Congenital hypothyroidism (CH): the re-evaluation of diagnosis in CH patients with in situ gland identified by newborn screening

Background: Congenital Hypothyroidism (CH) is the most common endocrine disorder in childhood. Levothyroxine treatment within the first 2-3 weeks of life prevent neurological damage. Newborn screening (NS) by TSH dosage on dried blood spot allowed to early identification of risk for CH. In the last years the reduction of TSH recall threshold has led to an increased detection of mild forms with in situ gland at the first diagnosis. Therefore, the re-evaluation of diagnosis has become an important procedure to distingue transient forms from permanent ones.Aetiology: Transient CH may be caused by maternal factors (deficiency/excess of iodine, TSH receptor blockers, drugs) or neonatal factors (preterm and NICU infants; heterozygous mutations of the DUOX2 and DUOXA2 genes). Epidemiology: Before NS, the incidence of CH was 1:7000-10000 live births. After the introduction of NS it increased to 1:3000-4000. Currently, it is 1:1600-2800. This increase is correlated with the lowering TSH recall threshold, the increase in multiple pregnancies and preterm infants, and demographic changes. Re-evaluation of CH: it is performed after third year of life. According to the European guidelines, two different strategies can be adopted: the discontinuation of therapy over a period of 4-6 weeks or by decreasing the dose of Levothyroxine by 30% for 2–3 weeks followed by the dosing of serum levels of TSH and fT4. CH is permanent if an increase in TSH ≥ 10 mU/L is demonstrated. The etiology of CH can be identified using thyroid ultrasound (US), Iodine-123 scintigraphy, and in selected cases the perchlorate test. If the US shows a normal thyroid volume and scintigraphy shows low/absent tracer uptake, TSH resistance is presumable. If the US shows a normal or increased volume of thyroid, with a greedy absorption of the tracer to scintigraphy, dyshormonogenesis by the perchlorate test could be investigated. A radiolabel wash out of 10% of baseline uptake 2 hours after administration of perclorate is indicative of a defect in organification (partial with a wash out between 10-90%; total with a wash out >90%). The US findings of a normal or increased thyroid volume associated with high TSH and very low/unmeasurable thyroglobulin levels point to a deficiency of thyroglobulin synthesis. In our regional program of NS in the last ten years 491/454024 children were recalled for TSH and the diagnosis of CH was confirmed in 82.5%. The incidence of CH was 1:1121 births. 280 patients showed CH with in situ gland. After re-evaluation of diagnosis a permanent form of CH was detected in 55% of the cases (29% with hyperthyrotropinemia). A partial form of organification defect was detected in 34.5% of subjects submitted to perchlorate test and a TSH resistance due to a heterozygous mutation of the TSH-receptor gene was detected in 28.6%. Birth at term, the thyroid hypoplasia and a higher therapeutic dose of Levothyroxine (>2 mcg/Kg) at the re-evaluation were predictive factors of a permanent form. The frequent persistence of thyroid dysfunction in patients with borderline TSH values at the NS underlines the importance of reducing the recall threshold.