Thyroid hormone resistance syndrome
Introduction
Introduction to thyroid hormone resistance syndrome Thyroid hormone resistance syndrome (Thyroidhormoneresistancesyndrome, SRTH) is also called thyroid hormone refractory syndrome or thyroid hormone insensitivity syndrome (THIS). It was first reported by Refetoff in 1967. The disease is more common in familial morbidity, and there are also a few. For sporadic cases, about one-third, mostly in children and adolescents, the youngest is newborn, both men and women can be sick, clinical manifestations of serum free T4 (FT4) and free T3 (FT3) continue to rise, while Thyroid stimulating hormone (TSH) is normal, and patients have no effects on drugs, non-thyroid diseases, and abnormal thyroid hormone transport. The most specific manifestation is that the patient's super-physiological dose of thyroid hormone does not inhibit the elevated TSH from falling to normal levels, and there is no response of peripheral tissues to excess thyroid hormone. basic knowledge The proportion of illness: this disease is rare, the incidence rate is about 0.001%-0.002% Susceptible population: more common in familial morbidity Mode of infection: non-infectious Complications: neurological deafness
Cause
Causes of thyroid hormone resistance syndrome
Cause:
The exact cause of SRTH is unclear, most of which is due to mutations in the thyroid hormone receptor gene. The most common mutation or deletion of the thyroid hormone receptor gene nucleotide causes the amino acid sequence of the thyroid hormone receptor to change, resulting in Changes in body structure and function, resistance or insensitivity to thyroid hormones, followed by a decrease in the number of thyroid hormone receptors, leading to a weakening of thyroid hormones, and impaired thyroid hormone receptors, can also cause SRTH.
Pathogenesis
The most common is the tyrosine hormone receptor (c-erbA) -type functional domain ligand binding defect, the gene is located on the short arm of chromosome 3; secondly, the thyroid hormone receptor affinity is reduced, due to different degrees of resistance, clinical manifestations are different Which organ is sensitive to thyroid hormone, the clinical manifestation of that organ is sensitive, if the heart is less resistant to thyroid hormone, the patient shows tachycardia.
Thyroid hormone resistance is mainly caused by T3 nuclear receptor defects, and lymphoblasts cultured in vitro also show resistance to thyroid hormone. Studies have shown that the affinity of T3 nuclear receptor and T3 in peripheral blood lymphocytes of patients is only 1/10 of that of normal control group; The authors demonstrate that the Ka value of lymphocytes in combination with thyroid hormone is normal, but the combined capacity is reduced; in other patients, lymphocyte T3 nuclear receptors are normal, but other tissues such as pituitary, liver, kidney, and heart have T3 nuclear receptor defects.
The thyroid hormone receptors TR- and TR- are located on chromosomes 17 and 3, respectively. Systemic SRTH studies have found that the gene of the T3 nuclear receptor region undergoes a point mutation, the thyroid hormone receptor gene. One of the nucleotides is replaced by another nucleotide, resulting in the amino acid at the corresponding position in the thyroid hormone receptor being replaced by another amino acid, causing abnormal function of the receptor; or deleting several base pairs; or a single nucleoside Acid deletion; or nucleotide insertion; or several base copies, etc., point mutations appear in the middle and hydroxyl terminals of the T3 nuclear receptor and T3 binding region, resulting in decreased hormone and receptor affinity, and patients are mostly heterozygous That is, as long as there is a point mutation in the T3 nuclear receptor allele, it is autosomal dominant, and there are a small number of patients with systemic hormone resistance. The T3 nuclear receptor gene is largely lost, that is, in the thyroid hormone receptor gene. A code that mutates the amino acid codon to a stop codon, causing the expressed thyroid hormone receptor to prematurely stop the codon, causing the thyroid hormone receptor to lose some of its amino acids. The basal acid deletion may be single or multiple, and appears in the recipient DNA binding region and the T3 binding region, and the patient is homozygous, that is, the gene must be deleted simultaneously with the two alleles, and the genetic pattern is Autosomal recessive inheritance, clinically characterized by diversity, may be due to the variability of gene mutations or deletions, rather than the diversity of receptor numbers, and thyroid hormone receptor alpha gene mutations have rarely been reported.
T3 nuclear receptor 2 gene mutations have also been found in patients with selective pituitary resistance. This gene is only distributed in the pituitary and some nerve tissues, so the clinical only shows pituitary resistance; another reason is the deiodination of T4 in pituitary tissue. The specific type II-5' deiodinase of R is defective and exhibits pituitary tissue resistance.
No abnormalities were found in the chromosomes under the microscope, and abnormalities occurred at the molecular DNA level. In general, the pathogenesis of SRTH is at the molecular level, which is a typical receptor disease.
There are few pathological changes in SRTH patients. From one patient's muscle biopsy, mitochondrial swelling was observed under electron microscope, similar to hyperthyroidism. Skin fibroblasts were stained with toluidine blue, and moderate to severe heterochromatic stains were found under light microscopy. This is also caused by the deposition of extracellular substance in the skin of hypothyroid edema. In SRTH, this performance may be caused by a decrease in the action of thyroid hormones in the skin tissue. Thyroid hormone therapy does not cause the disappearance of the stained cells of fibroblasts in SRTH patients. Biopsy or surgery to obtain the patient's thyroid tissue, see the follicular epithelium with varying degrees of hyperplasia, varying in size, some patients with adenomatoid goiter, or glia-like goiter, or normal thyroid tissue.
Prevention
Thyroid hormone resistance syndrome prevention
The disease is autosomal dominant, and should be educated for women of childbearing age who have a family history, preferably family planning or birth control. Intrauterine diagnosis of pregnant women who have had children with chromosomal diseases and pregnant women who have spontaneous spontaneous abortion and stillbirth; pay attention to environmental protection, strengthen occupational protection monitoring (see, radiation genetics); carry out genetic counseling and actively promote eugenics To do a good job in medical genetic guidance for marriage and childbirth, to avoid and promote age-appropriate births and family planning.
Complication
Complications of thyroid hormone resistance syndrome Complications, neurological deafness
Thyroid hormone refractory disease is a hereditary receptor disease. There is no specific treatment. Because of its different clinical classification, the treatment response is inconsistent. Most clinicians generally believe that the efficacy of pituitary thyroid hormone refractory is better and some targets. Tissue treatment of thyroid hormone refractory disease is more difficult, and early diagnosis of thyroid hormone resistance syndrome is more difficult, so a family history of newborns should be comprehensively examined, especially for patients with mental retardation and hoarseness and abnormal body size. It should be noted.
Symptom
Symptoms of thyroid hormone resistance syndrome Common symptoms Abdominal distension constipation Eyeball tremor Goiter tachycardia Mucoid edema Hypothyroidism Lower glucocorticoid secretion
The disease occurs mostly in adolescents and children. The incidence rate of males and females is 1.2:1. According to its pathogenesis and clinical manifestations, it can be divided into three types.
1. Systemic thyroid hormone refractory disease: pituitary and surrounding tissue are involved, this type can be divided into thyroid function compensatory normal type and hypothyroidism type.
(1) Compensatory normal type: mostly familial onset, a few are sporadic, the type of this type is more mild, family surveys are mostly non-nearly married, autosomal dominant inheritance, pituitary and surrounding tissue of this type of patient The thyroid hormone resistance or insensitivity is mild, the thyroid function status is compensated by high T3, T4, can maintain normal state, no clinical manifestations of hyperthyroidism, normal intelligence, no deafness, no bone tendon healing development delay, but can be different The degree of goiter and ossification center delayed performance, the blood thyroid hormone concentration (T3, T4, FT3, FT4) increased, TSH increased or normal, TSH is not inhibited by high T3 and T4.
(2) Hypothyroidism: This type is characterized by elevated levels of thyroid hormone in the blood, and clinical manifestations of hypothyroidism, mostly autosomal recessive inheritance. This type can be characterized by poor intelligence, poor development, and may have bone mature Performance, a little color-like bones, bones are backward, and may have abnormalities such as pterygopalatine, spinal deformity, chicken breast, bird-like face, scapular skull and fourth metacarpal. Some patients may still have congenital hoarseness and less movement. Abnormalities such as stun and nystagmus may have goiter, blood levels of T3, T4, FT3 and FT4 are elevated, TSH secretion is not inhibited by T3, TSH is enhanced by TRH, and this type of hypothyroidism and dyslexia There is a difference in mucinous edema.
2. Selective pituitary gland thyroid hormone refractory disease: This type is characterized by pituitary involvement, no response to thyroid hormone, while the rest of the peripheral tissues are not tired, can respond to thyroid hormones normal, its clinical manifestations are hyperthyroidism, but TSH The level is also higher than normal, and there is no pituitary secretion of TSH tumor, this type can be divided into the following 2 types.
(1) Autonomous type: According to the reactivity of TSH to TRH and T3, T4, this type of TSH is elevated, pituitary TSH has no obvious response to TRH, high level of T3, T4 only slightly inhibits TSH secretion, dexamethasone is only mild Reduce TSH secretion, so called autonomous, but no pituitary tumors, patients with goiter and hyperthyroidism clinical manifestations, but no neurological deafness, osteophytes can be delayed, can also be short stature, poor intelligence, poor calculation and other bones Dysplasia.
(2) Partial type: clinical manifestations can be the same as autonomic type, but not as obvious as autonomic type. The clinical manifestations may be hyperthyroidism, and TSH is elevated. Pituitary TSH is reactive to TRH and T3, but its reactivity can be partially T3. And T4 inhibition, this type can also have cystineuria.
3. Selective peripheral tissue on thyroid hormone refractory disease: This type is characterized by the surrounding tissue is not responsive or insensitive to thyroid hormone, but the pituitary is not involved, the normal response to thyroid hormone, clinical manifestations of goiter, no hoarseness and Changes in osteophytes, although normal thyroid hormone and normal TSH, but clinical manifestations of hypothyroidism, bradycardia, edema, fatigue, bloating and constipation, etc., patients with this type of thyroid preparations can be relieved after the larger dose, because Its thyroid function and normal level of TSH, so clinically, this type of patients often missed or misdiagnosed.
The clinical manifestations of the disease are complex and the general hospital examination conditions are limited or poorly recognized. Therefore, the diagnosis often has delays or missed diagnosis. When the disease is diagnosed, the patient's goiter is mostly Io or IIo, serum T3, T4 levels are elevated, and clinical manifestations When the thyroid function is normal or there is hypothyroidism, the possibility of the disease should be considered. For example, accompanied by familial disease, elevated or normal TSH levels, mental retardation, delayed growth of the callus, colored bones, congenital hoarseness, Negative perchlorate test and TGA and TMA negative are more typical thyroid hormone refractory diseases.
Examine
Examination of thyroid hormone resistance syndrome
In 1986, nuclear T3 receptors (TRs) were cloned by molecular biological methods. Since then, the research on TRs has progressed rapidly, and the pathogenesis has been further explained. This disease is related to TRs defects, and its defect manifestations are diverse. There may be two kinds of TRs in the disease. The abnormal receptor can inhibit the synthesis of nuclear T3 receptor complex and chromatin DNA. The Ta value of lymphocytes combined with thyroid hormone is normal, but the binding capacity decreases, suggesting that family biochemical defects may be It is a deficiency of TRs protein. Some patients do not have lymphocytes or fibroblasts, abnormal TRs, but do not rule out other target gland tissues of patients with this disease, such as pituitary, liver, kidney, heart, skin and other defects with TRs. It is possible that the defect is not at the receptor level, but at the post-receptor level. The current research has entered the genetic level, and its pathogenesis is related to molecular defects and the nature of the mutation, such as systemic thyroid hormone refractory disease, this type The patient's receptor gene change appears on TR, and no TR gene abnormality has been found, indicating that a single point mutation of the allele can cause the disease. Due to the multi-faceted dysregulation of TRs gene expression, it occurs at the receptor molecule level and is a typical receptor disease. Therefore, laboratory tests are very important for the diagnosis of this disease, and require molecular biology. Learn laboratory conditions.
1. Radioimmunoassay for detection of thyroid function: T3, T4, FT3, FT4, TSH, TBG, TRH stimulation test, etc. T3, T4 can be structurally normal and immunologically active, and its value is often more than three times normal.
2. The PBI value increased, the BMR was normal, the perchlorate test was negative, and the 131I iodine uptake rate was normal or elevated.
3. LATS negative in blood, TGA (-), TMA (-).
4. Abnormalities can be found in chromosome assays.
5. DNA, nuclear T3 receptor (TRs), gene TR, TR detection, TR gene point mutation, base substitution occurs in the middle and hydroxy end of T binding region of TR, ie exon 6,7,8 On the other hand, the receptor has a decreased affinity with T3. A few patients are autosomal recessive inheritors. The gene analysis revealed that the TR gene was deleted in large pieces, and the recipient DNA binding region and T3 binding region appeared. The patients were all homozygous and only one Members of the heterozygous family of TR allele deletions do not develop disease.
6. X-ray osteophyte examination: there are many delayed development of the epiphysis, point color ankle and other osteophytes.
7. Thyroid B-ultrasound: to understand the degree of thyroid enlargement, with or without nodules.
8. Other measurements: such as urinary cystine determination, biochemical detection such as 5'-deiodinase.
Diagnosis
Diagnosis and differentiation of thyroid hormone resistance syndrome
Differential diagnosis
Differential diagnosis should exclude Graves disease, nodular hyperthyroidism with hyperthyroidism, hereditary and acquired thyroid globulinemia, pituitary tumor TSH secretion syndrome, cretinism or some Pendred syndrome, etc., others must also prove There is no T4 to T3 transformation disorder, because some patients with non-thyroid disease sick syndrome have a decrease in T4 to T3 conversion, which increases serum TT4 or FT4, but T3 is low. Some drugs also produce this condition, and there are also reports of familiality. Increased binding of hereditary serum albumin to T4 leads to an increase in T4 but normal T3. Rarely, endogenous production of serum T4 or T3 antibodies interferes with T4 or T3 determination, causing a false increase in T4 or T3.
1. Hyperthyroidism: T3, T4, FT3, FT4, rT3 are elevated in general hyperthyroidism, and TSH is often decreased, while TSH values in patients with thyroid hormone refractory disease are significantly increased.
2. Pituitary hyperthyroidism: Pituitary hyperthyroidism is a pituitary hyperthyroidism in which TSH is secreted by pituitary tumors and accompanied by clinical hyperthyroidism. TSH can be inhibited by T3 and T4, and is not affected by TRH excitatory effects. Regulation, mostly for autoregulation and secretion, brain CT scan and MRI sphenoid examination can find pituitary tumors or microadenomas, and general hyperthyroidism is an autoimmune disease that can be differentially diagnosed.
3. Hereditary or acquired thyroid-binding proteinosis: thyroid-binding protein has thyroid-binding globulin (TBG), thyroid-binding pre-albumin (TBPA) and albumin, of which TBC is the most combined, TBG level is increased, and more T3, T4 increased, while FT3, FT4 values were normal.
4. Goiter - detained syndrome (pendred syndrome): This disease has three major characteristics, familial goiter, congenital neurological deafness and perchlorate release test positive, is an autosomal recessive hereditary disease, the main defects It is the deficiency and reduction of peroxidase in the thyroid gland, resulting in insufficient synthesis of thyroid hormone, compensatory goiter, thyroid function can be normal, and its 131I test can have moderate hyperthyroidism, which is different from thyroid hormone refractory. Differential diagnosis.
5. cretinism (small ailments): related to endemic goiter and iodine deficiency, the more the incidence of endemic goiter, the more serious the disease, the more the incidence of dying ailments, is a common disease, due to effective prevention and control measures, At present, the incidence rate is greatly reduced. The dysplasia is caused by the developmental differentiation disorder of the fetal and infant brain central nervous system caused by fetal embryonic period and postnatal iodine deficiency and hypothyroidism during pregnancy. Symptoms are rare, no epidemic, etc. can be used for differential diagnosis.
The differential diagnosis of thyroid hormone refractory disease and other diseases mainly relies on molecular biology techniques. The thyroid hormone receptor, the receptor and its genetic structure abnormalities and defects have been confirmed from the molecular biology level, which proves that it is a typical receptor. The disease is the most important.
If molecular biology methods are used to prove that the thyroid hormone receptor gene has a mutation or the thyroid hormone receptor affinity is decreased, it is more conducive to the diagnosis of this disease. Molecular biological methods have found that thyroid hormone receptor mutation is beneficial for prenatal diagnosis and family counseling, especially It is a consultation with members of the family who have growth and/or mental retardation.
