Differentiated thyroid cancer in children: Heterogeneity of predictive risk factors.

OBJECTIVE: To correlate clinical and pathological characteristics at diagnosis with patient long-term outcomes and to evaluate ongoing risk stratifications in a large series of paediatric differentiated thyroid cancers (DTC). STUDY DESIGN: Retrospective analysis of clinical and pathological prognostic factors of 124 paediatric patients with DTC (age at diagnosis <19 years) followed up for 10.4 ± 8.4 years. Patients with a follow-up >3 years (n = 104) were re-classified 18 months after surgery on the basis of their response to therapy (ongoing risk stratification). RESULTS: Most patients had a papillary histotype (96.0%), were older than 15 years (75.0%) and were diagnosed because of clinical local symptoms (63.7%). Persistent/recurrent disease was present in 31.5% of cases during follow-up, but at the last evaluation, only 12.9% had biochemical or structural disease. The presence of metastases in the lymph nodes of the lateral compartment (OR 3.2, 95% CI, 1.28-7.16, P = 0.01) was the only independent factor associated with recurrent/persistent disease during follow-up. At the last evaluation, biochemical/structural disease was associated with node metastases (N1a, N1b) by univariate but not multivariate analysis. Ongoing risk stratification compared to the initial risk classification method better identified patients with a lower probability of persistent/recurrent disease (NPV = 100%). CONCLUSIONS: In spite of the aggressive presentations at diagnosis, paediatric patients with DTC show an excellent response to treatment and often a favourable outcome. N1b status should be considered a strong predictor of persistent/recurrent disease which, as in adults, is better predicted by ongoing risk stratification.

Neonatal Screening for Congenital Hypothyroidism: What Can We Learn From Discordant Twins?

CONTEXT: Newborn screening program for congenital hypothyroidism (CH) adopting rescreening in at-risk neonates. OBJECTIVES: To estimate the concordance rate for CH in twin pairs discordant at the first screening; to verify whether long-term follow-up of healthy cotwins belonging to CH discordant pairs may be useful to diagnose thyroid hypofunction during development; to evaluate the importance of genetic and environmental influences on liability to permanent and transient CH. DESIGN AND PATIENTS: Forty-seven screening discordant twin pairs were investigated. Proband was defined as the twin in the pair with a positive test at the first screening and a confirmed diagnosis of CH. RESULTS: Seven screening discordant twin pairs became concordant for CH within the first month of life (pairwise concordance of 14.9%) because seven screening negative cotwins showed high TSH values when retested. During long-term follow-up (range, 3 to 21 years), hypothyroidism was diagnosed in two monozygotic screening negative cotwins at the age of 9 months and 12 years, respectively. Furthermore, the twin analysis showed that 95% of liability to transient CH was explained by genetic factors and 5% by environmental (unshared) factors, whereas 64% of phenotypic variance of permanent CH was explained by common environmental factors (shared during the fetal life) and 36% by unshared environmental factors. CONCLUSIONS: This study showed that the introduction of rescreening permits the diagnosis of CH in a greater number of twins. It also showed the importance of long-term follow-up in both twins in the pair, and the role of nongenetic factors in the etiology of permanent CH.

Longitudinal study of thyroid function in children with mild hyperthyrotropinemia at neonatal screening for congenital hypothyroidism.

OBJECTIVE: Long-term outcome of thyroid function in children with very short-lasting neonatal hyperthyrotropinemia ("false positive" at neonatal screening) was studied in an observational, prospective study. Thyroid function and morphology were evaluated in 44 "false positive" children up to advanced childhood (8.0 +/- 0.7 yr of age). In these children a high prevalence (50%) of subclinical hypothyroidism in early childhood (2.8 +/- 0.5 yr) had already been described. RESULTS: At an average of 5.3 yr, subclinical hypothyroidism persisted in 19 of 44 (43.2%) children and, more specifically, in two of three of those who had increased TSH in early childhood. Euthyroidism was present in all cases that were euthyroid in early childhood, although they had TSH and free T(3) values significantly higher than control children with a normal TSH at birth (TSH = 2.6 +/- 0.7 vs. 1.5 +/- 0.6 mU/liter, P < 0.001; free T(3) = 4.9 +/- 0.8 vs. 3.9 +/- 0.9 pmol/liter, P < 0.01). Thyroid morphology alterations were frequent in the group of children with subclinical hypothyroidism. At an average of 8.0 yr, subclinical hypothyroidism persisted in 14 of 44 (31.8%) children. In all other children, TSH and thyroid hormones were confirmed within the normal range. CONCLUSIONS: This prospective longitudinal study confirms that newborns "false positive" at neonatal screening have a high risk to develop persistent subclinical hypothyroidism. The prevalence of hypothyroidism decreases with increasing age, but it is still high (>30%) in late childhood. Even those "false positive" children that maintain euthyroidism in late childhood have an average TSH value that, although within the normal range, is higher than in normal controls, a possible marker of minor congenital thyroid function abnormalities.

Risk factors for congenital hypothyroidism: results of a population case-control study (1997-2003).

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 in normal children and effect on thyroid function.

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.

Subclinical hypothyroidism in early childhood: a frequent outcome of transient neonatal hyperthyrotropinemia.

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.

Genetics of specific phenotypes of congenital hypothyroidism: a population-based approach.

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 (1277(insGGCC)) 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.