Genetic defects in thyroid hormone transport and metabolism

INTRODUCTION — Genetic defects in thyroid hormone transport and metabolism are rare causes of impaired sensitivity to thyroid hormone. These conditions are characterized by abnormal relative concentrations of triiodothyronine (T3), thyroxine (T4), and reverse T3 (rT3), with diverse clinical manifestations.

There are two main categories:

●Thyroid hormone cell membrane transport defect (THCMTD) – Impaired uptake of thyroid hormone into selected target cells due to MCT8 gene mutations

●Thyroid hormone metabolism defect (THMD) – Impaired conversion of T4 to T3 in the cytoplasm of cells dependent on this process

These disorders will be discussed below. Other inherited disorders in which the secretion or action of thyroid hormone is impaired are far more common and are discussed separately:

●(See "Resistance to thyrotropin and thyrotropin-releasing hormone".)

●(See "Resistance to thyroid hormone and other defects in thyroid hormone action".)

MECHANISMS OF IMPAIRED SENSITIVITY — The normal physiology of thyroid hormone production and action is summarized in the figure and a separate topic review (figure 1). (See "Resistance to thyroid hormone and other defects in thyroid hormone action", section on 'Normal thyroid hormone physiology'.)

Several different mechanisms that cause impaired sensitivity to thyroid hormone have been described, and others are postulated. A classification and proposed nomenclature is outlined below (table 1) [1-3]. These defects should be considered in a patient with thyroid function tests that show a discrepancy of serum thyroid hormone and thyrotropin (thyroid-stimulating hormone [TSH]) concentrations, and each defect has its own constellation of test abnormalities and a different clinical presentation. The types of known defects are listed below according to the physiologic sequence of thyroid hormone cell transport, metabolism, and action rather than by clinical frequency.

●Thyroid hormone cell membrane transport defect (THCMTD) – Defects in one of the cell membrane transport proteins that allow thyroid hormone to enter cells cause reduced intracellular levels of thyroid hormone. Defective cell transport proteins may not reach their normal location on cell membrane or may not be able to transport the hormone. The resulting disorder depends on the specific hormone transporter affected.

The only known THCMTD is caused by a mutation in the MCT8 gene, which is characterized by elevated serum concentrations of triiodothyronine (T3) and low levels of thyroxine (T4) and reverse T3 (rT3) as well as a severe psychomotor deficit [4]. Lacking MCT8 function in humans alters thyroid hormone availability in the brain, which does not seem to be compensated by the presence of other thyroid hormone transporters (figure 2). This transporter is also involved in the secretion of thyroid hormone from the thyroid gland and uptake by the kidney [5,6]. (See 'Thyroid hormone cell membrane transport defect' below.)

●Thyroid hormone metabolism defect (THMD) – T4, the major product secreted by the thyroid gland, is a prohormone that must be activated by conversion to T3. Defects in any of the factors involved in this enzymatic deiodination reaction can cause diminished production of T3 and thus reduced availability of active thyroid hormone in tissues that depend upon the circulating T4 for local generation of T3. Known defects include mutations in the SBP2 gene (also known as SECISBP2 [selenocysteine insertion sequence-binding protein 2]) resulting in reduced selenoprotein synthesis including the three deiodinases or in mutations in the DIO1 gene (figure 3). Both disorders are characterized by an increased rT3:T3 ratio. (See 'Thyroid hormone metabolism defect' below.)

●Thyroid hormone action defects – Defects in thyroid hormone action are called resistance to thyroid hormone (RTH) and are usually due to a mutation in one of the genes encoding the thyroid hormone receptor. The types and clinical characteristics of RTH are discussed separately. (See "Resistance to thyroid hormone and other defects in thyroid hormone action".)

THYROID HORMONE CELL MEMBRANE TRANSPORT DEFECT — Mutations in the MCT8 gene cause an X chromosome-linked syndrome combining severe psychoneuromotor deficiency and characteristic abnormalities of thyroid function tests. The early hallmarks are hypotonia and high serum triiodothyronine (T3) levels in boys.

Prevalence and inheritance — The incidence of a thyroid hormone cell membrane transport defect (THCMTD) is not known. This X-linked form of intellectual disability with neuromotor disabilities was first described in 1944 and subsequently named the Allan-Herndon-Dudley syndrome [7]. In 2004, the syndrome was shown to manifest characteristic thyroid function abnormalities and to be caused by MCT8 gene mutations [4,8]. Since then, more than 300 individuals belonging to more than 137 families with MCT8 defects were identified, suggesting that this syndrome is more common than initially suspected [9-12] (and personal observations). Spontaneous MCT8 mutations can be maintained in the population because carrier females are asymptomatic; thus, no negative selection takes place.

The diagnosis of THCMTD is often delayed because the clinical symptoms are more suggestive of a neurologic defect rather than the consequence of a defect in thyroid hormone availability. Further, neonatal screening for thyroid hormone deficiency is based on the measurement of thyroid-stimulating hormone (TSH). A method for newborn screening has been proposed, consisting of measuring iodothyronines in dried blood spots [13]. This approach could become important for early diagnosis and for determining the prevalence of this condition. (See 'Treatment' below.)

Pathogenesis — MCT8, also known as SLC16A2 (MIM 300095), encodes monocarboxylate acid transporter 8, which transports thyroxine (T4) and T3 into cells, as shown in the figure (figure 2) [14]. This transporter plays an important role in the movement of thyroid hormone into the brain and is thus critical to the effect of thyroid hormone on brain development [15].

The main clinical manifestations of MCT8 deficiency are caused by thyroid hormone deprivation, particularly in the brain during embryonic life [16]. Indeed, the severity of the psychomotor retardation is correlated with the degree of functional impairment of the mutant transporter [17]. Several types of defects in MCT8 can interfere with its function as a carrier protein, including reduced protein expression, impaired trafficking to plasma membrane, or reduced substrate affinity.

MCT8 defects are characterized by an unusual mixed pattern of thyroid hormone deprivation in some tissues and thyroid hormone excess in others. Transgenic mice deficient in Mct8 have thyroid function test abnormalities similar to those of humans with MCT8 mutations and provide insight into the mechanisms responsible for the thyroid phenotype [18-20]. In this animal model, tissue levels of T3 varied depending on redundancy in thyroid hormone transmembrane transporters; liver T3 concentrations were high, and brain T3 concentrations were low. The resulting increase in liver type 1 deiodinase and brain type 2 deiodinase enhances the generation of T3 and has a consumptive effect on T4. In addition, the impaired T3 uptake in some tissues, such as the brain, prevents its degradation by type 3 deiodinase. Another study in mice demonstrated that Mct8 gene defects also cause impaired thyroid hormone secretion from the thyroid gland [5], suggesting for the first time that MCT8 mediates the molecular mechanism of thyroid hormone secretion, a process previously believed to be passive.

In addition to monocarboxylate transporters such as MCT8, other transport proteins belonging to different families of solute carriers, organic anions, and amino acids participate in the transport of thyroid hormone across cell membranes. It has been postulated that defects in some of these other transport proteins also could cause reduced sensitivity to thyroid hormone, but such mutations have not yet been identified [21]. Each transport protein has a distinctive role in the cell-specific delivery of thyroid hormone due to differences in cell distribution and kinetics as well as transport of other ligands [22]. Presumably, defects in each transport protein would result in a distinct phenotype.

Clinical features — Because MCT8 defects are X-linked, virtually all affected individuals are male. A female patient has been described with a phenotype identical to that of affected males, caused by a de novo balanced translocation involving the MCT8 locus [12].

The clinical phenotype, including thyroid test abnormalities, varies in severity but is otherwise quite consistent among affected individuals. Affected individuals have stigmata of thyroid hormone deficiency as well as excess. These include psychomotor abnormalities, which are caused by thyroid hormone deficiency in the brain, and a hypermetabolic state and difficulty to maintain weight, which are caused by T3 excess in some other tissues. This coexistence of thyroid hormone deficiency and excess in the same individual is due to cell-specific differences in the expression of the various thyroid hormone transporters. (See 'Pathogenesis' above.)

Gestation and birth are normal, and affected newborns have normal length, weight, and head circumference. Early signs, manifesting in the first few weeks of life, are hypotonia and feeding difficulties, followed by other neurodevelopmental abnormalities presenting during infancy or early childhood. Many infants have characteristic paroxysms of kinesigenic dyskinesias, consisting of body extension, opening of the mouth, and stretching or flexing of the limbs [23]. These paroxysms are usually triggered by somatosensory stimuli and last a few minutes or less. True seizures also can occur.

With advancing age, weight gain lags, while linear growth proceeds normally. Although truncal hypotonia persists, there is progressive development of limb rigidity, often resulting in spastic quadriplegia. Muscle mass is diminished and there is generalized muscle weakness with poor head control. Purposeless movements are common. A case series of children evaluated by video electroencephalogram described repetitive sleep starts (nonepileptic bilateral limb contractions during rapid eye movement sleep) in all four children studied and seizures in three [24]. Most affected children are never able to sit by themselves or walk and have no speech. Although early death has occurred in some families, some individuals live beyond the age of 70 years.

Female carriers do not manifest any of the psychomotor abnormalities described above.

In a retrospective study of 151 patients with 73 different MCT8 mutations, the median age at diagnosis was 24 months and the median overall survival was 35 years [25]. Thirty-two of 151 patients died; the main causes of mortality were pulmonary infection and sudden death in six patients each. The risk of death was higher in individuals who did not attain head control by age 1.5 years and those who were underweight between ages one and three years compared with those who had head control and normal body weight at this age.

Laboratory findings — Individuals with MCT8 gene defects have characteristically high serum T3 and low reverse T3 (rT3) concentrations, in contrast with the other three syndromes of impaired sensitivity to thyroid hormone (table 2). T4 tends to be low, and TSH levels are normal or slightly elevated. Heterozygous female carriers have serum thyroid hormone concentrations intermediate between affected males and unaffected family members (figure 4).

The diagnosis is confirmed by sequencing the MCT8 gene. A list of laboratories that perform this test is available at the Genetic Testing Registry website.

When brain magnetic resonance imaging (MRI) is obtained before the age of two or three years, delayed myelination is typically found [26]. Otherwise, MRI may be normal or show atrophy of the cerebrum, thalamus, corpus callosum, and basal ganglia [9,11,27-29].

Treatment — Treatment options for patients with MCT8 mutations are limited to supportive measures, including the use of braces to prevent contractures. Gastric tube feeding is used for severe weight loss due to difficulties in oral feeding. Diet is adjusted to prevent aspiration, and dystonia is treated with anticholinergics, levodopa, carbamazepine, and baclofen. Drooling may respond to treatment with glycopyrrolate or scopolamine. Seizures are treated with standard anticonvulsants.

Treatment of the low serum T4 concentration with physiologic doses of levothyroxine is ineffective. This is presumably because of the impaired uptake of the hormone in MCT8-dependent tissues such as brain, while its uptake is preserved in MCT8-independent tissues such as liver (which also has increased deiodinase 1 enzymatic activity, resulting in increased generation of circulating T3). In several cases, one of which has been reported, patients were treated with the combination of propylthiouracil (in doses that inhibit deiodinase 1 and reduced the amount of T3 generated from T4) with supraphysiologic doses of levothyroxine [30]. This was effective in improving serum thyroid tests and nutrition status.

The use of thyroid hormone analogs is a promising new strategy, designed to bypass the molecular defect by using alternative transporters and potentially resolve the issues of thyroid hormone deficiency and excess (thyrotoxicosis) [31]. One such analog, 3,5-diiodothyropropionic acid (DITPA), was studied in a mouse model and was able to ameliorate the brain thyroid hormone deficit without causing thyrotoxic effect in liver [32]. In a pilot study in four children with MCT8 deficiency, treatment with DITPA improved laboratory and clinical abnormalities [33]. In another larger trial, the analog triiodothyroacetic acid (TRIAC) was also associated with improvement in clinical manifestations of thyrotoxicosis [34]. The principal effect is reduction in the circulating T3 level through suppression of TSH and subsequent decrease in thyroid hormone synthesis and secretion. This ameliorates the hypermetabolism and its consequences.

Gene therapy is being considered, and preliminary data using a mouse model of THCMTD have shown transfer of the normal human MCT8 to choroid plexus with increased brain T3 and enhanced thyroid hormone effect [35,36].

A detailed questionnaire was formulated in collaboration with parents from 15 families to identify clinical endpoints that are relevant to the daily life of individuals with MCT8 deficiency and their caregivers [37]. Improvement in gross motor skills (head control, sitting ability) was most important to the parents, in addition to weight gain; improvement of expressive language skills; and reduction in spasticity, dystonia, dysphagia, and reflux. However, achievement of these goals is challenging, considering the detrimental effect of MCT8 deficiency in utero.

Pregnancy — In a family with a known history of an affected child and a known MCT8 mutation, male fetuses can be assessed in utero for the mutation. If the pregnancy with an affected male embryo is allowed to progress, weekly treatment with 500 mcg of levothyroxine injected into the amniotic fluid has resulted in improved outcome but not full rescue of the psychoneuromuscular deficit [38]. A trial with DITPA given to the pregnant mother carrying an affected fetus, beginning during the first trimester, is in progress (NCT04143295).

THYROID HORMONE METABOLISM DEFECT — Thyroid hormone metabolism defect (THMD) is characterized by impaired deiodination of the various iodothyronines.

Genetics — Two inherited forms of THMD have been identified in humans (figure 3):

●SBP2 gene mutations – Biallelic defects in SBP2 manifest as partial deficiencies of the three deiodinases, resulting in serum low triiodothyronine (T3) and high thyroxine (T4) and reverse T3 (rT3). SBP2 is required for selenoprotein synthesis, including the three selenoenzyme deiodinases that metabolize thyroid hormone [39]. The incidence of this disorder is unknown. The first three mutations in SBP2 were reported in 2005 [39]. More families were found subsequently; approximately 20 affected families have been identified worldwide, some of which have not yet been published (communication from AD; manuscript in preparation) [40-45]. The inheritance is recessive, either homozygous or compound heterozygous.

●DIO1 gene mutations – Heterozygous defects in DIO1 produce a high serum rT3:T3 ratio [46]. DIO1 encodes type 1 deiodinase, which participates in the conversion of T4 to T3. Two heterozygous missense mutations in DIO1 have been described in a case report of two unrelated families [46], and a third mutation was found to act as a phenotype modifier in a family with compound heterozygous thyroid peroxidase (TPO) gene mutations causing congenital hypothyroidism [47].

Of note, acquired disorders of thyroid hormone metabolism are far more common (eg, the "low T3 syndrome" of nonthyroidal illness) [48].

Pathogenesis

●Normal intracellular metabolism of thyroid hormone – Intracellular iodothyronine metabolism modulates the varying requirements of thyroid hormone, which depend on tissue, cell type, and time. Thyroid hormone is activated and inactivated by site-specific monodeiodination to provide the proper amount of active hormone at its site of action.

Deiodinases are selenoproteins that require a selenocysteine for their enzymatic function. Type 1 and 2 deiodinases catalyze the activation of thyroid hormone by 5'-deiodination that converts to T3. Type 3 deiodinase inactivates T4 and T3 by 5'-deiodination, leading to the generation of rT3 and T2, respectively.

●Consequences of SBP2 deficiency – Inactivating mutations in the SBP2 gene prevent incorporation of selenocysteine amino acid into the nascent selenoproteins and thus alter the protein structure and enzymatic activity, causing a global deiodination defect (figure 3) [49]. SBP2 is located on chromosome 9 and is expressed at a low level in all tissues and at a high level in testis [50].

Although SBP2 defects cause generalized deficiency of selenoproteins, the initial reports of families with this disorder described a relatively mild phenotype, with abnormal thyroid tests and early growth delay, due to partial SBP2 deficiency and preferential preservation of certain selenoproteins over other selenium-requiring functions [40,49,51].

Newer case reports describe a broader and more complex phenotype associated with different SBP2 mutations [41,42]. These mutations caused a severe SBP2 deficiency, resulting in reduced synthesis of most of the 25 known human selenoproteins, which alter diverse biologic processes. (See 'Clinical features' below.)

Clinical features — Patients with partial SBP2 deficiency have come to medical attention during childhood because of short stature and delayed bone age. These features prompted thyroid function testing, leading to the identification of thyroid abnormalities [39]. Pregnancy and birth were normal. In one case, the neonatal screen showed an elevated thyroid-stimulating hormone (TSH) level with high-normal T4.

In patients with more severe SBP2 deficiency, a wider variety of abnormalities may be seen [41,42]:

●Male infertility with azoospermia.

●Axial muscular dystrophy with impaired motor coordination.

●Intellectual disability.

●Hearing impairment.

●Photosensitivity and susceptibility to ultraviolet radiation-induced oxidative damage.

●Abnormal immune cell function – Impaired T lymphocyte proliferation, abnormal mononuclear cell cytokine secretion (excess interleukin-6, excess tumor necrosis factor-alpha, and reduced interferon-gamma), and telomere shortening.

●Enhanced systemic and cellular insulin sensitivity [41]. This was associated with raised reactive oxygen species, similar to findings in antioxidant selenoenzyme (GPx1) knockout mice.

In some of these patients, multiple tissues and organs show damage mediated by reactive oxygen species [41] and it is conceivable that other pathologies linked to oxidative damage such as neoplasia, neurodegeneration, and premature aging may manifest with time.

Laboratory findings — Typical laboratory findings are high T4, low T3, high rT3, and normal or slightly elevated serum TSH. A comparison with the other three syndromes of impaired sensitivity to thyroid hormone is shown in the table (table 2). No other hormonal abnormalities have been detected, and serum insulin-like growth factor 1 (IGF-1) concentrations are normal despite delayed growth.

Serum concentrations of selenium, selenoprotein P, and other selenoproteins are reduced. Skin fibroblasts have low selenoenzyme type 2 deiodinase activity but normal mRNA content, reflecting a defect in selenoenzyme synthesis [39]. One patient was reported to have higher serum levels of free radical-mediated lipid peroxidation products such as 7-beta-hydroxycholesterol than did controls [52].

Detailed evaluation of two cases with severe SBP2 deficiency demonstrated deficiencies in multiple selenoproteins [41]:

●Lack of testis-enriched selenoproteins, causing failure of the latter stages of spermatogenesis and azoospermia

●Selenoprotein N (SELENON)-like myopathy, causing axial muscular dystrophy

●Cutaneous deficiencies of antioxidant selenoenzymes, causing increased cellular reactive oxygen species and photosensitivity

●Reduced selenoproteins in peripheral blood cells, causing immune deficits [41]

●Deficiencies of other selenoproteins with unknown function (SELH, SELT, SELW, SELI) were also found, the consequences of which are not yet known

Treatment — No specific treatment is available, but several interventions appear to correct some of the related abnormalities, based on very limited evidence from case reports:

●Liothyronine appeared to correct delayed linear growth [40].

●Growth hormone administration improved height but was not able to compensate for the effects of T3 on bone maturation [43].

●Administration of vitamin E (alpha-tocopherol acetate) in a dose of 100 mg/day for two years normalized serum lipid peroxidation product levels, while withdrawal of this regimen for seven months reversed this effect [52].

●Administration of up to 400 mcg of selenium normalized the serum selenium concentration but had no effect on selenoprotein type 2 deiodinase activity and glutathione peroxidase concentration and failed to correct the abnormalities of serum iodothyronine levels [53].

SUMMARY AND RECOMMENDATIONS

●Causes of impaired sensitivity to thyroid hormone – Impaired sensitivity to thyroid hormone is seen in several inherited syndromes, with distinct mechanisms (see 'Mechanisms of impaired sensitivity' above):

•Thyroid hormone cell membrane transport defect (THCMTD) and thyroid hormone metabolism defect (THMD) are rare defects that cause reduced intracellular levels of thyroid hormone in a cell-specific manner, depending on the redundancy in transmembrane thyroid hormone transporters and the deiodinases expressed locally in various tissues.

•Resistance to thyroid hormone (RTH) is more common and is characterized by impaired thyroid hormone action, usually caused by a mutation in the genes encoding the thyroid hormone receptors. The types and clinical characteristics of RTH are discussed separately. (See "Resistance to thyroid hormone and other defects in thyroid hormone action".)

•These disorders can be distinguished by their characteristic abnormalities of serum thyroid function tests (table 2). In each disorder, mutations in a single gene are responsible for most or all identified cases (table 1).

●THCMTD – THCMTD is characterized by inadequate transport of thyroid hormone into some target cells, resulting in reduced intracellular levels of thyroid hormone, and an excess of intracellular hormone in cells that express alternative transporters.

•The only identified THCMTD is an X-linked mutation in MCT8, the gene encoding monocarboxylate transporter 8. (See 'Thyroid hormone cell membrane transport defect' above.)

•Typical laboratory findings of MCT8 deficiency are high serum triiodothyronine (T3) and low reverse T3 (rT3) concentrations; this pattern is distinct from other causes of reduced sensitivity to thyroid hormone (table 2). (See 'Laboratory findings' above.)

•The early hallmarks of MCT8 defects are hypotonia and high serum T3 levels in male infants. Affected individuals have stigmata of thyroid hormone deficiency, including severe neurodevelopmental abnormalities, as well as thyroid hormone excess, manifesting as inability to gain weight independent of nutrition. Carrier females have intermediate thyroid hormone concentrations and are asymptomatic. (See 'Clinical features' above.)

•Treatment options for patients with MCT8 mutations are limited to supportive measures; treatment of the low serum thyroxine (T4) concentration with physiologic doses of levothyroxine has been ineffective. (See 'Treatment' above.)

●THMD – THMD is characterized by impaired activity of the deiodinases that metabolize the different iodothyronines T4, T3, and rT3. (See 'Thyroid hormone metabolism defect' above.)

•THMD can be caused by biallelic mutations in the SBP2 (SECISBP2) gene or heterozygous mutations in the DIO1 gene. SBP2 mutations interfere with selenoprotein synthesis and have been identified in 20 families. Only three families with mutations in DIO1 have been reported. (See 'Genetics' above.)

•Clinical features of THMD are (see 'Clinical features' above and 'Laboratory findings' above):

-Biallelic SBP2 defects are associated with high T4, low T3, high rT3, normal or slightly elevated serum thyroid-stimulating hormone (TSH) (table 2), decreased serum selenium, and decreased selenoprotein levels and activity in serum and tissues. The clinical phenotype is complex and depends on the severity of the SBP2 defect. Affected individuals may have delayed growth and puberty and, in severe cases, failure to thrive, intellectual disability, infertility, myopathy, hearing impairment, photosensitivity, and immune deficits.

-Heterozygous DIO1 mutations are associated with increased serum rT3:T3 ratio and, possibly, increased cholesterol but no distinctive clinical abnormalities.

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Roy E Weiss, MD, PhD, who contributed to earlier versions of this topic review.