Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

48.Genetic Defects Causing Hypothyroidism

Thomas Vulsma

Jan J.M. de Vijlder

Congenital hypothyroidism is the term applied to hypothyroidism that is present at birth. It is usually caused by defects in the development of the thyroid gland, which may be genetic, or genetic defects in the synthesis and secretion of thyroxine (T4), the main product of the thyroid. Other, rarer causes include defects in the secretion and action of thyrotropin (TSH), the secretion and action of thyrotropin-releasing hormone (TRH), and the action of triiodothyronine (T3), the biologically active thyroid hormone.

Congenital hypothyroidism thus includes a heterogeneous group of defects. Most cases of genetic origin are due to disorders of the thyroid gland, and for a long time the inherited disorders of thyroid hormone biosynthesis were the only ones that had been characterized in detail, based on abnormalities in iodine metabolism. During the past two decades the discovery of genes involved in thyroid development and thyroid hormone synthesis or action has expanded the spectrum of genetic disorders of the thyroid.

The clinical expression and long-term consequences of these genetic defects are dependent on the severity of the hypothyroidism, the age of onset, and the presence of associated malformations or disabilities. Congenital hypothyroidism of any cause is difficult to recognize at birth or very soon thereafter, in part because it is mitigated to some extent in utero by maternal-fetal transfer of T4 (1,2). If therapy is not initiated very soon after birth, the result is irreversible damage to the developing brain (3,4). The difficulty in recognizing congenital hypothyroidism and the serious consequences of delayed therapy have led to the introduction of mass screening programs for newborn infants in many developed countries (see sections Neonatal Screening and Congenital Hypothyroidism in Chapter 75).

Approximately 70% to 80% of newborn infants with congenital hypothyroidism have an abnormality in thyroid development (thyroid dysgenesis) and 10% to 15% have an abnormality in one of the steps of thyroid hormone synthesis (thyroid dyshormonogenesis), they are said to have thyroidal congenital hypothyroidism. Most of the remainder have a hypothalamic or pituitary defect (central congenital hypothyroidism) (5,6). Disorders that affect the transport or metabolic action of thyroid hormone (peripheral hypothyroidism) are rare (see Chapter 81).

Early detection, made possible by neonatal screening, has increased the need for etiologic classification and DNA diagnosis, for adequate treatment of the affected infant and genetic counseling of the family. In this way, later progeny can be treated immediately after birth, or even prenatally. To obtain a good clinicopathologic classification (Table 48.1), sensitive immuno- and bioassays and imaging techniques are required, if necessary combined with in vivo radioiodine (123I) studies, evaluation of iodine metabolism, and analysis of the iodinated compounds excreted in the urine. The results provide information about the type of congenital hypothyroidism, the proteins or factors that might be involved, and point to candidate genes that may harbor the causal gene mutations. The contribution of molecular biology to the diagnosis of genetic types of congenital hypothyroidism is increasing, and analysis of DNA is gradually replacing in vitro studies of tissues (7,8,9). Still, the molecular basis for the disorder in most infants is not known.


Diagnostic Determinant vs. Etiologic Entity

Serum Free T4Concentrationa

Serum TSH Concentration

Serum Tg Concentration

Urinary Iodopeptide Excretion

Thyroid Location and Sizeb

Thyroid Radioiodide Uptakec

Radioiodide Release after NaClO4d

Mode of Inheritancee

Congenital hypothyroidism of central origin

  Hypothalamic/pituitary dysgenesis


Low to high


Not indicated

Normal or hypoplastic

Not indicated

Not indicated

Autosomal recessive or dominant in a few cases

Hypothalamic/pituitary dyshormonogenesis

  TRH hypo-responsiveness




Not indicated

Normal or hypoplastic

Not indicated

Not indicated

Autosomal recessive

  TSH synthesis defect




Not indicated

Normal or hypoplastic

Not indicated

Not indicated

Autosomal recessive

  TSH hypoactivity

Low or normal

Normal or high

Low or normal

Not known

Not known

Low or normal


Autosomal recessive

Congenital hypothyroidism of thyroidal origin

  Thyroid dysgenesis

 Autosomal recessive or dominant in a few cases



Very high






    Cryptic remnant


Very high

Low or normal





    Dystopic remnant

Low or normal


Low to high

Absent or low


Low or normal


    Eutopic remnant

Low or normal


Not known

Absent or low


Low or normal


  Thyroid dyshormonogenesis

    TSHR deficiency

Low or normal


Low or normal

Not known

Normal or hyperplastic



Autosomal recessive

    Gsa deficiency

Low or normal

Normal or high

Low or normal





Autosomal dominant

    Total sodium-iodide symporter defect

(Very) low

Very high

Very high


Normal or hyperplastic



Autosomal recessive

    Pendred's syndromeg

Low or normal

Normal or high

Normal or high


Normal or hyperplastic

Normal or high


Autosomal recessive

    Total iodide organi-fication defect


Very high

Very high


Normal or hyperplastic

Rapid and high


Autosomal recessive

    Partial iodide organi-fication defect

Low or normal


(Very) high

Absent or low

Normal or hyperplastic



Autosomal recessive

    Thyroglobulin-synthesis defect

Low or normal

Normal or high

Low or normal


Normal or hyperplastic

Rapid and high


Autosomal recessive

Congenital hypothyroidism due to defects in peripheral tissues

  Thyroidal and/or peripheral genetic defects

    Iodide recycling defect (dehalogenase defect)

Low or normal


Very high

Presence of MIT and DIT

Normal or hyperplastic



Autosomal recessive

    T4/T3transmembrane transporter defect

Low Very high T3

Normal or high

Not known Low reverse-T3

Not indicated

Normal or hyperplastic

Not known

Not indicated


    Thyroid hormone hyporesponsiveness


Normal or high

Normal or high

Not indicated

Normal or hyperplastic


Not indicated

Autosomal dominant

  Excessive loss of thyroid hormone

Normal or low

Normal or high

Not known

Not indicated

Normal or hyperplastic

Not known

Not indicated

Depends on etiology

aIn newborn infants who cannot produce any T4, maternal-fetal transfer results in cord serum T4 concentrations of 2.7–5.4 µg/dL (35–70 nmol/L) and comparable cord serum free T4 concentrations, which decline with a half-life of 2.7–5.3 days.

bThe thyroid's location in the neck region and its size is preferably examined by ultrasound imaging, or by radioiodide (Na123I) imaging.

cNa123I is administered intravenously [27 µCi (1 MBq) for infants younger than 1 year and 54 µCi (2 MBq) for older children]. In general, the radioiodide uptake is a function of the amount of thyroid tissue and the degree of stimulation by TSH.

dSodiumperchlorate is administered intravenously 2 hours after Na123I (10 mg/kg body mass, maximum 400 mg). Discharge of thyroidal radioiodide after 1 hour: < 10% is normal; 10%–20% is borderline; >20% is abnormal.

eWhen the full-blown disease has an autosomal-recessive pattern of inheritance, some heterozygous relatives have mild abnormalities in the relevant tests.

fThe most characteristic abnormality in patients with a total sodium-iodide symporter defect is a (very) low saliva/serum ratio of radioiodide: for neonates >10 is normal, 3–10 is borderline, < 3 is abnormal. The saliva/blood ratio is 1.17 times the saliva/serum ratio (95% confidence interval 1.15–1.19). Partial iodide transport defect is an ill-defined condition; if it exists, the diagnostic test results depend entirely on the iodine intake, which varies greatly worldwide.

gThe most important determinant of Pendred's syndrome is the sensorineural hearing defect.

DIT, diiodotyrosine; MIT, monoiodotyrosine; T3, triiodothyronine; T4, thyroxine; Tg, thyroglobulin; TSH, thyrotropin.


To detect central congenital hypothyroidism by neonatal screening, it is necessary to measure T4 as well as TSH in the filter paper blood samples used for screening (see section Neonatal Screening in Chapter 75). In the Netherlands, where both T4 and TSH are measured, the incidence of central hypothyroidism is about 1:20,000 newborn infants, substantially higher than usually assumed (5,10,11,12).

Central congenital hypothyroidism is a heterogeneous group of conditions. Although most cases are sporadic, they presumably originate from genetic defects. It is more common in males than females (11), for unknown reasons, but only a small percentage of cases can be ascribed to mutated genes located on the X chromosome.

Many infants with central congenital hypothyroidism, especially those with multiple pituitary hormone deficiencies, have a characteristic developmental abnormality of the infundibulum, also known as ectopic posterior lobe of the pituitary (posterior pituitary ectopia). This entity presents a distinctive appearance on T1-weighted magnetic resonance imaging (MRI), with the hyperintense posterior lobe characteristically seen at the median eminence below the floor of the third ventricle.

Defects in Ontogeny of Hypothalamus and Pituitary Gland

The hypothalamus develops from the infundibulum, a region of the ventral diencephalons (see Chapter 2). It contains several nuclei that produce releasing and inhibiting hormones to regulate the synthesis and secretion of the various pituitary hormones. Defective neural migration in the developing infundibulum, resulting in posterior pituitary ectopia, is often accompanied by other malformations in the brain (e.g., periventricular heterotopia) (13) or elsewhere, and the functional problem may vary from isolated growth hormone deficiency to panhypopituitarism. The less visible the pituitary stalk by MRI, the more severe the anterior lobe hypoplasia and hormonal deficiencies (14). The etiology of the developmental defects is unknown. Almost all cases appear to be sporadic, with a strong male predominance. To date, HESX1 is the only gene (rarely) associated with posterior pituitary ectopia (13,15).

The pituitary gland develops from two distinct ectoderm-derived structures, the infundibulum (a region of the ventral diencephalon) and Rathke's pouch (a derivative of the oral ectoderm). The posterior lobe develops from the infundibulum, and the intermediate and anterior lobes derive from Rathke's pouch (see Chapter 2). In the absence of the infundibulum the pituitary gland does not develop properly. Once the pituitary is developed, its secretory functions are controlled by hypothalamic neurons from the same region in the ventral diencephalon.

Mutations in several homeobox genes, including HESX1, LHX3, LHX4, PHF6, PROP1, and POU1F1, may cause central congenital hypothyroidism. In mice, the first four genes code for transcription factors that are required for the development of the forebrain, eyes, and other anterior structures, such as the hypothalamus, the pituitary gland, and the olfactory bulbs. The latter two genes code for pituitary-specific transcription factors.

Defects in HESX1 in mice cause disorders that are comparable with septooptic dysplasia in humans (16). This entity is characterized by optic nerve hypoplasia, various forebrain defects, and multiple pituitary hormone deficiencies, including TSH deficiency. In a study of 38 patients with septooptic dysplasia, two siblings with agenesis of the corpus callosum, optic nerve hypoplasia, and panhypopituitarism were homozygous for an Arg53Cys mutation in the HESX1 gene, resulting in a gene product incapable of binding to DNA (16). The affected siblings had consanguineous parents; heterozygous family members were normal. HESX1 mutations have been described in other patients with congenital pituitary defects; the patients have had varying hormonal deficiencies, and some have had optic nerve hypoplasia or abnormalities of the corpus callosum and septum pellucidum (17,18).

Homozygous mutations in the LHX3 gene have been described in two unrelated consanguineous families. The patients had severe deficiency of all anterior pituitary hormones, except corticotropin, and a rigid cervical spine that limited head rotation. One missense mutation (Tyr116Cys) in LHX3 inhibits transcription of target genes but does not prevent DNA binding and interaction of LHX3 with partner proteins. Another mutation, an intragenic deletion, causes loss of the entire homeodomain, preventing binding of LHX3 to DNA (19).

In a family with short stature, pituitary and cerebellar defects, a poorly developed sella turcica, and multiple pituitary hormone deficiencies, including TSH deficiency, an intronic mutation in the LHX4 gene was identified that abolishes normal splicing of the LIM-homeobox transcription factor LHX4 (15). The inheritance was autosomal dominant.

The Börjeson-Forssman-Lehmann syndrome is a rare X-linked condition, characterized by early onset of multiple pituitary hormone deficiencies (most affected males are short and have hypogonadism), optic nerve hypoplasia, mild to moderate intellectual handicap, epilepsy, and the gradual development of coarse facial features. The heterozygous females are variably affected (20,21). This syndrome has been ascribed to mutations [Lys8Stop, Arg342Stop (22), and Asp333del (23)] in the PHF6 gene. The function of the gene product is unknown, but the clinical features suggest that it plays an important role in midline neurodevelopment, including that of the hypothalamus and pituitary gland. There is a case report of a boy with a Börjeson-Forssman-Lehmann-like syndrome who had a duplication in chromosome Xq26.3-q28 (24).

Some cases of X-linked-recessive hypopituitarism have been explained by chromosomal duplication, leading to increased dosage of a still unknown gene that must be critical for pituitary development. The duplicated region, mapped to chromosome Xq26.1-q27.3, spans 9 Mb (25,26). Surviving patients had mild to moderate mental retardation.

The transcription factor POU1F1 acts as one of the main stimulators of TSH, growth hormone, and prolactin synthesis. Heterozygous, compound heterozygous, and homozygous POU1F1 deletions, and missense and nonsense mutations have been reported (27); the phenotype varies even between siblings with the same mutation (28,29,30,31,32). A heterozygous Arg271Try mutation exerts a dominant-negative effect (33). Hypothyroidism may be present at birth and has been detected in the screening program for congenital hypothyroidism in the Netherlands.

Mutations in PROP1 account for the majority of cases of familial multiple pituitary hormone deficiencies. The disorder is recessively inherited; families with homozygosity or compound heterozygosity for inactivating point mutations and deletions in the PROP1 gene have been described (34). These mutations are responsible for subtypes of a multiple pituitary hormone deficiency syndrome that include TSH, growth hormone, prolactin, gonadotropin, and corticotropin deficiencies. The mutation is often a 2-bp deletion in an AG-rich region in exon 2 of the gene, resulting in a premature stop codon; another mutation (149delGA) resulting in the same stop codon has been described (see reference 34 for review).

The clinical abnormalities in patients with inactivating mutations in PROP1 differ from those of patients with inactivating POU1F1 mutations. The hormonal deficiencies emerge in a typical order, rather than being present at birth. Neonatal features of hypothyroidism such as prolonged jaundice have been described only once, and growth appears to be normal during infancy (35,36). Growth hormone deficiency becomes evident before TSH deficiency in 80% of patients, and gonadotropin deficiency comes later, although most patients fail to enter puberty spontaneously. Corticotropin deficiency is the last manifestation, often occurring several decades after birth. The degree of prolactin deficiency is variable. Although all untreated patients end up extremely short and sexually immature, their intelligence is normal, indicating that they were euthyroid during the first few years after birth. Central hypothyroidism caused by deficiency of PROP1 deficiencies has not been detected in the Dutch neonatal screening program for hypothyroidism.

Pituitary morphology in patients with PROP1 deficiency varies from hypoplastic to hyperplastic, without involvement of the surrounding tissues. The distinct MRI characteristics of pituitary enlargement may originate from the intermediate lobe (37).

Developmental defects such as solitary maxillary central incisor, nasal pyriform aperture stenosis, and variants of holoprosencephaly can be clues to the presence of deficiencies of one or more pituitary hormones (38). These entities have been associated with inactivating mutations in the SHH and SIX3 genes; loss of one SHH allele is sufficient to cause holoprosencephaly (39). There are no case reports of isolated central hypothyroidism in patients with SHH or SIX3 mutations.

Defects in Thyrotropin-Releasing Hormone

Thyrotropin-releasing hormone (TRH), the tripeptide pyroglutamyl-histidyl-prolineamide, is the major hypothalamic mediator of the synthesis and secretion of TSH. It is present throughout the brain, but is found in highest concentrations in the paraventricular nuclei and median eminence of the hypothalamus (see section Regulation of Thyrotropin Secretion in Chapter 10). Hypothyroidism occurs in mice in which the TRH gene is deleted (40). However, no patient with a mutation in the gene for the precursor of TRH (preproTRH) or the gene for the enzymes that cleave prepro-TRH to its component TRH molecules has been described.

Central congenital hypothyroidism with complete absence of increases in serum TSH and prolactin concentrations in response to exogenous TRH has been described (41). The affected patient was compound heterozygous for two mutations in the TRH receptor. Both mutations resulted in production of receptors unable to bind TRH. The patient had mild hypothyroidism, short stature, and markedly delayed bone maturation. The parents and eldest brother, who were heterozygous for one of the mutations, were normal.

Defects in Synthesis of Thyrotropin

Thyrotropin is a heterodimer composed of noncovalently linked α- and β-subunits. It shares the α-subunit with follicle-stimulating hormone, luteinizing hormone, and chorionic gonadotropin; each has a different β-subunit (see section Chemistry and Biosynthesis Of Thyrotropin in Chapter 10). TSH stimulates the growth and function of the thyroid via interaction with its specific plasma membrane receptor.

Genetic disorders of TSH synthesis are rare. They include patients whose TSH has decreased bioactivity, resulting in mild hypothyroidism and high serum concentrations of immunoreactive TSH (42), as well as patients with totally inactive TSH and severe congenital hypothyroidism (43).

A variety of inactivating mutations has been described in the gene for the β-subunit of TSH. A nonsense mutation (Glu12X) was found in two Greek families (44). Three Japanese families had a Gly29Arg mutation in the [Cys-Ala-Gly-Tyr-Cys] region of the gene, which results in synthesis of β-subunits that cannot combine with α subunits (45). Other mutations include a Glu49X mutation that resulted in a truncated inactive TSH (46,47), a Cys85Arg mutation (48), and a defect in the donor splice site of intron 2 (G → A + 5) (49). The most frequent mutation is a single-base deletion in codon 105 in exon 3, resulting in a frame shift and a premature stop codon (Cys105FS114X). A disulfide bond between Cys19 and Cys105 in the β-subunit is predicted to form the “buckle” of a “seat-belt” that surrounds the subunit and maintains the conformation and bioactivity of the hormone (50,51,52,53,54,55,56). Another mutation, 313deltaT, is recognized as a founder effect in several German families (57).

Most patients with defects in TSH had severe hypothyroidism when discovered, mostly after the neonatal period. They are not identified by screening programs that measure only blood-spot TSH concentrations (56) (see section Neonatal Screening in Chapter 75).


The overall incidence of thyroidal congenital hypothyroidism is on average 1:4,000, but varies considerably in different countries and among different racial and ethnic groups (5) (see section Neonatal Screening in Chapter 75).

The majority of patients with thyroidal congenital hypothyroidism have abnormal thyroid development (thyroid dysgenesis). Therefore, diagnostic evaluation should include an imaging procedure. If the infant has a normally shaped and located thyroid gland, irrespective of its size, and a high serum TSH concentration, further studies with radioiodide will provide information about thyroidal iodide metabolism. Measurements of serum thyroglobulin and low-molecular-weight iodopeptides in the urine help to discriminate between the various types of defects, and measurement of urinary iodide excretion helps to differentiate genetic defects from iodine deficiency or excess (Fig. 48.1 and Table 48.1). Because it is essential to treat newborn infants with congenital hypothyroidism immediately, blood and urine samples must be obtained immediately after referral. Radioiodide studies can be conducted a few days after T4therapy is started, before the infant's serum TSH concentration decreases to normal. Alternatively, these studies can be performed at 3 to 4 years of age, when T4 therapy can be interrupted safely for several weeks.

FIGURE 48.1. Flow chart for etiologic classification of disorders causing congenital hypothyroidism (CH). A: Neonatal screening by measurements of thyroxine (T4) and thyrotropin (TSH) in dried blood samples on filter paper. B: Confirmation by measurement of serum TSH and serum free T4C: If the serum free T4 concentration is inappropriately high in relation to the serum TSH concentration, clinical evaluation of the infant and measurement of maternal TSH receptor–stimulating antibodies and urinary iodine excretion are indicated. D: Decide whether the serum free T4 and TSH values indicate the presence of thyroidal or central congenital hypothyroidism. E: Perform thyroid radionuclide imaging or ultrasonography to distinguish between thyroid dysgenesis or thyroid dyshormonogenesis. F: Perform magnetic resonance imaging of the hypothalamus and pituitary. G: Measure serum thyroglobulin and thyroid radioiodide uptake (including discharge after perchlorate), and test urine for iodopeptides or iodotyrosines. H: Evaluate other components of hypothalamic–pituitary function. I: Perform mutation analysis to identify the specific defect.

Defects in Ontogeny of the Thyroid Gland

The development of the thyroid gland starts with an invagination of the ventral endoderm of the future oral cavity (median anlage). This invagination develops into a bilobar structure, and subsequently each lobe fuses with an ultimobranchial body (lateral anlage) derived from the fourth pharyngeal pouches while migrating to the distal part of the neck (see Chapter 2). Thyroid follicles appear at 10 weeks of gestation, indicating that the thyroid follicular cells can synthesize thyroglobulin. At the same time, iodine accumulates in the fetal thyroid, indicating that thyroid oxidase and peroxidase are active. By mid-gestation the thyroid is able to secrete substantial amounts of T4. Serum free T4 concentrations gradually increase until adult values are reached at about 36 weeks of gestation (see Chapter 74).

Thyroid dysgenesis, the most common cause of congenital hypothyroidism in iodine-sufficient areas), is easy to recognize, but its cause is not known. The great majority of cases are sporadic (5), but multiple cases occur in a few families (8), and up to 5% of patients have other congenital, mainly cardiac malformations (58). Some observations point to genetic defects. Thyroid dysgenesis is more prevalent among people of European origin than African or Asian origin, and the patients are predominantly (~70%) female (5,58). A peculiar phenomenon is the striking discordance of monozygotic twins for thyroid dysgenesis (5,59), a major argument against an exogenous (maternal) factor as its primary cause. Among the rare descriptions of monozygotic twins concordant for thyroid dysgenesis, the rudiments of thyroid tissue were concordant or discordant (5,60).

The clinical consequences are highly variable, from severe hypothyroidism due to thyroid agenesis to moderate hypothyroidism due to ectopic (usually sublingual) thyroid rudiments to subclinical hypothyroidism (high serum TSH but normal serum free T4 concentrations) in patients with thyroid hemiagenesis.

In mice, the transcription factors Nkx2.1 (Ttf1), FoxE1 (Ttf2; Fkhl15), Pax8, and Shh are essential for thyroid development (61,62,63,64), whereas thyroid development is normal in the absence of TSH or TSH receptors (65). Few humans with thyroid dysgenesis have had mutations in the human homologues NKX2.1 (TTF1), FOXE1 (TTF2, FKHL15), or PAX8. The thyroid phenotype is highly variable, including agenesis, hypoplastic eutopic or ectopic rudiments, and an (apparently) normally developed thyroid gland (8). Mutations in the human homologue of Shh causing thyroid dysgenesis have not been described.

Several infants with both neonatal thyroid dysfunction and respiratory failure who had a deletion of chromosome 14q12–13.3 containing the homeobox gene NKX2.1 have been described (66,67). Other patients with congenital hypothyroidism caused by mutations in the NKX2.1 gene had a variable degree of hypothyroidism, as well as mental retardation, choreoathetosis, hypotonia, pulmonary problems, and hypothalamic abnormalities (68,69).

A homozygous missense mutation in FOXE1 (Ala65Val, within the forkhead-binding domain) was found in two siblings with the Bamforth-Lazarus syndrome (cleft palate, choanal atresia, and thyroid dysgenesis). The defect resulted in impaired DNA binding and loss of transcriptional function (70). Another biallelic Ser57Asn mutation in the DNA-binding domain was found in patients with thyroid agenesis and cleft palate, but no choanal atresia (71). The less severe phenotype in the latter patients suggests partial function of the mutated FOXE1 gene.

In a study of 145 patients with congenital hyperthyroidism, several were found to have mutations in one allele of the PAX8 gene (72). One patient with a hypoplastic thyroid gland had a de novo Arg108Stop mutation. Another had a dysgenetic eutopic thyroid gland and an Arg31His mutation. A Leu63Arg mutation was found in one allele of this gene in a mother and two of her children with dysgenetic eutopic thyroid glands, hypothyroidism, and low serum thyroglobulin concentrations; the father was normal. In vitro expression experiments revealed that the differently mutated PAX8 molecules were unable to bind DNA and activate gene expression (72). The dominant expression of the PAX8 inactivating mutations is noteworthy. One explanation for the severe changes is that transcription of one wild-type allele yields insufficient amounts of the gene product, perturbing the binding equilibrium with competitors or cofactors, a phenomenon called haploinsufficiency (73). Mutations in the genes for these competitors or cofactors would have a similar effect. One of these factors is Ref-1, a nuclear protein that augments the DNA binding of PAX8 (74).

Williams' syndrome is a complex multisystemic syndrome that includes a characteristic elfin facies, cardiovascular malformations, and mental and growth retardation. The prevalence is between 1:10,000 and 1:20,000; almost all cases are sporadic. The syndrome arises because of a deletion that includes the elastin gene (ELN). Mild hypothyroidism has been recognized as a component of this syndrome; some patients have had thyroid dysgenesis (sublingual rudiment, hemiagenesis) (75).

The Young-Simpson syndrome is a rare syndrome characterized by thyroidal congenital hypothyroidism, mental retardation, peculiar facies, growth retardation, cryptorchidism, congenital heart defects, and many other milder malformations (76). The reported cases have all been sporadic. The congenital hypothyroidism is detectable by neonatal screening. Its severity varies considerably, depending on the extent of thyroid dysgenesis, which varies from agenesis to mild hypoplasia (77).

Finally, congenital hypothyroidism due to thyroid agenesis has been described in association with the CHARGE association (coloboma, heart defects, choanal atresia, retarded growth and development or central nervous system anomalies, genital hypoplasia, and ear anomalies or deafness) (78). The CHARGE association also has been associated with congenital hypopituitarism (79).

Hyporesponsiveness to Thyrotropin

Thyrotropin exerts its biologic activity by binding to the TSH receptor, a glycoprotein containing an extracellular amino-terminal region, seven transmembrane domains with three extra- and three intracellular loops, and an intracellular carboxyl-terminal domain. Activation of the receptor leads to activation of a stimulatory guanine nucleotide-binding (G) protein, resulting in stimulation of adenylyl cyclase and therefore increased production of cyclic adenosine monophosphate, and, at high TSH concentrations, stimulation of the phospholipase C and inositol pathway as well (see the section Thyrotropin Receptor in Chapter 10). Hyporesponsiveness (or resistance) to TSH may occur as a result of mutations in the TSH receptor, G protein, or specific proteins or factors further downstream in the signal transduction pathways.

Defects in the Thyrotropin Receptor

Mutations in the TSH receptor gene causing loss of function result in thyroidal congenital hypothyroidism. Patients with mutant receptors that can bind TSH, albeit with less affinity than normal receptors, may have, with TSH stimulation, near-normal serum T4 and T3 concentrations and no thyroid enlargement (80). Patients whose mutant receptors have little or no affinity for TSH have severe hypothyroidism, despite high serum TSH concentrations (81,82,83). These patients have a normal-sized thyroid gland and low serum thyroglobulin concentrations. A list of the known mutations is available online (84). The inheritance is usually autosomal recessive; most patients have been found to be compound heterozygotes.

Abnormalities in the G Protein α Subunit

Another type of TSH hyporesponsiveness is found in patients with pseudohypoparathyroidism type 1a (Albright's hereditary osteodystrophy), a variably expressed disorder with autosomal-dominant inheritance (85,86). These patients have an approximately 50% reduction in the activity of the α-subunit of the stimulatory G protein. Multiple mutations have been found in the GNAS1 gene coding for this protein. The patients often have low-normal serum T4concentrations, and little clinical evidence of hypothyroidism. Although early detection by neonatal screening has been described (4,87), the blood-spot TSH and T4 concentrations usually do not reach the cut-off values for recall.

Several families have been reported in which some family members had congenital hypothyroidism with no goiter and in whom no TSH receptor or G protein mutations were detected (88). In two families the hyporesponsiveness was inherited as an autosomal-dominant trait. These findings suggest the presence of mutations in other steps in the TSH signaling pathway.

Defects in Thyroidal Iodide Transport

Iodide has to be transported from the extracellular fluid via thyroid follicular cells into the follicular lumen before it can be used to form T4 and T3. Therefore, iodide has to cross both the basolateral and apical membranes of the cells, after which it is oxidized and bound to tyrosine residues in thyroglobulin (see sections Thyroid Iodine Transport and Thyroid Hormone Synthesis in Chapter 4).

Iodide transport across the basolateral membrane, the crucial first step in thyroid hormone synthesis, is mediated by the sodium-iodide symporter (89). Iodide transport across the apical membrane is mediated by pendrin (90), and perhaps also another apical iodide transporter (AIT, SLC5A8) (91,92). Pendrin is encoded by the PDS gene (SLC26A4) (93,94,95).

The transport of iodide from the circulation into the thyroid can be traced by administration of radioiodide. Inhibition of radioiodide uptake by anions of similar molecular size and charge, such as perchlorate or thiocyanate, allows detection of the efflux of any accumulated iodide back into the circulation, and thus provides indirect information about the activity of the oxidation and organification processes.

Defects in Basolateral Iodide Transport

The postulated existence of genetic defects in thyroidal iodide transport in 1956 (96) has been confirmed by studies in patients with congenital hypothyroidism who had a low thyroid radioiodide uptake and a well-developed, often enlarged thyroid gland (97,98,99). In the first months of life, when the thyroid gland may not yet be visible or palpable, it can be difficult to distinguish iodide transport defects from thyroid agenesis. Measurement of serum thyroglobulin and ultrasonography of the thyroid can help to discriminate between the two disorders (99) (Table 48.1). The iodide transport defect is characterized by hypothyroidism, gradual goiter formation, low or very low serum T4 concentrations, high serum TSH and thyroglobulin concentrations, undetectable or very low radioiodide uptake by the thyroid, and a saliva/serum ratio of radioiodide of about 1. The inheritance pattern is autosomal recessive (Table 48.1). The severity of the hypothyroidism, and as a consequence the neurodevelopmental impairment of affected patients, varies considerably, in part because of variation in dietary iodine intake. The patients can be treated with large doses of iodine, but treatment with T4 is preferable, especially at young ages.

The sodium-iodide symporter gene was cloned in 1996, and since then some patients with this defect have been found to have mutations in this gene (89). The structural change has been defined for a few mutations. For instance, in the Thr235Pro mutation (100), the substituted threonine lies in the middle of a well-conserved putative transmembrane segment of the symporter that is essential for transport function, most likely for Na+ binding and translocation (101). Another amino acid important for symporter activity is the glycine residue at position 395. Substitutions of large amino acid residues at this position diminished the maximal transport rate without affecting the Michaelis-Menten constant (Km) values for I- or Na+ (102). One patient with an iodide transport defect was heterozygous for two different mutations. The paternally derived allele had a Gln267Glu mutation, resulting in an inactive cotransporter, and the maternally derived allele had a C1940G transversion, which created a downstream cryptic splice acceptor site in exon 13, resulting in a 67-bp deletion and a frame shift resulting in an unstable messenger RNA (mRNA). The predicted transcript would code for a truncated protein lacking 129 amino acids (103).

Defects in Apical Iodide Transport

Over 100 years ago Pendred described a syndrome characterized by overt, or more often subclinical, hypothyroidism, goiter, and moderate to severe sensorineural hearing loss (104). This syndrome has an autosomal-recessive inheritance. The prevalence varies between 1:15,000 and 1:100,000; it may be the most common genetic defect causing congenital hypothyroidism. Usually thyroid hormone synthesis is only mildly impaired, and therefore few patients with Pendred's syndrome are detected by neonatal screening (4).

One of the characteristic features of Pendred's syndrome is partial discharge of thyroidal radioiodide after administration of perchlorate, indicating that defective pendrin molecules result in intracellular iodide accumulation (105) (Table 48.1). This explains why, before the molecular defect was elucidated, Pendred's syndrome was classified as a partial iodide organification defect. Even in patients in whom the PDS gene mutation results in complete loss of function of pendrin, the radioiodide discharge after perchlorate is partial (90), an (indirect) indication that pendrin is not the exclusive apical cell membrane transporter.

PDS mutation analysis has been performed in many families. Frame shift mutations, mutations leading to aberrant splicing, and nonsense and missense mutations have been found. Two of them, Leu236Pro and Thr416Pro, are recurrent mutations (106). Recently a Val138Phe mutation was described as a founder mutation in German families (107). Usually, mutations in the PDS gene cause subclinical hypothyroidism and gradual thyroid enlargement combined with hearing loss, but mutations in the PDS gene have also been found in patients with large vestibular aqueduct defects who have normal thyroid function (108).

No mutations in the apical iodide transporter gene have been reported.

Defects in Iodide Organification

Iodine oxidation and organification are catalyzed by thyroid peroxidase. This enzyme is located primarily in the apical cell membrane, but its active center protrudes into the follicular lumen. It catalyzes not only iodide oxidation and organification, but also the coupling of iodotyrosine residues in thyroglobulin to form iodothyronines, mainly T4 (109,110). The oxidizing agent used for iodination and coupling of iodotyrosine residues is hydrogen peroxide, synthesized by the thyroid oxidases THOX1 and THOX2 (111,112,113) (see section Thyroid Hormone Synthesis in Chapter 4).

In patients with defects in iodide oxidation and organification, little or no iodide is oxidized and organified, and T4 and T3 production is decreased or even absent, whereas iodide transport and thyroglobulin synthesis are strongly stimulated by TSH. Therefore, radioiodide uptake and serum thyroglobulin concentrations are high. The block in iodide oxidation and organification results in increased intracellular iodide concentrations, which can be quantified by measuring the amount of radioiodide lost from the gland after the administration of sodium or potassium perchlorate (Table 48.1).

Iodide oxidation and organification defects can be the result of abnormalities of thyroid peroxidase (114) or the H2O2 generating system (115,116).

Defects in Thyroid Peroxidase

Iodide oxidation and organification defects, transmitted as autosomal-recessive traits, are caused by abnormalities in thyroid peroxidase. The abnormalities include the inability to produce the enzyme, defects in its heme- or substrate-binding site, and abnormalities in the distribution of the enzyme in the thyroid (114,117,118,119,120). Most of the patients have a total inability to oxidize and organify iodide and consequently cannot produce T4 or T3 (Fig. 48.2). In a study of 29 Dutch families with this disorder, 16 different mutations in the thyroid peroxidase gene were found; 13 families were homozygous, and 16 were compound heterozygous (121). In four families only one mutated allele could be detected; in one family with a total iodide organification defect no mutation in the gene could be found (116). The most frequent mutation (14 of 36 alleles) was duplication of a GGCC sequence in exon 8. In one patient with severe hypothyroidism due to a total organification defect, partial maternal isodisomy of chromosome 2p was demonstrated. The mother was heterozygous for the same mutation (T2512del in exon 14) as her son had in both alleles, whereas the father had normal alleles (122). Apparently partial maternal isodisomy (2pter-2p12) is compatible with normal physical and mental development (122). Another total iodide organification defect was found in three siblings with a single mutated allele (Arg693Trp) inherited from the unaffected father; mutations in the maternal allele, maternal imprinting, and major deletions of the maternal chromosome at 2p25 were excluded (123). Several other inactivating mutations have been described in patients with total or partial iodide organification defects, including monoallelic and biallelic mutations, indicative of substantial allelic heterogeneity (124,125).

FIGURE 48.2. Newborn infant with congenital hypothyroidism due to a total iodide organification defect caused by mutations in both alleles of the thyroid peroxidase (TPO) gene (maternal allele, 20-bp duplication in exon 2, most likely resulting in a stop codon in exon 3; paternal allele, G2485A mutation translated into a Glu799Lys substitution, rendering TPO inactive, as proven by in vitro expression) (114). Because it was already known that the infant's brother had this disease, diagnosis could be made immediately after birth. A: Photograph of the infant showing periorbital edema and depressed nasal bridge, indicative of delayed bone maturation. B: Ultrasound image showing a symmetric, enlarged thyroid gland, not detected by physical examination. C: Plot of serial measurements of thyroidal 123I uptake after intravenous administration of 123I- [25 µCi (0.9 MBq)] and then, at 120 minutes, administration of NaClO4 (100 mg intravenously). The 123I was taken up more rapidly than normal, and then some was released. Blocking the uptake with NaClO4resulted in immediate release of the remaining 123I, indicating that it was nonoxidized and nonorganified iodide. The release of all 123I within 30 minutes after NaClO4 administration indicates the complete inability of the patient's thyroid to oxidize and organify iodide. D: Images of the patient's thyroid during the 123I- uptake and release study showing rapid uptake, and then rapid release after administration of NaClO4 at 120 minutes. (From De Vijlder JJM, Vulsma T. Congenitale hypothyreoïdie. In: Wiersinga WM, Krenning EP, eds. Schildklierziekten. Houten, The Netherlands: Bohn, Stafleu & Van Loghum, 1998, with permission.)

Mutations in thyroid peroxidase have also been reported in three siblings with onset of mild hypothyroidism in childhood and a partial iodide organification defect. The patients were compound heterozygous for a missense mutation (G1687T, exon 9) and a deletion (1808–13del, exon 10) (126). In expression studies, the protein with the missense mutation was retained in the cytoplasm of the cell, and the deleted protein had diminished enzyme activity.

Defects in Thyroid Oxidase

One patient with a total iodide organification defect has been described who was homozygous for a premature stop codon in the THOX2 gene. The resulting truncated protein had no functional domain. Monoallelic inactivating THOX2 mutations were found in three other patients who had a partial iodide organification defect. These patients had mild hypothyroidism at birth but were euthyroid later in childhood (116).

Questions remain about the role of THOX1 in thyroid physiology; no patients with mutations in the THOX1 gene have been reported.

Defects in Thyroglobulin Synthesis

Thyroglobulin is exclusively synthesized in the thyroid gland, and its production is essential for thyroid hormone synthesis. The thyroglobulin gene is greater than 300,000 bp in size, and the coding sequence has 8307 nucleotides, divided over 48 exons, of which 66 are triplets coding for tyrosine (127,128). Thyroglobulin is a homodimer with subunits of 330,000 daltons (330 kd) that contains several repeated amino acid sequences, about 60 disulfide bridges, and 10% carbohydrate (129) (see Chapter 5). Its structural conformation, which is dependent on the extent of glycosylation, is important for T4 and T3 synthesis. Defects in transcription, translation, or posttranslational processing cannot be distinguished by clinicopathologic classification; therefore, all these defects are classified as being defects in thyroglobulin synthesis (130).

Patients with defects in thyroglobulin synthesis have moderate to severe hypothyroidism. Most have low serum thyroglobulin concentrations, especially in relation to the degree of TSH stimulation (4); iodoproteins (mainly iodoalbumin) may be found in the circulation and iodopeptides in the urine (131,132). The processes of iodide uptake, oxidation, and organification are intact.

The exceptional size of the thyroglobulin gene has made it difficult to identify mutations in the regulatory or coding regions of the gene. Several mutations have been described in animals (see reference 133 for review); five mutations have been described in humans. A homozygous Arg227Stop mutation resulted in a short 30-kd fragment of thyroglobulin; the patients had mild hypothyroidism (134). Another patient had a homozygous mutation at the acceptor site of intron 3, resulting in an in-frame deletion of exon 4. The aberrant thyroglobulin lacked the donor tyrosine 130, resulting in less efficient T4 and T3 production, and a CysTrpCys repeat that could lead to misfolding and accumulation of the protein in the endoplasmic reticulum and subsequent proteolysis; this patient had severe hypothyroidism (135). In a third patient, a homozygous Arg1510Stop mutation gave rise to a truncated thyroglobulin molecule missing 57 amino-acid residues due to alternative splicing of exon 22; the patients had hypothyroidism and large goiters (136). A Cys1263Arg mutation in thyroglobulin caused a defect in intracellular transport due to an arrest in the endoplasmic reticulum; the patients had mild hypothyroidism, indicating that some thyroglobulin reached the follicular lumen (137). In a family with severe hypothyroidism, the thyroglobulin mRNA lacked 138 nucleotides between positions 5590 and 5727, resulting in retention of the protein in the endoplasmic reticulum (138,139). Based on the location of the mutations, it seems that shorter thyroglobulin molecules are associated with less severe hypothyroidism. It may be that shorter molecules are more easily secreted into the follicular lumen, where T4 and T3are formed (133).

In six patients with the clinicopathologic features of a thyroglobulin synthesis defect, no mutations in the thyroglobulin gene other than polymorphisms were detected (130). These patients may have defects in posttranslational processing of thyroglobulin, for example, in glycosylation or intracellular chaperoning, or deficiencies of transcription factors such as NKX2.1 (140).


Defects in Recycling of Iodide

Thyroglobulin, after internalization by pinocytosis from the follicular lumen into thyroid follicular cells, is incorporated into early and late endosomes. These organelles, containing proteolytic enzymes, hydrolyze thyroglobulin to its constituent amino acids, including monoiodotyrosine (MIT) and diiodotyrosine (DIT), as well as T4 and T3. Subsequently, the iodotyrosines are deiodinated by specific dehalogenases present not only in the thyroid but also in peripheral tissues. Genetic defects in dehalogenases lead to loss of the iodotyrosines from the thyroid and their rapid excretion by the kidneys. The result is excessive loss of iodine, mimicking hypothyroidism due to iodine deficiency (141,142,143,144) (Table 48.1).

The inheritance is autosomal recessive, but some features of the disorder are expressed in heterozygotes, for example, goitrogenesis, a relatively high thyroid radioiodide uptake, and increased urinary excretion of DIT (144). The clinical expression depends strongly on the dietary iodine intake, which may explain why autosomal-dominant inheritance has been suggested (145). The disorder is not detected by neonatal screening, probably because maternal dehalogenase activity prevents loss of the iodotyrosines prenatally.

A single case report described a remarkable young woman with goitrous hypothyroidism due to a dehalogenase defect who also had hypogonadotropic hypogonadism, hyperprolactinemia, and hyperaldosteronism. She had very high serum MIT and DIT concentrations, which apparently inhibited tyrosine hydroxylase activity, decreasing dopamine synthesis, which in turn caused the hyperprolactinemia and hyperaldosteronism. The latter resolved with T4 therapy (146).

Mutations in the DEHAL1 gene, isolated from a thyroid library, are the likely cause of thyroid dehalogenase defects (147). This gene encodes a protein with a conserved nitroreductase domain that is capable of dehalogenating iodotyrosines (147,148); however, no mutations have as yet been detected.

Defects in Transmembrane Transport of Thyroxine and Triiodothyronine

T4 and T3 are carried into cells by several cell membrane transport systems. They include monocarboxylate transporter 8 (MCT8), located on the X chromosome (149,150). Males with MCT8 mutations have severe neurologic defects, psychomotor retardation, and mild hypothyroidism, with high serum T3concentrations (151,152). The MCT8 genes of these patients contained deletions, frame shifts, and missense and nonsense mutations. Whether all the abnormalities are a result of decreased T4 transport into the brain or other substances important in neurodevelopment are not transported normally, is not clear. What is clear is that these males are not protected against neurologic defects and hypothyroidism in utero by maternal-fetal transfer of T4.


Newborn and older infants with Down syndrome may have slightly high serum TSH concentrations and slightly low serum total and free T4 concentrations, which tend to disappear as the infants age (153). The etiology is unclear. The infants do not have thyroid enlargement, and TSH bioactivity is normal (154). Although the relationship with trisomy 21 is obscure, the changes seem to be specific for Down's syndrome.

The Wolcott-Rallison syndrome is a rare autosomal-recessive disorder characterized by infancy-onset type 1 diabetes mellitus, spondyloepiphyseal dysplasia with short-trunk dwarfism, recurrent hepatitis, renal insufficiency, and developmental delay. The presence of collagen fibers of varying thickness and intracellular collagen-like fibers suggest an abnormality in collagen synthesis or processing. The syndrome is associated with mutations in the EIF2AK3 gene, which encodes translation initiation factor 2α kinase-3 (155). Some patients also have central hypothyroidism, with no MRI abnormalities (156).

The Pallister-Hall syndrome has as its common features hypothalamic hamartoma, mental retardation, seizures, polydactyly, bifid epiglottis, imperforate anus, and cardiac, renal, and pulmonary anomalies. The syndrome is often sporadic, but is sometimes inherited in an autosomal-dominant pattern. Mutations in the GLI3 gene are thought to be responsible for the syndrome. Some patients have pituitary dysgenesis, and as a consequence multiple pituitary hormone deficiencies, and others have thyroid dysgenesis (157).

The Johanson-Blizzard syndrome is a rare syndrome characterized by multiple anomalies, with autosomal-recessive inheritance (158,159,160). Approximately 25% of patients have thyroidal hypothyroidism, of unknown cause. Other features include intrauterine and postnatal growth retardation, developmental brain defects, midline ectodermal scalp defects, aplasia or hypoplasia of the nasal alae, congenital sensorineural hearing loss, absent permanent teeth, pancreatic exocrine insufficiency with malabsorption, and rectourogenital abnormalities. A few autopsy reports mention grossly and microscopically normal thyroid glands with abundant scalloping of colloid (161,162,163). In some of these infants thyroid function is sufficiently abnormal at birth that the hypothyroidism can be detected by neonatal screening.

Patients with several other syndromes (e.g., the Beckwith-Wiedemann syndrome, Ascher syndrome, and hypohydrotic ectodermal dysplasia syndrome) sometimes have hypothyroidism as one of many abnormalities (164). No doubt other syndromes that include congenital hypothyroidism will be recognized (165).

Finally, infants with congenital hypothyroidism detected by neonatal screening have a high frequency of additional congenital anomalies. In a large group of infants with congenital hypothyroidism in Italy, the prevalence of congenital malformations was more than four times higher than in the normal population (166). They included cardiac anomalies, anomalies of the nervous system and eyes, and multiple congenital malformations.


In general, treatment of a patient with a genetic defect in thyroid hormone secretion is similar to the treatment of any other patient of the same age with hypothyroidism. In the neonatal period, the primary goal of treatment is prevention of brain damage, with irreversible motor and cognitive impairment. That these problems occur in infants with severe hypothyroidism is clear. Although the risk for lesser degrees of hypothyroidism is less clear, prudence dictates that treatment be initiated immediately in any infant with hypothyroidism, irrespective of severity and etiology (167). As noted above, treatment can be stopped at age 3 to 4 years, and the child evaluated in detail to confirm, or refute, the diagnosis of hypothyroidism, and if it is present to determine its cause.

The goal of treatment in infants with thyroidal hypothyroidism should be to normalize serum TSH concentrations; for infants with central hypothyroidism the goal should be a serum free T4 concentration near the upper limit of the normal range for age (168). The details of treatment and follow-up are discussed in detail in the section on congenital hypothyroidism in Chapter 75.

In most of the genetic disorders that impair thyroid hormone synthesis, the thyroid gland will eventually become hyperplastic and nodular if serum TSH concentrations are even slightly elevated for a prolonged period. However, if T4 treatment is started at a very young age, and serum TSH concentrations are maintained within the normal range, goitrogenesis should not occur.

The treatment of infants with peripheral congenital hypothyroidism depends on the underlying defect. In case of an iodide recycling defect, euthyroidism can be restored by administration of high doses of iodine, but it is easier to give T4. Treatment of thyroid hormone resistance depends on its severity and the relative responsiveness of peripheral tissues and the pituitary; judicious administration of T4 may be indicated in infants with marked resistance (see Chapter 81).

Whether infants with defects in the thyroid hormone transmembrane transport might benefit from T4 (or T3) therapy is not known.


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