A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals

ABSTRACT Objective: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. Subjects and methods: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. Results: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. Conclusions: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

A pioneering RET genetic screening study in the State of Ceará, Brazil, evaluating patients with medullary thyroid cancer and at-risk relatives: experience with 247 individuals.

OBJECTIVE: Initial diagnosis of medullary thyroid carcinoma (MTC) is frequently associated with advanced stages and a poor prognosis. Thus, the need for earlier diagnoses and detection in relatives at risk for the disease has led to increased use of RET genetic screening. SUBJECTS AND METHODS: We performed RET screening in 247 subjects who were referred to the Brazilian Research Consortium for Multiple Endocrine Neoplasia (BRASMEN) Center in the State of Ceará. Direct genetic sequencing was used to analyze exons 8, 10, 11, and 13-16 in MTC index cases and specific exons in at risk relatives. Afterward, clinical follow-up was offered to all the patients with MTC and their affected relatives. RESULTS: RET screening was performed in 60 MTC index patients and 187 at-risk family members. At the initial clinical assessment of the index patients, 54 (90%) were diagnosed with apparently sporadic disease and 6 (10%) diagnosed with hereditary disease. After RET screening, we found that 31 (52%) index patients had sporadic disease, and 29 (48%) had hereditary disease. Regarding at-risk relatives, 73/187 were mutation carriers. Mutations in RET codon 804 and the rare p.M918V mutation were the most prevalent. CONCLUSIONS: Performing RET screening in Ceará allowed us to identify a different mutation profile in this region compared with other areas. RET screening also enabled the diagnosis of a significant number of hereditary MTC patients who were initially classified as sporadic disease patients and benefited their relatives, who were unaware of the risks and the consequences of bearing a RET mutation.

M918V RET mutation causes familial medullary thyroid carcinoma: study of 8 affected kindreds.

Germline mutations in codon 918 of exon 16 of the RET gene (M918T) are classically associated with multiple endocrine neoplasia type 2B (MEN 2B) with highly aggressive medullary thyroid cancer (MTC), pheochromocytoma and a unique phenotype. The objectives of this study are to describe the rare M918V RET mutation discovered in 8 MTC kindreds from Brazil lacking the MEN 2B phenotype classically observed in M918T patients and to investigate the presence of a founder effect for this germline mutation. Eight apparently sporadic MTC cases were diagnosed with the germline M918V RET mutation. Subsequently, their relatives underwent clinical and genetic assessment (n = 113), and M918V was found in 42 of them. Until today, 20/50 M918V carriers underwent thyroidectomy and all presented MTC/C-cell hyperplasia; the remainder carriers are on clinical follow-up. None of the M918V carriers presented clinical features of MEN 2B. Their clinical presentation was heterogeneous, and the age at tumor diagnosis ranged from 24 to 59 years. Lymph node metastases were present in 12/20 patients, and presumable distant metastases in 2/20; in contrast, we observed a carrier of up to 87 years of age without evidence of MTC. Ethnographic fieldwork and haplotype analyses suggested that the founder mutation first settled in that area fifteen generations ago and originated from Portugal. Our study is the first to demonstrate the RET M918V mutation co-segregating in 8 familial MTC kindreds with validated evidence of a founder effect. We suggest that M918V MTC should be clinically considered an American Thyroid Association (ATA) moderate-risk category.

Low iodine diet does not improve the efficacy of radioiodine for the treatment of Graves’ disease

Objective Consuming a low-iodine diet (LID) is a widely accepted practice before administering radioiodine (131I) to evaluate and to treat thyroid disease. Although this procedure is well established for the management of patients with differentiated thyroid cancer, its use in patients with benign disease is unclear. So, we aimed to evaluate the influence of a LID on the outcome in patients with Graves’ disease (GD) treated with131I. Subjects and methods We evaluated 67 patients with GD who were divided into 2 groups: one group (n = 31) consumed a LID for 1-2 weeks, and the second group (n = 36) was instructed to maintain a regular diet (RD). Results The LID group experienced a 23% decrease in urinary iodine after 1 week on the diet and a significant 42% decrease after 2 weeks on the diet. The majority (53%) of the patients in the LID group had urinary iodine levels that were consistent with deficient iodine intake. However, there was no difference in the rate of hyperthyroidism’s cure between the LID and the RD groups 6 months after 131I therapy. Furthermore, the therapeutic efficacy did not differ in patients with varying degrees of sufficient iodine intake (corresponding urinary iodine levels: < 10 μg/dL is deficient; 10-29.9 μg/dL is sufficient; and > 30 μg/dL is excessive). Conclusion In the present study, we demonstrated that although a LID decreased urinary iodine levels, those levels corresponding with sufficient or a mild excess in iodine intake did not compromise the therapeutic efficacy of131I for the treatment of GD.

Low iodine diet does not improve the efficacy of radioiodine for the treatment of Graves' disease.

OBJECTIVE: Consuming a low-iodine diet (LID) is a widely accepted practice before administering radioiodine (131I) to evaluate and to treat thyroid disease. Although this procedure is well established for the management of patients with differentiated thyroid cancer, its use in patients with benign disease is unclear. So, we aimed to evaluate the influence of a LID on the outcome in patients with Graves' disease (GD) treated with 131I. SUBJECTS AND METHODS: We evaluated 67 patients with GD who were divided into 2 groups: one group (n = 31) consumed a LID for 1-2 weeks, and the second group (n = 36) was instructed to maintain a regular diet (RD). RESULTS: The LID group experienced a 23% decrease in urinary iodine after 1 week on the diet and a significant 42% decrease after 2 weeks on the diet. The majority (53%) of the patients in the LID group had urinary iodine levels that were consistent with deficient iodine intake. However, there was no difference in the rate of hyperthyroidism's cure between the LID and the RD groups 6 months after 131I therapy. Furthermore, the therapeutic efficacy did not differ in patients with varying degrees of sufficient iodine intake (corresponding urinary iodine levels: < 10 µg/dL is deficient; 10-29.9 µg/dL is sufficient; and > 30 µg/dL is excessive). CONCLUSION: In the present study, we demonstrated that although a LID decreased urinary iodine levels, those levels corresponding with sufficient or a mild excess in iodine intake did not compromise the therapeutic efficacy of 131I for the treatment of GD.

Clinical follow-up of two Brazilian subjects with glucokinase-MODY (MODY2) with description of a novel mutation / Seguimento clínico de dois pacientes brasileiros com MODY-glicoquinase (MODY2) e descrição de uma nova mutação

Mutations in the glucokinase gene (GCK) account for many cases of monogenic diabetes featuring maturity-onset diabetes of the young type 2 (MODY2). The clinical pattern of this form of hyperglycemia is rather stable, with a slight elevation in blood glucose, which is usually not progressive. Patients rarely require pharmacological interventions and microvascular complications related to diabetes are unusual. We describe the clinical follow-up of two cases of MODY2 with two different mutations in GCK gene, one in exon 7, p.Glu265Lys (c.793 G> A), which has been previously described, and a novel one, in exon 2, p.Ser69Stop (c. 206C> G). The clinical course of both cases shows similarity in metabolic control of this form of diabetes over the years. Arq Bras Endocrinol Metab. 2012;56(8):490-5.

Mutações no gene da glicoquinase (GCK) são determinantes de uma forma de diabetes monogênico denominada de MODY2 (maturity-onset diabetes of the young, tipo 2). O padrão clínico dessa forma de distúrbio glicêmico é bastante estável, com hiperglicemia leve, geralmente não progressiva. Intervenções farmacológicas raramente são necessárias e complicações crônicas secundárias ao diabetes são infrequentes. Descrevemos o acompanhamento clínico de dois casos de MODY2 com duas mutações diferentes, uma no éxon 7, p.Glu265Lys (c.793 G>A) já descrita anteriormente, e outra inédita no éxon 2 p.Ser69Stop (c. 206C>G). A evolução clínica de ambos os casos demonstra uma semelhança no padrão metabólico dessa forma de diabetes ao longo dos anos. Arq Bras Endocrinol Metab. 2012;56(8):490-5.

Desenvolvimento de um método para a determinação da iodúria e sua aplicação na excreção urinária de iodo em escolares brasileiros / Development of a semi-automated method for measuring urinary iodine and its application in epidemiological studies in brazilian schoolchildren

Desenvolvemos método semi-automatizado em placa para a determinação de iodo urinário; utilizamos, primeiramente, a digestão das amostras de urina com persulfato de amônio e, a seguir, estimamos a quantidade de iodo pela redução do sulfato cérico amoniacal. O método foi validado no inquérito nacional de monitoração da deficiência de iodo, realizado em 1994, que empregou um sistema de amostragem mista da população brasileira e analisou a iodúria em 16.803 amostras de urina de escolares obtidas por coleta casual. Em 401 municípios estudados encontramos 4 com deficiência de iodo de grau moderado (Almas, Arraias e Paraná, em Tocantins, e Cocos, na Bahia) e 116 de grau leve. Desta forma, este estudo mostrou a presença de regiões com deficiência de iodo em 1994, a despeito do programa de iodação do sal. Dados recentes de outros autores, com número menor de municípios, indicam excesso de ingestão de iodo. Assim, num país de dimensões continentais e heterogêneo como o Brasil, é necessária a realização de avaliações periódicas de amplitude nacional para a verificação da ingestão de iodo da população. O método apresentado neste estudo apresenta as características de simplicidade e eficiência necessários para este tipo de estudo populacional.

In this study we developed a semi-automated method for the measurement of urinary iodine using firstly ammonium persulfate for digestion of urine followed by estimation of iodine content in the Sandell-Kolthoff reaction, in which iodine acts as a catalyst for the reduction of cerium. This method was validated in the 3rd Brazilian National Survey of iodine deficiency in 1994. We studied 16,803 casual urine samples from schoolchildren of 401 cities and found 4 moderately-deficient towns (Almas, Arraias, and Parana, in the State of Tocantins, and Cocos, in the State of Bahia), and 116 mildly-deficient. This work suggests that despite the salt iodization program, there was some iodine-deficient areas in Brazil in 1994. Recent surveys, involving less cities, are indicating an excess of iodine ingestion. Therefore, in a country of continental dimensions and very heterogeneous in terms of public health, periodical evaluations are necessary to monitor the real situation of iodine nutrition in Brazil. The method developed in this paper is suitable for these surveys.

[Development of a semi-automated method for measuring urinary iodine and its application in epidemiological studies in Brazilian schoolchildren]. / Desenvolvimento de um método para a determinação da iodúria e sua aplicação na excreção urinária de iodo em escolares brasileiros.

In this study we developed a semi-automated method for the measurement of urinary iodine using firstly ammonium persulfate for digestion of urine followed by estimation of iodine content in the Sandell-Kolthoff reaction, in which iodine acts as a catalyst for the reduction of cerium. This method was validated in the 3rd Brazilian National Survey of iodine deficiency in 1994. We studied 16,803 casual urine samples from schoolchildren of 401 cities and found 4 moderately-deficient towns (Almas, Arraias, and Parana, in the State of Tocantins, and Cocos, in the State of Bahia), and 116 mildly-deficient. This work suggests that despite the salt iodization program, there was some iodine-deficient areas in Brazil in 1994. Recent surveys, involving less cities, are indicating an excess of iodine ingestion. Therefore, in a country of continental dimensions and very heterogeneous in terms of public health, periodical evaluations are necessary to monitor the real situation of iodine nutrition in Brazil. The method developed in this paper is suitable for these surveys.

Diabetes mellitus do tipo MODY / Diabetes mellitus of the MODY type

Estima-se que perto de 5 por cento dos indivíduos classificados como portadores de diabetes mellitus (DM) tipo 2 e 10 por cento daqueles considerados como tipo 1 (anteriormente classificado como juvenil) sejam, na verdade, portadores de mutaçöes MODY. Nesta forma de DM ocorre uma co-segregaçäo evidente de algumas mutaçöes com a hiperglicemia, fato este reproduzido em inúmeras famílias estudadas em várias populaçöes do mundo. Caracteriza-se por ser uma das poucas causas de DM cujo modo de transmissäo da predisposiçäo genética ocorre de uma forma autossômica-dominante, compondo o grupo chamado de DM monogênicos, onde os outros representantes têm uma prevalência bastante rara. As mutaçöes nos genes MODY, mesmo no estado heterozigoto, apresentam um forte impacto no fenótipo (alta penetrância), sendo que 95 por cento dos indivíduos nascidos com alguma mutaçäo MODY seräo diabéticos ou apresentaräo alteraçöes no âmbito do metabolismo glícídico antes dos 55 anos de idade. Este trabalho objetiva a discussäo desta forma de DM, enfatizando suas características clinicas e genéticas mais relevantes. A pesquisa sistemática de mutaçöes MODY começa a ser feita de forma rotineira em vários países, havendo uma tendência de se colocar este recurso diagnóstico como um exame na prática da diabetologia.

Implantaçäo do programa de rastreamento do hipotiroidismo congênito na Fundaçäo Hospitalar do Distrito Federal: metodologia, resultados, dificuldades e propostas: estudo comparativo de recém-natos de outros Estados / Impantation of the screening program of congenital hypothyroidism in the Fundaçao Hospitalar do Distrito Federal: methodology, results, difficulties and proposals: comparative study with newborns of other States

Foram estudados 71.262 recém-nascidos (RN) vivos através de dosagem de TSH pelo método imunofluorométrico no sangue do cordão umbilical colhido em papel de filtro, considerando-se valor de corte 40 mUI/ml, durante o período de 1990-1991. Deste total, 29.870 provenientes de sete maternidades da Fundação hospitalar do Distrito Federal (FHDF) e 41.392 de areas suficientes de iodo, consideradas controle. A implantação do programa foi realizada de forma gradativa nas maternidades, observando-se porcentagem total de cobertura de 62 por cento com índices variáveis entre as maternidades, provavelmente devido a problemas administrativos. Dentre os 29.870 RN da FHDF, 0,144 por cento apresentaram valores acima de 40 mUI/L, frequência de 1:695 casos, enquanto no grupo controle observamos 0,075 por cento e frequência de 1:1335 casos. Nos primeiros, encontramos 10 casos com valores de TSH acima de 100 mUI/L, com freqúência de 1:2.980 casos diagnosticados da doença, e no grupo controle, cinco casos e frequência de 1:8.278. O rastreamento de hipotiroidismo congênito tem condições de instalar-se definitivamente no Distrito Federal com algumas medidas de ajuste ao programa. Observamos maior incidência da doença no Distrito Federal em relação as regiões suficientes de iodo no Brasil, tornando-se necessário a comprovação de deficiência de iodo nessa região.