Familial Aggregation of Endemic Congenital Hypothyroidism Syndrome in Congo (DR): Historical Data.

Familial aggregation of endemic congenital hypothyroidism (CH) in an iodine-deficient population from northern Congo (Democratic Republic (DR)) was analysed on data collected four decades ago (1979-1980). During a systematic survey of 62 families, 46 endemic CH subjects (44 myxedematous and 2 neurological) were identified based on clinical evidence within a village cohort of 468 subjects. A distribution analysis showed that two families presented significant excess of cases versus a random background distribution. Both families were characterised by two healthy parents having all of their five offspring affected by some form of endemic CH. Goitre prevalence in endemic CH was lower than that in the general population, while goitre prevalence in the unaffected part of the cohort (parents and siblings) was similar to that of the general population. Some unidentified genetic/epigenetic factor(s) could contribute to the evolution of some iodine-deficient hypothyroid neonates through irreversible and progressive loss of thyroid functional capacity during early childhood (<5 years old). Besides severe iodine deficiency, environmental exposure to thiocyanate overload and selenium deficiency, factors not randomly distributed within families and population, intervened in the full expression of endemic CH. Further exploration in the field will remain open, as iodine deficiency in Congo (DR) was eliminated in the 1990s.

Involvement of inducible costimulator ligand (ICOSL) expression in thyroid tissue in hyperthyroidism of Graves' disease patients.

BACKGROUND: The role of costimulatory molecules expressed on lymphocytes and thyrocytes in hyperthyroidism has attracted increasing attention and research has shown a close correlation between variant expression of these molecules on lymphocytes and thyrocytes and the development of GD. MATERIALS AND METHODS: [corrected] Thyroid tissues were collected from GD patients during surgery and from Hashimoto disease (HT) and non-toxic goiter (NTG) patients as controls. ICOSL expression on infiltrated B cells and TFC was detected by flow cytometry (FCM), reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry (IHC). Variation in ICOSL expression on TFC in primary cultures was analyzed in the absence or presence of cytokines using FCM assays. The role of ICOS-ICOSL signaling in proliferation, thyroid hormone production and thyroglobulin (Tg) release was investigated in primary TFC cultures using ICOS gene transfected L929 cells (ICOS-L929 cells) and the blocking ICOSL antibody (11 C4) in MTT assays and radioimmunoassays. RESULTS AND DISCUSSION: ICOSL expression on infiltrated B cells and TFC was detected in GD patient tissue. However, ICOSL expression was only detected on infiltrated B cells in control HT and NTG patient tissue. ICOSL expression on TFC was induced in vitro by the proinflammatory cytokines IFN-γ, IL-6 and TNF-α. Compared with mock transfected L929 (mock-L929) control cells, ICOS-L929 cells promoted significant proliferation of primary cultured TFC, with increased thyroid hormone and Tg production (all P < 0.01). TFC proliferation and production of thyroid hormones and Tg were inhibited significantly in the presence of ICOSL blocking antibody (11 C4) (all P < 0.05). Our observations suggest that ICOS-ICOSL signal plays a direct role in proliferation and differentiation of TFC and may exert important effects in the initiation, maintenance and exaggeration of autoimmune responses in local tissue.

[Peculiarities of formation, clinical presentations and therapy of diffuse nontoxic goiter of children].

The paper deals with the peculiarities of formation, clinical presentations and therapy of diffuse nontoxic goiter of children. The paper highlights the connection of the disease with the genetic predisposition, the impact of natural and anthropogenic strumagenes, immune processes. The clinical presentations of the diffuse nontoxic goiter are diffuse enlargement of thyroid gland, normal or high level of thyrotropichypophysis hormone when the content of thyroxin and triiodothyronine is normal, which is treated as the subclinic hypothyroidism syndrome. The variety of the disease pathogenesis theories leads to testing of different therapeutic methods, the principal ones among them are the use of iodine preparation and replacement therapy.

[Results of a cytogenetic study of children from radionuclide-contaminated goiter endemic zone of the Rivno region of Ukraine ]. / Rezul'taty tsytohenetychnoho obstezhennia ditei, iaki meshkaiut' na kontaminovanii radionukidamy terytoriï zony zobnoï endemiï Rivnens'koï oblasti Ukraïny.

Under the conventional cytogenetical examination of 6 different children groups (with and without non-stohastic thyroid pathology, exposed and nonexposed to the iodine isotopes in 1986) from the goiter endemic zone of Ukraine which belongs to the territory contaminated by 137Cs radionuclides, the identical to the spontaneous level of somatic chromosome mutagenesis of the last decade in all observed groups with the tendency to increasing of stable aberrations in some persons had been established.

Genetic and environmental factors in the aetiology of simple goitre.

The aetiology of simple goitre, affecting up to 5% of a population in iodine-sufficient areas and over 10% in endemic areas, is incompletely understood. It is generally believed that the development of simple goitre, whether endemic or sporadic, depends on complex interactions between genetic, environmental and endogenous factors. The importance of genetic factors is evident from the clustering of simple goitre within families and from a higher concordance rate for goitre in monozygotic than in dizygotic twins. Recently, studies assessing the role of specific candidate genes or genetic markers in the aetiology of simple goitre have given conflicting data in various families. However, there may well be single genes playing a major role within certain families, eg the thyroglobulin (Tg) gene, the thyroid-stimulating hormone receptor (TSHR) gene, the Na+/I- symporter (NIS) gene, and the multinodular goitre marker 1 (MNG1) on chromosome 14, but the genes will vary from family to family. In addition, family and twin studies also indicate a modest to major role for environmental factors in the aetiology of simple goitre. Clearly, iodine deficiency and cigarette smoking are the most important environmental risk factors associated with the genesis of simple goitre. Other suggested risk factors include naturally occurring goitrogens, emotional stress and certain drugs and infections. Ongoing studies focus on whole-genome screening in multiplex families as well as on large population-based case-control studies. However, the possibility that simple goitre is a heterogeneous disease without a single well-defined genotype and phenotype should be left open.

[Geographical differences of thyroid carcinoma and basic molecular principles]. / Geographische Differenzen des Schilddrüsenkarzinoms und molekulare Grundlagen.

Geographical differences have been demonstrated for the cancer incidence and histology of differentiated thyroid cancer. Iodine intake and specific external noxes, such as nitrosamine ingestion or external radiation are important factors. It is still questionable whether histologically identical differentiated thyroid cancers are prognostically different in low and rich iodine areas. Despite increased knowledge of molecular and genetic changes in differentiated cancer, the present therapy is primarily related to patient age, tumor stage and histology.

Genetic factors in iodine deficiency disorders: a general review.

This review presents a summary of what is known about genetic factors possibly involved in iodine deficiency disorders. After an overview on thyroid iodine metabolism and the role of environmental factors in endemic goitre, we analyse genetic studies on endemic goitre reported in the literature. We hypothesize that endemic goitre is a multifactorial disease in which the major factor would be of environmental nature (iodine deficiency) with a lesser role for genetic factors. Mutations, in a heterozygote state, of one of the genes involved in tiered hormonogenesis could lead to a less effective metabolic pathway in the iodine transport or hormonogenesis. We also briefly review various hereditary disorders which may be involved in endemic goitre. Then, we postulate that the presence of some genetic variants in the population or the heterozygote status of individuals for thyroid hereditary disorders may influence the degree of the thyroid enlargement and/or hypothyroidism.

Endemic goitre: a research protocol elaboration for eradication.

The iodine deficiency (ID), which affects 1 person out of 6, is relatively neglected by the responsible of Public Health Service, particularly in developing countries. Consequences of ID are far from being negligible: mental retardation, hypofertility, hyperplasia, carcinoma, early ageing and, in very exposed areas, endemic cretinism. Nevertheless, eradication is easy and cheap but it requires rigorous protocols and control of results. The elaboration of these protocols is complex because it must be adapted to environment, population and financial possibilities of concerned countries. Based on our experience in this field, we propose a combined protocol, between the Public Health too liberal approach and that of too expensive research, which can be adapted to several situations.

[Endemic goiter in Latium: environmental and genetic factors]. / Gozzo endemico nel Lazio: fattori ambientali e fattori genetici.

Most studies on the pathogenesis of endemic goiter focus above all on iodine deficiency. In some endemic goiter areas (i.e. Nigeria) there is no evidence of iodine deficiency; therefore, we suggest the taking into account of various factors, both environmental and non-environmental. We report the results of two studies carried out in three different areas in Latium: one of them (Cerveteri, RM) could be classified as high prevalence of goiter area, while the two others (Roccasecca dei Volsci, LT and Castel San Pietro Romano, RM) are true endemic goiter areas. The role of environmental factors, radioactivity and electromagnetism, foodstuff, the hydrogeological and chemical composition of natural water and the importance of genetics are here discussed, assuming that the endemic goiter could have a multifactorial pathogenesis.

Thyroglobulin exon 10 gene point mutation in a patient with endemic goiter.

Iodine deficiency is the most relevant etiologic factor in endemic goiter. However, the fact that not all residents in the same area eventually develop goiter suggests that individual factors might also be involved in the etiology of endemic goiter. We have previously reported a point mutation in thyroglobulin exon 10 associated with nonendemic simple goiter. In an attempt to determine whether the mutation in thyroglobulin exon 10 might be linked to endemic goiter, we studied the genomic organization of thyroglobulin exon 10 in 36 patients diagnosed with endemic goiter by Southern blot, PCR, and sequencing analysis. We also analyzed by Southern blot the organization of the genomic region that contains thyroglobulin exons 1 to 11. In one case, we observed a point mutation in thyroglobulin exon 10. Sequencing analysis revealed a mutation at position 2610 of the cDNA, which implies a G to T substitution. This single base change results in a glutamine to histidine substitution and is the same as that previously reported by our group in patients with nonendemic goiter. To our knowledge, this is the first time that a mutation in the thyroglobulin gene has been described in a patient with endemic simple goiter and further confirms the association between the exon 10 mutation and development of goiter.

[Hypothyroid iodine deficiency struma in 2 siblings as a sequela of alternative nutrition]. / Hypothyreote Jodmangelstruma bei 2 Geschwistern als Folge einer alternativen Ernährung.

Two siblings aged 4 and 7 years presented with a goitre and growth retardation. Laboratory data revealed hypothyroidism with elevated TSH, low T4 und T3, and a decreased urinary iodine excretion. Both children suffered from neurodermitis and because of that for already two years on a vegetarian diet free of any milk products; their nutrition contained sufficient calories but not enough iodine or vitamin B.

Clinical study of endemic cretinism in south Sikkim.

One hundred individuals suffering from Endemic Cretinism were studied. There were 55 males and 45 females. 62% of the cretins had visible goitre. Thirty nine (62.9%) goitrous cretins had grade II goitre. Neurological cretinism was the predominant type encountered (99%) and Myxoedematous cretinism was seen in only one patient. The most salient neurological feature was deaf-mutism seen in 74%. Findings in the motor system were, apart from deaf-mutism, the most characteristic feature of the condition on clinical examination. 58% had exaggerated deep tendon reflexes and 31% had extensor plantar response. Squint was noticed in 29%. Familial aggregation was noticed and was striking. Endemic cretinism is a distinctive and easily identifiable clinical entity and is an important indicator of the severity of iodine deficiency in a community.

Pendred's syndrome.

Although 5% of all cases of congenital deafness are caused by Pendred's syndrome, there are few reports in the literature. Seven patients with Pendred's syndrome in three families living in the same village were detected. For that reason, the syndrome is reviewed in light of the literature. The sex distribution of the patients with Pendred's syndrome and their families was recorded. We tested for thyroxine, triiodothyronine, thyroid-stimulating hormone, triiodothyronine resin uptake, and perchlorate, and performed caloric testing. In one patient, subtotal thyroidectomy was performed. In the histopathologic study, a thyroid nodule filled with colloid was found. Chromosome studies showed no anomalies in any patient. Five of the patients were deaf-mutes. We observed that the parents were cousins in all three families. These families also had healthy children, and the existence of the syndrome in both sexes points to an autosomal recessive trait.

A new polymorphism of thyroxin-binding globulin in three African groups (Mali) with endemic nodular goitre.

The thyroxin-binding globulin (TBG) polymorphism was investigated in three African groups: two belonged to the Bwa villages of Mali, and the third was a Dogon group living in the same area. The Bwa groups were characterized by the occurrence of nodular goitres, whereas the Dogon population did not show similar pathological symptoms. Females were more affected by goitre than males in the affected villages. The TBG polymorphism enabled us to demonstrate the presence of an undescribed allele (TBG C1) in these populations. The frequency of the TBG S allele was also higher than previously published in other African groups. We observed a disequilibrium in the distribution of the C and S alleles in the population, with an excess of homozygous TBG S individuals. No clear relationship between the TBG polymorphism and the number of nodules can be drawn.

Biocultural belief and iodine prophylaxis.

Iodine prophylaxis, the most cost-effective public health intervention as yet known, has been slow to be adopted even where goiter and cretinism--the most common expressions of iodine deficiency disorders (IDD)--have long been known to be endemic and where underdevelopment cannot explain the absence of prophylaxis. Belief in the hereditary causation of IDD tends to be high in societies where familial goiter is common and endogamy is high. This belief props up opposition to prophylaxis, making dietary intervention appear both useless and wasteful. The examination of genealogies (pedigrees) alongside dietary history can erode support for hereditary causation. This can be done by charting the incidence of IDD against social and dietary changes.

Endemic goitre in Finland and changes during 30 years of iodine prophylaxis.

Endemic goitre of moderate severity was mainly found in the East of Finland still in the 1950s but the whole country was moderately iodine deficient. The daily iodine intake determined both from food consumption and from the urinary excretion in population samples was 50-70 micrograms being lower in the East. The main iodine sources were milk products, about 50% of the daily intake being derived from these. Iodized salt was available but its use was very low and the iodine content insufficient so that only about 20% came from this source. In the late 1950s iodine prophylaxis was activated and since then only salt containing 25 mg KI/kg has been imported. However, during the last decades the consumption of salt has declined from 7-8 g to less than 4 g per day. Today the iodine intake in Finland is about 300 micrograms per day, the highest in Europe. The main sources are milk products and eggs which provide about 2/3 of the daily iodine intake due to an active iodine prophylaxis of house animals and only 20% comes from iodized salt. The origin of endemic goitre in Finland has obviously been multifactorial autoimmunity, natural goitrogens and possibly genetic factors being superimposed upon the basic iodine deficiency. The iodine supply is now adequate and there is no more goitre in neonates and no endemic goitre in school children in whom the prevalence is usually below 1%. Concomitantly, the nosology of hyperthyroidism has changed. Whereas more than 80% of hyperthyroid patients in the 1950s had nodular goitre the main type of hyperthyroidism today is Graves' disease proper with a small or normal-sized thyroid gland without nodules obviously due to disappearance of the endemic nodular goitre.