Thyroid hormone resistance syndrome, also known as thyroid hormone undersensitivity syndrome or thyroid hormone insensitivity syndrome, was first reported by Refetoff in the United States in 1967 and is therefore also known as Refetoff syndrome. The disease is characterized by familial onset in most cases, with a few sporadic cases. It occurs mostly in children and adolescents, with the youngest being a neonate, and can affect both sexes. The most specific manifestation is the inability to suppress the fall of elevated TSH to normal levels after administration of supraphysiologic doses of thyroid hormone, as well as the absence of peripheral tissue response to excess thyroid hormone. The etiology may be due to thyroid hormone receptor or post-receptor defects that diminish the action of thyroid hormones, producing a range of pathophysiological and clinical manifestations.
Epidemiology
More than 500 cases of SRTH have been reported from abroad, but fewer cases have been reported in China. Because thyroid hormone resistance is often a congenital condition that manifests at birth, routine screening of neonatal thyroid function can detect this disorder. The exact prevalence of SRTH is unclear, and although there are more females than males with thyroid disease, SRTH is equal in both sexes. Since thyroid hormone resistance is mostly genetic mutations and genetically related to familial onset in 75-85% and disseminated cases in 15-25%, true acquired SRTH is extremely rare, and some authors question some reports of acquired SRTH. In terms of genetic characteristics, SRTH is autosomal dominant, and only one family case has been reported in the literature as recessive. The condition is severely resistant if the patient combines two genetic mutations, and simultaneous SRTH in identical twins has been reported.
Etiology
The exact etiology of SRTH is unclear; the vast majority is due to mutations in the thyroid hormone receptor gene. Most commonly, changes or deletions in the nucleotides of the thyroid hormone receptor gene result in changes in the amino acid sequence of the thyroid hormone receptor, leading to changes in the structure and function of the receptor and resistance or insensitivity to thyroid hormone; secondly, a decrease in the number of thyroid hormone receptors, leading to a reduction in the action of thyroid hormone; and a disorder in the post-action of the thyroid hormone receptor can also cause SRTH.
The most common is a ligand binding defect in the beta functional region of thyroid hormone receptors (TRs), the gene of which is located on the short arm of chromosome 3; the second is reduced affinity for thyroid hormone receptors. The clinical manifestations vary due to the degree of resistance, with prominent clinical manifestations in organs sensitive to thyroid hormone. If the heart is less resistant to thyroid hormone, the patient shows tachycardia, etc.
Thyroid hormone resistance is mainly due to defective T3 nuclear receptors, and lymphoblastoid cells cultured in vitro also show resistance to thyroid hormone. Studies have demonstrated that the affinity between T3 nuclear receptors and T3 in peripheral blood lymphocytes of patients is only 1/10 of that in normal controls; some authors have also demonstrated that the Ka value of lymphocytes binding thyroid hormone in patients is normal, but the binding capacity is reduced; other patients have normal T3 nuclear receptors in lymphocytes but other tissues such as pituitary, liver, kidney, and heart have T3 nuclear receptor defects.
The thyroid hormone receptor TR-α and TR-β genes are located on chromosome 17 and chromosome 3, respectively. Studies of systemic SRTH have identified point mutations in the beta gene of the T3 nuclear receptor region, where one nucleotide in the thyroid hormone receptor beta gene is replaced by another nucleotide, resulting in abnormal functional performance of the receptor due to substitution of an amino acid at the corresponding position in the thyroid hormone receptor by another amino acid; or several base pair deletions; or single nucleotide deletions; or nucleotide insertions; or the occurrence of several base duplications, etc. Point mutations occur in the middle and hydroxyl terminus of the T3 nuclear receptor and T3 binding region, resulting in reduced hormone and receptor affinity. Patients are mostly heterozygous, i.e., they only need one point mutation in the T3 nuclear receptor beta allele to develop the disease, which is autosomal dominant. A small number of patients with systemic hormone resistance have a large loss of the T3 nuclear receptor beta gene, i.e., one of the coding, amino acid codons in the thyroid hormone receptor gene is mutated to a stop codon, causing premature termination of the expressed thyroid hormone receptor resulting in partial loss of the thyroid hormone receptor, either singly or in multiple amino acid deletions. It occurs in the DNA-binding region of the receptor and in the T3-binding region. Patients are pure gametes, i.e. both alleles must be missing at the same time for the disease to develop, and the mode of inheritance is autosomal recessive. The clinical presentation is diverse, probably because of the variability of the mutations or deletions rather than the diversity of the reduced number of receptors, whereas mutations in the thyroid hormone receptor alpha gene have rarely been reported.
Mutations in the T3 nuclear receptor β2 gene have also been found in patients with selective pituitary resistance, which is distributed only in the pituitary gland and some neural tissues, so that clinical manifestation is only pituitary resistance; another reason is a defect in the specific type II-5′ deiodinase that makes T4 deiodination to T3 in pituitary tissue, manifesting pituitary tissue resistance. Microscopic chromosomal abnormalities were not found, and the abnormalities occurred at the molecular DNA level. In conclusion SRTH pathogenesis is at the molecular level and is a classic receptor disease.
There are few reports on pathological changes in patients with SRTH, from one patient with muscle biopsy, mitochondrial swelling similar to hyperthyroidism was found by electron microscopy. Staining of skin fibroblasts with toluidine blue revealed moderate to severe heterochromatic granules on light microscopy. This extracellular heterochromatic material was also deposited in the skin of hypothyroid mucinous edema. In SRTH this manifestation may be caused by reduced thyroid hormone action in the skin tissue, and thyroid hormone treatment did not cause the heterochromatic granules to disappear from fibroblasts in patients with SRTH. Thyroid tissue obtained from biopsies or surgical procedures shows varying degrees of follicular epithelial hyperplasia, and some patients present with adenomatous goiter or glioid goiter or normal thyroid tissue.
Clinical manifestations
Due to the different ranges of hormonal hypo-resistance, three categories can be distinguished.
1. Systemic thyroid hormone resistance syndrome: Both pituitary and peripheral tissues are resistant. Due to the different degrees of hypo-resistance, it is divided into normal thyroid function (compensated type) and hypothyroidism (decompensated type).
The compensated type is milder, with normal thyroid function, but with varying degrees of goiter and delayed ossification center, elevated serum T4, T3, FT4 and FT3, and increased or normal TSH. TSH secretion is increased or normal after TRH excitation test, but TSH secretion cannot be suppressed after exogenous administration of large amounts of T4 or T3.
The loss of compensation is characterized by elevated serum thyroid hormone with clinical manifestations of hypothyroidism such as mental retardation, goiter, short fourth metacarpal, congenital deafness, etc. Serum T4, T3, FT4 and FT3 are elevated, but TSH is normal; TSH secretion is increased after TRH excitation test, but TSH secretion is not suppressed after exogenous administration of large amounts of T4 or T3.
2. Selective peripheral tissue resistance to thyroid hormone syndrome: This disease is characterized by peripheral tissue resistance to thyroid hormone, but not pituitary resistance to thyroid hormone. Clinical manifestations include enlarged thyroid gland without neurogenic deafness and delayed epiphyseal healing. Serum T4, T3, FT4, FT3 and TSH are normal, but accompanied by clinical hypothyroidism, which can be improved by giving high doses of thyroid hormone. Because the thyroid function and TSH levels are normal in laboratory tests, this type of patient is often missed or misdiagnosed clinically.
3. Selective pituitary resistance to thyroid hormone syndrome: This disease is characterized by pituitary gland involvement, insensitivity to thyroid hormone, and no peripheral tissue involvement, normal response to thyroid hormone.
This disease is more difficult to diagnose because of the different degree and extent of tissue resistance to thyroid hormones, the complexity and variety of clinical manifestations, and the limitations of general hospital examination conditions or lack of awareness; therefore, diagnosis is often delayed or missed. Anyone with enlarged thyroid gland (mostly degree I or II), elevated thyroid hormone levels, and normal clinical thyroid function or hypothyroid manifestations should suspect this disease. If T4 and T3 are elevated and TSH is normal or elevated, a TRH excitation test should be performed to further confirm the diagnosis of the disease. If there is also familial onset, elevated or normal TSH levels, mental retardation, delayed epiphyseal maturation, dotted skeleton, negative perchlorate test for congenital deafness and negative TGAb and TMAb (TPOAb), then the disease is more typical of SRTH.
Thyroid hormone resistance syndrome needs to be differentiated from the following examples of diseases.
1. Thyrotoxic hyperthyroidism: T4, T3, FT4, and FT3 are elevated, while TSH is significantly suppressed; TSH is normal or elevated in SRTH; sex hormone-binding globulin is normal in SRTH patients, while it is elevated in hyperthyroidism.
2. Pituitary hyperthyroidism: TSH of pituitary TSH tumor causing hyperthyroidism is not only elevated, but also not stimulated by excitation of TRH. Cranial CT and MRI examination can detect the lesion, which is helpful for diagnosis.
3 Hereditary or acquired thyroid binding globulinopathy: Thyroid binding globulinopathy can cause elevated T4 and T3, but FT4 and FT3 are normal.
Treatment
The clinical manifestations of SRTH are different, so the treatment is different. Gene therapy may be used in the future, and the following issues should be noted for current treatment.
1. whether to apply antithyroid drug therapy It is known that SRTH is not due to elevated thyroid hormone levels, but rather to receptor (T3 nuclear receptor) insensitivity to thyroid hormone and elevated blood levels of thyroid hormone with compensatory significance. The use of antithyroid drugs to artificially lower the blood T3 and T4 levels may aggravate the manifestation of hypothyroidism, promote the aggravation of goiter, and promote the increase of TSH secretion and the proliferation and hypertrophy of pituitary TSH-secreting cells, especially in children, hypothyroidism is detrimental to growth and development, so antithyroid drug therapy is not recommended. Only for some patients with unresponsive target organs, antithyroid drug therapy can be tried under observation, and if the efficacy is not good, it should be discontinued in time. For pituitary SRTH, the symptoms of hyperthyroidism should be controlled, and anti-thyroid drugs or 131Ⅰ treatment can be applied, etc.
Thyroid hormone therapy can be applied and adjusted according to the condition and type. Patients with systemic SRTH generally do not need thyroxine therapy, and hypothyroidism can be treated with T4 and T3, which are especially beneficial for infants and adolescents to promote growth and development, reduce goiter and TSH secretion, and generally use levothyroxine sodium (L-T4) tablets, 100-200 μg each time, 2 times/d. , application of T3 preparations is also effective. For peripheral tissue SRTH should be given a larger dose of thyroid preparations can make the condition better.
Glucocorticoid therapy Glucocorticoids can reduce the excitatory response of TSH to TRH, but there is no uniform opinion on whether patients with SRTH have a response. side effects are greater.
Prognosis and prevention
SRTH is a hereditary receptor disease with no specific treatment yet. Due to its different clinical classifications, treatment responses are mostly inconsistent, and most clinicians generally agree that pituitary SRTH is more effective, while some target tissues are more difficult to treat SRTH. Because early diagnosis of SRTH is often difficult, newborns with a family history should be thoroughly examined, especially in patients with mental retardation deafness and physical abnormalities.The vast majority of SRTH is autosomal dominantFor women of childbearing age with a family history should be educated, preferably through family planning or birth control.