The lower part of the body is shorter than the upper part

Introduction Physical dysplasia and dysplasia in patients with endemic cretinism are another feature of the disease. The body is short and uneven, and the lower part of the body is shorter than the upper part. The etiology of endemic cretinism has been relatively clear and is the result of severe iodine deficiency during embryonic and neonatal periods. In addition to the iodine deficiency theory, there are also people who raise genetic problems, autoimmune problems and goiter problems. Mental retardation caused by the disease is more severe with mental retardation. There are data showing that the moderate and severe are above 60%. Most of the clinical manifestations are quiet, dull, wilting, and reduced activity. A small number of temperament is violent, and laughter is impermanent.

Cause

(1) Causes of the disease

The etiology of endemic cretinism has been relatively clear and is the result of severe iodine deficiency during embryonic and neonatal periods. In addition to the iodine deficiency theory, there are also people who raise genetic problems, autoimmune problems and goiter problems.

1. Iodine deficiency:

(1) Endemic goiter and Dick disease are prevalent in areas with severe iodine deficiency. Iodine deficiency is not serious or there is no Dick disease in new wards and light wards. In the non-thyroid epidemic area, no one has reported typical Dick disease. In the epidemic area of Dick disease, the iodine content of drinking water is often <1g/L. The local residents including the nail disease and the patient's 24h urine iodine are often <25g, even close to zero. The incidence of goiter in this ward is >40%, the prevalence of men and women is close, and there are more adult nodular goiters. The above indicates that areas with severe iodine deficiency have a long epidemic time and disease in the old ward. There are individual serious areas of endemic disease, no or little gram, and the reasons are pending.

(2) Dick disease often has varying degrees of goiter. Foreign statistics account for about 50% to 85%. Domestic patients in Heba Township, Guizhou Province, have thyroid enlargement, accounting for 30%, Chengde City, Hebei Province, 40%, and Xujiawopu Village, Chifeng County, Inner Mongolia, 29%. In addition, the mothers of patients with Dick disease have many goiters. The results of the suburban survey in Chengde City, the mother has a goiter rate of 71%, which can explain the close relationship between Dick disease and endemic goiter.

(3) The iodine metabolism of patients with gram disease is basically the same as that of patients with thyroid disease, but the degree of the former is more serious. For example, the urinary iodine is low, the 131I rate of thyroid is "iodine starvation curve", and the thyroid rate of 131I is increased. And serum T4 can be maintained or reduced (the decline in Dick disease is more pronounced). TSH is normal or elevated (the increase in Dick disease is more pronounced), while T3 maintains normal or compensatory elevation.

(4) Animal experiments have shown that pregnant animals are fed with iodine-deficient diet, and young animals after birth may have similar manifestations of human growth and stagnation.

In 1976, in the experimental study of rats, he observed the effect of maternal iodine deficiency on brain development in intrauterine rats. The brain of iodine-deficient animals has low brain weight, brain cells are significantly reduced, serum T3 content is also low, and thyroid function is low. which performed.

In recent years, many scholars in China have been engaged in animal experiment research. They have successfully replicated animal models of low iodine gram disease in rats and mice, and observed that brain development is lagging, animal learning ability is low, and growth and development are obviously hindered. The pituitary gland, the thyroid system also has a significant change in hypothyroidism.

(5) In the endemic area of endemic goiter, the iodized salt is used for prevention and treatment, and the disease is also disappeared, that is, there will be no new disease. For example, Switzerland, Germany, Austria, etc. in the European Alps have been seriously ill-affected areas for decades. After decades of prevention and treatment of iodized salt, no new patients with Dick disease have occurred. Before the supply of iodized salt in the suburbs of Chengde City, the prevalence of Dick disease in several villages was 2%. Since the supply of iodized salt in 1962, no new Dick disease patients were found in the 1975 review. Before the prevention and control of Heba Township in Guizhou Province (1979), the infant's low detection was 40.5%. After the prevention and treatment with 1:5000 iodized salt, it decreased to 7.8% in the first year (1980) and decreased to 1.4% in the second year. In the 5th year, no baby was born.

The above explanation shows that the basic cause of Dick disease is iodine deficiency in the environment.

2. Genetic factors: Dick disease has a tendency to have multiple families, and there are a large number of reports at home and abroad. A history of 208 cases of cretin patients with cretinism was investigated in a ward of Ningwu County, Shanxi Province. Among the family members, 127 (59.9%) had no cretinism, and 3 (1.5%) had cretins. There were 23 cases (10.9%) of mothers with cretinism, 1 case (0.5%) of parents with cretinism, 59 cases (27.6%) of brothers and sisters with cretinism, and a total of cretins among family members. 40.5%. One of the six mothers in the village had mental retardation, and each child had 2 to 3 children with cretinism. However, the above situation cannot be considered that the disease is a hereditary disease, because the congenital factors other than heredity also have similar phenomena in a family. In 1938, Wagner-Jaurig observed 20 young couples in Switzerland, and gave birth to 6 normal children before moving into the ward. After moving into the ward, they gave birth to 4 typical cretin children. The last time they were pregnant, A healthy boy was born because of the preventive treatment of thyroid tablets. There is a family in a certain ward in Xinjiang. In 1964 (that is, before the prevention of iodized salt), all three children were all cretinism. After prevention with iodized salt, four children were born and developed normally. It is indicated that genetic factors are not the main factors in the above two families.

In recent years, domestic studies on the genetics of Dick disease have been studied in many aspects. Most scholars believe that the disease does not conform to the dominant or recessive inheritance of single genes, nor does it find abnormalities in the number or morphology of chromosomes. In short, this issue remains to be seen. further research.

3. Autoimmune problems: Whether there is autoimmune factor in Dick disease, the current research data is no. Brazil (26 cases), Uele region (11 cases) in Congo (Golden), New Guinea (10 cases) mothers of children with cretinism, etc., were tested for thyroglobulin antibodies in patients with citrate hemagglutination and a few families. . The results of serum globulin examination in 11 patients in Ningxia, Gansu Province were normal. In addition, patients with severe cretinism often have thyroid atrophic lesions, and uneven punctate distribution can be seen during thyroid scan. Some people mention whether it is related to autoimmunity. Anti-thyroid home immune antibodies are now known. In addition to TGAb and TMAb, there are TSAbs (thyroid stimulating hormone antibodies) that induce Graves' disease. TSAbs can be divided into thyroid growth stimulating antibodies and thyroid stimulating antibodies, which can cause simple goiter or simple hyperthyroidism, respectively. . In recent years, Doniach has proposed a thyroid growth inhibitory antibody, which may be caused by this antibody in some patients with thyroid atrophy. In particular, whether thyroid atrophy of visceral dysplasia is related to this is worth studying.

4. Thyroid-causing substances cause a lot of thyroid substances, but the more obvious is cassava, Delange and other three villages in the Congo (Golden) survey of 9,993 residents, found that one of the villages Ubangi and two other villages, residents 24h urine The average iodine ratio was similar (16.15g, 20g each), but the rate of thyroid enlargement in this village was 77% higher (13% and 2% in the other two villages), and there was cretinism, and the prevalence was 4.7%. (There are no other two villages). The reason for this is that the cassava eaten in the village of Ubangi contains glucosides, which can form thiocyanate compounds under the action of enzymes in the body.

(two) pathogenesis

The pathogenesis of Dick disease may be related to two factors: the lack of thyroid hormone synthesis and the direct independent effect of iodide deficiency.

1. insufficient synthesis of thyroid hormone

The role of thyroid hormone in physical development (including bone development, sexual development) has been recognized, however, the relationship between thyroid hormone and brain development has been a hot topic in the pathogenesis of Dick disease.

Dobbing pointed out that there are two main periods in the growth phase of the human brain: the first phase is the proliferative phase of nerve cells, which begins about 12 to 18 weeks of gestation and is completed in the second trimester. This period is extremely sensitive to external environmental factors such as radiation exposure and maternal infection. The second phase is the most important period of brain development, which is characterized by brain cell differentiation, migration, myelination, dendritic development, sudden triggering, establishment of neural connections and proliferation of glial cells. This period begins in the second trimester and peaks before and after birth and continues until a period of time after birth. This period may last until the age of 2 years, and the first 6 months after birth is the most critical moment of postnatal brain development. About 5/6 of the brain development is completed after birth. The second phase is extremely sensitive to nutritional factors and hormone deficiency (including hypothyroidism). A large number of animal experiments have confirmed that the effect of thyroid hormone on brain development has a certain time. During this period of time, hypothyroidism will cause brain development. Once this period of time is added to thyroid hormone, brain development disorder can not be corrected. (irreversible), so this limited period of time is also called the critical period of brain development. Brain development is performed in a strict and orderly manner, and thyroid hormone is considered to be a "clock" that terminates neuronal proliferation and stimulates differentiation. During the critical period, thyroid hormone promotes the differentiation and migration of nerve cells, the development of neuronal microtubules, the extension of axons, the branching of dendrites and the development of dendritic spines, the development of synapses, and the establishment of neural connections. Myelinization, synthesis of neural mediators (possibly affecting the synthesis of neuronal synthetases, enzymatic activity, metabolism of mediators), development of specific neurons (choline, adrenergic and GABAergic nervous systems) These are all essential hormones.

Nunez noted that brain cell death was increased due to decreased synapse formation during hypothyroidism, and the number and volume of brain cells were reduced. Patel believes that the key role of thyroid hormones in the development of nerve cells is to promote their migration and differentiation, but less affected by the proliferation of neurons. During the critical period, the expression of surface recognition factors in thyroid hormone-sensitive neuronal migration is affected by thyroxine deficiency. Various cell maturation is not synchronized, and the spatio-temporal relationship between neurons is abnormal, resulting in abnormal neural pathways or nerve cell stagnation. Nerve cells die due to loss of mutual nutrient dominance. Therefore, abnormal and wrong pathways of brain cells are one of the mechanisms of irreversible damage caused by thyroid hormone deficiency in critical period. The most fascinating feature of the central nervous system is the complex and precise network connection between various neurons, which is the structural basis for accomplishing various behaviors. Modern psychology believes that the material basis of intellectual activity is related to the level of development of dendrites, dendritic spines, synapses, and nerves in brain tissue.

Oppenheimer first confirmed that T3 binds to nuclear receptors and plays a role in hormones. T3 is the main active form of thyroid hormone. T3 on the nuclear receptors of surrounding tissues is mainly derived from T3 in plasma. Larson found that brain cells are different from surrounding tissues. The nuclear receptor-bound T3 is mainly derived from plasma T4. T4 enters brain cells and is converted to T3 by deiodinase (type II) and then combined with T3 receptor (T3R). And play a role. The first involvement of the thyroid axis in iodine deficiency is a decrease in T4, but T3 is normal. Therefore, if T3 is normal, the surrounding tissues will be affected little, and the decrease of T4 will directly affect brain development and brain function. In the absence of iodine, the activity of type II deiodinase is compensatory, but long-term hypothyroidism, type II deiodinase compensation failure, decreased enzyme activity, and even decreased brain T3R, so low T4 and brain development There is a direct relationship. It is currently believed that the role of thyroid hormone is mediated by T3R, T3 and T3R combine to form a complex, T3R is activated, and it is converted from non-DNA binding to DNA binding. It then interacts with or interacts with certain genes to regulate the transcription of specific genes or the synthesis of corresponding proteins. T4 declines, affecting both levels of transcription and translation of genes. T3R is a non-histone in the nucleus. The content of different nerve cells is different. The cerebral cortex, hippocampus and amygdala are the most abundant; the hypothalamus, thalamus, striatum and olfactory bulb are the second; the cerebellum and brainstem are the least; The content of T3R in cells is 2 to 3 times higher than that of glial cells. Therefore, the effect of thyroid hormone on nerve cells is to exert its biological effects through the specific nuclear receptor T3R.

Hypothyroidism caused by iodine deficiency is the basic pathogenesis of Dick disease. Hypothyroidism in different stages of embryonic development and infant development may be related to the pathogenesis of Dick disease.

(1) Fetal hypothyroidism: Fetal hypothyroidism is the main mechanism of brain development after the disease. At present, we are unable to obtain direct evidence from the development of human embryos to verify fetal hypothyroidism caused by iodine deficiency. There are two evidences that can indirectly suggest the presence of fetal hypothyroidism: one is found in aborted fetuses in areas with severe iodine deficiency. Fetal hypothyroidism can occur as early as the fourth month of pregnancy, and hormonal hypothyroidism occurs earlier than goiter. Another evidence is that the incidence of hypothyroidism in the critically ill areas of the fetus is quite high, some as high as 10% to 30%, which was confirmed in Zaire, India, Tanzania and other wards. So far we do not know to what extent the neonatal hypothyroidism truly reflects the existence of fetal hypothyroidism. Amniocentesis may be another way to detect fetal hypothyroidism. Animal experiments have confirmed that fetal hypothyroidism caused by iodine deficiency is the main cause of brain development. Potter cuts the thyroid gland of the fetus at different gestational times, and the newborn sheep show a cretin-like change. The earlier the thyroid is removed, the more serious the brain develops. Potter also fed the ewes with low-iodine feed. At 56 days of gestation, T4 decreased and goiter appeared at 70 days. The brain development of the born lambs is very similar to that of the thyroid gland, which means that the brain wet weight decreases; the brain DNA and protein content decrease; the brain movement zone, the visual zone and the hippocampus cell density increase, and the extracorporeal granule layer thickens. Prompt cell migration disorder; Purkinje cell dendritic development disorder. In the low-iodine rat model, the authors also found that fetal hypothyroidism is the main mechanism of brain development, and it can prevent iodine supplementation or thyroid hormone supplementation during the critical period. This proves that fetal hypothyroidism is the main mechanism of brain developmental disorders.

(2) maternal hypothyroidism: maternal hypothyroidism is common in areas with iodine deficiency (especially in areas where visceral cretinism predominates). In Zaire, there is a unique specificity between maternal hypothyroidism and visceral cretinism, so Delange believes that maternal hypothyroidism is associated with fetal neurodevelopmental disorders. It has also been suggested that children born to mothers with low T4 have lower IQ than normal children. It is unclear to what extent mother's hypothyroidism affects fetal brain development. Potter mated the ewes after they had removed the thyroid. After the pregnancy, the fetal sheep were found to have poor brain development in the early and middle stages of pregnancy. However, the brain development of the sheep was not different from the control group at the late pregnancy and at birth. This result suggests that the mother's thyroid function is necessary to maintain fetal brain development, which is evident in early pregnancy and has little effect in late pregnancy. He also found that ewes and fetal sheep were removed at the same time, and the brain development of the sheep was more serious than that of the low-iodine-born lambs, which also indicated the effect of maternal hypothyroidism on the fetus. Mano further confirmed that in the mid-pregnancy, a low-iodine ewes model was injected with DIMIT (3,5-dimethyl-isopropyl-L-thymidine), which is iodine-free but has thyroid hormone action. Sheep's hypothyroidism was corrected, but the delivery of the litter still showed the same severe brain development as the low-iodine group (DIMIT could not pass through the placenta), indicating that the mother's hypothyroidism had little effect on the fetus. The above experimental results suggest that maternal hypothyroidism only has a certain effect on fetal brain development in early pregnancy. The mechanism may be that the mother's T3 and T4 can pass through the placenta in the early pregnancy, but not in the middle and late stages. The brain development at this time depends mainly on the brain development. The thyroid function of the fetus itself. In fact, as Escobar puts it, T3R is already present in the fetal brain before the fetal thyroid gland functions, so the mother's thyroid hormone may affect fetal brain development. As far as the pathogenesis is concerned, compared with the importance of fetal hypothyroidism, maternal hypothyroidism is unlikely to be the most important mechanism for the onset of disease. Mother's hypothyroidism may play a role in:

1 Before the formation of fetal thyroid function, the amount of mother T3 and T4 entering the fetus is insufficient due to maternal hypothyroidism.

2 When severe iodine deficiency, the mother's thyroid gland still has a good ability to take iodine. The developing fetal thyroid gland is at a disadvantage when competing with the mother to ingest the inorganic iodine of the mother's plasma, thus exacerbating fetal hypothyroidism and iodine deficiency.

3 pregnant women due to increased estrogen levels, liver thyroid hormone binding globulin increased, so that total plasma T3, total T4 increased, while FT3, FT4 decreased. This change will be more prominent when iodine is absent.

4Coutras confirmed that during normal pregnancy, kidney iodine clearance increased and blood iodine decreased. Loss of endogenous iodine under such physiological conditions, such as accompanied by insufficient iodine intake, can exacerbate fetal iodine deficiency.

5 During lactation, the mammary gland has the ability to concentrate iodine to ensure the iodine supply of infants and young children. Hypothyroidism in lactating mothers will inevitably affect the supply of iodine to infants through milk. In the Zairian ward, it is found that infants have hypothyroidism after weaning.

(3) Neonatal hypothyroidism: In areas with normal iodine supply, the incidence of hypothyroidism in newborns is less than 0.02%, mostly sporadic cretinism. The incidence of hypothyroidism in neonates in low-iodine areas is greatly increased, ranging from 4% to 15% in India and 10% to 30% in Zaire. In recent years, the number of neonatal TSH high values in the iodine concentration of iodized salt in China is much higher than that in non-disease areas. Neonatal hypothyroidism will undoubtedly affect brain development. Within 2 years of life, it is still the critical period of brain development. At this time, it is mainly the development of cerebellum, myelination, glial cell proliferation and establishment of neuronal connections.

(4) transient hypothyroidism or subclinical hypothyroidism: these two hypothyroidism are found in low iodine wards. In particular, a slight increase in TSH may also affect the brain tissue and cause organ hypothyroidism, which may also affect brain development or brain function to some extent.

2. The independent role of iodine is a controversial point of view. People who hold this view believe that the brain development of the fetus depends mainly on the thyroid function of the fetus itself. The fetal thyroid function is formed after 12 weeks of gestation, so the brain development in the first 3 months of the fetus may be related to iodine. The basis is: 1 non-deficiency iodine factors cause congenital hypothyroidism in the fetus, such as sporadic cretinism, its clinical manifestations are significantly different from Dick disease, Dick's disease, hoarseness and upper motor neuron damage symptoms in sporadic gram Ting disease is not significant; 2 mothers throughout pregnancy hypothyroidism (non-iodine deficiency reasons), the birth of the baby does not appear typical cretinism, or even completely normal; 3Corti development is in the 10 to 18 weeks of pregnancy, just in the fetus Before thyroid formation; 4Firro and Pharoach found that pre-pregnancy injection of lipiodol was more effective than mid-pregnancy injections to prevent the development of Dick disease.

Recent studies, especially Escobar, have confirmed that mother T3 and T4 can enter the fetus through the placenta before fetal thyroid formation. This finding changes the traditional view that mothers T3 and T4 cannot pass through the placenta; This permeability has dropped. According to recent research, fertilized eggs begin to receive maternal thyroid hormone supply on the third day after implantation. Therefore, before the formation of thyroid function, the fetus mainly depends on the mother's T3 and T4. Even after the fetal thyroid function is formed, the mother's T3 and T4 are still accepted. It is found that 10% of the thyroid hormone in the fetus is born from the mother. Animal experiments have also confirmed that the development of the inner ear is also dependent on thyroid hormones rather than iodine. Therefore, Hetzel pointed out: "There is no evidence that iodine has a direct effect on brain development."

Therefore, it is generally believed that the lack of thyroid hormone synthesis during the critical period of brain development is the main pathogenesis of Dick disease.

an examination

Related inspection

Electrocardiogram EEG examination

Mental retardation caused by the disease is more severe with mental retardation. There are data showing that the moderate and severe are above 60%. Most of the clinical manifestations are quiet, dull, wilting, and reduced activity. A small number of temperament is violent, and laughter is impermanent. Both speech and hearing impairments are common. A county in Hubei Province had observed 936 patients and found that there were different levels of speech disorders, including 545 cases (58.4%) with total dumbness, 737 cases (78.8%) with hearing impairment, and 252 cases (accounting for total). 26.9%).

Physical retardation and dysplasia are another feature of the disease. The patient's body is short and uneven, the lower part of the body is shorter than the upper part, and the bone development is slow. It is characterized by late development of the bone nucleus, small development, and small metacarpophalangeal bone. Many patients have poor motor function and severe sputum. Sexual stunting, mild patient development and fertility. Weighing less than the same age.

Checked: body temperature, pulse, blood pressure are generally normal, thyroid function is basically normal. The serum protein combined with iodine and butanol extracted iodine was mostly reduced, the thyroid absorption 131 iodine rate increased, showing iodine starvation curve, serum cholesterol was normal or low. X-ray examination showed that the bone age was behind the normal age, and the skull back pressure traces increased, and the saddle saw occasionally increased. The basic frequency of EEG is low, and the rhythm is not complete. Most of them have paroxysmal bilateral synchronous waves, and waves are visible. In the severely ill patients, the electrocardiogram showed low voltage, T wave low or double phase, QT interval prolongation and incomplete right bundle branch block.

Differential diagnosis

The dividing point of the upper and lower body is the upper edge of the pubic symphysis. The ratio of the upper and lower sides is 1.7 at birth, 1.3 at 5 years old, and 1 at 10 years old. The difference in body proportion under normal conditions should be distinguished.

Mental retardation caused by the disease is more severe with mental retardation. There are data showing that the moderate and severe are above 60%. Most of the clinical manifestations are quiet, dull, wilting, and reduced activity. A small number of temperament is violent, and laughter is impermanent. Both speech and hearing impairments are common. A county in Hubei Province had observed 936 patients and found that there were different levels of speech disorders, including 545 cases (58.4%) with total dumbness, 737 cases (78.8%) with hearing impairment, and 252 cases (accounting for total). 26.9%). Physical retardation and dysplasia are another feature of the disease. The patient's body is short and uneven, the lower part of the body is shorter than the upper part, and the bone development is slow. It is characterized by late development of the bone nucleus, small development, and small metacarpophalangeal bone. Many patients have poor motor function and severe sputum. Sexual stunting, mild patient development and fertility. Weighing less than the same age.

Checked: body temperature, pulse, blood pressure are generally normal, thyroid function is basically normal. The serum protein combined with iodine and butanol extracted iodine was mostly reduced, the thyroid absorption 131 iodine rate increased, showing iodine starvation curve, serum cholesterol was normal or low. X-ray examination showed that the bone age was behind the normal age, and the skull back pressure traces increased, and the saddle saw occasionally increased. The basic frequency of EEG is low, and the rhythm is not complete. Most of them have paroxysmal bilateral synchronous waves, and waves are visible. In the severely ill patients, the electrocardiogram showed low voltage, T wave low or double phase, QT interval prolongation and incomplete right bundle branch block.

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