Screening for congenital hypothyroidism.
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Biomedical subjects
Publications and source records attributed to R Illig.
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The antidepressive efficacy of TRH was investigated in 15 endogenous depressive patients in a double-blind cross-over design. The Hamilton depression scale, the AMP (PAS) system, v. Zerssen scale and thermometer scales were used. No therapeutic effect could be demonstrated. The blunted TSH-response to TRH, which has been described by other investigators, was confirmed. There was suggestive evidence of a psychoendocrinological relationship in the sense that the more severe the "somatic depressive" syndrome as calculated from the AMP system, and the more marked the diurnal variation of the endogenous type is, the lower are the basal TSH-values and the smaller the response to TRH. Thus, TRH may become a useful tool to identify subgroups of depressive patient populations.
The case of a 6-year-old mentally retarded boy is described, who was delivered by breech presentation and who was later found to have adrenal calcifications. He presented with severe hypoglycemia during infancy and early childhood. Subsequent examinations revealed the coexistence of pituitary growth hormone and ACTH-deficiency and of adrenal medullary insufficiency. The hypothalamus-pituitary-thyroid and -gonadal axes were apparently normal. It is concluded that both, the pituitary and adrenal medullary insufficiency are probably due to the same complications at birth (hypothalamic or pituitary asphyxia and adrenal hemorrhage) and that both conditions contributed to the development of hypoglycemia.
Mass newborn screening for primary hypothyroidism was introduced in Switzerland on January 1st, 1977, using a radioimmunoassay of TSH in dried blood spotted on filter paper. After incubation for 38 h at 20 degrees C, bound and free TSH is separated by double antibody precipitation. The filter paper discs of 6.5 mm diameter remain in the test tubes. At present, one TSH determination costs approx. SFr. 4.40. All reagents used are commercially available and their costs amount to not more than 15% of the total expenses. During the first 8 months of 1977, of 21862 newborns tested routinely on day 5 (together with the Guthrie-test), 7 infants with primary hypothyroidism were discovered owing to blood TSH values of greater than 100 muU/ml. Diagnosis was not recognized clinically although all of the infants showed some symptoms. Thyroxin therapy was started within the second week of life. The incidence of about 1 in 3000 newborns is higher than reported so far. It has to be shown whether this is due to genetic or geographic factors, to the occurrence of transitory forms, or to a higher efficiency of screening by the TSH (versus T4) assay.
In congenital hypothyroidism the TSH level reaches at age 5 days values about 100-times of the normal. Due to this fact, and having a good RIA-method for TSH in the own lab at hand, the possibility of TSH-determination in dried wholeblood on a filter-paper was examined. Control studies with normal blood-samples proved that the values of dried-blood samples had sufficient accuracy. On the 5th day of life the normal TSH-values were below 20 muU/ml while values above 100 muU/ml were suspicious for hypothyroidism. In 1200 newborns the TSH-screening was performed in combination with the routine Guthrie-test. Among them one child with a value above 100 muU/ml proved to have hypothyroidism. The results show that the determination of TSH in dried blood is possible, and that the method described is a useful tool for the early diagnosis of primary hypothyroidism.
In a follow-up study of 48 young men who had been surgically treated for cryptorchidism before puberty testicular function was assessed by examining the genitalia, testicular volume, secondary sex characteristics, semen, plasma luteinising hormone (LH) and follicle-stimulating hormone (FSH) concentrations after luteinising hormone-releasing hormone stimulation, and plasma testosterone concentrations. Clinical androgen effects were normal. The mean testicular volume of both testes was in the low normal range in those who had had unilateral cryptorchidism and below normal in those who had had bilateral cryptorchidism. Of 37 patients whose sperm counts were recorded (14 bilateral) six showed azoospermia (all bilateral), five had severe oligospermia (four bilateral), and 10 had moderate oligospermia (one bilateral). In nearly all those who had had bilateral cryptorchidism and most of those who had had unilateral cryptorchidism plasma gonadotrophin levels were increased. Four cases of possible partial LH deficiency were identified. Plasma testosterone concentrations were normal in all except two patients.
By a modification of the radioimmunoassay of TSH in plasma, a method has been introduced for the measurement of TSH in dried blood spotted on filter paper. On incubation of filter paper discs (6.5 mm diameter, corresponding to approx. 10 mul blood) for 38 hs has the lower limit of detection was 10 muU/ml TSH 68/38. In 100 blood samples, TSH was measured in plasma as well as in dried blood; the results were comparable and showed complete agreement in patients with high TSH concentrations suffering from primary hypothyroidism. In 16 out of 72 newborn children examined during the first 8 hs of life. TSH was slightly elevated. It would appear that our method is sensitive enough for detection of the physiological postnatal rise in TSH. Among 1400 infants in whom Tsh was measured on the 5th or 6th day simultaneously with routine screening for phenylketonuria (PKU), we found 1 case with markedly elevated TSH levels of greater than 100 muU/ml. The child suffered from congenital goiter. The results of our study show that the measurement of TSH in dried blood spots is possible without particular difficulty. Becasue of the simplicity of blood-sampling, the stability of the TSH, the relatively low cost and the low number of false positive results, this method seems to be suitable for screening of new born infants. It could be carried out conveniently in combination with the screening program for metabolic diseases, which covers practically 100% of infants born in Switzerland. Congenital hypothyroidism is a relatively frequent disease (1:3000-1:7000) in which early commencement of treatment is of great importance for mental development. It would therefore be desirable for all infants to be screened during the first days of life for congenital hypothyroidism.
An evaluation of twenty-one boys, including a discordant pair of identical twins, is presented in whom bilateral anorchia was found with a negative family history and without history of breech presentation or of postnatal testicular trauma, torsion or orchitis. The most likely cause is prenatal testicular torsion. The incidence of the condition in our hospital is 1 in 177 cases of cryptorchidism. Prepubertal growth was normal before treatment, and testosterone replacement therapy allowed a normal pubertal growth spurt and skeletal maturation. Although demonstrable basal urinary testosterone was found in the subjects with a postpubertal bone age, most patients tested showed no increase after stimulation with human chorionic gonadotrophin. In the presence of a normal penis and scotum, such findings, together with a high basal FSH and an increased response of plasma LH to LHRH, make surgical exploration unnecessary. In the rare patient who shows a positive but subnormal response of testosterone to HCG, Leydig cells are presumed to be present either ectopically or in rudimentary testes, and further surgical exploration is indicated.
In a girl with latent diabetes mellitus, glucose tolerance and insulin release were regularly examined from 6 to 12 years of age. Under diet height and weight increased normally, the glucose intolerance disappeared, and the hypoinsulinism turned into hyperinsulinism with reactive hypoglycemia. This observation demonstrates that in a longitudinal study, the same patient may present in one period with glucose intolerance (latent diabetes) and insulin deficiency and in another period with normal glucose tolerance (prediabetes) and insulin excess.
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In two adult patients with congenital poikiloderma (Rothmund-Thomson syndrome) the following endocrine abnormalities were found: Patient 1, female, with short stature had primary amenorrhoea and did not develop secondary sexual characteristics. Despite lacking an oestrogen effect on the vaginal smear and the low urinary oestrogen excretion, basal LH and FSH and their response to LH-RH were normal. At age 36 a parathyroid adenoma was diagnosed because of increased immunoreactive plasma parathyroid hormone and persistent hypercalcaemia. After removal of the tumour the patient remained normocalcaemic. The result of growth hormone response to insulin in the intermediate range was suggestive of partial deficiency. In patient 2, male, hypergonadotrophic hypogonadism with small testes and high basal LH and FSH levels as well as increased LH and FSH response to LH-RH were found. Plasma testosterone was normal. Endocrine abnormalities in previously published cases are summarized.
The effect of synthetic alpha-MSH injected intravenously in a uniform dose of 3 mg was studied in 19 prepubertal children. A marked growth hormone (GH) response was seen only in 2 out of 8 constitutionally small children with a normal GH response to insulin and arginine stimulation. Three of of 11 children suffering from hypopituitarism with documented GH and other hormone deficiencies, unexpectedly, showed a significant rise of GH after alpha-MSH: all three had craniopharyngiomas. Alpha-MSH led to an increase of plasma cortisol in all except 3 patients who had secondary adrenal insuffciency. The increase of cortisol after alpha-MSH and after insulin was of the same extent: but the hypoglycemia and stress responsible for the insulin effect were not observed after alpha-MSH. It is possible that alpha-MSH acts by an ACTH-like direct stimulation on the adrenals. There was no effect of alpha-MSH on plasma TSH or on blood glucose.
Basal TSH levels were found to be elevated in 6 patients with documented growth hormone deficiency and hypothyroidism. TRH (200 mug/m2 administered intravenously) led to an exaggerated TSH response. This is in contrast to the results in other GH-deficient children, with either a delayed rise of TSH (hypothalamic hypothyroidism due to TRH deficiency, n = 22), an absent TSH response (pituitary hypothyroidism due to TSH deficiency, n = 7), or a normal increase of TSH (isolated GH deficiency, n = 20). Elevated plasma TSH in the presence of hypothyroidism as seen in 6 of our patients with idiopathic hypopituitarism or craniopharyngioma, indicates an intact feedback action between the pituitary and the thyroid gland. TSH, however, seems to be inadequate for the maintenance of normal thyroid function. It is suggested that in certain patients with hypothalamic disorders, TSH is secreted in a biologically less active form.
Stimulation with LH-RH (luteinizing hormone-releasing hormone) was performed in 29 children and adolescents with Turner's syndrome (15 less than 13 years old), and in 11 patients with Klinefelter's syndrome (7 before puberty). Synthetic LH-RH was injected intravenously in a dose of 25 mug/m2; plasma LH and FSH were determined radioimmunologically. The results show that patients with Turner's syndrome had pathologically elevated LH and FSH values at all ages. Normal LH and FSH results before and after LH-RH were found in 3 patients with X0/XX karyotype who had spontaneous menstruation. The 2 adult patients with Klinefelter's syndrome showed an exaggerated LH response and excessively high FSH levels before and after LH-RH, consistent with hypergonadotropic hypogonadism. Six out of 7 prepubertal boys with Klinefelter's syndrome, had a normal LH and FSH response to LH-RH. Only 1 prepubertal boy with cryptorchidism and genital maliformation in addition to the Klinefelter's syndrome had pathological values. The normal gonadotropin results in prepubertal patients with Klinefelter's syndrome show that their testes apparently loose the negative feedback activity on gonadotropin secretion only during puberty, at a time when tubular hyalinization appears. This is in contrast to Turner patients with gonadal dysgenesis who have hypergondadotropic hypogonadism already early in childhood.
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