This article summarizes the ontogenesis and genetics of the thyroid with regards to its possible congenital dysfunction and briefly refers to the roles of the mother-placenta-fetal unit, iodine effect, and organic and functional changes of the negative feedback mechanism, as well as maturity and illness, in some forms of congenital hypo- and hyperthyroidism. This article also describes the published literature and the authors’ data on the clinical aspects of congenital hypothyroidism, on the alternating hypo- and hyperthyroidism in the neonatal period, and on neonatal hyperthyroidism.
This article summarizes the ontogenesis and genetics of the thyroid with regards to its possible congenital dysfunction and briefly refers to the roles of the mother-placenta-fetal unit, iodine effect, and organic and functional changes of the negative feedback mechanism, as well as maturity and illness, in some forms of congenital hypo- and hyperthyroidism. This article also describes the published literature and the authors’ data on the clinical aspects of congenital hypothyroidism, on the alternating hypo- and hyperthyroidism in the neonatal period, and on neonatal hyperthyroidism.
Ontogenesis of thyroid function and genetic background of altered thyroid function
The ontogenesis of thyroid function involves the development of the fetal thyroid gland and its maturation, as well as the evolution of the hypothalamic-pituitary-thyroid axis. The developing thyroid is first visible in the floor of the primitive pharynx by embryonic day E20 to E22. Endodermal epithelium cells form the thyroid anlage, distinguishing themselves from their neighbors in a process defined as specification . A defect in this process should result in thyroid agenesis. During the second stage of early thyroid morphogenesis, the thyroid anlage invades the surrounding mesenchyme, forming a bud that proliferates and migrates from the pharyngeal floor through the anterior midline of the neck. The thyroid primordium becomes a bilobed structure by day E24 to E32 and reaches its final position around day E48 to E50. At the same time, small rudimentary follicles become evident and migrating C cells, derived from the ultimobranchial bodies, disseminate into the thyroid. Around day E51, the process of lobulation is complete, resulting in the definitive external form of the gland. An error during lobulation results in hemiagenesis, and an impaired descent results in ectopic thyroid tissue. Usually, the terminal differentiation of the thyroid follicular cells occurs when migration is complete (by 10–12 weeks). Specific proteins essential for thyroid hormone biosynthesis and secretion appear progressively: thyroglobulin (10–11 weeks), thyroid peroxidase, sodium/iodine symporter (12–13 weeks), thyrotropin receptor, thyroid oxidases, and pendrin. Defected, decreased, or absent production of these proteins results in dyshormonogenesis. All inborn errors of thyroid hormonogenesis are associated with a normally placed gland. In the last stages of embryonic life, the thyroid increases in size and continues to grow until term.
The hypothalamic-pituitary-thyroid axis is functional at midgestation. Thyrotropin is detectable in fetal serum as early as the 12th week and increases from the 18th week until term. The maturation of the hypothalamic-pituitary-thyroid feedback control is demonstrated by a fetal thyrotropin response to exogenously administered thyrotropin-releasing hormone at around 25 weeks’ gestation and also by the observation in the third trimester of a progressive rise in the ratio of free thyroxine (FT 4 ) to thyrotropin.
Congenital hypothyroidism is a heterogeneous condition resulting from a decreased or absent action of thyroid hormone. It is usually a sporadic disorder with 85% of cases caused by abnormal thyroid gland development (dysgenesis) and the remaining 15% due to inborn error of thyroid hormonogenesis. Less common causes are thyroid hormone resistance, decreased thyroxine (T 4 ) cellular transport, thyrotropin resistance, and decreased thyrotropin synthesis or secretion. Growing evidence confirms that almost every thyroidal and nonthyroidal disorder has a molecular genetic component ( Table 1 ).
| Phenotype (by Morphology or Function ) | Gene | Role of Gene in Organogenesis/ Protein Function | Associated Disorders |
|---|---|---|---|
| Dysgenesis | |||
| Aplasia or hemiagenesis or hypoplasia (ectopic or eutopic) | TITF1/NKX2.1 | Development of both follicular and C-cells | Choreoathetosis, respiratory distress syndrome, pulmonary disease |
| PAX8 | Thyroid follicular cell development | Renal agenesis | |
| TITF2/FOXE1 | Migration of thyroid precursor cells | Cleft palate, choanal atresia, bifid epiglottis, spiky hair (Bamforth syndrome) | |
| Resistance to thyrotropin | GNAS1 | Signaling protein | Osteodystrophy (hereditary Albright syndrome) |
| Hypoplasia (eutopic); resistance to thyrotropin | TSHR | Thyroid differentiation, thyrotropin receptor | – |
| Inborn error of thyroid hormonogenesis | |||
| Enlarged thyroid | TITF1, PAX8, TITF2/FOXE1 | During later stages, regulation of thyroid-specific gene expression | – |
| TPO | Thyroid differentiation; iodide organification | – | |
| TG | Thyroid differentiation ; structural prohormone | – | |
| NIS | Iodide transport from the blood into thyroid cell (basal membrane) | – | |
| PDS | Iodide transport from thyroid cell to follicular lumen (apical membrane) | Sensorineural deafness (Pendred syndrome) | |
| DUOX1/THOX1 DUOX2/THOX2 | Thyroidal hydrogen peroxide generation | – | |
| DEHAL1 | Deiodination for iodide recycling | – | |
| Thyroid hormone transporter defect | |||
| Thyroid hormone resistance | MCT8 | Transmembrane T 4 , triiodothyronine, reverse triiodothyronine, diiodothyronine transport | Severe neurologic abnormalities |
| THRB | Nuclear thyroid hormone receptor | Hyperactivity, learning disability | |
| Abnormal thyroid function test | SBP2 | Synthesis of selenoproteins | Delayed puberty (suspected) |
| Impaired hypothalamic-pituitary-thyroid axis | |||
| Secondary/tertiary hypothyroidism | LHX3 | Early pituitary development | CPHD, pituitary mass, rigid cervical spine |
| LHX4 | CPHD, sella turcica defect | ||
| PROP1 | Expression of all pituitary cell lineage | CPHD, pituitary mass | |
| POU1F1 | Generation and cell-type specification | Growth hormone, prolactine deficiency | |
| HESX1, PHF6 | Forebrain, midline, and pituitary development | Septo-optic dysplasia, Chronic pulmonary heart disease, epilepsy | |
| TRHR | Thyrotropin-releasing hormone receptor | – | |
| TSHB | Thyrotropin β subunit | – | |
| Other | |||
| Transient congenital hypothyroidism | DUOX2/THOX2 | Partial defect in hydrogen peroxide production | – |
| Permanent hyperthyroidism | TSHR | Gain-of-function of thyrotropin receptor | – |
Some other aetiopathogenetic factors
In addition to developmental and genetically determined damage to the thyroid, transient or permanent congenital hypo- or hyperthyroidism may also be affected by factors related to the mother-placenta-fetal unit, the iodine effect (deficiency or excess), organic and functional changes of the negative feedback mechanism, and the status of maturation and health/illness at birth and in the first period of life. These factors are discussed below.
Mother-Placenta-Fetal Unit
It is well established that in iodine-deficient areas, the maternal thyroid hormone level can be too low to provide an adequate fetal hormone level, especially in the first trimester. However, convincing data suggest that maternal thyroid disorders (eg, overt or subclinical hypothyroidism, hypothyroxinemia) during pregnancy in iodine-sufficient areas can also result in neurointellectual impairment of children.
Maternal hyperthyroidism can also cause significant risk for the offspring (see below). One of the reasons for such a close connection is the importance of the mother-placenta-fetus unit with regards to the hypothalamic-pituitary-thyroid axis and influencing factors. Other maternal autoimmune thyroid diseases can be risk factors of primary dysfunction in the offspring as well. Fig. 1 shows the potential role of the mother-placenta-fetus unit in some congenital thyroid dysfunctions.
Iodine Deficiency or Excess
Iodine deficiency can cause transient hypothyroidism or even impaired neurocognitive development. The deficiency is more common in known mild or moderate iodine-deficient areas in Europe. However, recent data suggest that women of reproductive age remain the most likely group to have low iodine excretion in the United States, which is a risk to their offspring. Urinary iodine excretion is a good indicator of the status of iodine supplementation at the population level. Neonatal thyrotropin screening results can also reflect the prevalence of iodine deficiency in a population.
Iodine excess also can cause thyroid suppression. This excess can be caused by drugs, contrast agents, antiseptic solutions, or nutrition (eg, seaweed in Japan). Premature infants are especially sensitive to both iodine deficiency and excess.
Organic and Functional Changes of the Negative Feedback Mechanism (Central Resistance; Change of “Set Point”)
The normal range for serum thyrotropin versus FT 4 in healthy infants (depicted between the first and 90th percentiles) were published by Fisher and colleagues. The elevation of serum thyrotropin relative to FT 4 (values to the right of the line marking the 99th percentile) indicates pituitary resistance to the negative feedback of T 4 on thyrotropin secretion. There are organic (mainly genetic) and functional (mainly environmental) forms of these changes : In permanent thyroid hormone resistance or in central congenital hypothyroidism with hypothalamic-pituitary organic damage, both parameters (thyrotropin and FT 4 ) are low. Recently, evidence has confirmed central congenital hypothyroidism in the offspring of insufficiently treated pregnant Graves patients (both parameters are low, mostly transiently; see below). In cases where maturity of the negative feedback is delayed (serum thyrotropin remains elevated in the presence of high or high-normal FT 4 concentration) mostly transient and functional (both parameters are high). Researchers have found similar, but more permanent changes in children with Down syndrome: Thyrotropin may be elevated with normal T 4 /FT 4 .
Role of Maturation and Illness
Despite the birth rates have decreased in developed countries, the proportion of premature, very low birth weight and ill newborns needing intensive care for weeks or months has increased. Parallel to this trend have been improved effectiveness of medical treatment and higher survival rates. Thyroid function in premature, very low birth weight, and seriously ill infants is characterized by either slightly decreased or markedly low thyrotropin and T 4 levels after birth and during the first weeks of life. This transient hypothyroidism may occur because of delay in maturation of the hypothalamic-pituitary-thyroid axis, the effect of medications used on the intensive care unit (eg, dopamine, glucocorticoid), or recovery from the sick euthyroid syndrome. In some cases, the iodine content of antiseptics can cause suppression of thyroid function.
Several trials on T 4 supplementation have been published and are in progress in this group of infants, but the results so far have been controversial. Further studies are needed to determine the indications, protocols, and duration of such a supplementation. Recently, Fisher reviewed this topic.
Cases of primary congenital hypothyroidism have been identified amongst these infants. Thyroid function of these neonates should also be monitored by serial serum thyrotropin measurements to detect its late rise and to start early T 4 replacement in proven cases of primary hypothyroidism.
Congenital hypothyroidism
Screening
Congenital hypothyroidism is the most common congenital endocrine disorder and treatable cause of mental retardation. The published incidence of primary hypothyroidism increases: at present it varies from 1 in 1000 to 1 in 3500 live births depending on the iodine sufficiency, laboratory methods, screening practice (changes in test cutoffs), demographic and other unknown factors. Depending on the iodine sufficiency, the incidence of primary hypothyroidism varies from 1 in 2500 to 1 in 4000 live births. Permanent secondary (thyrotropin deficient) and tertiary (thyrotropin-releasing hormone deficient) hypothyroidism is rare, with an incidence of 1:50,000 and 1:100,000 respectively. Prevention of cretinism and optimal neurologic development can be achieved in affected infants by early introduction of hormonal replacement. Screening, based on measurement of hormone levels, aims to pick up hypothyroid children soon after birth because clinical features are not specific during the perinatal period.
The cost/benefit ratio determines the method and ultimately the strategies of the screening program. A full drop of whole blood is obtained by skin puncture on day 1 to 4 of life and is dried on filter paper. Samples are sent to screening laboratories via mail. Measurement of T 4 , thyrotropin, or both is performed after an eluation process and a two-tiered approach is used. In Europe, Japan, and Australia, a primary thyrotropin determination was introduced as its sensitivity and specificity is greater than T 4 measurement. In North America the primary T 4 test is followed by backup thyrotropin determination in cases with a low T 4 level (usually the lowest 10th–20th percentile). Nowadays Canada and some states in the United States have switched to a primary thyrotropin program. Recently in the Netherlands, a primary T 4 /backup-thyrotropin program was supplemented by a thyroxin-binding globulin measurement. Using the three-arm method, the incidence of congenital hypothyroidism increased up to 1:1800 in the Netherlands. A second TSH determination in newborns with borderline TSH results also elevates the incidence mostly with milder forms, in which cases thyroid in situ is present.
Despite the technical development in laboratory methods, some false-negative results still occur with both the commonly used screening programs. A primary thyrotropin strategy will miss the rare secondary and tertiary hypothyroidism, thyroxin-binding globulin deficiency, and hyperthyroxinemia, while a primary T 4 /backup-thyrotropin program will miss compensated hypothyroidism. Apart from those infants missed depending on the exact strategy employed, infants with atypical congenital hypothyroidism (delayed thyrotropin rise) will be missed because their thyrotropin and T 4 levels are normal on initial screening.
Clinical Manifestation
Classic features of congenital hypothyroidism (lethargy, hypotonia, large tongue, hoarse cry, umbilical hernia, mottled dry skin, poor feeding, constipation) develop in the first 3 months of life and cannot be seen practically in countries where screening programs have been introduced. Babies identified by an abnormal laboratory result typically present with only some vague clinical symptoms during the first few postnatal weeks. After the 10 years of screening for congenital hypothyroidism, we evaluated the clinical signs of 87 recalled newborns suspected for thyroid hypofunction and developed a scoring system, which was subsequently evaluated.
Thyrotropin measurement was used from the blood spot taken from newborns aged 4 to 5 days. All newborns with elevated thyrotropin level were admitted to our hospital for further investigation and treatment. They were assessed by history and complete physical examination. More than 10 unspecific signs and history data were analyzed from their records to identify any factors that could predict congenital hypothyroidism: thyroid disorder in the family, concomitant congenital defect, large posterior fontanel, exuberant hair, enlarged tongue, constipation, umbilical hernia, hypoactivity, lethargic cry, wide nasal bridge, dry skin, and icterus.
The congenital hypothyroidism group (true positive, n = 67) and the reference group (false positive, n = 20) did not differ significantly in regard to the length of gestation (40 vs 39 weeks), birth weight (3330 vs 3240 g) and age at investigation (20 vs 22 days). By linear discriminant analysis, there were some significant differences ( P ≤.05) and some nonsignificant differences ( P >.05) between the two groups ( Table 2 ).
