High incidence of molecular defects of the CYP21 gene in patients with premature adrenarche

On the basis of hormonal studies, the incidence of defective steroidogenesis in children with premature adrenarche (PA) in the various reports ranges from 0-54%. Molecular studies have not been reported to date. The aim of the present study was to search for defects in the CYP21 gene in children with PA and to detect possible correlations of the molecular defect to pertinent hormonal and clinical data. In 48 children with PA (40 females and 8 males) and without signs of virilization, a Synachten test and molecular studies were carried out. DNA analysis was performed using the Southern blot technique and allele-specific PCR. Synachten (0.25 mg) was given iv, and 17-hydroxyprogesterone and cortisol were determined at 0 and 60 min. At baseline, Delta(4)-androstenedione, dehydroepiandrosterone sulfate, and 11-deoxycortisol were also determined. Bone age was evaluated using the Greulich and Pyle atlas. Abnormal genotype was detected in 45.8% of the studied subjects; 8.3% were homozygotes, with genotypes concordant with the nonclassical phenotype of 21 hydroxylase deficiency, and 37.5% were heterozygotes for 9 different molecular defects of the CYP21 gene. The children with no detectable molecular defect were designated normal. The 60 min post-Synachten values in homozygotes(17.9 +/- 7.1 ng/mL) and heterozygotes (7.1 +/- 3.6 ng/mL) were significantly higher than that in normal subjects (3.3 +/- 1.5 ng/mL,), but with significant overlapping of values. The mean difference between bone age and chronological age differed in the three groups with overlapping values. The basal Delta(4)-androstenedione level was lower in the normal subjects (0.65 +/- 0.3 ng/mL) than in those with abnormal genotype (1.1 +/- 0.8 ng/mL). The data indicate that the incidence of molecular defects in PA is quite high. The CYP21 heterozygocity is clinically expressed in some subjects prepubertally. In a significant number of cases the genotype cannot be predicted by the age of onset of PA, the mean difference between bone age and chronological age, or the results of a Synachten test. Follow-up of these children through puberty is imperative and may reveal the clinical significance of the molecular defect, namely more hypertrichosis, intense acne, early puberty, possible abnormal menses, and/or fertility problems in the affected

Urinary free cortisol and its nyctohemeral variation in adolescents and young adults with IDDM: Relation to endothelin 1 and indices of diabetic angiopathy

The existence of a hyperactive hypothalamic pituitary adrenal (HPA) axis in diabetics and its relevance to diabetic complications has been controversial. In this study we determined the 24 hour urinary excretion of free cortisol (UFC), its nyctohemeral variation and its relation to indices of diabetic angiopathy. In 130 subjects with IDDM, aged 15.2 ± 4.8 years and diabetes duration 7.3 ± 5 years, and in 48 controls of comparable age, UFC, urinary endothelin (UET1), urinary albumin, HbA(1c), and plasma renin were determined. The total 24-hour UFC excretion was greater in diabetics than in controls (p=0.002) and also greater in diabetic males than in females (p=0.006), while no sex difference was detected in the controls. Day UFC excretion was greater than night UFC excretion (p<0.001) in all subjects. UFC correlated to carotid intimal plus medial thickness (r=0.48, p=0.002), urinary albumin (r=0.50, p<0.001), UET1 (r=0.56, p<0.001), diastolic, systolic and mean blood pressure (r=0.27, p=0.003; r=0.41, p<0.001; r=0.34, p<0.001), BMI (r=0.50, p<0.001), serum creatinine (r=0.35, p<0.001), total cholesterol (r= -0.19, p=0.036), HDL r= -0.22, p=0.038), LDL (r= -0.23, p=0.032), age (r=0.61, p<0.001) and diabetes duration (r=0.37, p<0.001). These results suggest that hyperactivity of the HPA axis or of the adrenals, due to chronic stress, hypoglycemic episodes or other factors, possibly contributes to the establishment or progression of diabetic micro- or macro- angiopathy

Hepatic enzyme abnormalities in Turner syndrome: A case report

Background: Liver dysfunction has been described in subjects with Turner syndrome. The mechanism involved is not known. Methods: Using appropriate methodology, we evaluated the hepatic enzymes serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase and γ-glutamyl transpeptidase (γ-GT) in a girl with 45 XO/46 Xr mosaic karyotype. She was monitored from age 9 to 20 years while she underwent various therapeutic regimens. Results: Serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase and particularly γ-GT concentrations ranged from normal to elevated values during human growth hormone therapy, estrogen replacement therapy (conjugated estrogens were replaced after 1 year with transdermal estrogens and medroxyprogesterone), and periods without therapy. The type of the therapeutic regimen did not seem to influence the hepatic enzyme values. A correlation was found between γ-GT values and body mass index (BMI). Conclusions: In our patient the waxing and waning of the liver enzymes was not influenced by the therapeutic regimen, but γ-GT seemed to correlate with BMI. Copyright © 2007 S. Karger AG

National data on the epidemiology of IDDM in Greece: Cases diagnosed in 1992

OBJECTIVE - To detect the incidence, geographic distribution, and seasonal variation of insulin-dependent diabetes mellitus (iddm) in all of Greece. RESEARCH DESIGN AND METHODS - One hundred and thirty-seven children (75 boys and 62 girls) up to 14.9 years of age were diagnosed with IDDM in Greece in 1992. RESULTS - The age-adjusted incidence of IDDM in Greece in 1992 was 6.25/100,000 population (boys: 6.17/100,000; girls: 6.28/100,000). There was a significant pubertal peak. The incidence of IDDM was significantly higher in metropolitan (10.0/100,000) than in rural (4.21/100,000), semirural (748/100,000), or urban areas (5.36/100,000) of Athens. There was a marginal difference between rural and semirural areas. No significant seasonal variation in the incidence of IDDM was observed. CONCLUSIONS - We conclude that the incidence of IDDM in Greece is among the five lowest in Europe. An impressive clustering of cases was observed in the Athens metropolitan area compared with the rural and semirural areas, an observation that possibly underlines the importance of environmental factors (stressful situations, infections, dietary habits, and others) in the expression of IDDM

Urinary endothelin in adolescents and young adults with insulin-dependent diabetes mellitus: Relation to urinary albumin, blood pressure, and other factors

Endothelin (ET) is a potent vasoconstrictive peptide that may play a role in vascular pathology in general and diabetic nephropathy in particular. The aim of this study was to investigate (1) alterations of urinary ET1 (UET1) in adolescents and young adults with insulin-dependent diabetes mellitus (IDDM) and (2) the relation of UET1 to other indices of diabetic nephropathy and to risk factors of diabetic angiopathy in general. In 130 IDDM subjects aged 15.2 +/- 4.9 years with a diabetes duration of 7.3 +/- 5.1 years, UET1 by radioimmunoassay, urinary albumin by nephelometry, plasma renin by immunoradiometric assay, hemoglobin A(1c) (HbA(1c)) by high-performance liquid chromatography, and routine biochemistry analyses were determined. Forty-eight controls, healthy siblings of the diabetics of comparable age, were similarly studied. Total 24-hour UET1 excretion was higher in diabetics than in controls (10,866 +/- 7,270 and 6,598 +/- 3,294 pg/24 h, respectively, P = .000). This difference was also noted if male and female diabetics were separately compared with controls. In diabetics with normoalbuminuria (<20 mu g/min), total 24-hour UET1 excretion was also higher than in controls (P = .002). In diabetics but not in controls, 24-hour UET1 values were higher in males than in females (P = .018). In IDDM subjects, UET1 showed a linear relationship with age (P = .002), urinary albumin (P = .000), serum creatinine (P = .001), systolic blood pressure (P = .038), triglycerides (P = .003), and HbA(1c) (P = .041). Multiple regression analysis demonstrated that the variables interacting independently with UET1 were urinary albumin (P = .003) and serum creatinine (P = .038). UET1 is elevated early (in adolescence) in IDDM subjects, and it is positively correlated with the degree of albuminuria. These data suggest that the amount of UET1 possibly reflects the severity of diabetic renovascular damage. It may thus be speculated that UET1 could be used as another index of diabetic nephropathy or its progress. Copyright (C) 1998 by W.B. Saunders Company