Patrícia Künzle Ribeiro Magalhães

Programa de Triagem Neonatal do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brasil

The Neonatal Screening Program at the University Hospital of the Ribeirão Preto School of Medicine, São Paulo University, Brazil, was introduced in 1994. As of December 2005, congenital hypothyroidism had been diagnosed in 76 infants, phenylketonuria in 10, and hemoglobinopathies in 25, representing incidence rates of 1:2,595, 1:19,409, and 1:4,120, respectively. A total of 2,747 newborns had the sickle cell trait, i.e., were heterozygous for the sickle mutation (1:37.5 live births). The programs mean coverage during this period was 94.5%. There was major improvement in the parameters for evaluating the programs quality, although they were still far from ideal. Public-awareness campaigns on the importance of neonatal screening are needed to increase the programs coverage. Setting postnatal day 3 as the standard Day for the Heel Stick Test would help ensure treatment at earlier ages, thus improving prognosis for affected infants.O Programa de Triagem Neonatal do Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Brasil, instituido em 1994 diagnosticou, ate 2005, 76 criancas com hipotireoidismo congenito, 10 com fenilcetonuria e 25 com hemoglobinopatias, o que representou uma incidencia de 1:2.595, 1:19.409, 1:4.120, respectivamente. Foram diagnosticadas 2.747 criancas com traco falciforme (1:37,5 nascidos vivos). A cobertura media do programa foi de 94,5%. Houve uma consideravel melhora nos parâmetros de avaliacao da qualidade do programa no periodo, porem, sem atingir os indices ideais. Campanhas visando a maior divulgacao da importância da triagem neonatal sao necessarias para aumentar a cobertura e a instituicao do 3o dia de vida do recem-nascido como sendo o Dia do Teste do Pezinho poderia contribuir para que idades mais precoces de tratamento fossem atingidas, melhorando o prognostico das criancas acometidas.

Hipotireoidismo congênito: recomendações do Departamento de Tireoide da Sociedade Brasileira de Endocrinologia e Metabologia

Congenital hypothyroidism (CH) is the most common congenital endocrine disorder, with an incidence of 1:2,000 to 1:4,000 live births and it is a leading preventable mental retardation. Neonatal Screening Programs allow early identification of the disease and the adequate treatment of affected children can avoid the complications related to deprivation of the hormone. Most cases of primary congenital hypothyroidism (85%) are due to thyroid dysgenesis (ectopia, hypoplasia or agenesis) while the remaining result from defects in hormone synthesis. Affected children (> 95%) usually have no symptoms suggesting the disease at birth. The most frequent symptoms and signs are prolonged neonatal jaundice, hoarse cry, lethargy, slow movements, constipation, macroglossia, umbilical hernia, large fontanelle, hypotonia and dry skin. Around the world, various strategies are used for the screening of the CH. In Brazil, screening for CH is mandatory by law and usually done by serum TSH in dried blood collected from the heel. The recommended age for performing this test is after 48 hours of life until the 4th day. Diagnostic confirmation is required dosing TSH and free T4 or total T4 in serum.

Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia, which may occur on sporadic form or on a hereditary basis. Germ line mutations in the RET proto-oncogene is responsible for hereditary MTC. However, most MTC occur in individuals without family history where the pathogenesis is still unclear. Single nucleotide polymorphisms (SNPs) of the RET gene have been described in the general population as well as in patients with MTC. Even though these allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET protein, cumulative studies suggest that they could modify disease susceptibility and clinical phenotype in patients with sporadic or hereditary MTC. Polymorphisms located in exons 11 (G691S), 13 (L769L), 14 (S836S), and 15 (S904S) seem to be over-represented in sporadic MTC patients from American and European countries. Here, we discuss the results obtained in different studies as well as describe the frequency of RET polymorphisms in Brazilian patients with sporadic MTC.

Primary hyperparathyroidism as the first clinical manifestation of multiple endocrine neoplasia type 2A in a 5-year-old child.

BACKGROUND Primary hyperparathyroidism occurs in only 10%-30% of patients with multiple endocrine neoplasia type 2A (MEN2A), rarely as the sole clinical manifestation, and is usually diagnosed after the third decade of life. SUMMARY A 5-year-old girl was referred for prophylactic thyroidectomy as she carried the p.C634R RET mutation. She was clinically asymptomatic, with a normally palpable thyroid and with the cervical region free of lymphadenopathy or other nodules. Preoperative tests revealed hypercalcemia associated with elevation of parathyroid hormone (PTH) (calcium = 11.2 mg/dL, calcium ion = 1.48 mmol/L, phosphorus = 4.0 mg/dL, alkaline phosphatase = 625 U/L, parathyroid hormone (PTH) PTH = 998 pg/mL). A thyroid ultrasound was normal and parathyroid scintigraphy with (99m)Tc-Sestamibi revealed an area of radioconcentration in the upper half of the left thyroid lobe suggesting hyperfunctioning parathyroid tissue. She underwent total thyroidectomy and parathyroidectomy and developed hypocalcemia. The anatomopathological examination showed no histopathological changes in the thyroid tissue and an adenoma of the parathyroid gland, confirming the diagnosis of hyperparathyroidism. CONCLUSIONS Primary hyperparathyroidism can be a precocious manifestation of MEN2A. This case report highlights that asymptomatic hypercalcemia should be scrutinized in children related to patients with MEN2A who carry a mutation in the RET proto-oncogene, especially mutations in the codon 634, before the currently recommended age of 8 years.

HLA-G Is Differentially Expressed in Thyroid Tissues

BACKGROUND HLA-G is a nonclassical major histocompatibility complex molecule that has well-recognized immunomodulatory properties. The expression of HLA-G in tumor cells has been considered to be detrimental, permitting tumor spreading and decreased survival. We evaluated the expression of HLA-G in histologically normal thyroid tissue, goiter, and benign and malignant thyroid tumors, and studied the relationship between HLA-G expression and patient clinical variables. PATIENTS AND METHODS The immunohistochemistry expression of HLA-G was performed on 72 specimens of papillary thyroid carcinoma (PTC), 19 follicular thyroid carcinomas (FTC), 22 follicular adenomas (FA), 22 colloid goiters (CG), and 14 histologically normal thyroid glands (NT). The percentage of HLA-G staining was graded from absent (-) to intense (+++). RESULTS HLA-G was faintly expressed in areas of hyperplasia in NT and CG. In PTC, FTC, and FA, the percentage of cell staining was significantly higher than in NT and CG (p<0.001 for each comparison). The tumor area with HLA-G expression was greater in FTC (p=0.0059) and PTC (p=0.0330) compared to FA. According to the magnitude of HLA-G staining, PTC tumors >1 cm exhibited increased HLA-G staining when compared to smaller tumors (p=0.03). Aggressive histologic subtypes of PTC have a higher median stained tumor area. No association was found between HLA-G expression and tumoral staging or patient disease-free survival. CONCLUSIONS The gradual increase of HLA-G expression from hyperplasia to carcinomas, and the association of strong HLA staining with some variables implicated in poor prognosis corroborate the unfavorable role of HLA-G in tumor thyroid cells, inhibiting cytotoxic immune system cells and facilitating tumor evasion and progression.

E449X mutation in the thyroid hormone receptor β associated with autoimmune thyroid disease and severe neuropsychomotor involvement

OBJECTIVE To report the clinical and molecular aspects of a patient with a diagnosis of Resistance to Thyroid Hormone (RTH) harboring the E449X mutation associated with autoimmune thyroid disease and severe neuropsychomotor retardation. METHODS We present a case report including clinical and laboratory findings, and molecular analysis of a Brazilian patient with RTH. RESULTS A 23-year old male presented hyperactivity disorder, attention deficit, delayed neuropsychomotor development, and goiter. Since the age of 1 year and 8 months, his mother had sought medical care for her son for the investigation of delayed neuropsychomotor development associated with irritability, aggressiveness, recurrent headache, profuse sudoresis, intermittent diarrhea, polyphagia, goiter, and low weight. Laboratory tests revealed normal TSH, increased T3, T4, antithyroglobulin and antimicrosomal antibody titers. Increasing doses of levothyroxine were prescribed, reaching 200 microg/day, without significant changes in his clinical-laboratory picture. Increasing doses of tiratricol were introduced, with a clear clinical improvement of aggressiveness, hyperactivity, tremor of the extremities, and greater weight gain. Molecular study revealed a nonsense mutation in exon 10, in which a substitution of a guanine to tyrosine in nucleotide 1345 (codon 449) generates the stop codon TAA, confirming the diagnosis of RTH. CONCLUSION This patient has severe neuropsychomotor retardation not observed in a single previous report with the same mutation. This may reflect the lack of a genotype-phenotype correlation in affected cases with this syndrome, suggesting that genetic variability of factors other than beta receptor of thyroid hormone (TRbeta) might modulate the phenotype of RTH.

Carcinoma medular de tireóide: da definição às bases moleculares

Medullary thyroid carcinoma (MTC) is a rare malignant tumor arising from thyroid C cells. It represents 3-10% of all thyroid tumors and is responsible for a great number of deaths in patients with thyroid carcinoma. In 75-90% of patients, MTC is sporadic; in the remaining cases, it is an autosomal dominant disease with a high degree of penetrance and variability of expression which may be part of 3 distinct syndromes: multiple endocrine neoplasia (MEN) type 2A, MEN 2B, and familial MTC. Different clinical forms of MTC, mainly those hereditary forms, are related to mutations in the RET proto-oncogene, which result in a constitutive activation of the transmembrane tyrosine kinase receptor. The distinction between sporadic and familial forms is of extreme clinical relevance because of differences in prognosis and the need for family screening, genetic counseling and close clinical follow up in the inherited forms. Genetic study of the proto-oncogene RET allows the identification of asymptomatic carriers of RET mutations, leading to an early and effective surgical management reducing the morbidity and mortality associated with this disease.

A Giant Primary Hemangioma of the Thyroid Gland

An 80-yr-old woman was referred with a 40-yr history of a slowly enlarging anterior neck mass. She had no compressivesymptoms,historyoftrauma,previousfine-needle aspiration biopsy, or other neck procedures. There was no family history of thyroid diseases. Physical examination showedagiant (circumference,50cm)painlessgoiter (Fig.1, A and B). Serum TSH (1.97 mIU/liter; normal range, 0.4– 4.0) and free T4 (18.0 pmol/liter; normal range, 10.3–24.5) levels were normal, and no antithyroid antibodies were detected.Computedtomography(Fig.1C)showedalargesolid mass (16 16 17 cm) with multiple peripheral calcifications in the left lobe of the thyroid, with deviation of the tracheaandcervical structures to theright side.Noabnormal findings in the right lobe of the thyroid were found, and surrounding lymph nodes were not detected. Cytological examination obtained by aspiration was inconclusive because only blood could be aspirated. A left-side hemithyroidectomy was performed, and a 22 21 17-cm encapsulated mass weighing 2800 g was removed (Fig. 1D). A cavernous hemangiomawasdiagnosedbyhistologicalanalysis.Thepatient had no complications after surgery and 3 yr later remains asymptomatic. Hemangiomas are an extremely rare category of thyroid nodules that often escape preoperative diagnosis. In most cases, a hemangioma of the thyroid gland is secondary to trauma or fine-needle aspiration biopsy, and they may be considered as a development of vascular proliferation that follows the organization of a hematoma (1). Primary thyroid hemangiomas are infrequent, and they are a development anomaly resulting from the inability of the angioblastic mesenchyma to form canals (2). The hemangioma presents as a hypoechoic area within the thyroid gland, without specific, distinct characteristics. Even experienced radiologists may find this lesion difficult to diagnose. Coarse calcifications, when present, are suggested as a reliable sign of the presence of a hemangioma. More specific studies such as magnetic resonance imaging, single photon angiography, and red blood cellscansmayimprovediagnosticability.Atpresent,mostofthe reported cases had the diagnosis confirmed only after pathological examination of a surgical specimen. There are only nine casesofprimarythyroidhemangiomareportedintheliterature. These cases have had male predominance with variable age at diagnosis and clinical features (Table 1). The present case appears to represent the largest size hemangioma.

Medullary thyroid carcinoma – Adverse events during systemic treatment: risk-benefit ratio

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from parafollicular C cells of the thyroid and associated with mutations in the proto-oncogene REarranged during Transfection (RET). The prognosis of MTC depends on clinical stage, with a 95.6% 10-year survival rate among patients with localized disease and 40% among patients with advanced disease. Standard chemotherapy and radiotherapy have no significant impact on the overall survival of these patients and two tyrosine kinase receptor inhibitors (TKIs), vandetanib and cabozantinib, have been recently approved for the systemic treatment of locally advanced or metastatic MTC. However, since patients with MTC and residual or recurrent disease may have an indolent course with no need for systemic treatment, and since these drugs are highly toxic, it is extremely important to select the patients who will receive these drugs in a correct manner. It is also essential to carefully monitor patients using TKI regarding possible adverse effects, which should be properly managed when occurring.

Thyroid hormone resistance detected by routine neonatal screening

We report the clinical and laboratory findings, and molecular analysis of a Brazilian patient with resistance to thyroid hormone syndrome (RTH) detected by neonatal screening. The index case was born at term by normal delivery with 2,920 g and 45 cm. TSH of the neonatal screening test performed on the 5(th) day of life was of 13.1 µU/mL (cut-off = 10 µU/mL). In a confirmatory test, serum TSH level was 4.3 µU/mL, total T4 was 19 µg/dL (confirmed in another sample, Total T4 = > 24.0 µg/dL), free T4 was 3.7 ηg/dL, and free T3 was 6.7 pg/mL. Direct sequencing of the beta thyroid hormone receptor gene revealed mutation c.1357C>A (P453T), confirming the diagnosis of RHT. Family study demonstrated the presence of RTH in his 1-year-and-3-month-old sister, in his 35-year-old father, and in his 68-year-old paternal grandfather. All of them had goiter and only his father had received an erroneous diagnosis of hyperthyroidism. The present case shows that clinical evaluation and a judicious interpretation of total T4/free T4 concentrations in a newborn recalled due to slightly altered neonatal TSH can contribute to the diagnosis of RTH.