OBJECTIVE:To identify risk factors for permanent and transient congenital hypothyroidism (CH).DESIGN:A population-based case-control study was carried out by using the network created in Italy for the National Register of Infants with CH.METHODS:Four controls were enrolled for each new CH infant; 173 cases and 690 controls were enrolled in 4 years. In order to distinguish among risk factors for permanent and transient CH, diagnosis was re-evaluated 3 years after enrollment when there was a suspicion of transient CH being present. Familial, maternal, neonatal and environmental influences were investigated.RESULTS:An increased risk for permanent CH was detected in twins by a multivariate analysis (odds ratio (OR) = 12.2, 95% confidence interval (CI): 2.4-62.3). A statistically significant association with additional birth defects, female gender and gestational age >40 weeks was also confirmed. Although not significant, an increased risk of CH was observed among infants with a family history of thyroid diseases among parents (OR = 1.9, 95% CI: 0.7-5.2). Maternal diabetes was also found to be slightly associated with permanent CH (OR = 15.7, 95% CI: 0.9-523) in infants who were large for gestational age. With regard to transient CH, intrauterine growth retardation and preterm delivery were independent risk factors for this form of CH.CONCLUSION:This study showed that many risk factors contribute to the aetiology of CH. In particular, our results suggested a multifactorial origin of CH in which genetic and environmental factors play a role in the development of the disease.

Thyroid hemiagenesis prevalence was studied by neck ultrasound examination in 24,032 unselected 11- to 14-yr-old schoolchildren from southeastern Sicily. Twelve cases of thyroid hemiagenesis were identified, with a prevalence of 0.05%. The female to male ratio was 1:1.4. Thyroid hemiagenesis was always due to the absence (11 cases) or severe hypoplasia (1 case) of the left lobe. The hemiagenetic thyroid volume was within the normal total thyroid volume range normalized to age in 4 of 12 cases, enlarged in 3, and significantly reduced in 5. Thyroid function (thyroid hormones and TSH, both basal and 30 min after administration of 200 micro g TRH, iv) was evaluated in 9 of 12 children and was always within the normal range. However, children with thyroid hemiagenesis had an average serum TSH significantly higher than that of 18 matched controls (2.8 +/- 0.6 vs. 1.9 +/- 0.5 mU/liter; P < 0.001). This study confirms that thyroid hemiagenesis is nearly always due to left lobe defect, and that its prevalence is similar to the cumulative prevalence of thyroid agenesis and ectopia. Compensatory hypertrophy of the residual thyroid lobe occurs in most, but not all, cases and is due to thyroid tissue overstimulation by TSH. The high risk of goiter and hypothyroidism suggests systematic follow-up of all identified cases of thyroid hemiagenesis.

Congenital hypothyroidism (CH) may cause severe and irreversible neurologic and developmental abnormalities when not recognized early. Many millions of newborns have now been screened and many thousands of patients with CH have been identified. Approximately 80%-85% have defects of thyroid gland development, while 15%-20% have congenital errors of thyroid hormone biosynthesis. An entire population screened for CH over a long period of time, was studied in the present report, using a population-based approach. In particular, two CH phenotypes, both presenting with in situ thyroid gland (patients with either goiter or with thyroid gland volume ranging from normal to hypoplasic) were analyzed. Mutations were searched in some of the most likely candidate genes: thyroperoxidase (TPO) in patients with CH goiter, Pax8 and thyrotropin receptor (TSHR) in the other group. In the former group (n = 8), four TPO gene mutations were identified in three patients. One patient was a compound heterozygous. In two cases an already described mutation (1277(insGGCC)) was present; in two other cases mutations not previously described (1996(G --> T) and 2295(G --> A)), which induced aminoacid variations with a Glu --> Stop and Val --> Ile changes, respectively, were identified. In all patients mutations were inherited from one of the parents. In the case of the compound heterozygous patient, one mutation was inherited from the mother (1277insGGCC) and the other from the father (1996(G --> T), Glu --> Stop). In the latter group (n = 8). a patient with a 16-base pair C(T)(13)CC deletion in TSHR gene intron 8, 42-bp distal to exon/intron 8 splice junction, was identified. No mutation was identified in Pax8 gene.

Newborns with high TSH at birth and with normal free T(4) and normal or slightly elevated TSH at the confirmatory examination are considered false positive for congenital hypothyroidism. We evaluated thyroid function, thyroid antibodies, thyroid volume and morphology, thyroperoxidase and TSH receptor genes, and auxological data in 56 false positive children at 16-44 months of age. In these children thyroid function at confirmatory examination was fully normal in 33 (TSH, 0.8-4.9 mU/liter; group I) and nearly normal (borderline elevated TSH, 5.0-11.7 mU/liter) in the other 23 (group II). Compared with 65 control children with normal TSH at birth, false positive children had significantly higher basal serum TSH (mean +/- SD, 4.38 +/- 2.2 vs. 1.4 +/- 0.8 mU/liter; P < 0.01). Subclinical hypothyroidism, indicated by increased basal TSH and/or increased TSH response to TRH, was present in 36% children in group I and 70% in group II. Free T(4) was within the normal range in all children. Compared with the control group, false positive children had significantly higher free T(3) values (4.9 +/- 0.8 vs. 3.7 +/- 1.0 pmol/liter; P < 0.01) and a higher prevalence of antithyroid antibodies (25% vs. 1.5%; P < 0.001). Frequent thyroid morphology abnormalities and frequent thyroperoxidase and TSH receptor gene sequence variations were also observed. In conclusion, newborns classified false positive at congenital hypothyroidism screening have a very high risk of subclinical hypothyroidism in infancy and early childhood.

OBJECTIVE In view of the fact that, during the first period of life, thyroid hormones are critical for brain development, we investigated whether even transient congenital hypothyroidism could affect the long-term intellectual development of affected infants.DESIGN A case-control study of intellectual development, auxometric parameters and thyroid function performed in late infancy in children with documented transient congenital hypothyroidism or hyperthyrotrophinaemia at birth.PATIENTS Nine children born in an endemic goitre area who had short-term transient congenital hypothyroidism or hyperthyrotrophinaemia after birth (TCH) were studied and compared to nine matched children born in the same area at the same time but having normal thyroid function at birth (N).MEASUREMENTS Global, verbal and performance IQs were evaluated on the Wechsler scale. Height, bone age, total and free thyroid hormones, thyroid volume, thyroglobulin, basal and TRH stimulated TSH were also measured.RESULTS Height and bone age were similar in the two groups. Thyroid function tests were also similar in the two groups except for basal and TRH stimulated serum TSH and serum Tg which were higher in the TCH than in the control group. Global, verbal and performance IQs were systematically lower in the TCH than in the N group. (78.3+/-11.1 vs 90.9+/-14.2, P < 0.05; 84.4+/-15.4 vs 96.2+/-14.8, P NS; 75.0+/-8.5 vs 89.2+/-12.5, P < 0.01 respectively).CONCLUSION Infants born and living in an endemic goitre area, who had biochemical signs of thyroid hypofunction at birth, had a lower intelligence quotient at the age of 7-8 years than matched controls living in the same environmental conditions but with normal thyroid function at birth, The present findings strongly suggest that abnormalities in thyroid function at birth, even when transient, can adversely affect long-term intellectual development.

Ultrasound scanning is an accurate and objective method to assess thyroid volume; therefore it is useful to evaluate the effectiveness of L-thyroxine treatment in reducing goiter size, especially in children where clinical evaluation is inaccurate. In this prospectic study we evaluated the effectiveness of one-year L-thyroxine treatment in a group of children with nontoxic diffuse goiter coming from an area with low iodine intake. We examined 11 children (7 females, 4 males), age range 9–14 years. At clinical examination, 6 patients had a goiter classified la (according to WHO criteria), 4 had a class lb and only 1 had a class II goiter. In order to achieve an accurate goiter evaluation, the thyroid volume was determined by ultrasonic scanning with a 5 MHz linear probe before and after treatment. Patients were given a dose of L-thyroxine (1.5–2.0 µg/kg/die) in order to significantly reduce serum TSH levels (from 1.8 ± 0.6 to 0.8 ± 0.5 mU/l, mean ± SD). Patients were reexamined at 12 months of therapy and again at 10 months after therapy withdrawal. A significant reduction of the goiter volume (> 20%) was obtained in 6/11 (54%) patients, although serum TSH levels were fully suppressed only in one. The mean goiter size reduction in “responders” was −31.2 ± 9.3 % (m ± SE). After therapy withdrawal goiter size increased in the majority of cases (in 4/11, > 20%). Our study demonstrates that L-thyroxine treatment is effective in reducing goiter size in the majority of children with a diffuse goiter. Full TSH suppression is not necessary to obtain goiter volume reduction because a decrease of TSH levels to low values can already mediate a good therapeutical response. Since the majority of patients shows an increase of thyroid volume after therapy withdrawal, L-thyroxine administration should be a long term therapy.

In this study we report the prevalence of endemic cretinism in the general population of two iodine deficient areas in Northeastern Sicily that were described more than 10 yr ago. In addition, the individual characteristics of endemic cretins are considered in order to define the typical expressions of this major iodine deficiency disorder in Sicily. Forty-three mental defectives were identified: 22 were living in an area with three bordering and closely connected municipalities within the province of Messina and with a population of 17,485 inhabitants (prevalence = 0.13%). Three out of the 22 were school-age children. The other community, in the province of Catania, was constituted by a unique and mostly agricultural hamlet, and showed a prevalence of cretinism that was 0.68% (21/3,100). Among the 43 mental defectives, 16 (37%) presented prominent neuromotor and neurosensorial disorders, including deafmutism and were euthyroid, thus conforming to the neurological type of cretinism; 13 (30%) were hypothyroid and exhibited stunted growth without significant neuromotor and neurosensorial impairment (myxedematous cretins). In the remaining 14 individuals (33%) neurological disorders were associated with stunted growth and clinical or biochemical hypothyroidism. These data indicate that also in Sicily endemic cretinism is a continuum of a variety of forms: among these the pure neurological and pure myxedematous forms represent the two extremes. Our observations also indicate that endemic cretinism still represents a major public health problem in Sicily. The finding of 3 endemic cretins younger than 13 yr suggests the persistence of this disorder even in the presence of improved economic, social and nutritional conditions.

In order to evaluate the possible role of genetic factors in the pathogenesis of congenital hypothyroidism (CH), we investigated the occurrence of chromosome aberrations in a consecutive series of 47 patients with CH and 208 matched healthy controls. No abnormal karyotype was found in CH patients. In 5 CH patients and in 3 healthy controls a number of heterochromatin variants was detected. Although chromosomal variants are devoid of phenotypic effects, the frequency of these variants was higher in CH patients than in the control group (10.6% vs 1.4%, p < 0.005). These findings suggest that the association of congenital hypothyroidism with chromosomal variants may reflect more than chance concurrence.

Congenital hypothyroidism, if not treated in very early life, severely impairs the neuropsychological development of affected subjects. We have carried out a detailed analysis of cognitive functioning and personality traits in 18 congenital hypothyroid patients treated late and/or unproperly. Significant cognitive defects were observed, the most important being a defective learning ability and an impaired capacity to judge socially significant events and to project complex actions in a temporal perspective. A mental retardation (IQ < 70) was observed in 8/18 (44.4%) of these patients, a moderate intellective deficit in 5/18 (27.8%) and an IQ > 85 in the remaining 5 patients (27.8%). These data indicate that the mental defect of congenital hypothyroid patients may be overstimated. The patients personality was characterized by dependence on the mother, worrying about their body, maladjustement and socialization problems. Since the intellective prognosis of these patients may significantly improve when the environmental conditions are optimized, social and psychological help must always be suggested.

An analysis of thyroid cancer morbidity was carried out in two adjacent areas of Sicily differing in iodine intake. A consecutive series of 911 patients with "cold" nodules from an iodine-deficient area (IDA) and 2537 from a control area (CA) were examined by fine needle aspiration and selected for surgery and pathologic examination. Malignancies were found in 27 of the patients (2.96%) from the IDA and in 139 patients (5.48%) from the CA. Based on a population survey indicating that "cold" thyroid nodules were 2.5 times more frequent in the IDA with respect to the CA, we calculated a prevalence of 127 thyroid cancers per 10(5) inhabitants in the IDA versus 93 in the CA (P less than 0.001). Moreover, follicular and anaplastic carcinomas were three times more frequent in the IDA than in the CA (75 versus 24 cases per 10(5) inhabitants, respectively). These studies indicate that iodine deficiency may be one factor in the development of certain thyroid malignancies in man.

Newborn infants have elevated serum thyroglobulin (Tg) levels and reduced iodination of Tg. To determine whether a relationship exists between serum Tg levels and the degree of Tg iodination, 699 newborn infants were studied in 3 areas of Sicily: a normal iodine-sufficient (control) area and 2 iodine-deficient areas. In the iodine-sufficient area, the mean cord serum Tg level was 25.8 ng/ml (median, 18.0; n = 183). In the iodine-deficient areas, the serum Tg levels in newborns were significantly higher, with mean levels of 43.4 ng/ml (median, 29.7; n = 304; P less than 0.01) and 60.1 ng/ml (median, 48.0; n = 212; P less than 0.005), respectively. The higher serum Tg level at birth was not entirely due to increased cord serum TSH levels, since newborns from the iodine-deficient areas with serum TSH levels at birth similar to those in infants from the control area had higher serum Tg levels. Serum Tg levels correlated with the serum T3 to T4 ratio, but not with serum TSH, T4, or T3 levels. These data suggest that iodine availability, which affects the degree of thyroid Tg iodination, partially determines serum Tg levels at birth.

Thyroid function was studied in newborn from 3 areas of Sicily in which iodine intake is normal (area A), moderately decreased (area B), and severely decreased (area C). In the latter 2 areas, there is a high incidence of goiter and in area C endemic cretinism is present. TSH and T4 were measured in the cord serum of 5673 newborn from area A, 2096 from area B, and 184 from area C. The mean TSH value was significantly higher in areas C (P less than 0.001) and B (P less than 0.005) when compared to area A; moreover, in both endemic goiter areas the mean cord serum T4 was significantly reduced (P less than 0.01). All infants with cord serum TSH levels above 50 microU/ml were recalled because of the suspicion of congenital hypothyroidism. Such values were found in 41 of the 7953 infants (0.52%) with an increasing frequency from area A (9:5673 = 0.16%) to area B (14:2096 = 0.67%) to area C (18:184 = 9.78%). At the time of the recall examination [mean age, 32 +/- 8 (SD) days], 3 of the 41 recalled infants had died. Of the remaining 38 infants, 3 patterns evolved: 1) 23 had normal serum TSH and T4 values and were not studied further (false positives). 2) Eleven had elevated serum TSH and normal T4 values. They were reevaluated again after 3-6 weeks: all had normal values (transient hyperthyropinemia ). 3) Four infants had both high serum TSH and low serum T4 values (2 from area A and 2 from area C). They were diagnosed as having congenital hypothyroidism and treated with T4. At 10-13 months of age, after treatment withdrawal, the 2 infants from area A had permanent congenital hypothyroidism due to thyroid agenesis whereas the 2 infants from area C were euthyroid (transient congenital hypothyroidism). The present studies indicate, therefore, that in newborn from areas of iodine deficiency there is a higher frequency of elevated TSH levels and low T4 values than is found in areas where iodine intake is normal. This frequency is correlated to the degree of the iodine deficiency. The data suggest that the impairment of thyroid function at birth may be a transient phenomenon. The duration and the severity of the transient neonatal hypothyroidism, however, is greatly variable and its evolution unpredictable.

The serum thyroglobulin (Tg), T3, and T4 responses to graded endogenous TSH stimulation were examined in 30 normal subjects for up to 96 h after TRH administration. Increasing TSH rises were elicited by TRH administration as follows: 1) 500 micrograms iv as a single bolus in 10 subjects [mean peak serum TSH, 14.3 +/- 1.8 (SE) microU/ml]; 2) 1000 micrograms infused iv in 2 h in 10 subjects (mean peak TSH, 25.5 +/- 2.6 microU/ml); 3) 40 mg orally in 10 subjects (mean peak TSH, 27.5 +/- 3.0 microU/ml, with a delayed and more prolonged rise). Nine subjects received saline and were used as controls. A significant serum T3 and T4 rise followed the TSH increase in all subjects, and the mean peak value was always reached 4 h after TRH. In contrast, a significant serum Tg increase occurred only in 3, 6, and 9 subjects after 500 micrograms, 1000 micrograms, and 40 mg TRH, respectively. In addition, the time of the Tg peak and its duration was extremely variable but it was always delayed in respect to serum T3 and T4 peaks, occurring 6 to 72 h after TRH administration. No correlation was found between serum Tg and T3 or T4 increases after TRH in any of the three groups. These studies indicate that a significant Tg release in man usually occurs only after intense and prolonged TSH stimulation of the thyroid. In addition, the Tg increase is delayed in respect to the thyroid hormone increase and it is not correlated with them.

The prevalence, characteristics, and evolution of autonomously functioning thyroid nodules (AFTN) were studied in two population groups from northeastern Sicily. One group was living in an iodine-deficient area and another was living in an iodine-sufficient area. The prevalence of AFTN was significantly higher in the iodine-deficient area (4.4% of total patients vs. 2.7%). No significant difference between the two areas was observed in sex and age distribution and size of the nodules. In addition, a higher percentage of patients with toxic nodules (1.3%) was found in the group from the iodine-deficient area. Furthermore, in a selected group of patients followed for 1-6 yr, a higher percentage of patients from the iodine-deficient area had either an increase in the size of the lesion or an increase in thyroid hormone production leading to toxicity. These data suggest that iodine deficiency is one possible factor in the development of AFTN and that iodine deficiency may also be involved in the increased frequency of toxic evolution of these lesions.