Andrea Prader Award. Clinical Steroidology. Coming of age.

The determination of steroid concentrations in urine and plasma is an indispensable part of the diagnostic work-up in endocrinology. Since the description of the color reaction for determination of 17-ketosteroids by Zimmermann in 1935, a vast amount of work has been invested in the specialty of clinical chemistry, which we called 'clinical steroidology'. Until the early fifties, color reactions for block determinations of C19 and C21 steroids in urine and plasma were the strongholds of steroid clinical chemistry. Around 1952, paper chromatography, and later on column chromatography were added, which afforded fractionation and individual determinations of steroids in body fluids. The final achievement and almost absolute quantification of almost 50 steroid metabolites ('profile') in urine was achieved by capillary glass column chromatography-mass spectrometry (GC-MS), which came into clinical usage around the mid-eighties. For estimation of plasma steroids radioimmunoassays (RIA) were introduced during the sixties. A whole body of physiology and pathology was erected on the basis of steroid RIAs. Recent investigation, however, revealed that steroid RIAs yield unreliable results at low concentrations due to cross reactions and interferences by impurities of samples. The newly (nineties) developed method of isotope dilution/GC-MS produced highly accurate values of small amounts of steroids and became the gold standard of plasma steroid determinations. Thus 'clinical steroidology' has certainly come of age.

Combined pituitary deficiencies of growth hormone, thyroid stimulating hormone and prolactin due to Pit-1 gene mutation: a case report.

UNLABELLED: A child exhibited postnatal obstipation and icterus together with severe growth failure during the 1st year of life, a small facial skull and a prominent forehead. Endocrine work-up established the diagnosis of combined pituitary deficiencies of growth hormone, TSH and prolactin. Subsequently, the Pit-1 gene was analysed in the patient and both parents. A single point mutation was detected in exon 6 of the child: a C to G transversion on one allele, causing arginine in position 271 to be substituted by tryptophan (R271 W). This position is known as a "hot spot" for mutations. The inheritance is autosomal-dominant, as the mutated gene product interferes with DNA-binding of the wild-type protein. In contrast, other mutations in the PIT-1 gene are inherited in an autosomal-recessive mode. CONCLUSION: Diagnosing Pit-1 gene mutations as a rare cause of combined pituitary deficiency is important both for genetic counselling as well as for predicting the future course in the patient (spontaneous puberty, no glucocorticoid substitution necessary during stress periods).

Insulin resistance with altered secretory kinetics and reduced proinsulin in cystic fibrosis patients.

BACKGROUND: Impaired glucose tolerance and secondary diabetes are frequent in older patients with cystic fibrosis (CF), associated with increased frequency of infections and reduced life expectancy. Studies on the pathophysiology of islet cell secretion in CF are a prerequisite for a scientifically based therapeutic approach. METHODS: Oral glucose tolerance tests were performed in 71 patients (14.2 +/- 0.5 years; mean +/- SE) and 56 control subjects (16.5 +/- 0.9 years). Glucose, insulin, C-peptide, and proinsulin were measured every 30 min. RESULTS: Glucose tolerance in CF patients was classified as normal (NGT, n = 48), impaired (IGT, n = 14), or diabetic (DM, n = 9). Even in CF patients with NGT, blood glucose was significantly elevated at 30, 60, and 90 min of the test. Surprisingly, the secretory responses of insulin and C-peptide were not reduced in CF patients with IGT or DM compared with both healthy controls or CF patients with normal glucose tolerance. However, peak insulin concentration was reached at 90 min in CF-IGT or CF-DM patients compared with 30 min in controls. The ratio of glucose to insulin, an indicator of insulin resistance, increased in CF patients with progression of carbohydrate intolerance. Proinsulin was significantly reduced in all CF patients compared with controls (p < 0.001; Wilcoxon's rank sum test). CONCLUSIONS: In CF patients with impaired glucose tolerance or diabetes, integrated insulin release is not diminished, indicating that insulin resistance is likely to contribute to hyperglycemia in CF patients with IGT or DM. Reduced proinsulin levels in CF patients are compatible either with enhanced conversion of proinsulin to insulin in compensation for reduced beta-cell mass, or enhanced clearance of proinsulin.

[Body composition in type 1 diabetes mellitus. Bio-impedance measurements in 274 diabetic children, adolescents and young adults]. / Körperzusammensetzung bei Typ-I-Diabetes mellitus. Bioimpedanzmessungen bei 274 diabetischen Kindern, Jugendlichen und jungen Erwachsenen.

BACKGROUND AND OBJECTIVE: Weight gain is a common undesirable side effect of insulin treatment in type 1 diabetics. This study tested the assumption that this is due to an increase in fat mass. PATIENTS AND METHOD: Bioelectric impedance measurements were performed on 157 young male and 117 female diabetics (age 17.6 +/- 4.9 years; diabetes duration 8.9 +/- 5.7 years) and the fat-free mass (FFM) calculated according to the equation of Schfer et al. The data of the diabetics were compared with those of healthy controls and normal values published by Barlett et al. RESULTS: The average weight of the diabetic cohort was 2.0 +/- 0.7 kg higher than in the reference groups, adjusted for sex and age. FFM was higher by 2.9 +/- 0.7 kg in diabetics than in the healthy cohort of Barlett et al (P < 0.005), being equally high in males and females (+2.9 +/- 0.7 kg and 2.9 +/- 0.6 kg, respectively). But compared with the values in metabolically normal controls the percentage fat proportion was lower in the diabetics than the controls, but not significantly (-1.3 +/- 0.6%). Weight gain was greater in females than males (+3.8 +/- 0.9 kg vs +1.2 +/- 0.9 kg, P < 0.05). After correcting for age, there was a partial correlation between good metabolic control and FFM in males. The form of treatment had no effect on body composition. CONCLUSION: These data indicate that weight gain in young diabetics is due not to an increase in fatty tissue but in muscle mass. This is probably the result of peripheral hyperinsulinism combined with hyperglycaemia.

[Diagnosis of the adrenogenital syndrome caused by 11beta-hydroxylase deficiency using gas chromatographic-mass spectrometric analysis of the urinary steroid profile]. / Diagnostik des adrenogenitalen Syndroms vom Typ des 11beta-Hydroxylase-Mangels mit der gaschromatographisch-massenspektrometrischen Harnsteroidrofilanalyse.

PROBLEM AND OBJECTIVE: In 5-7% of all cases of congenital adrenogenital hyperplasia (AGH) there is 11 beta-hydroxylase deficiency (11 beta-HM). Its clinical picture is characterised by hyperandrogenism and, in some cases, arterial hypertension. The diagnosis of the enzyme deficiency depends on a reliable method of analysing the hormone in plasma and urine. As little is known and data often contradictory about the pattern of urinary steroid excretion in 11 beta-HM, these steroid metabolites were measured by a highly specific method. PATIENT AND METHOD: The pattern of urinary excretion of steroids was determined by gas chromatography and mass spectrometry (GC/MS) in 16 children and adults (11 males, 5 females: mean age 9(8)/12 [2/12-20(3)/12] years) with 11 beta-HM. RESULTS: In all patients there was greatly increased excretion of tetrahydrated (TH) and hexahydrated (HH) metabolites of 11-desoxycortisol (S) and desoxycorticosterone (DOC). The excretion of THS and THDOC was extremely increased in all patients. The metabolites 5 alpha-THS as well as 20 alpha- and 20 beta-isomers of HHS, not normal found in healthy persons, were present in 15 patients (94%), while the 20 alpha- and 20 beta-isomers of 5 alpha-HHS were demonstrated in 14 (88%). For the first time, 20 alpha- and 20 beta-isomers of 5 alpha-HHS were shown to be typical urinary steroid metabolites in 11-HM. The excretion of cortisol metabolites is typically decreased in 11 beta-HM. No corticosterone metabolites were found. CONCLUSION: The urinary steroid excretion pattern, measured by GC/MS, is a noninvasive, highly specific and nonselective method in the differential diagnosis of abnormal steroid metabolism.

[Gas chromatography-mass spectrometry determination of plasma 5 alpha-androstane-3 alpha,17 beta-diol and 5 alpha-androstane-3 alpha,17 beta-diol glucuronide in children with premature and normal puberty ]. / Gaschromatographisch-Massenspektrometrische Bestimmung von 5 alpha-Androstan-3 alpha,17 beta-diol und 5 alpha-Androstan-3 alpha, 17 beta-diol-glucuronid im Plasma von Kindern mit prämaturer und normaler Pubarche.

Using stable isotope dilution/gas chromatography-mass spectrometry, we determined the plasma concentrations of 5 alpha-androstane-3 alpha,17 beta-diol (AD) and 5 alpha-androstane-3 alpha,17 beta-diol-glucuronide (ADG) in 20 patients with premature pubarche (16 patients with idiopathic premature pubarche, 4 patients with late onset 21-hydroxylase deficiency) and in 55 healthy children with Tanner stages P1 to P4. No differences between sexes were found in healthy children with Tanner stages P1 and P2. Patients with idiopathic premature pubarche (median, range, nmol/1: 0.22; 0.12-0.31) or late onset 21-hydroxylase deficiency (0.27; 0.23-0.29) had higher plasma AD concentrations than healthy prepubertal children (0.09; 0.00-0.17). Regarding ADG, patients with idiopathic precocious puberty (1.35; 0.25-4.74) or late onset 21-hydroxylase deficiency (4.01; 3.50-4.58) had also higher plasma concentrations than healthy prepubertal children (0.35; 0.00-0.75). Thus, AD and ADG, which both represent end metabolites of peripheral androgen metabolism, can be regarded as markers of androgenicity. Steroid analysis by mass spectrometry is recommended, whenever uncertainties of immunological determinations are to be avoided.

Mitogenic and antiadipogenic properties of human growth hormone in differentiating human adipocyte precursor cells in primary culture.

Children with GH deficiency have enlarged fat cells but a reduced number of fat cells compared with healthy children. After treatment with human GH (hGH) both fat cell volume and number are shifted toward normal. To clarify the role of hGH in fat cell formation in human adipose tissue, we investigated the effect of hGH on the proliferation and the differentiation of cultured human adipocyte precursor cells obtained from five children and 10 adults. In a chemically defined serum-free medium treatment of adipocyte precursor cells with hGH led to an increase in IGF-I production and a stimulation of cell proliferation, which could be blocked by a MAb raised against human IGF-I. hGH dose-dependently reduced the number of differentiating cells and suppressed the expression of glycerol-3-phosphate dehydrogenase (GPDH), a marker of adipose differentiation. No significant differences in the hGH effects on proliferation and differentiation capacities were seen between cultures obtained from children and adults. In newly differentiated adipocytes, hGH inhibited glucose uptake and lipogenesis, and stimulated lipolysis. Scatchard analysis of hGH competition experiments using 125I-labeled hGH yielded a linear plot with an apparent Kd of 1.08 nM and an estimated number of 7000 hGH receptors per cell. These data suggest that hGH is able to enlarge the human adipocyte precursor pool via induction of IGF-I synthesis but exhibits a direct antiadipogenic activity. hGH is also able to reduce fat cell volume by reducing lipogenesis and increasing lipolysis.

Semilente-insulin at bedtime is superior to NPH-insulin for the suppression of the dawn-phenomenon in adolescents with type-I-diabetes.

The dawn-phenomenon causes high fasting glucose values in IDDM patients during puberty. Even a bedtime injection of intermediate-acting insulin does not reliably suppress glucose rises during the morning hours. We therefore examined whether Semilente, an amorphous zinc insulin with kinetics different from NPH insulin, is better suited to alleviate the dawn-phenomenon in adolescent patients with long-standing diabetes. This prospective study included 15 adolescent patients (age 15.5 +/- 0.4 years; mean +/- SE) well beyond the remission phase of diabetes (mean duration: 7.5 +/- 0.8 years). On an inpatient basis, blood glucose profiles following bedtime injections of NPH or semilente insulin were compared, using a sequential cross-over design for intra-patient comparison. Fasting blood glucose was significantly lower following bedtime injections of Semilente (183 +/- 21 mg/dL [10.2 +/- 1.1 mmol/L]) compared to nights where NPH had been injected (235 +/- 22 mg/dL [13.1 +/- 1.2 mmol/L]). In addition, the morning postprandial blood glucose was significantly improved. The frequency of nocturnal hypoglycemia was not different, and the dose of Semilente insulin was slightly lower compared to the dose of NPH-insulin injected. For adolescent IDDM patients with suboptimal metabolic control due to a marked dawn-phenomenon, with high fasting glucose concentrations despite a bedtime injection of NPH insulin, bedtime injection of Semilente insulin may result in reduced fasting hyperglycemia on the next morning.

5 alpha-androstane-3 alpha, 17 beta-diol and 5 alpha-androstane-3 alpha, 17 beta-diol-glucuronide in plasma of normal children, adults and patients with idiopathic hirsutism: a mass spectrometric study.

We investigated the developmental patterns of 5 alpha-androstane-3 alpha, 17 beta-diol (AD) and 5 alpha-androstane-3 alpha, 17 beta-diol-glucuronide (ADG) in plasma of normal children and adults of both sexes and in patients with idiopathic hirsutism using a physicochemical method: high-resolution gas chromatography/mass spectrometry (HRGC/MS). In children below the age of 11 years, AD and ADG increased with age showing no differences between sexes (mean +/- SD, nmol/l): normal subjects 3-6 years: AD in females 0.08 +/- 0.03, in males 0.07 +/- 0.03; ADG in females 0.15 +/- 0.05, in males 0.14 +/- 0.04; normal subjects 7-10 years; AD in females 0.17 +/- 0.03, in males 0.17 +/- 0.07; ADG in females 0.59 +/- 0.12, in males 0.47 +/- 0.14. Thereafter, AD and ADG showed a greater increase in males (normal subjects 11-15 years: AD in females 0.24 +/- 0.06, in males 0.41 +/- 0.14; ADG in females 1.47 +/- 0.36, in males 3.36 +/- 1.22). In adults, plasma levels did not overlap between females and males (AD in females 0.24 +/- 0.07, in males 0.99 +/- 0.31; ADG in females 2.32 +/- 0.68, in males 13.01 +/- 3.05). 5 alpha-Androstane-3 alpha, 17 beta-diol-glucuronide discriminated better between sexes than AD. In idiopathic hirsutism, mean plasma concentrations of AD and ADG were higher than those of healthy females (ages 11-15 years: AD 0.31 +/- 0.10, ADG 3.48 +/- 2.00; ages > 16 years: AD 0.44 +/- 0.27, ADG 6.46 +/- 3.11), but 54% of patients had normal plasma concentrations of AD and 29% had normal ADG values. Thus, ADG reflected androgenicity better than AD. However, both metabolites were imperfect markers of androgenicity in idiopathic hirsutism. Therefore, our findings do not support the concept of increased 5 alpha-reductase activity in all patients with idiopathic hirsutism.

Biological effects of human growth hormone in rat adipocyte precursor cells and newly differentiated adipocytes in primary culture.

The effects of human growth hormone (hGH) on proliferation and differentiation of primary adipocyte precursor cells isolated from rat epididymal fat pads were studied under serum-free culture conditions. hGH markedly reduced the formation of new fat cells and the expression of glycerophosphate dehydrogenase activity, a marker enzyme of adipose differentiation, in a dose-dependent manner. To find an explanation for this inhibitory effect, we investigated the action of GH on (1) cell proliferation and on (2) lipid accumulation, the latter in the absence and presence of corticosterone. In undifferentiated cells, 5 nmol/L hGH increased both cell number and [3H]-thymidine incorporation (1.3- and 2.6-fold over basal, respectively). This effect was mediated by insulin-like growth factor-I (IGF-I), since hGH stimulated IGF-I production in undifferentiated cells by 12-fold and addition of an anti-IGF-I monoclonal antibody (IGF-I MAb) abolished the mitogenic effect of hGH but did not prevent hGH-induced suppression of adipose differentiation. In developing fat cells, hGH significantly reduced cellular 2-deoxyglucose uptake and glucose incorporation into lipids. In addition, hGH exhibited a lipolytic action in the presence of insulin and triiodothyronine. These effects were not prevented by IGF-I MAb. Specific binding of [125I]-hGH to precursor cells increased significantly during adipose conversion. In differentiated cells Scatchard analysis yielded linear plots with an apparent Kd of 0.16 nmol/L and 8,400 sites per cell. Taken together, these data show that hGH reduces adipose conversion in primary cultures of rat adipocyte precursor cells while promoting cell proliferation through an increase in IGF-I production.

Expression of osteoblastic markers in cultured human bone and fracture callus cells.

We compared the expression of osteoblastic markers in cultured human cells isolated from fracture calluses of various histological states of development with that in cells from adult and fetal bone. Adult osteoblasts and all callus cells produced almost exclusively type I collagen, whereas fetal osteoblasts produced also considerable amounts of type III collagen in vitro. 1,25-Dihydroxyvitamin D3 induced the synthesis of osteocalcin in all bone and callus cells but to varying extents. Fetal bone cells and early-stage callus cells synthesized less than 10% the amount of osteocalcin produced by adult bone cells. Late-stage callus cells produced intermediate levels of osteocalcin. Fetal bone cells and early-stage callus cells responded to parathyroid hormone with a less pronounced increase in intracellular cAMP than did adult bone cells. Late-stage callus cells showed the best response to parathyroid hormone. The activity of alkaline phosphatase was highest in fetal bone cells. These observations show that cells isolated from fetal bone and from fracture callus tissues express a pattern of markers clearly relating them to the osteoblastic lineage. On the basis of the different patterns of osteoblastic markers expressed in vitro we conclude that functionally distinct subtypes of osteoblasts do exist in different mineralized tissues and at different developmental stages.

The role of growth hormone/insulin-like growth factors in adipocyte differentiation.

Growth of the adipose tissue results from both the enlargement of mature adipocytes and the formation of new adipocytes from adipocyte precursor cells. The differentiation process of adipocyte precursor cells is controlled by a variety of hormones. Clinical observations indicate that growth hormone (GH) and insulin-like growth factor I (IGF-I) are able to influence the growth of the adipose organ. Recent in vitro studies using cultures of clonal and primary adipocyte precursor cells have elucidated the role of GH and IGF-I in adipocyte differentiation. From the studies it can be concluded that GH is able to enlarge the pool of adipocyte precursor cells capable of differentiating into mature adipocytes, which occurs under the control of other adipogenic hormones. However, due to its metabolic action, GH is also able to reduce the volume of mature adipocytes and thus the net result of its biological action is aimed at reducing body fat. IGF-I stimulates the differentiation process by inducing critical cell divisions of adipocyte precursor cells necessary for their differentiation. IGF-I, which is known to be regulated by GH and several nutritional factors, may exert its effects in the adipose tissue in an autocrine/paracrine and endocrine way. This review summarizes the results of recent studies investigating the role of GH and IGF-I in adipocyte differentiation.

Assessment of hypothalamic-pituitary-adrenocortical axis function in dexamethasone treated very low birth weight infants by a single dose metyrapone test and gas chromatographic mass spectrometric determination of urinary steroids.

In order to assess hypothalamic-pituitary-adrenocortical axis function, we conducted low and single oral dose metyrapone tests (35 mg/kg) in dexamethasone treated very low birth weight infants with bronchopulmonary dysplasia (n = 12). The responses to metyrapone of tetrahydro-11-deoxycortisol (THS) and cortisol metabolites were analyzed by gas chromatography and mass spectrometry in 24-h urinary specimens. For comparative reasons, morning plasma 11-deoxy-cortisol and cortisol were measured by radioimmunoassay before and after metyrapone. No side effects of metyrapone were observed in our patients. In 5 of 12 patients, no urinary THS could be stimulated after metyrapone and most of the other patients had small increases in urinary THS. These findings suggest suppressed or strongly impaired hypothalamic-pituitary-adrenocortical axis function in most patients. While the concentrations of plasma 11-deoxycortisol showed little variation, those of plasma cortisol were grossly different from the respective urinary values. We recommend steroid analysis in 24-h urinary specimens by gas chromatography and mass spectrometry, because urinary steroids provide more information and the highly specific analytical technique is independent of phenomena such as cross reactivity or matrix effects. The low and single oral dose metyrapone test in combination with urinary steroid analysis by gas chromatography and mass spectrometry therefore provides a noninvasive, convenient and safe means of evaluating the integrity of the hypothalamic-pituitary-adrenocortical axis in very low birth weight infants.

17 alpha-hydroxyprogesterone, 4-androstenedione, and testosterone profiled by routine stable isotope dilution/gas chromatography-mass spectrometry in plasma of children.

Using stable isotope dilution/gas chromatography-mass spectrometry (ID/GC-MS), a physicochemical method, we have profiled the plasma steroids 17 alpha-hydroxyprogesterone, 4-androstenedione, and testosterone in normal children of various age groups. Comparison of our values with those obtained by direct immunologic assays and those using an extraction or purification step showed that immunoassays in general overestimate steroid concentrations. This was especially true for plasma samples in the neonatal period and was most expressed for the concentrations of 17 alpha-hydroxyprogesterone. Our study demonstrated the applicability of ID/GC-MS to routine clinical steroid analysis. The application of ID/GC-MS is recommended whenever problems from matrix effects or cross-reactivity are likely to arise or suspicious results by immunoassays need to be rechecked.

Reduced pancreatic insulin release and reduced peripheral insulin sensitivity contribute to hyperglycaemia in cystic fibrosis.

Traditional opinion holds that patients with cystic fibrosis (CF) develop impaired glucose tolerance or diabetes due to insulinopenia caused by fibrosis of the pancreas. However, studies on the dynamics of insulin secretion and peripheral insulin action have yielded conflicting results. We studied 18 patients with CF (9 male, 9 female, age 15-29 years) and 17 healthy control subjects (8 male, 9 female, 20-32 years). Oral glucose tolerance tests and combined i.v.-glucose-tolbutamide-tests were performed on separate days in fasting subjects. Bergman's "Minimal Model" was used to quantitate both peripheral insulin sensitivity (SI) and insulin-independent glucose disposal (glucose effectiveness; SG). Based on National Diabetes Data Group criteria, 4 patients were classified as diabetic (22%; CF-DM), 3 patients (17%) had impaired glucose tolerance (CF-IGT) while glucose metabolism was normal in 11 patients (61%; CF-NGT). Irrespective of the degree of glucose tolerance, the insulin response to oral glucose was not reduced but delayed, up to 60 min in the CF-IGT/DM group. First-phase insulin release (0-10 min) after i.v.-glucose was significantly lower in CF patients (29% of healthy controls; P < 0.0001), with no difference between the CF-NGT and CF-IGT/DM groups. Insulin release following tolbutamide injection was only marginally reduced in CF patients (64% of controls). In contrast, SI was significantly reduced in the subgroup of CF patients with abnormal glucose metabolism (CF-IGT/DM: 0.97 +/- 0.16 x 10(-4) l/min/pmol; control group: 1.95 +/- 0.25; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and management of laryngeal obstruction in childhood pachyonychia congenita.

Pachyonychia congenita is a genetic syndrome of epithelial dysplasia. In infants and young children, laryngeal involvement can present a life threatening complication: obstruction of the patient's airway due to leukokeratosis can lead to severe respiratory distress. This report concentrates on the diagnosis and successful microsurgical management of laryngeal obstruction in the first female case, a 19-month-old girl with pachyonychia congenita.

Serum and urinary steroids in girls with precocious pubarche and/or hirsutism due to mild 3-beta-hydroxysteroid dehydrogenase deficiency.

To obtain data on the correlation of serum and urinary steroids in nonclassical 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) deficiency, 9 girls with precocious pubarche and 33 adolescent girls with mild to severe hirsutism were studied. Urinary steroid profiles were analyzed by capillary gas chromatography. Serum 17-OH-pregnenolone (17-OHPreg) and 17-OH-progesterone (17-OHP) were determined by RIA after column-chromatographic separation. One out of 9 girls with precocious pubarche and 4/33 girls with hirsutism had elevated ratios of 17-OHPreg to 17-OHP after ACTH stimulation in serum and elevated urinary excretion of 5-ene steroids under basal conditions. These patients were defined to have decreased adrenal 3 beta-HSD activity. Basal and ACTH-stimulated serum 17-OHPreg levels in patients with mild 3 beta-HSD deficiency overlapped those of healthy controls and peripubertally virilized female patients without enzyme deficiency. Post-ACTH 17-OHPreg/17-OHP ratios in serum discriminated patients with and without 3 beta-HSD deficiency using a cutoff value of 13 instead of mean + 2 SD for age-related control values (6.7 and 11.6 for girls with Tanner stage II-III and IV-V, respectively). Sums of urinary 5-ene steroids in patients with 3 beta-HSD deficiency overlapped those in patients without enzyme deficiency. Results showed that an abnormal post-ACTH serum 17-OHPreg/17-OHP ratio may not be associated with elevated urinary 5-ene steroid excretion, and vica versa. In conclusion, patients with simultaneous elevation of post-ACTH serum 17-OHPreg/17-OHP ratio and basal urinary 5-ene steroid excretion are supposed to have mild 3 beta-HSD deficiency.

Longitudinal analysis of somatic development in paediatric patients with IDDM: genetic influences on height and weight.

Normal growth and development, as well as the prevention of overweight, are major goals in the treatment of paediatric patients with insulin-dependent diabetes mellitus (IDDM). We therefore evaluated longitudinally the anthropometric measurements of height and weight, as well as bone age, in an unselected group of 389 patients with IDDM treated at one institution. In order to identify genetic influences on these parameters, height and weight were determined in 186 unaffected siblings and 177 pairs of parents. At diagnosis, patients were slightly taller than average (median z score: +0.37). During the subsequent course of diabetes, age-adjusted heights decreased progressively for the first 9 years, catching up again after more than 10 years of diabetes. Bone ages were progressively retarded with increasing duration of diabetes. In 76 patients of 18 years or older, median z-score for height was +0.30, not different from their unaffected siblings (median z-score: +0.22). The correlation with midparental height was identical for diabetic and nondiabetic siblings (r = 0.43). In contrast, children with diabetes were significantly heavier (z-score for weight: +0.74 compared to +0.34 in unaffected siblings; p < 0.002). Obesity developed primarily during and after puberty. We conclude that: 1) during the course of diabetes, longitudinal growth is temporarily reduced and maturation is delayed in children with diabetes compared to unaffected siblings. However, this effect of diabetes is transient and small compared to genetic influences on height in an individual child. 2) As a group, children with IDDM become significantly overweight, which is likely to increase the cardiovascular risk during adulthood.

Successful prenatal treatment of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

A mother carrying a fetus affected with 21-hydroxylase deficiency received prenatal treatment with dexamethasone (0.5 mg, tid, p.o.) started from the very beginning of the 8th week of gestation. Prenatal diagnosis had to rely on amniocentesis with karyotyping and steroid hormone determination, because HLA and DNA data from the deceased index case or direct molecular genetic techniques were not available. The pre- and postnatal diagnosis of 21-hydroxylase deficiency was based on mass spectrometric determination of 17-hydroxyprogesterone. Dexamethasone was discontinued for 5 days prior to amniocentesis. Monitoring of cortisol, dehydroepiandrosterone-sulphate and oestriol in maternal plasma revealed suppressed maternal and fetal adrenal glands throughout pregnancy. Plasma dexamethasone levels confirmed excellent maternal compliance. At term, an eutrophic girl with normal female genitalia was delivered. The diagnosis of 21-hydroxylase deficiency and salt loss was confirmed postnatally. Regarding the side-effects of dexamethasone, the benefit/risk ratio was in favour of prenatal dexamethasone therapy.