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ML Hartoft-Nielsen, AK Rasmussen, A Kaas, U Feldt-Rasmussen, and K Buschard

OBJECTIVE: Changes in the functional state of beta cells by neonatal stimulation or adolescent suppression have reduced the incidence of type 1 diabetes mellitus in animal models. The aim of this study was to evaluate the effect of manipulation of the activity of the thyroid gland by neonatal stimulation or by adolescent suppression on the prevalence of spontaneous autoimmune thyroiditis (AIT) in rats. METHODS: Bio-Breeding/Worcester (BB) rats were treated neonatally with sodium iodine (NaI) or thyroid stimulating hormone (TSH), or during adolescence by triiodothyronine (T(3)), and the lymphocytic infiltration in the thyroid gland was evaluated. RESULTS: Neonatal treatment with NaI decreased the prevalence of AIT to 32+/-9% compared with 66+/-5% in the controls (P<0.002), mainly caused by a reduction among the female rats (13+/-9% vs 52+/-8%, P<0.006). TSH had no effect. Post neonatal suppression of the thyroid gland by T(3) had a biphasic response. Early in adolescence the overall prevalence was 14+/-7% compared with 66+/-5% in the controls (P<10(-5)); for female rats AIT was prevented (0+/-0%) compared with 52+/-8% in the controls (P<0.0003) and in male rats the values were 29+/-13% compared with 80+/-6% in the controls (P<0.001). Treatment with T(3) later in adolescence increased the overall prevalence to 81+/-7% compared with 66+/-5% in the controls (not significant). For female rats the prevalence increased to 78+/-9% compared with 52+/-8% in the controls (P=0.04). The degree of thyroiditis among the affected animals was similar in all groups. CONCLUSION: Neonatal stimulation of the thyroid gland by iodine or early adolescent suppression by T(3) reduced the prevalence of AIT whereas T(3) given later increased the prevalence of thyroiditis in rats. Thyroid activity at various ages seems to be of importance for the development of autoimmune thyroiditis.

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H Schmidt and HP Schwarz

OBJECTIVE: A sex difference in fetal and neonatal pituitary-gonadal function has been well documented. The aim of the following study was to determine sex differences and patterns of basal LH/FSH in the neonatal period. DESIGN: Peripheral venous blood was obtained from 164 healthy full term newborns (91 males, 73 females) for clinically indicated laboratory examinations. RESULTS: In male newborns, LH values were initially low (days 1-5), increased between days 6 and 10, and reached maximum levels between days 16 and 20. Levels of FSH were initially low (days 1-5), increased between days 6 and 10 and reached maximum levels between days 11 and 15. In female newborns, LH levels were generally lower than in newborn boys; levels were initially low, then increased between days 11 and 15 and reached maximum levels at the end of the newborn period. FSH values were generally higher than in newborn boys; there were initially low values with a first peak between days 11 and 15 and a second peak between days 21 and 28. CONCLUSIONS: LH values in male newborns were higher and exceeded values in female newborns, whereas FSH values in female newborns exceeded male newborn values. Male newborns do not exhibit any peaks of LH and FSH activity, whereas female newborns exhibit two FSH peaks during this period.

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J Pohlenz, W Ahrens, and O Hiort

OBJECTIVE: To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with l-thyroxine. CASE REPORT: A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and shortened 1st, 4th and 5th metacarpals were found. METHODS AND RESULTS: Further investigation confirmed AHO with pseudohypoparathyroidism (PHP) type Ia. The boy had a mild resistance to parathyroid hormone and a reduced adenylyl cyclase stimulating protein (Gsalpha) activity in erythrocytes. DNA analysis detected a new heterozygous mutation (L338N) in the Gsalpha protein (GNAS1) gene. This mutation was also present in the patient's brother who had similar features and was also treated with thyroid hormone because of CH, and in the phenotypically normal-looking mother who had a normal calcium metabolism but a reduced Gsalpha protein activity in erythrocytes suggestive of pseudopseudohypoparathyroidism. CONCLUSION: In patients with CH, in whom the neurological outcome is poor even under adequate thyroid hormone substitution, PHP Ia may be suspected, especially when symptoms of AHO are present.

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Klemens Raile, Michele O'Connell, Angela Galler, George Werther, Peter Kühnen, Heiko Krude, and Oliver Blankenstein

Background

Mutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene.

Methods

Location and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion.

Results

The 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5–16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22).

Conclusion

Complete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age.

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M Peter, K Bunger, SL Drop, and WG Sippell

We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2). presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

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Z. Laron, M. Karp, M. Nitzan, and A. Pertzelan

ABSTRACT

The insulin tolerance test (ITT) was performed in 102 children and adolescents belonging to the following 6 groups: controls (56 subjects), pituitary insufficiency (17 patients), delayed puberty (13 patients), obesity (6 patients), idiopathic precocious sexual development (6 patients) and congenital adrenal virilization (4 patients). All subjects showed hypoglycaemia. The mean percentage of maximal reduction in the blood sugar from the fasting concentration varied from 41 to 50 in all the groups. The control subjects and the patients with delayed puberty, obesity, precocious sexual development and congenital adrenal virilization showed an increase in plasma 11-hydroxycorticosteroids (11-OHCS) to a mean peak value ranging between 20 and 25 μg/100 ml, measured 60 min after the injection of insulin. From these results it was concluded that a rise in plasma 11-OHCS to a value of 20 μg/100 ml or more after hypoglycaemic stress denotes a normal corticotrophin releasing factor (CRF) and corticotrophin (ACTH) reserve. The patients with pituitary insufficiency showed 3 types of response independent of the degree of hypoglycaemia: nine patients showed a normal response, four had a medium response and four showed no response. There was a good correlation between lack of response of plasma 11-OHCS induced by hypoglycaemia and the urinary 17-OHCS response during the metopiron test, indicating that both these tests act at the hypothalamic level. Although the rise in plasma 11-OHCS after ITT was less marked than after the lysine vasopressin (LVP) test, it is suggested that the ITT is to be preferred as a clinical screening test, as it permits concomitant evaluation of both ACTH and growth hormone reserve. Another advantage of performing the ITT before the LVP test is that it allows of the diagnosis of a hypothalamic disturbance in ACTH secretion.

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M. S. Laurent de Angulo and H. H. van Gelderen

ABSTRACT

An attempt has been made to determine the value of the lysine-8-vasopressin test when used together with the insulin-induced hypoglycaemia and the metyrapone test for the differentiation between hypothalamic and pituitary secondary adrenocortical insufficiency. This study was carried out in 65 children and adolescents with various disorders associated with growth retardation or overweight. The criteria for normal responses to the tests were based on findings in a 'control' group consisting of children with short stature without endocrinological disease. These criteria have been discussed in detail.

In the control group, the concordance between the results of each of the tests was good. As far as the groups with proven or possible hypothalamic and/or pituitary disorders were concerned, discrepancies between the LVP test results and those of the ITT were found in a considerably higher proportion of cases. The combination of an abnormal ITT and a normal LVP test was encountered significantly more often than the reverse situation. This is in agreement with the hypothesis that LVP acts directly on the adenohypophysis while ITT acts at the hypothalamic or higher levels. The LVP test seems to be a valuable additionto the tests of hypothalamic-hypophyseal function.

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Paul Starr and John Nicoloff

ABSTRACT

Measurement of PBI values in healthy pre-adolescent Negro school children (N = 437) revealed a mean value of 6.4 ±.06 mg/100 ml while in a similar population of Caucasian children (N = 614) a normal mean value of 5.6 ±.07 mg/100 ml was observed. The difference had a P value <.001. Comparison of 131I T3 red cell uptake values in these two groups demonstrated a significant depression (P <.01) in the Negro children. TBG saturation capacities of Caucasian children were 24.7 ± 0.6 (S.E.M.) for ages 6 to 11 years and 21.3 ± 1.1 for ages 12 to 19 years which were not different from the adult values of 22.9 ± 0.8. In Negro children these values were 28.9 ± 0.7 for ages 6 to 11 and 25.4 ± 1.9 for ages 12 to 19 which were significantly different from their Caucasian counterparts. Adult Negro PBI values of 5.6 ± 0.25 and TBG of 24.5 ± 1.5 were not different from adult Caucasian values. Thyroxine-binding pre-albumin (TBPA) saturation capacities were significantly depressed in pre-adolescents (Caucasian 71 ± 7; Negro 69 ± 4) and adolescents (Caucasian 105 ± 13; Negro 109 ± 19) below the normal adult values but no racial difference was displayed. It is now apparent that racial origin must be a consideration in the evaluation of pre-adolescent and adolescent PBI and 131I T3 red cell uptake results and that TBPA and TBG capacities may normally alter during puberty in a manner independent of each other rather than reciprocally as has been recently proposed.

Free access

Paul Lips, Kevin D Cashman, Christel Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara Obermayer-Pietsch, Maria Luisa Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan, and Roger Bouillon

Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) <50 nmol/L or 20 ng/mL) is common in Europe and the Middle East. It occurs in <20% of the population in Northern Europe, in 30–60% in Western, Southern and Eastern Europe and up to 80% in Middle East countries. Severe deficiency (serum 25(OH)D <30 nmol/L or 12 ng/mL) is found in >10% of Europeans. The European Calcified Tissue Society (ECTS) advises that the measurement of serum 25(OH)D be standardized, for example, by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people (especially the institutionalized) and non-Western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-Western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long-term non-skeletal outcomes such as cancer.

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Mikael Knip, Päivi Tapanainen, Fredrika Pekonen, and Werner F Blum

Knip M, Tapanainen P, Pekonen F, Blum WF. Insulin-like growth factor binding proteins in prepubertal children with insulin-dependent diabetes mellitus. Eur J Endocrinol 1995:133:440–4. ISSN 0804–4643

To study the possible role of insulin-like growth factor binding proteins (IGFBPs) in the discrepancy between normal or only slightly retarded growth and substantially reduced concentrations of insulin-like growth factor I (IGF-I) in prepubertal children with insulin-dependent diabetes mellitus (IDDM), we measured the plasma concentrations of IGF-I, IGFBP-1, IGFBP-2 and IGFBP-3 and free insulin in 24 prepubertal diabetic subjects and 12 control children. In addition, the growth hormone response to exercise was evaluated. The diabetic children had significantly decreased peripheral IGF-I levels (8.2 + 1.1 (sem) vs 16.7 + 2.5 nmol/l; p < 0.001), whereas the concentrations of free insulin were increased (217 + 14 vs 103 + 21 pmol/l; p < 0.001). The concentrations of IGFBP-1 and IGFBP-3 were of the same magnitude in both groups. The diabetic children had significantly increased levels of IGFBP-2 (465 + 13 vs 416 + 14 μg/l; p = 0.029), which were inversely related to the circulating IGF-I levels (r = −0.35; p = 0.034). The diabetic and control children had comparable growth hormone responses to exercise. Diabetic children with poor glucose control had even lower IGF-I levels than those with moderate metabolic control (6.0 + 0.8 vs 10.3 + 1.7 nmol/l; p = 0.037). No differences could be observed in the plasma concentrations of various IGFBPs between these two groups of diabetic subjects. The absence in prepubertal diabetic children of increased IGFBP-1 levels observed in adolescent and adult patients with IDDM may contribute to their maintained linear growth, despite definitely decreased IGF-I concentrations. The role of increased IGFBP-2 levels in prepubertal children with IDDM remains open, but the inverse relationship between IGF-I levels and IGFBP-2 concentrations suggests that IGF-I may be involved in the regulation of IGFBP-2.

Mikael Knip, Department of Pediatrics, University of Oulu, FIN-90220 Oulu, Finland