Luiz de Lacerda Filho

GH-releasing hormone receptor gene: a novel splice-disrupting mutation and study of founder effects.

Background: Mutations in GH-releasing hormone receptor gene (GHRHR) are emerging as the most common cause of autosomal recessive isolated GH deficiency (IGHD). Objective: To search for GHRHR mutations in patients with familial or sporadic IGHD and to investigate founder effects in recurring mutations. Methods: The coding region of GHRHR was entirely amplified and sequenced from DNA of 18 patients with IGHD (16 unrelated) with topic posterior pituitary lobe on MRI. Haplotypes containing promoter SNPs and microsatellites flanking GHRHR were analyzed in patients with c.57+1G>A (IVS1+1G>A) mutation of our previously published kindred and also a Brazilian patient and 2 previously reported Japanese sisters with c.1146G>A (p.E382E) mutation. Results: A novel homozygous intronic GHRHR c.752-1G>A (IVS7-1G>A) mutation, predicting loss of the constitutive splice acceptor site, was identified in two siblings with IGHD. A compound heterozygous c.[57+1G>A];[1146G>A] and a heterozygous c.527C>T (p.A176V) were found in two sporadic cases. Haplotype analysis provided evidence for a founder effect for the c.57+1G>A mutation and independent recurrence for the c.1146G>A mutation. Conclusion: We report a novel splice-disrupting mutation in GHRHR in 2 siblings and provide evidence that all c.57+1G>A (IVS1+1G>A) mutant chromosomes have the same haplotype ancestor, indicating the occurrence of a founder effect in Brazilian patients with IGHD.

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.

Densidade mineral óssea de crianças e adolescentes com hipotireoidismo congênito

Realizou-se estudo transversal com 60 pacientes (9,9 ± 1,8 anos) com hipotireoidismo congenito (HC) (grupo A): 40 meninas (23 pre-puberes) e 20 meninos (18 pre-puberes), com grupo controle (grupo B) constituido por 28 individuos (10,4 ± 2,1 anos): 18 meninas (8 pre-puberes) e 10 meninos (9 pre-puberes). OBJETIVOS: Avaliar a densidade (DMO) e o conteudo mineral osseo (CMO) e correlaciona-los com idade cronologica e ossea (IO), sexo, maturacao sexual, dose de l-T4, TSH, TT4, FT4, e etiologia do HC. IO, DMO e CMO de corpo total (DXA) foram obtidos dos 2 grupos; TSH, TT4 e FT4, apenas dos pacientes. DMO foi menor no grupo A (0,795 ± 0,075 g/cm2 vs. 0,832 ± 0,092; p = 0,04) e maior nas meninas puberes do que nas pre-puberes (p = 0,004). Nao houve diferenca significativa de DMO e CMO quanto ao sexo e etiologia do HC. Nosso estudo mostra que a DMO foi significativamente menor no grupo com HC, diferente dos dados da literatura.

Relação entre autoavaliação vocal e dados da avaliação clínica em indivíduos disfônicos

PURPOSE: to associate the rates of vocal self-assessment and clinic evaluation data from of dysphonic individuals. METHODS: observational, descriptive and retrospective study. It was studied medical records of patients treated at a school-clinic of Speech Language Patology in the period from 2007 to 2011. Data were presented regarding the vocal self-assessment (voice related quality of life, vocal handicap index and assignment of note regarding the impact vocals), anamnesis (gender, age, occupation, type of abuse, duration of abuse, previous treatment for dysphonia), perceptual evaluation (vocal quality, degree of alteration, pitch, loudness, resonance, articulation and CPFA) and objective data (maximum fonation time and relation between consonants s / z). Data were statistically analyzed. RESULTS: there was no difference in comparing the scores of voice related quality of life, vocal handicap index with variables related to gender, vocal quality, grade of dysphonia, pitch, resonance, articulation, rhythm of speech and type of dysphonia. Individuals with pneumophonoarticulatory incoordination, who use their voice professionally and who have made previous treatments for dysphonia were the worst rates in the vocal self-assessment. There were no correlations between rates of vocal self-assessment and other continuous variables (age, duration of abuse, maximum phonation time and relation s / z). CONCLUSION: the vocal self-assessment is a very subjective impression, and is independent of most of data collected in the clinical evaluation. Being professional voice, already have had other previous treatments for dysphonia, and incoordination pneumophonoarticulatory seem to influence negatively on the individuals self-assessment about the impact of dysphonia in his/her daily life.

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.

Estatura final (EF) em síndrome de Turner (ST): experiência de 76 casos acompanhados na Unidade de Endocrinologia Pediátrica do Hospital de Clínicas da Universidade Federal do Paraná

OBJECTIVE To report the final height (FH) of 76 patients with Turner syndrome (TS). MATERIALS AND METHODS Review of the files and calculation of z scores: of target height (TH), and FH according to NCHS/CDC/2000 and FH according to Lyon and cols. RESULTS Patients were classified in three groups: A (n = 16), treatment with estrogens and progestogens; B (n = 21), treatment with oxandrolone (OX); C (n = 39), growth hormone (GH) plus OX. The z score of TH was not different among the groups and z score of FH was not different between A e B. Z score of FH of group C was greater than the other groups, > 2SDS of Lyons curve and fitted on the 3(rd) percentile of NCHS/CDC. Multiple regression analysis showed type of treatment (p < 0.001) and maternal height (p = 0.02) as most influencing factors on FH. CONCLUSION GH plus OX and maternal height contributed significantly to enhance FH of TS patients.

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.

Reappraisal of serum insulin-like growth factor-I (IGF-1) measurement in the detection of isolated and combined growth hormone deficiency (GHD) during the transition period

OBJECTIVE To evaluate the accuracy of serum IGF-1 in the detection of isolated (IGHD) or combined growth hormone deficiency (CGHD) at the transition phase. SUBJECTS AND METHODS Forty nine patients with GHD during childhood [16 with IGHD (10 men) and 33 with CGHD (24 men); age 23.2 ± 3.5 yrs.] were submitted to an insulin tolerance test (ITT) with a GH peak < 5 µg/L used for the diagnosis of GHD at the transition phase. Pituitary function and IGF-1 measurements were evaluated in the basal sample of the ITT. Transition patients were reclassified as GH-sufficient (SGH; n = 12), IGHD (n = 7), or CGHD (n = 30). RESULTS Five (31%) patients with IGHD and 32 (97%) with CGHD at childhood persisted with GHD at retesting. One patient with IGHD was reclassified as CGHD, whereas 3 patients with CGHD were reclassified as IGHD. Mean GH peak was 0.2 ± 0.3 µg/L in the CGHD, 1.3 ± 1.5 µg/L in the IGHD, and 18.1 ± 13.1 µg/L in the SGH group. Serum IGF-1 level was significantly higher in the SGH (272 ± 107 ng/mL) compared to IGHD (100.2 ± 110) and CGHD (48.7 ± 32.8) (p < 0.01). All patients reclassified as CGHD, 86% reclassified as IGHD, and 8.3% reclassified as SGH had low IGF-1 level, resulting in 97.3% sensitivity and 91.6% specificity in the detection of GHD at the transition period; the cutoff value of 110 ng/mL showed 94.5% sensitivity and 100% specificity. Mean IGF-1 values did not differ in IGHD or CGHD associated with one, two, three, or four additional pituitary deficiencies. CONCLUSION IGF-1 measurement is accurate to replace ITT as initial diagnostic test for IGHD and CGHD detection at the transition phase.

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.