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Query: UMLS:C0025362 (mental retardation)
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Resistance to the action of thyroid hormone can involve both peripheral tissues and the pituitary (global resistance), the pituitary only or peripheral tissues alone. Global resistance is of variable severity and has been observed in more than 60 individuals, the majority occurring in 17 families. Affected subjects are commonly eumetabolic and have goiters, elevated plasma levels of total and free thyroxine and triiodothyronine, normal thyroid hormone metabolism, and normal serum TSH levels (albeit high for the corresponding levels of thyroid hormone). A variable degree of delayed bone maturation, mental retardation, learning disabilities, and hearing defects have been reported; and a variety of treatment regimens, most of which are aimed at reducing the level of plasma hormones and/or goiter, have been attempted before the correct diagnosis has been reached. The clinical disorder is equally common in males and females and appears to be due to one or more autosomal gene mutations. The causes for the hormone resistance may be heterogeneous, either influencing the receptor for thyroid hormones or some unidentified steps in hormone action. At present, the diagnosis is one of exclusion; no effective therapy is available, and all measures designed to lower serum thyroid hormone levels should be avoided.
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PMID:Syndromes of thyroid hormone resistance. 628 48

Forty patients with the Prader-Willi syndrome have been examined. The typical features begin in gestational life with poor fetal vigor and difficulties with birth and post-partum feeding. The classical features of hypotonia, small hands and feet, cryptorchidism can be identified at this time. The delayed milestones, mental retardation and obesity become more prominent later. The average height of the patients in this series who were admitted to the Clinical Study Center was 149 cm and their weight was 114 kg. The weight and height curves show that Prader-Willi individuals are consistently shorter and heavier than normal children. Tests of endocrine function showed normal glucose tolerance. Insulin secretion was increased in relation to obesity. The rise in growth hormone (hGH) after injecting insulin to induce hypoglycemia and after the infusion of arginine was comparable to other obese individuals but was low in comparison to normal weight subjects. There was no rise in growth hormone with L-dopa administration, but there was a rise in hGH with the administration of 2-deoxy-D-glucose. The hypoglycemia produced by insulin was greater in the Prader-Willi patient than in obese controls. The rise in TRH (thyrotropin-releasing hormone) following the injection of TSH (thyrotropin stimulating hormone) was greater in the Prader-Willi patients than in the obese controls. Hypogonadism was routine in this series, and the response to LRH (luteinizing releasing hormone) was absent in all tested subjects. Treatment with clomiphene for 30 to 90 days significantly increased the response to LRH in three adult individuals who had not been treated with gonadal steroids previously and who were hypogonadal. Rectal temperature declined in three of the five Prader-Willi patients during exposure to an ambient temperature of 4 degrees C, but none of the three obese controls showed a decline. Food intake averaged 5167 kcal/d when six patients were given trays containing more food than they could eat. Food intake was not reduced when tryptophan was added to the diet. Salivary secretion was reduced in the Prader-Willi patients. A number of pulmonary function tests were significantly reduced in the study patients compared to obese or normal weight controls. The anatomic findings in four autopsied patients with the Prader-Willi syndrome showed no significant differences from those of obese subjects without this syndrome. The chromosomal pattern showed a deletion or translocation at chromosome 15 in 3 of 12 patients in whom this test was performed. These findings in 40 patients with the Prader-Willi syndrome have been compared with the information contained in 159 reports published in the medical literature.
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PMID:The Prader-Willi syndrome: a study of 40 patients and a review of the literature. 633 43

In 20 patients with congenital brain disorders, the influence of the CNS maldevelopment on the neuroendocrine system was investigated by assessment of the hypothalamic-pituitary function through measurements of the secretory reserve of pituitary hormones (GH, PRL, TSH, LH and FSH) in response to injections of insulin, TRH and LH-RH, and of the secretion of sleep-dependent pituitary hormones with polygraphic recording. The subjects consisted of 9 patients with midline anomalies of the brain and face, 3 patients with hydrocephalus, hydroencephalodysplasia or microcephalus, and 8 patients with the malformation syndrome associated with mental retardation. Ten of the 18 patients examined showed normal responses of GH secretion in the loading test (secretory peaks: greater than 10 ng/ml). But only 4 of these patients were found normal in respect of GH secretory peaks of more than 10 ng/ml during sleep. Of these 17 children, 5 showed abnormal values for basal secretion of PRL, and/or the secretory peak of PRL on injection of TRH. Two children showed hypersecretion of PRL during sleep. One patient out of the 19 examined was unresponsive in gonadotropin secretion to injection of LH-RH and 2 patients displayed excessive responses. During sleep, 4 of the 13 patients studied were found to be hypersecretory and 2 hyposecretory of gonadotropin. These results suggest that abnormalities in pituitary hormone secretion are frequently present in patients with CNS maldevelopment, and growth disturbances and abnormal sexual development may in some instances be due to endocrine abnormalities.
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PMID:Hypothalamic-pituitary function in patients with congenital malformations accompanied by central nervous system disorders. 681 79

Thirty-one children under the age of 15 years with verified medulloblastoma were treated at Addenbrookes Hospital from 1940 to 1976. In addition to surgical treatment, all received high dose irradiation to the whole neuraxis. Nine were still alive in 1979, of whom eight were examined. All these patients showed some residual problems, but five were leading active lives and had only minor physical disability. There was evidence of disturbance in growth, with shortening of the spine in relation to the limbs, in all the children. The height centile was lower than expected from parental height in four and one was severely dwarfed. Growth hormone secretion in response to exercise was, however, normal in five of six patients tested. Three children also showed failure of growth of the jaw sufficiently severe to be a cosmetic problem. Frank mental retardation was present in three children. A raised resting TSH level was found in two children, one of whom had a multinodular goiter. Of the three children with severe problems, two had been treated when under two years of age. Long-term follow-up of children who survive medulloblastoma is clearly necessary and consideration should perhaps be given to revision of current treatment regimes in very young children.
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PMID:Medulloblastoma in childhood: long-term results of treatment. 723 89

Summing up, we can say that, basing on the hypothyreosis screening results obtained in the Federal Republic of Germany, a rate of 100 to 160 new hypothyreosis patients must be expected annually for every 500.000 births. Of these more than half is recognized at a time only at which irreparable damage of the central nervous system has already occurred. With the help of TSH screening, a large proportion of these patients can be saved from several mental retardation and damage, with all its severe social consequences, by enabling early institution of appropriate therapeutics measures. Hence, it would be desirable to achieve, throughout the territory of the Federal Republic, comprehensive hypothyreosis screening in combination with already introduced programme of screening in respect of metabolism, covering without exceptions all newborn and comprising responsible, rapid and efficient co-operation without "red tape", between obstetricians or midwives on the one hand and screening centers on the other.
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PMID:[Hypothyreosis--screening in newborn (author's transl)]. 746 22

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by reduced tissue responsiveness to thyroid hormone. Subjects have elevated serum thyroid hormone levels in association with a nonsuppressed TSH. Goiter and thyroid test abnormalities have most often led to further investigation, underscoring the paucity of specific clinical manifestations of RTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis when dealing with attention deficit or hyperactivity. Failure to recognize the inappropriate persistence of TSH secretion, in spite of elevated thyroid hormone levels, has commonly resulted in erroneous diagnosis leading to treatment aimed to normalize the thyroid hormone level. More than 400 subjects with this syndrome have been identified. The mode of inheritance appears to be autosomal dominant in the majority of families. It has long been suspected that RTH is most likely caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TR alpha and TR beta, located in chromosomes 17 and 3, respectively. TR beta gene mutations have been recently identified in 68 families with RTH. All mutations are located in the T3-binding domain, straddling the putative TR-dimerization region. Mutant TRs exhibit hormone-binding impairment, the degree of which does not correlate with the severity of clinical manifestations. This finding, and the fact that heterozygous subjects with complete TR deletion are not affected, while those with point mutations are, indicated that interactions of the mutant TRs with normal TRs and with other factors, are responsible for the dominant inheritance of RTH and its clinical heterogeneity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Resistance to thyroid hormone: an historical overview. 783 74

This paper reviews present knowledge on the etiology, pathophysiology, complications, prevention, and therapy of the disorders induced by iodine deficiency. The recommended dietary allowances of iodine are 100 micrograms/day for adults and adolescents, 60-100 micrograms/day for children aged 1 to 10 years, and 35-40 micrograms/day in infants aged less than 1 year. When the physiological requirements of iodine are not met in a given population, a series of functional and developmental abnormalities occur including thyroid function abnormalities and, when iodine deficiency is severe, endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death, and infant mortality. These complications, which constitute a hindrance to the development of the affected populations, are grouped under the general heading of iodine deficiency disorders (IDD). At least one billion people are at risk of IDD. Iodine deficiency, therefore, constitutes one of the most common preventable causes of mental deficiency in the world today. Most of the affected populations live in mountainous areas in preindustrialized countries, but 50 to 100 million people are still at risk in Europe. The most important target groups to the effects of iodine deficiency from a public health point of view are pregnant mothers, fetuses, neonates, and young infants because the main complication of IDD, i.e., brain damage resulting in irreversible mental retardation, is the consequence of thyroid failure occurring during pregnancy, fetal, and early postnatal life. The main cause of endemic goiter and cretinism is an insufficient dietary supply of iodine. The additional role of naturally occurring goitrogens has been documented in the case of certain foods (milk, cassava, millet, nuts) and bacterial and chemical water pollutants. The mechanism by which the thyroid gland adapts to an insufficient iodine supply is to increase the trapping of iodide as well as the subsequent steps of the intrathyroidal metabolism of iodine leading to preferential synthesis and secretion of triiodotyronine (T3). They are triggered and maintained by increased secretion of TSH, which is ultimately responsible for the development of goiter. The acceleration of the main steps of iodine kinetics and the degree of hyperstimulation by TSH are much more marked in the pediatric age groups, including neonates, than in adults, and the development of goiter appears as an unfavorable side effect in the process of adaptation to iodine deficiency during growth. The most serious complication of iodine deficiency is endemic cretinism, a syndrome characterized by irreversible mental retardation together with either a predominant neurological syndrome or predominant hypothyroidism, or a combination of both syndromes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The disorders induced by iodine deficiency. 805 57

Normal development of the CNS requires adequate thyroid hormone exposure. Since iodine is an essential component of the thyroid hormone molecule, its deficiency during fetal development can cause hypothyroidism and irreversible mental retardation. The full-blown syndrome, called cretinism, includes deaf-mutism, short stature, spasticity, and profound mental retardation. The clinical spectrum can vary in degree and combination of these features. Screening programs in iodine-deficient countries show that up to 10% of neonates have elevated serum TSH levels, putting them at theoretical risk for permanent brain damage. About one billion people worldwide risk the consequences of iodine deficiency, all of which can be prevented by adequate maternal and infant iodine nutrition. Iodized salt is usually the preferred prophylactic vehicle, but iodized vegetable oil, iodized water, and iodine tablets are also occasionally used. The United Nations and the heads of state of most countries have pledged the virtual elimination of iodine deficiency by the year 2000. This goal is technically feasible if pursued with sufficient vigor and resources.
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PMID:Iodine supplementation and the prevention of cretinism. 849 59

Rubinstein-Taybi syndrome (RTS) is a genetic syndrome characterized by broad thumbs and halluces, growth retardation, mental retardation, and craniofacial abnormalities. This condition recently was found to be caused by mutations in the gene encoding cAMP response element-binding protein (CREB)-binding protein. As CREB-binding protein has been shown to be a critical coactivator for thyroid hormone receptors, it is plausible that RTS would be characterized by thyroid hormone resistance. In fact, features of RTS, such as mental retardation and short stature, are consistent with thyroid hormone deficiency or resistance. To assess the function of the thyroid axis in RTS, free T4 and TSH were measured in 12 subjects with this syndrome. The free T4 level was normal in all 12 (mean +/- SD, 0.97 +/- 0.20 ng/dL; normal range, 0.73-1.79), as was the TSH level (2.24 +/- 0.87 microU/mL; normal range, 0.3-6.5). Thus, overt thyroid hormone resistance does not appear to be a typical feature of RTS.
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PMID:Thyroid function in Rubinstein-Taybi syndrome. 932 50

Congenital hypothyroidism is a common preventable cause of mental retardation. The overall incidence is approximately 1:4000; females are affected about twice as often as males. Approximately 85% of cases are sporadic, while 15% are hereditary. The most common sporadic etiology is thyroid dysgenesis, with ectopic glands more common than aplasia or hypoplasia. While the pathogenesis of dysgenesis is largely unknown, some cases are now discovered to be the result of mutations in the transcription factors PAX-8 and TTF-2. Loss of function mutations in the thyrotropin (TSH) receptor have been demonstrated to cause some familial forms of athyreosis. The most common hereditary etiology is the inborn errors of thyroxine (T4) synthesis. Recent mutations have been described in the genes coding for the sodium/iodide symporter, thyroid peroxidase (TPO), and thyroglobulin. Transplacental passage of a maternal thyrotropin receptor blocking antibody (TRB-Ab) causes a transient form of familial congenital hypothyroidism. The vast majority of infants are now diagnosed after detection through newborn screening programs using a primary T4-backup TSH or primary TSH test. Screening test results must be confirmed by serum thyroid function tests. Thyroid scintigraphy, using 99mTc or 123I, is the most accurate diagnostic test to detect thyroid dysgenesis or one of the inborn errors of T4 synthesis. Thyroid sonography is nearly as accurate, but it may miss some cases of ectopic glands. If maternal antibody-mediated hypothyroidism is suspected, measurement of maternal and/or neonatal TRB-Ab will confirm the diagnosis. The goals of treatment are to raise the serum T4 as rapidly as possible into the normal range, adjust the levothyroxine dose with growth to keep the serum T4 (or free T4) in the upper half of the normal range and the TSH normal, and maintain normal growth and development while avoiding overtreatment. An initial starting dose of 10-15 microg/kg per day is recommended; this dose will decrease on a weight basis over time. Serum T4 (or free T4) and TSH should be monitored every 1-2 months in the first year of life and every 2-3 months in the second and third years.
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PMID:Congenital hypothyroidism: etiologies, diagnosis, and management. 1044 22


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