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.
M Peter, K Bunger, SL Drop, and WG Sippell
Anna Nordenström and Henrik Falhammar
Non-classic congenital adrenal hyperplasia (NCAH) is a relatively common disorder regardless of ethnicity, but most cases are never diagnosed, especially in males. A baseline 17-hydroxyprogesterone measurement may be used for screening, but 17-hydroxyprogesterone measurement after ACTH stimulation is the gold standard. We advocate a CYP21A2 mutation analysis to verify the diagnosis, for genetic counselling and for better prognostic and treatment guidance. Most patients are diagnosed in adolescence and adult life with hirsutism, acne, a PCOS-like picture and fertility issues. Many men with NCAH never seek medical attention and escape diagnosis. Although treatment is somewhat controversial, an early diagnosis and start of treatment may have positive implications on growth and be relevant for preventing and ameliorating the symptoms and consequences of androgen excess that develop over time, including fertility issues. Long-term treatment with glucocorticoids will improve the androgen symptoms but may result in long-term complications, such as obesity, insulin resistance, hypertension, osteoporosis and fractures. The glucocorticoid doses should be kept low. However, complications seen in NCAH, assumed to be caused by the glucocorticoid treatment, may also be associated with long-term androgen exposure. Oral contraceptive pills are a common treatment option for young females with NCAH. Regular clinical monitoring to improve the clinical outcome is recommended. It is important to acknowledge that glucocorticoid treatment will lead to secondary cortisol insufficiency and the need for stress dosing. Studies focusing on the specific difficulties patients with NCAH face, both those with a late clinical diagnosis and those with a neonatal diagnosis obtained by screening, are warranted.
M Salerno, T Lettiero, A Esposito-Del Puente, V Esposito, D Capalbo, A Carpinelli, S Padula, and A Del Puente
OBJECTIVE: To evaluate whether long-term l-thyroxine therapy in young adults with congenital hypothyroidism may affect bone mineral density (BMD). DESIGN: Thirty-seven subjects with congenital hypothyroidism, detected by neonatal screening and longitudinally followed from the time of diagnosis and treatment (26+/-4 days) up to the age of 17.8+/-1.0 years, were studied. METHODS: Spinal (L2-L4) BMD, measured by dual-energy X-ray densitometry, and bone quality, measured as amplitude-dependent speed of sound (Ad-SoS) by quantitative ultrasound, were evaluated. RESULTS: Z-score mean values (+/-s.d.) of BMD (-0.3+/-0.7) and Ad-SoS (-0.7+/-1. 1) were slightly below the average but within the normal range. Ad-SoS resulted in a z-score below -1 in 38% of patients as compared with BMD which resulted in a z-score below -1 in only 13.5% of subject. No significant differences were observed between males (BMD, -0.3+/-0.7; Ad-SoS, -0.9+/-1.0) and females (BMD, -0.3+/-0.7; Ad-SoS, -0.5+/-1.2) or when dividing patients on the basis of aetiological defects; ectopic gland (BMD, -0.3+/-0.6; Ad-SoS, -0.8+/-0.9), athyreosis (BMD, -0.3+/-0.9; Ad-SoS, -0.8+/-1.0) and eutopic gland (BMD, -0.3+/-0.8; Ad-SoS, -0.4+/-1.3). No significant relationships were observed between BMD or Ad-SoS z-score and hormonal status or l-thyroxine dosages at the time of the study or during the pubertal period. CONCLUSIONS: The careful monitoring of serum thyroid-stimulating hormone and adjustment of l-thyroxine dosage avoided the significant deleterious effects of prolonged l-thyroxine replacement therapy on bone tissue in adolescents and young adults with congenital hypothyroidism treated from the neonatal period.
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.
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.
Z. Laron, M. Karp, M. Nitzan, and A. Pertzelan
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.
M. S. Laurent de Angulo and H. H. van Gelderen
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.
Paul Starr and John Nicoloff
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.
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.
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