitive Adaptive Test/Clinical Linguistic & Auditory Milestone Scale (CAT/CLAMS test), were normal. CONCLUSION Evaluation of thyroid function and mental development should be performed if AMD is used during pregnancy. Treatment of TCH must be started as soon as the diagnosis is made.

Clinical and laboratory features of children and adolescents with congenital hypothyroidism due to dyshormonogenesis in southern Brazil

OBJECTIVE To characterize the phenotype of patients with congenital hypothyroidism (CH) due to dyshormonogenesis, and to hypothesize on the degree of genetic defect. SUBJECTS AND METHODS Patients with dyshormonogenesis were subdivided into G1 (radioactive iodine uptake, RAIU > 15%; n = 62) and G2 (RAIU < 15%; n = 32). Thyroglobulin (TG) was measured in all patients; perchlorate discharge test (PDT) was performed in G1; and saliva-to-plasma radioiodine ratio (I- S/P) in G2. RESULTS Levels of TSH, TT4, and FT4 before treatment and upon diagnosis confirmation were significantly different in both groups, but not between groups. In G1, 27 patients developed goiter; 17 had positive PDT (14%-71% discharge), 11 had TG < 2.5 ng/dL (one with high TSH), and one developed thyroid carcinoma. In G2, four patients developed goiter, and three had low I- S/P. CONCLUSION These data suggest an iodide organification defect in 17 cases; an iodide transport defect (NIS defect) in three, probable TSH resistance in 10, and a TG synthesis defect in two cases.

Tratamento do tumor do córtex adrenal na infância

Adrenocortical tumors (ACT) in children are uncommon. However, the incidence of these tumors in Paraná is 15 times higher than that worldwide. A germline mutation, R337H TP53, present in more than 95% of our patients, is probably the reason for the higher incidence in our state. A hundred twenty-five patients were treated in the period of 1966 to 2003. Surgery is the only curative treatment. In our experience, disease stage I, absence of spillage during surgery and absence of intravenous thrombus are associated with better survival rates. Preliminary data with the combination of etoposide, doxorubicin, cisplatin, and mitotane have shown that in some patients a complete remission is observed both of the tumor and metastasis. Side effects due to these drugs are common and adrenal insufficiency may occur. Glucocorticoid and mineralocorticoid reposition should be done with 2 to 3 times the physiological doses.

[Assessment of diastolic function in children and adolescents with type 1 diabetes mellitus - are there early signs of diabetic cardiomyopathy?].

OBJECTIVES To evaluate diastolic function (DF) of children and adolescents with type 1 diabetes mellitus (DM1). SUBJECTS AND METHODS Cross-sectional study of 67 otherwise healthy diabetic patients, and a control group (n = 84) in regard to age, sex, body mass index (BMI), Dopplere-chocardiography, and ECG for both groups; and disease duration, HbA1C, microalbuminuria, and serum lipids for DM 1 patients. RESULTS Diastolic alterations [(A and E mitral waves, E/A ratio, isovolumic relaxation time (IVRT) and E wave deceleration time (EWDT)] were found in diabetic patients, with higher prevalence among pubertal girls (13-17 years old). IVRT and EWDT correlated positively with BMI (p = 0.028). Chronological age and disease duration were predictive factors for mitral A wave (p = 0.004 and 0.033, respectively). CONCLUSIONS DF alterations were detected in the group of diabetic patients, with greater prevalence among pubertal girls; disease duration and age influenced parameters of DF.