Iodide transport defects (ITD), caused by impaired Na(+)/I(−) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Low to absent radioiodide uptake at scintigraphy represents the diagnostic tool. Hereditary molecular defects in NIS have been shown to cause ITD [9].

Iodide organification defects (IOD) due to thyroid peroxidase (TPO), dual oxidase 2 (DUOX2), and the DUOX maturation factor 2 (DUOXA2) gene inactivating mutations. TPO is a heme-binding protein localized on the apical membrane of the thyrocyte, and TPO enzymatic activity is essential for thyroid hormonogenesis. Currently, 61 properly annotated mutations in the TPO gene have been reported, of which the majority are missense mutations [10]. Hydrogen peroxide (H2O2) is the substrate used by TPO for oxidation and incorporation of iodine into thyroglobulin (Tg), a process known as organification. The main enzymes composing the H2O2-generating system are DUOX2 and DUOXA2. Affected patients show a positive perchlorate discharge test and high phenotypic variability, ranging from transient to permanent forms of CH. Up to now, only two cases of CH due to DUOXA2 defects have been published. The phenotypic expression is probably influenced by genetic background and environmental factors. DUOX and DUOXA constitute a redundant system in which DUOX1/DUOXA1 can at least partially replace the function of DUOX2/DUOXA2. Furthermore, increased nutritional iodide could ensure a better use of H2O2 provided by DUOX1 [11]. To identify IOD, a ¹²³I scintiscan with KClO4 discharge test should be performed. A ¹²³I discharge >90 % of the basal uptake measured 2 h after ¹²³I administration is typical of total IOD, while discharge ranging 10–90 % indicates partial IOD [12].

Pendred Syndrome characterized by sensorineural deafness, goiter, and a partial defect in iodide organification. The degree of goiter and hypothyroidism varies and appears to depend on nutritional iodide intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4 gene, which encodes pendrin, a multifunctional anion exchanger. Pendrin is mainly expressed in the thyroid, the inner ear, and the kidney. In the thyroid, pendrin localizes to the apical membrane of thyrocytes, where it may be involved in mediating iodide efflux. Loss-of-function mutations in the SLC26A4 gene are associated with a partial iodide organification defect, presumably because of a reduced iodide efflux into the follicular lumen. In the kidney, pendrin functions as a chloride/bicarbonate exchanger. In the inner ear, pendrin is important in the maintenance of a normal anion transport and the endocochlear potential [13].

Thyroglobulin (Tg) biosynthesis defects. Impaired Tg synthesis is one of the putative causes for dyshormonogenesis of the thyroid gland. This type of hypothyroidism is characterized by intact iodide trapping, normal organification of iodide, and usually low or undetectable Tg levels in relation to high TSH [14]. When untreated, the patients develop goiter.

Iodotyrosine deiodinase defects (ITDD) result from mutations in the DEHAL1 gene that encodes for the thyroidal enzyme that deiodinates mono- and diiodotyrosines (MIT, DIT). In fact, MIT and DIT are by-products formed in excess during TH synthesis, and this enzymatic activity represents an efficient system for iodide recycling within the thyroid gland [15]. ITDDs are characterized by hypothyroidism, compressive goiter, and variable mental retardation, whose diagnostic hallmark is the elevation of iodotyrosines in serum and urine. However, the specific diagnosis of this type of hypothyroidism is not routinely performed, due to technical and practical difficulties in iodotyrosine determinations [16].

Transplacental passage of maternal antibodies/goitrogens. Women with autoimmune thyroid diseases may produce antibodies that cross the placenta, resulting in fetal and neonatal goiter and thyroid dysfunction. Antithyroid drugs (ATDs) (propylthiouracil, methimazole, or carbimazole) for the treatment of maternal Graves’ disease or other iodine-containing drugs (expectorans, amiodarone, nutritional supplements, skin disinfectants) all cross the placenta and can cause fetal hypothroidism and goiter. Transplacental passage of TSH receptor blocking antibodies is rarely accompanied by goiter (though typically the gland is normal size or small). In maternal Graves’ disease, transplacental passage of TSH receptor stimulating antibodies (TRAb) that mimic the action of TSH can cause fetal and neonatal thyrotoxicosis and goiter [1]. Although transplacental passage of maternal TRAb does occur early in gestation, the fetal concentration is low until the end of the second trimester when placental permeability increases. Therefore, measurement of maternal TRAb concentration during 24–28 weeks of pregnancy is recommended. If the value is over three times normal, close follow-up for fetal and neonatal thyrotoxicosis is needed [21, 22]. Even women who are euthyroid due to ATD or hypothyroid due to thyroidectomy or radioiodine ablation can have persistent high levels of TRAb which can cause fetal or neonatal thyrotoxicosis. The clinical features of fetal hyperthyroidism are tachycardia (>160 beats/min), intrauterine growth retardation, advanced bone maturation, and goiter. Fetal goiter can also be present in fetal hypothyroidism due to transplacental passage of ATD given to the mother, and this iatrogenic fetal goiter usually regresses on reduction of doses of ATD [21]. Today, serial fetal ultrasonographic monitoring carried out by a highly experienced operator can be an important tool [6, 23]. Symptoms of neonatal thyrotoxicosis can be apparent at birth or may be delayed due to the effect of transplacental passage of maternal ATD or effect of coexisting blocking antibodies, but they are apparent by 10–15 days of life [24]. The clinical manifestations of neonatal hyperthyroidism are related to the involvement of central nervous system (irritability, restlessness), cardiovascular system (tachycardia, cardiac failure, systemic and pulmonary hypertension), and eye (periorbital edema, lid retraction, exophthalmos). Signs of hypermetabolism include hyperphagia with poor weight gain, diarrhea, and sweating. Other signs are hepatosplenomegaly, acrocyanosis, and thrombocytopenia. Diffuse goiter, usually small but occasionally large enough to cause tracheal compression, is present in most infants. Neonatal thyrotoxicosis patients require emergency treatment. The goal of the treatment is to normalize thyroid functions as quickly as possible by ATD administration, to avoid iatrogenic hypothyroidism while providing management and supportive therapy for the infant’s specific signs. The mortality is 12–20 % due to heart failure [6]. Neonatal thyrotoxicosis usually resolves spontaneously between 3 and 12 weeks of life, until the maternal antibodies have disappeared, although it can persist for 6 months or even longer.

Severe iodine deficiency (ID). Various studies have shown that during pregnancy not only severe but also moderate ID may cause significant maternal-fetal complications. Normal levels of TH are essential for neuronal migration and myelination of the fetal brain. For the first 12 weeks of gestation, the fetus is completely dependent upon maternal thyroxine. Subsequently, the fetal thyroid becomes able to concentrate iodine and synthesize iodothyronines. However, little hormone synthesis occurs until the 18th–20th week. As ID affects both maternal and fetal thyroid, the risk of goiter development and hypothyroidism is increased in both the mother and fetus. Cretinism represents the most severe form of the broad spectrum of developmental changes caused by maternal ID, with various grades of intellectual impairment depending on ID severity [22, 25].