Value of the ultrasensitive assay of plasma TSH for the surveillance of replacement treatment in children with congenital hypothyroidism

This study proposes some improvements in monitoring congenital hypothyroidism (CH) using an ultrasensitive plasma TSH assay (usTSH). Patients were 42 CH treated with levo-thyroxine (L-T4) for at least 6 months. Controls were 25 age-matched children (C). Comparative determinations of plasma TSH with classical radioimmunoassay (RIA), on one hand, and usTSH on the other hand, revealed RIA values to be beneath the sensitivity threshold in 3 C and in 15 CH. With usTSH, all the TSH values were assayed over the sensitivity threshold. Therefore the CH could be placed into 3 subgroups according to whether their values were below (n = 17), equal to (n = 15) or above (n = 10) those determined for C. Mean plasma levels of thyroxine (T4) or free thyroxine (FT4) were higher in the CH group, considered as a whole, than in C (p less than .01). Furthermore these values did not appear to be correlated with those in the TSH subgroups, anymore than they were with those of therapeutic doses of L-T4 administered. These discrepancies may be explained in terms of metabolism of exogenous thyroid hormones. UsTSH plasma values would therefore reflect the action of thyroid hormones on thyreotropic cells. To this extent the assay constitutes a sensitive index in detecting both therapeutic insufficiencies and overtreatments.     

Bone mineral density and metabolism in children treated with L-thyroxine.

It has been suggested that long term treatment with L-thyroxine could reduced bone mineral density (BMD). The purpose of this study was to determine whether BMD is decreased by L-thyroxine treatment in children. Dual energy X-ray absorptiometry (DEXA) was used to assess lumbar spine (L2-4) and femur neck BMD in 40 children aged 9-15 years, taking L-thyroxine (100 micrograms/m2/day) for a mean period of 1.45 +/- 0.60 years for colloid diffuse goiter. Patients were matched with controls for age, sex, weight, height and pubertal stage. BMD at both the femur neck and lumbar spine was not significantly different from that of the control group. No correlation was found between BMD values and TSH levels which is the index of tissue hyperthyroidism. BMD was also not correlated with duration of the therapy. Osteocalcin, alkaline phosphatase, calcitonin and parathormone levels were measured to asses bone turnover; none of them were significantly different from those of controls and they did not change during follow up. In conclusion we suggest that long-term L-thyroxine therapy in children has no adverse effect on BMD.     

Screening for congenital hypothyroidism with an immunoradiometric assay (IRMA) for thyroid stimulating hormone

A commercial immunoradiometric assay (IRMA) for thyroid stimulating hormone (TSH) was modified to be used with dried blood on filter paper of our neonatal screening programme. Sensitivity and precision were as good as with the conventional radioimmunoassay (RIA), but the IRMA was faster. In addition the IRMA was extremely cheap, because all kit reagents could be prediluted 1:4. Our screening procedure for congenital hypothyroidism now combines a determination of TSH with the IRMA technic and a determination of free thyroxin (FT4) by radioimmunoassay. The kit for FT4 can be diluted 1:3, as described earlier. The combination of TSH-IRMA und FT4-RIA to our knowledge is not only much faster but also considerably cheaper than measuring one parameter with consecutive retesting of suspicious samples, which is the procedure in some countries. As the combination gives two independent results it is also of greater clinical value than measuring TSH in dublicates, which is still officially recommended in the Federal Republic of Germany.     

Quantitative computed tomography measurements of bone mineral density in prepubertal children with congenital hypothyroidism treated with L-thyroxine

Low bone density (BD) has been reported in patients with hyperthyroidism. Whether or not levothyroxine (LT4) therapy in children with congenital hypothyroidism (CH) affects BD is unclear. Medical records of 45 patients with various etiologies of CH who had at least one BD measurement (32 female, mean age 7.6 +/- 2.6 years) were reviewed. The mean LT4 dose was 3.6 +/- 0.88 microg/kg/day. Cancellous bone density (CaBD) was measured by quantitative computed tomography (CT) in all 45 patients and 20 had measurements of cortical bone density (CoBD), cross-sectional area (CSA) and cortical bone area (CBA) of the femur. TSH levels were considered partially or completely suppressed when values were <1.0 or <0.5 microIU/ml, respectively. The control group consisted of age- and gender-matched healthy children. No significant differences were found in CaBD, CoBD, CSA, or CBA between patients with CH and controls. There were no significant differences between initial and subsequent BD measurements. No correlations were found between CaBD and etiology of CH, dose or duration of LT4 therapy, or serum TSH. In pre-pubertal children with CH, LT4 appears to have no significant effect on BD. Moreover, absence or hypoplasia of the thyroid parenchyma appears to have no significant impact on bone formation within the first 10 years of life.     

The effects of intranasally sprayed synthetic TRH on TSH and on PRL secretion in children

The effects of intranasally applied TRH on serum TSH and PRL were investigated in ten healthy, prepubertal children. Serum levels of T4, T3, TSH, and PRL were all in the normal range. Synthetic TRH, 500 micrograms, in water was insufflated in one nostril. Intranasal TRH induced a prompt rise of TSH and PRL in all children with peak values at 30 min. TSH: 10.29 +/- 1.24 microU/ml; PRL: 25.12 +/- 3.53 ng/ml (mean +/- SEM). TSH values were still significant raised 120 min after the insufflation (P less than 0.025) whereas the PRL values did not differ significantly. A dose-dependent TSH release following intranasal sprayed TRH was shown. delta TSH and TSH values at 120 min were significantly higher in children receiving greater than 10 micrograms/kg TRH than in children receiving less than 10 micrograms/kg (P less than 0.025; P less than 0.05). Dose dependent differences in PRL release following intranasal TRH were not shown. Any side effects of intranasally applied TRH were not observed. Intranasal insufflation of synthetic TRH seems to be a valuable and harmless tool for the evaluation of pituitary TSH and PRL secretory reserve.     

Early and late neutropenia in children treated with cotrimoxazole (trimethoprim-sulfamethoxazole)

The incidence of hematologic abnormalities was evaluated in 120 children with otitis media treated respectively with cotrimoxazole (trimethoprim-sulfamethoxazole) (group 1), cotrimoxazole plus folinic acid (group 2) and amoxicillin (group 3) in therapeutic doses for ten days. Only eosinophilia (an absolute count greater than or equal to 0.5 X 10(9)/l) (group 1 = 10%, 2 = 5%, 3 = 7.5%) and neutropenia (polymorphonuclear neutrophilic leucocyte count less than or equal to 1.5 X 10(9)/l) (group 1 = 35%, 2 = 17.5%, 3 = 13.3%) were noted. Early neutropenia (evident on the 5th day of therapy) occurred in all the treatment groups, thus it is not related to cotrimoxazole administration and in most cases neutrophil count reversed to normal in few days without drug discontinuation. Late neutropenia (evident after 10 days of treatment) appeared only in cotrimoxazole treated children (p less than 0.05). No superimposed bacterial infection was demonstrated in any case. Late neutropenia seems to be strictly related to the sequential blockage of folinic acid metabolism and can be prevented by the concomitant administration of folinic acid.     

Learning difficulties in children treated for acute lymphoblastic leukaemia (ALL)

Concern about the adverse affects of brain irradiation used in treatment for childhood leukaemia on children's learning have been put forward since the 1960s. Early work based on assessment of IQ suggested considerable problems associated with CNS irradiation of 2400cGy, and that children who were younger on diagnosis (below 5 years) were particularly at risk. Consequently, new protocols were introduced in which the amount of irradiation was reduced, or children were treated by chemotherapy alone. There is some evidence that reduction from 2400 to 1800cGy irradiation is beneficial, especially for younger children, as is treatment by chemotherapy alone. Methodological problems in conducting this work and limitations in relying on IQ tests are discussed. Where there are no indications of differences in survival, there would seem to be implications for reducing as far as possible the use of CNS directed therapy among young children treated for leukaemia.     

Growth hormone secretion and long-term growth data in children with psychosocial short stature treated by different changes in environment

OBJECTIVES: We assessed auxological and endocrine data of 65 children (32 girls) from 51 families with an average age of 6.6 years (range, 0.9 to 16.5 years, all but five prepubertal) with psychosocial short stature. METHODS: Fifty-one patients had an assessment of growth hormone (GH) secretion. Thirty-four were subjected to repeated testing with the first test being performed when the child was still in the adverse environment and the next testing after the child was removed. Twenty-five out of those 34 were repeatedly tested during one uninterrupted hospital admission with limited parental access. Thirty patients had a definite, long-term change in their environment (13 were separated from their families) and were assessed concerning their auxological data. RESULTS: Of the 34 patients who had repeated endocrine testing, 11 (32%) showed reversible GH deficiency (GHD), nine (26%) increased their previously normal peak GH concentration, and six (18%) had apparently irreversible GHD. Patients who had a change in environment increased their mean height velocity SDS from -0.9 (SD 1.5) to +1.5 (2.3) (p < 0.0001). Accordingly, height SDS increased from -2.9 (SD 0.8) before to -2.6 (SD 0.8) after the change (p < 0.001). CONCLUSION: One of the diagnostic features of psychosocial short stature is reversible GH insufficiency, which usually normalises after the child is separated from the adverse environment. Catch-up growth is always found after a positive change in the environment, and may occur within the family. However, if a change in environment is not possible, GH therapy may be an option.     

Pulsatile secretion of LH and FSH in prepubertal and early pubertal boys revealed by ultrasensitive time-resolved immunofluorometric assays

Pulsatile secretion of LH and FSH was examined in 10 prepubertal (aged 4.5-12.9 y) and seven early pubertal (aged 12.8-14.5 y) boys with ultrasensitive (0.019 and 0.014 IU/L) time-resolved immunofluorometric assays. Plasma LH and FSH levels were measured every 15 or 20 min for 6 h during the day and night. The lowest mean LH level in a prepubertal boy was 0.02 IU/L and in eight other prepubertal boys mean LH levels were less than 0.4 IU/L. In early pubertal boys the mean LH levels ranged from 0.3 to 6.5 IU/L. The difference in mean FSH level between prepubertal (0.61 IU/L) and early pubertal boys (1.85 IU/L) was smaller than the difference in LH level. All boys had significant LH and FSH pulses. The LH interpulse interval was 135 +/- 86 min (mean +/- SD) and 76 +/- 65 min for the prepubertal and pubertal boys, respectively (p less than 0.01). For FSH, the respective values were 150 +/- 122 and 221 +/- 157 min (p = NS). The mean LH pulse amplitudes were 11-fold greater in the early pubertal boys than in the prepubertal boys, whereas the mean FSH pulse amplitudes were similar between the two groups. The present method shows that the mean LH levels in prepubertal boys are much lower, and the increase during puberty larger, than previously reported. The increase is apparently due to increased pulse frequency and amplitude. The increase in mean FSH level is smaller and evidently not caused by an increase in pulse frequency or pulse amplitude.     

Height,weight, and growth hormone secretion in children treated for acute leukemia

Growth, weight gain, and human growth hormone secretion were studied for 3 to 7 years in 27 children with acute leukemia in complete continuous remission. Growth and weight gain were matched for sex and age by calculating the standard deviation score. The mean SD score for height velocity was subnormal during the three years of therapy. A catch up in growth and weight gain occurred during the first year after the cessation of therapy. The loss of final attained height was small. HGH secretion was studied at the end of therapy and at yearly intervals thereafter by two provocative tests; glucagon and sleep. No significant difference in secretion was seen between the group studied and a control group of children. Acute leukemia, children, growth, growth hormone, irradiation, weight gain.     

Estradiol levels in girls with Turner's syndrome compared to normal prepubertal girls as determined by an ultrasensitive assay

Based on growing evidence that estradiol is produced in small amounts even in the prepubertal ovary, we hypothesized that estradiol levels in girls with Turner's syndrome (TS) are lower than in normal prepubertal girls secondary to the lack of normally functioning ovaries. Estradiol levels in untreated girls with TS have not been previously well defined because of the lack of adequate sensitivity of previously available estradiol assays. We utilized an ultrasensitive assay to study estradiol levels in 34 girls with TS and 34 normal age-matched prepubertal girls between the ages of 5 and 12 years. The average estradiol level in the girls with TS (6.4 +/- 4.9 pmol/l estradiol equivalents) was significantly lower than in the normal prepubertal girls (12.7 +/- 10.8 pmol/l estradiol equivalents; p < 0.01). Girls with TS were significantly shorter, and weighed less than the normal prepubertal girls, as expected. The estradiol level was not significantly correlated with height, bone age, or degree of bone age delay. In conclusion, girls with TS have significantly lower estradiol levels than normal age-matched prepubertal girls. This report is consistent with the hypothesis that the lack of normal ovarian function in girls with TS is evident even before puberty.     

Cerebral concussion in children: assessment of injury by electroencephalography

An examination was made of 967 initial and follow-up electroencephalograms of 371 children with clinically diagnosed cerebral concussion to determine whether the EEG could provide an objective measure of injury. For each patient, the degree and distribution of EEG abnormalities, as well as their rate of resolution, were correlated with the severity of clinically assessed injury. A close relationship was found between the severity of both initial and longitudinal EEG disturbances and the clinically suspected grade of concussion. Serial EEGs of individual patients showed a similar relationship between time elapsed since injury and degree of abnormality. The rate at which the sequence of EEG resolution took place varied in direct relation to the severity of concussion. It was concluded that the initial EEG and the rate and degree of resolution of EEG abnormalities, together with the time elapsed since injury, can provide objective and reliable information to the clinician for the establishment of the diagnosis and assessment of severity of cerebral concussion in children.     

Analysis of failures of screening for congenital hypothyroidism by the assay of TSH in capillary blood

Screening for congenital hypothyroidism was started in France in 1979. The system was rapidly extended to the whole country and works very efficiently. The number of children who escaped the system is very small. However, these children represent a severe failure of the system. From 1980 to 1983, 32 cases escaped the screening. Retrospective analysis of these cases should help in improving the present system.     

Evaluation of sodium L-thyroxine (T4) requirement in replacement therapy of hypothyroidism

Sodium-L-thyroxine (T4) was utilized in the treatment of 15 pediatric patients with hypothyroidism. Adequacy of replacement therapy was confirmed by clinical evaluation in conjunction with determination of serum thyroxine, tri-odothyronine, and thyrotropin concentrations. Daily dose of thyroxine capable of including clinical and biochemical euthyroidism ranged from 2.5 to 5 mug/kg of body weight with a mean of 3.5 +/- 0.3 mug in the 4- to 17-year-old age group. Two infants with congenital hypothyroidism diagnosese observations imply that physiologic requirements of thyroxine are distinctly lower than previously recommended dosages. Further studies to establish more precise therapeutic guidelines are needed.     

Physiological assessment of growth hormone secretion in the diagnosis of children with short stature

Many advances characterize the research into the diagnosis of short stature in children. Increasing evidence shows a continuous spectrum of growth hormone (GH) output among GH-deficient patients and short normal children. Although biosynthetic human GH could theoretically offer the chance of treating most slowly growing children, it is not certain that all short normal children with a poor height velocity could benefit from therapy. Indeed, besides auxological findings, the assessment of GH secretion remains essential in selecting candidates for therapy. In this respect the evaluation of GH secretion by means of tests that can explore the physiological pathways involved in the hormone output appears important. Moreover some clinical evidence suggests that pharmacological stimuli cause the pituitary release of stored GH perhaps unavailable in physiological conditions. Among the classical physiological tests, the exercise test, the standardization of which has been debated, is commonly used in clinical practice. The sleep test, i.e. the evaluation of sleep-associated GH secretion, is the most important. It has no side effects and does not require the administration of exogenous stimuli. Several studies have demonstrated its reliability in diagnosing growth disorders in childhood, mainly if performed with EEG monitoring. Among the new physiological diagnostic approaches the most reliable test is the evaluation of 24-hour GH secretion. Knowledge of the integrated hormone concentrations appears particularly important in studying children who may have more subtle disturbances in GH secretion. These cases show normal GH response to provocative stimuli but show a reduced hormone output over 24 h. Indeed they respond well to human GH treatment.