The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene.

BACKGROUND: Nonclassical congenital adrenal hyperplasia (NC-CAH) is caused by mutations of the CYP21A2 gene. The clinical manifestations and hormonal derangements of NC-CAH are quite variable. OBJECTIVES: (i) To define the phenotype and its relation to genotype according to gender and age and (ii) to evaluate the validity of currently applied hormonal criteria for establishing the diagnosis of NC-CAH. PATIENTS AND METHODS: The clinical, hormonal and molecular data of 280 subjects (235 female) with NC-CAH and a median age of 17·6 years were analysed. CYP21A2 genotyping was performed in all subjects. RESULTS: The majority of females aged less than 8 years presented with premature pubarche (88·3%), while those older than 8 presented with a polycystic ovary-like phenotype (63·2%). A total of 7·7% of the females and 51·1% of the males were asymptomatic at the time of diagnosis. In the total group, 50·4% of the subjects were compound heterozygotes for one classical (C) and one nonclassical (NC) mutation, while 46% of the alleles studied carried the p.V281L mutation. Basal 17OHP values were below 6 nm (2 ng/ml) in 2·1% of the subjects with NC-CAH, but none had peak 17OHP values post-ACTH lower than 30 nm (10 ng/ml). CONCLUSIONS: NC-CAH has a variable phenotype depending on the age, gender and the presence of a classical mutation. A peak cut-off value of 17OHP post-ACTH lower than 30 nm excludes the diagnosis of NC-CAH, whereas basal 17OHP <6 nm may represent a false-negative result. A significant number of patients harboured a classical mutation, a finding which requires genotyping of the partner for genetic counselling.

HNF1A gene mutations and premature ovarian failure (POF): evidence from a clinical paradigm combining MODY 3 and POF.

Premature ovarian failure (POF) defines the occurrence of ovarian failure prior to the age of 40. It occurs in one out of 100 women but is very rare before age 20 (1:10,000). Maturity-onset diabetes of the young (MODY), caused by mutations in the HNF1A gene, is also a rare disorder; all types of MODY account for 1-2% of adult diabetic cases. These two rare nosologic entities coexisted in an adolescent girl evaluated for delayed puberty. Although this combination could represent a chance association, an interrelation might exist. We examined HNF1A expression in human fetal and adult ovaries by immunohistochemistry using a polyclonal HNF1A antibody. HNF1A protein was expressed in both the fetal and adult human ovaries. Based on these findings, we hypothesize that HNF1A participates in ovarian organogenesis and/or function and that mutations in the HNF1A gene might represent another molecular defect causing POF, possibly in combination with other genetic factors. The study underlines the importance of rare clinical paradigms in leading the way to elucidation of the pathogenetic mechanisms of rare diseases.

CYP21A2 mutations in women with polycystic ovary syndrome (PCOS).

The question of the contribution of CYP21A2 heterozygosity to the development of polycystic ovary syndrome (PCOS) has repeatedly been raised in the literature. The available data, however, do not offer a satisfactory answer. The discrepancy must be attributed, primarily, to the small number of subjects in the various studies, the type of selected phenotype, and the number of searched mutations. The aim of the study was to define the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS. We searched for 14 molecular defects of the CYP21A2 gene in 197 PCOS women, employing allele specific PCR. Androgen levels were determined at baseline by appropriate methodology in the follicular phase. PCOS women with 17-hydroxyprogesterone (17OHP) basal values >2 ng/ml and/or post-ACTH >10 ng/ml were excluded. Appropriate controls were included. The frequency of the CYP21A2 heterozygous mutations in PCOS women and in controls was 7.6% and 5.9%, respectively [p-value (PCOS vs. controls): 0.663]. Homozygosity for CYP21A2 gene defects was not detected. In conclusion, the contribution of CYP21A2 heterozygous mutations to the pathogenesis of PCOS is not substantiated by our data. Moreover, 17-hydroxyprogesterone values of < 10 ng/ml post-ACTH exclude homozygosity of CYP21A2 mutations.

Gender, age, puberty, and BMI related changes of TSH and thyroid hormones in schoolchildren living in a long-standing iodine replete area.

The aim of the work was to assess thyroid function in children and adolescents in an iodine replete area and to explore possible effects of age, gender, puberty, and adiposity. Thyrotropin (TSH), total triiodothyronine (T (3)), total thyroxine (T (4)), free thyroxine (FT (4)), and the T (4)/T (3) ratio were determined for 440 schoolchildren (200 boys and 240 girls), aged 5-18 years, living in an iodine replete region. Body Mass Index (BMI), BMI standard deviation score (BMI-SDS), and Body Surface Area (BSA) were calculated. In girls there was a negative correlation of TSH, T (3), and FT (4) values with age. In boys there was a negative correlation only of T (3) values with age. Girls had lower TSH, T (4), and T (3) values, whereas boys had only lower T (3) values at puberty compared to the prepubertal stage. Girls had lower TSH values than boys (p<0.03) only at puberty. BMI-SDS in boys and girls were 0.21 and 0.03, respectively. BMI-SDS was not related to TSH, T (4), or T (3) in either gender, whereas it was negatively related to T (4)/T (3) ratio in boys and to FT (4) in girls. We conclude that estrogens may exert a suppressive effect on the pituitary-thyroid axis after puberty. TSH values are not correlated with BMI-SDS, whereas T (4)/T (3) ratio in boys and FT (4) in girls are negatively correlated with BMI-SDS.

Effect of prolonged illumination (phototherapy) on concentrations of luteinizing hormone in human infants.

Concentrations of luteinizing hormone in the serums of human neonates were altered when the neonates were exposed to prolonged, intense illumination (phototherapy) with their eyes covered. Concentrations decreased after 48 to 72 hours of exposure, increased 6 to 9 days after phototherapy, and subsequently returned to levels similar to those of controls. These data suggest that light may affect pituitary-gonadal function in the human neonate.

Psychological stress as a factor potentially contributing to the pathogenesis of Type 1 diabetes mellitus.

UNLABELLED: Diabetes mellitus Type 1 (T1D) is an autoimmune disorder attributed to both genetic and environmental factors. The aim of this study was to identify certain stressful conditions potentially associated with the pathogenesis and/or expression of T1D. The study group included 107 children with diabetes (CD) and 153 controls of comparable age and gender distribution at diagnosis of T1D (10.73+/-3.62 yr vs 9.59 +/-3.42 yr, respectively). The parents of both groups completed a questionnaire on socioeconomic status and stressful life events or adverse situations at home and school. RESULTS: Lower social class was more prevalent among the mothers of CD (p=0.002) in comparison with the controls. Stressful life events (parental death, divorce, parental job loss), problems at home (parental abuse, parental dispute) and at school (poor performance) were more frequently observed in the CD group than in the controls (parental death: p=0.05, job loss: p=0.05, parental abuse: p=0.002, quarrels between parents: p=0.05, and among siblings p=0.002, poor school performance: p=0.037). A stepwise logistic regression analysis indicated that lower maternal social class [odds ratio (OR): 3.86, 95% confidence interval (CI): 1.37,10.9], parental dispute or divorce (OR: 2.78, 95%CI: 0.97,7.95), body mass index (OR: 0.87, 95%CI: 0.78,0.97), increasing age (OR: 1.14, 95%CI: 1.02,1.27) were the factors potentially influencing the occurrence of T1D, while the 2-yr period prior to diabetes occurrence emerged as the most important one (OR: 2.49, 95%CI: 1.14,5.42). CONCLUSION: Children with diabetes seem to experience certain stressful conditions with significantly increased frequency compared to controls, especially during the 2 yr preceding the diagnosis of T1D, with a higher clustering in those of lower social class. The resultant stress possibly contributes to the development of T1D in genetically susceptible individuals.

Prevalence of thyroid dysfunction in Turner's syndrome: a long-term follow-up study and brief literature review.

Thyroid dysfunction, especially hypothyroidism caused by Hashimoto's thyroiditis is more frequently observed in girls with Turner's syndrome (TS). The aim of the present study was to evaluate prevalence, etiology, karyotype distribution and age at onset of thyroid pathology in girls with TS. Data recorded in 84 girls with TS attending our clinic were analyzed. The mean age +/- standard deviation [SD] at their initial evaluation was 10.3 +/- 3.7 years (range, 0.5 to 19 years) and the mean period of observation was 8.4 +/- 4.4 years. The thyroid function had been evaluated at least once per year in all patients and thyroid autoantibodies (ATA) were available in 51 (60.7%). Hypothyroidism was detected in 24% of the studied subjects and hyperthyroidism in 2.5%. Elevated values of thyroid autoantibodies were detected in 42% of girls with TS, whose ATA had been determined, and 65% had hypothyroidism. Thyroid dysfunction was first noted after the age of 8 years with no difference in the distribution of new cases at the different ages or pubertal stages. There was no difference in the incidence of thyroid dysfunction related to the type of karyotype abnormality. Thyroid dysfunction is more frequently encountered in girls with TS (hypothyroidism: 24% in the total group and 65% in those with positive ATA, hyperthyroidism: 2.5%). Thyroid dysfunction was observed after the age of 8 years with no difference in the occurrence of new cases in the various age groups thereafter. Hence, thyroid function should be evaluated yearly in girls with TS past the age of 8 years and more frequently in those with positive thyroid autoantibodies.

National data on the epidemiology of IDDM in Greece. Cases diagnosed in 1992. Hellenic Epidemiology Study Group.

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 (7.48/100,000), 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.

Carotid atherosclerosis in adolescents and young adults with IDDM. Relation to urinary endothelin, albumin, free cortisol, and other factors.

OBJECTIVE: To investigate 1) alterations of carotid intimal-plus-medial thickness (IMT) in subjects with IDDM and 2) the relation of IMT to indexes of diabetic angiopathy and to risk factors of atherosclerosis. RESEARCH DESIGN AND METHODS: IMT was assessed by ultrasound B-mode imaging in 39 subjects with IDDM (23 male, 16 female young adults aged 17.5 +/- 5.2 years, diabetes duration 8.8 +/- 5.9) and in 22 control subjects (healthy siblings of the IDDM subjects) of comparable age. Urinary endothelin (UET1) and urinary free cortisol (UFC) were determined by radioammunoassay (RIA), urinary albumin by nephelometry, HbA1c by high-performance liquid chromatography (HPLC), and plasma renin by immunoradiometric assay (IRMA). RESULTS: The IMT values were greater in IDDM subjects than in control subjects (0.49 +/- 0.1 mm, 0.44 +/- 0.09 mm, respectively; P = 0.048) and greater in IDDM male subjects than in control male subjects (0.52 +/- 0.09 and 0.44 +/- 0.06 mm, respectively; P = 0.015), with no difference between IDDM and control female subjects. The IMT values were greater in diabetic male subjects than in female subjects (0.52 +/- 0.09 and 0.45 +/- 0.1 mm, respectively; P = 0.017). In IDDM subjects, but not in control subjects, there was a positive correlation of IMT to urinary albumin (P = 0.008), systolic blood pressure (P = 0.023), UET1 (P = 0.016), UFC (P = 0.002), and BMI (P = 0.021). Multiple regression analysis demonstrated that in IDDM subjects the variable that interacts independently with IMT was the BMI (P = 0.001). CONCLUSIONS: IMT, an index of atherosclerosis (macroangiopathy), is increased in IDDM subjects quite early (already in adolescence), and it is positively related to urinary albumin, UET1, blood pressure, and UFC.

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 i.v., and 17-hydroxyprogesterone and cortisol were determined at 0 and 60 min. At baseline, delta4-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 delta4-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.

The spectrum of molecular defects of the CYP21 gene in the Hellenic population: variable concordance between genotype and phenotype in the different forms of congenital adrenal hyperplasia.

Defective steroid synthesis due to 21-hydroxylase deficiency is the most common form of congenital adrenal hyperplasia. Knowledge of the molecular defects causing 21-hydroxylase deficiency in different populations is of both theoretical and practical interest. The types and the relative frequencies of molecular defects and the correlation between the genotype and the phenotype were examined in the Hellenic population. We searched for deletions, conversions, and 11 of the most frequent mutations of the CYP21 gene by Southern blot and allele-specific PCR in 222 chromosomes from 111 unrelated subjects and their parents. The most frequent molecular defects were 1) in the salt wasting form, I(2) splice (42.9%), deletions and conversions (24.5%), and Q318stop (14.3%); 2) in the simple virilizing form, I172N (35.3%), I(2) splice (29.4%), and P30L (19.1%); and 3) in the nonclassical form, V281L (41.1%), P30L (21.4%), and P453S (14.3%). Compared with other populations, Greek patients had a higher frequency of Q318stop in the salt-wasting form, of P30L in both simple virilizing and nonclassical forms and of P453S in the nonclassical form. The concordance of genotype to phenotype in the total sample was 87%. However, the concordance rate was different in the three forms of the disease. Thus, complete concordance was detected in the genotypes predicting the salt-wasting phenotype, a slightly lower concordance (95.2%) was detected in the genotypes predicting the simple virilizing phenotype, and the lowest concordance (67.6%) was observed in genotypes predicting the nonclassical phenotype. In conclusion, the concordance between genotype and phenotype decreases as the severity of the disease diminishes. This should be taken into consideration in genetic counseling and antenatal intervention.

Irradiation of the head. Immediate effect on growth hormone secretion in children.

Plasma growth hormone (GH) was determined in samples obtained hourly from 1000 h to 0700 h before, and after a 3 week course of "prophylactic" cranial irradiation, in ten leukemic children who had no clinical or laboratory evidence of central nervous system involvement. The mean per hour value of GH prior to irradiation (4.1 +/- 2.4 ng/ml) was similar to that of 7 endocrinologically normal children (4.09 +/- 2.4 ng/ml), a finding strongly suggesting normal pituitary function prior to irradiation. Following irradiation GH levels at each hour were, in general, lower than before. The difference is statistically significant at 0100 h. The peak GH responses were lower following than preceeding irradiation (p less than 0.02). The findings suggest an immediate suppressive effect of irradiadiation on the apparently normal hypothalamic pituitary axis in children.

Macroglossia, transient neonatal diabetes mellitus and intrauterine growth failure: a new distinct entity?

A newborn infant, small for her gestational age with macroglossia and transient insulinopenic diabetes mellitus is described. Two similar cases have been found in the literature. Flat glucose tolerance test results were found in the mother, the mechanism of which was not disclosed; there was no evidence of hyperinsulinism or malabsorption syndrome and the response of plasma growth hormone, and cortisol, and of urinary epinephrine to insulin-induced hypoglycemia was adequate. It is suggested that the triad of intrauterine growth retardation, macroglossia, and transient neonatal diabetes mellitus constitutes a distinct clinical entity. The link to the maternal abnormalities of carbohydrated homeostasis remains speculative.

The growth pattern and final height of girls with Turner syndrome with and without human growth hormone treatment.

BACKGROUND: Shortness is the most frequent and quite disturbing characteristic of girls with Turner syndrome (TS). Human growth hormone administration (hGH) to girls with TS increases growth velocity (GV), but a favorable effect on final height (FH) has not been documented. The aim of this study was to evaluate the effect of hGH administration on the growth pattern and FH in girls with TS. METHODS: The study group was comprised of 123 girls with TS who were cared for in our center. Eighty-two of these girls received hGH (mean dose, 0.78 +/- 0.12 IU/kg/week), given subcutaneously 5 to 7 times per week for a period of 2.2 +/- 1.2 years (hGH group). The mean chronological age (CA) and bone age (BA) at hGH initiation were 11.5 +/- 2.5 years and 9.7 +/- 2.3 years, respectively. The remaining 41 girls did not receive hGH and are designated as the untreated control group. In both groups, gonadal steroids were given for pubertal initiation and maintenance. RESULTS: The GV during the first year of hGH therapy (GV1) was higher than the year before hGH (6.3 cm/year vs 4.0 cm/year) and higher than the GV of the untreated group at a similar CA (4.4 cm/year). The GVs during the second (GV2) and third (GV3) year of hGH treatment (5.4 and 4.9 cm/year, respectively) were lower, but still higher in the hGH group, in comparison with the untreated group (GV2, 4.2 cm/year; GV3, 3.4 cm/year). GV1, GV2, and GV3 were negatively related to age and to BA at hGH initiation. The FH of the 35 hGH-treated girls was not significantly different from the FH of the 27 untreated girls (146.1 cm vs 144.0 cm). The Delta target height-FH was not significantly different in the two groups. The FH standard deviation score of the hGH-treated group was positively related to height standard deviation score for CA at treatment initiation (r = +0.73), maternal height (r = +0.57), target height (r = + 0.66), and birth weight (r = +0.54), but was unrelated to CA or BA at start of therapy or to hGH dose. CONCLUSIONS: hGH therapy in girls with TS, in the dose and duration of treatment applied in this study, significantly accelerated GV but did not significantly improve FH.

Increased frequency of HLA B17 antigen in girls with Turner syndrome and their fathers.

HLA-A, -B and -DR antigen distribution was studied in 49 girls with Turner Syndrome (TS), in 43 of their parents, as well as in 433 controls. No increased frequency of DR3, DR4 was found in our group. However, an increased frequency of HLA B17 antigen was disclosed (18.3% in TS versus 6.4% in the controls, p < 0.001 and pc < 0.01). Furthermore, the HLA B17 antigen was of paternal origin in 77.7% of the cases. The interpretation of the present findings is quite difficult. Most likely, the findings are related to the chromosomal abnormality rather than to autoimmunity. It is quite possible that genes within the region of class I genes create unfavorable circumstances leading to the loss of the sex chromosome or, alternatively, genes in this region confer protection and prevent miscarriage of the affected fetus.

Congenital adrenal hyperplasia complicated by central precocious puberty: treatment with LHRH-agonist analogue.

Eight children with congenital adrenal hyperplasia and late initiation of corticosteroid treatment are included in the present study. Four of them received LHRHa treatment for the arrest of central precocious puberty, while the other four served as controls. The administration of LHRHa was effective in arresting the manifestations of puberty. The final height in the LHRHa-treated group was 158.2 +/- 7.3 cm (SDS -1.1 +/- 0.5) and did not differ from the target height of 158.9 +/- 6.5 cm (SDS -1.1 +/- 0.2), while the final height in the controls was 153 +/- 11 cm, a value significantly lower than their target height of 164.5 +/- 8.3 (SDS -0.6 +/- 0.7) with p < 0.05. The data showed that LHRHa is effective in arresting central precocious puberty and appears to improve final height, bringing it closer to that expected from the genetic potentials.

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 A1c (HbA1c) 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 microg/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 HbA1c (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.

Persistent hyperinsulinemic hypoglycemia of infancy: long-term results.

Data from 15 infants with persistent hyperinsulinemic hypoglycemia of infancy (PHHI), presented to our hospital from 1976 to 1995, were retrospectively analyzed. Nine patients were successfully managed with prolonged (1.25-13 yr) diazoxide therapy and frequent, low protein feeds. Three of them are still being treated with diazoxide, 7.75, 9.25 and 13 yr post diagnosis. Four patients were managed only with frequent, low protein feeds. One patient had 2/3 pancreatectomy, and another had excision of a focal lesion which proved to be focal nesidioblastosis. Two patients were lost to follow up. No patient has shown neurological damage. One girl developed seizures at age 11.5 yr without hypoglycemia. The patient with 2/3 pancreatectomy developed diabetes mellitus at the age of 20 years. Although conservative management of PHHI is very laborious for the family and the physician, it should be applied as long as euglycemia is accomplished. Definition of the anatomical lesion (focal or diffuse) prior to pancreatectomy is recommended.

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, HbA1c, 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 macroangiopathy.

Genetic aspects of congenital adrenal hyperplasia.

Data related to genetics of congenital adrenal hyperplasia with emphasis on CYP21 gene defects are briefly outlined. Mutations of the StAR gene lead to impaired translocation of cholesterol from the outer mitochondrial membrane to the inner mitochondria, a rate limiting step in steroidogenesis in the adrenals and the gonads. The clinical picture is characterized by adrenal and gonadal insufficiency and sex reversal in XY individuals. Molecular defects of the CYP17 gene encoding 17alpha-hydroxylase can cause hypertension, impaired sexual maturation and impaired sexual differentiation in XY individuals. Molecular defects of the CYP11B1 gene lead to 11-hydroxylase deficiency, which is clinically expressed with virilization of the external genitalia of the female and precocious puberty in the male, as well as hypertension in both sexes. The HSD3beta1 and HSD3beta2 genes encode two isoenzymes (3betaHSDI and 3betaHSDII). The clinical picture results from either absence or diminished activity of type II 3betaHSD, resulting from mutations of the HSD3beta2 gene. The most frequent form of CAH (90% of all patients) is due to deletions, conversions or point mutations of the CYP21 gene, which encodes the enzyme 21-hydroxylase. There is a wide range of clinical expression primarily explained by the type of the molecular defect. The ratio of genotype to phenotype concordance varies in the different forms of the disease, the highest one being encountered in the non-classical form. Heterozygosity of CYP21 mutations may be expressed as premature pubarche.