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Early disruption of steroids affects the development of mammalian neural circuits underlying affective processes. In humans, patients with classic congenital adrenal hyperplasia (CAH) can serve as a natural model to study early hormonal alterations on functional brain development. CAH is characterized by congenital glucocorticoid insufficiency, leading to altered hypothalamic-pituitary-adrenal (HPA) function, and hyperandrogenism. Using fMRI, we compared fourteen adolescents with CAH to 14 healthy controls on amygdala response to a face viewing task. In response to negative facial emotions, CAH females activated the amygdala significantly more than healthy females, whereas CAH males did not differ from control males. Furthermore, females with CAH showed a similar pattern of amygdala activation to control males, suggesting virilized amygdala function in females with CAH. These findings suggest a prominent effect of early hyperandrogenism on the development and function of the amygdala in females with CAH, whereas no effects were detected in males with CAH. This study provides data that can be further tested in a model of the neurobiological mechanisms underlying early androgen organizational effects on amygdala function.

Recently discovered sexual dimorphism within developing brain structures such as the amygdala and hippocampus suggests that biological factors may account for many of the sex differences in stress reactivity. In this study, we have relied on studies of naturally occurring anomalous processes, such as congenital adrenal hyperplasia (CAH) and Klinefelter's syndrome (XXY), to observe the effects of hormones and sex chromosomes on brain structures thought to influence an individual's vulnerability to stress. Brain magnetic resonance imaging (MRI) scans were obtained both from 16 boys with classic CAH and 34 age- and sex-matched controls and from 20 XXY children and 40 age-matched controls. Smaller amygdala volumes were observed in boys with CAH than in matched controls, and in XXY patients than in matched controls. XXY patients were also found to have smaller hippocampus volumes when compared with matched controls. Acknowledging that hormone and sex chromosome effects upon the developing human brain are widespread and complex, it is difficult to conclude, with any certainty, the etiology of the differences found in this study. Future studies that examine longitudinal data and/or other diagnostic groups, however, may help to better elucidate specific hormone and sex chromosome effects upon stress-related structures in the brain.

Bilateral adrenalectomy is an acceptable alternative treatment in salt-wasting 21-hydroxylase deficiency when conventional steroid replacement therapy fails to control hyperandrogenism. Objections to surgical adrenalectomy have been based on surgical risk, possible loss of protective adrenal function, and the risk of ACTH-induced activation of adrenal rest tissue. We report a young female with salt-wasting CAH, who underwent bilateral adrenalectomy and developed severe hyperpigmentation, progressively marked corticotropin hypersecretion to concentrations seen in Nelson's syndrome (5,000-7,000 pg/ml), a pituitary microadenoma 5 years postoperatively, and probable ectopic adrenal rest tissue. Corticotropin concentrations failed to respond to ovine corticotropin-releasing hormone (oCRH) (1 microg/kg given as an i.v. bolus), but did suppress following both hydrocortisone administration (100 mg given as an i.v. bolus) and a low dose (0.5 mg given orally every 6 h for 48 h) dexamethasone suppression test. Patients with CAH have hyperactivity of the hypothalamic-pituitary-adrenal axis and are at risk for pituitary tumor formation.

Carriers of congenital adrenal hyperplasia due to 21-hydroxylase (21-OH) deficiency demonstrate increased secretion of cortisol precursors after ACTH stimulation, suggestive of impaired cortisol production and compensatory increases in hypothalamic CRH secretion. Because both cortisol and CRH have behavioral effects, and hypothalamic CRH hypersecretion has been associated with chronic states of anxiety and depression, we performed endocrine and psychologic studies in consecutively admitted parents of patients with classic congenital adrenal hyperplasia due to 21-OH deficiency and parents of children with other chronic endocrine disorders. The number of excluded carriers because of pathologic reasons was higher than that of controls (P = 0.05). Carriers of 21-OH deficiency had a lower mean 24-h urinary free cortisol excretion (26.4 +/- 3.4 vs. 42.7 +/- 6.4 microg/d, P = 0.03) and higher peak ACTH (75.7 +/- 8.1 vs. 54.2 +/- 5.9 pg/ml, P = 0.04) and 17-hydroxyprogesterone (224.2 +/- 28.1 vs. 107.1 +/- 12.5 ng/dl, P < 0.001) concentrations post CRH stimulation than control subjects. Cortisol and androstenedione responses were similar in the two groups. Psychometric assessment performed by administering the State-Anxiety Inventory, Beck Depression Inventory, Profile of Mood States, Symptom Checklist-90R, and Temperament and Character Inventory revealed no differences between the two subject groups. Interestingly, a stepwise multiple linear regression model analysis in each population sample revealed that in carriers of 21-OH deficiency but not in the control subjects, a lower mean 24-h urinary free cortisol excretion and a higher ACTH response to ovine CRH stimulation predicted predisposition to obsessive-compulsive behavior, novelty seeking, reward dependence, and harm avoidance. We conclude that carriers of 21-OH deficiency appear to have mild hypocortisolism and compensatory changes of CRH secretion secondary to lower cortisol concentrations. These changes might predict mild predisposition of these subjects to physical and psychologic pathology, suggesting that larger studies are necessary.

The primary mechanism that initiates puberty is unknown. One possible clue is that pubertal maturation often parallels skeletal maturation. Conditions that delay skeletal maturation also tend to delay the onset of puberty, whereas conditions that accelerate skeletal maturation tend to hasten the onset of puberty. To examine this relationship, we studied boys with congenital adrenal hyperplasia (n = 13) and familial male-limited precocious puberty (n = 22), two conditions that accelerate maturational tempo, and boys with idiopathic short stature (n = 18) in which maturational tempo is sometimes delayed. In all three conditions, the onset of central puberty generally occurred at an abnormal chronological age but a normal bone age. Boys with the greatest skeletal advancement began central puberty at the earliest age, whereas boys with the greatest skeletal delay began puberty at the latest age. Furthermore, the magnitude of the skeletal advancement or delay matched the magnitude of the pubertal advancement or delay. This synchrony between skeletal maturation and hypothalamic-pituitary-gonadal axis maturation was observed among patients within each condition and also between conditions. In contrast, the maturation of the hypothalamic-pituitary-gonadal axis did not remain synchronous with other maturational processes including weight, height, or body mass index. We conclude that in boys with abnormal developmental tempo, maturation of the skeleton and the hypothalamic-pituitary-gonadal axis remains synchronous. This synchrony is consistent with the hypothesis that in boys, skeletal maturation influences hypothalamic-pituitary-gonadal axis maturation.

Children with classic congenital adrenal hyperplasia (CAH) have multiple endocrine imbalances, including prenatal glucocorticoid and adrenomedullary deficiency and androgen excess, with possible postnatal iatrogenic glucocorticoid excess, hyperandrogenism, and adrenomedullary hypofunction. Prenatal masculinization of the brain has been suggested in girls with classic CAH. Hormones of the hypothalamic-pituitary-adrenal axis and sex hormones interact with extrahypothalamic regulatory centers of the brain, including the amygdala and hippocampus. The amygdala is important in the processing of emotion and generation of fear, whereas the hippocampus plays an important role in memory. Chronic hypercortisolemia has been shown to be associated with hippocampal damage, while glucocorticoids and corticotropin-releasing factor play a major role in the regulation of amygdala function. We performed magnetic resonance imaging of the brain on 27 children with classic CAH and 47 sex- and age-matched controls. Volumes of the cerebrum, ventricles, temporal lobe, amygdala, and hippocampus were quantified. Females with CAH did not have brains with male-specific characteristics. In contrast, a significant decrease in amygdala volume was observed in both males and females with CAH (males, P = 0.01; females, P = 0.002). Iatrogenic effects on the hippocampus due to glucocorticoid therapy were not observed in children with CAH. These results suggest that prenatal glucocorticoid deficiency with resulting alterations in hypothalamic-pituitary-adrenal axis regulation, sex steroid excess, or some combination of these preferentially affect the growth and development of the amygdala, a structure with major functional implications that warrant further exploration.

A critical amount of body fat is necessary for the initiation of puberty, and leptin, an adipocyte-derived hormone, is necessary for pubertal development. The sympathoadrenal system modulates body fat stores and leptin secretion and interacts with adrenocortical androgen production, suggesting a possible role in sexual maturation. We studied sympathetic nerve and adrenomedullary activity at rest in 80 healthy children (ages, 5–17 yr; 37 boys and 43 girls) in relation to age, pubertal stage, gender, physical activity, body mass index, and serum levels of sex steroids, dehydroepiandrosterone sulfate, cortisol, leptin, and insulin. Plasma concentrations of the adrenomedullary hormone, epinephrine (E), and its metabolite metanephrine (MN), decreased significantly with advancing puberty and were higher in boys than in girls. E and MN correlated significantly and inversely with dehydroepiandrosterone sulfate, estradiol, testosterone, leptin, and insulin. Plasma norepinephrine, which is primarily derived from sympathetic nerve endings, increased significantly with advancing puberty and increasing testosterone levels in boys. Stepwise multiple regression analysis revealed that E was best predicted by pubertal stage and leptin, and MN by estradiol and leptin. Our data suggest that sympathoadrenal hormones may play a role in the complex process of sexual maturation. Further studies are needed to investigate a possible modulatory role of the adrenal medulla in the body weight-related timing of adrenarche and/or gonadarche.

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by decreased synthesis of glucocorticoids and mineralocorticoids, adrenal hyperandrogenism, and impaired development and function of the adrenal medulla. Although genotype can usually predict phenotype, genotype-phenotype discordance has been described. We investigated the association between adrenomedullary function, disease severity, and genotype in 37 children [22 males and 15 females; age range, 4.7-14.9 yr; 28 salt-wasting (SW) and 9 simple virilizing (SV) CAH] with classic 21-hydroxylase deficiency. Plasma and 24-h urinary catecholamines and their metabolites, and the 21-hydroxylase genotype were determined in all patients. The disease-causing mutations were divided into 4 groups (Null, A, B, and C) according to in vitro 21-hydroxylase activity as previously described. Genotype groups Null (n = 9) and A (n = 15) were predicted to result in SW CAH, group B (n = 8) was predicted to have the SV phenotype, and group C (n = 1) was predicted to have nonclassic CAH. A fifth group, D (n = 4), included patients in whom mutations were detected in only 1 allele. Plasma total metanephrine (420.1 +/- 60.0 vs. 657.7 +/- 67.8 pg/ml; P = 0.04) and free metanephrine (13.4 +/- 1.7 vs. 24.0 +/- 4.1 pg/ml; P = 0.008) concentrations were significantly lower in children with SW CAH than in those with the SV form of the disease. Plasma free metanephrine concentrations best predicted phenotype, with accuracy similar to that of genotype. Concordance rates between genotype and phenotype were higher in the most severely affected patients (Null, 88.9%; A, 93.3%; B, 75%; plasma free metanephrine

Measurements of plasma free metanephrines, normetanephrine (NMN) and metanephrine (MN), provide a sensitive test for diagnosis of pheochromocytoma in adults but have not been evaluated in children. We therefore established reference ranges for plasma and urinary metanephrines and the catecholamines, norepinephrine (NE) and epinephrine (E), in 86 healthy children (age 5-17). A group of 158 healthy adults (age 18-72) served as a comparison group. Pediatric reference ranges were applied to examine the diagnostic utility of the various tests in 45 children evaluated for pheochromocytoma (age 8-17; 38 with von Hippel-Lindau syndrome), with tumors found on 12 occasions. Upper reference limits for E and MN were higher and those for NE and NMN lower in children than in adults. Boys had higher plasma levels of E and MN and higher urinary excretion of all four amines than girls. Plasma free metanephrines provided a diagnostic test with values for sensitivity (100%) and specificity (94%) that were equal to or higher than those of other tests. In two children screened for pheochromocytoma on multiple occasions, use of pediatric reference ranges for plasma free metanephrines indicated the tumor a year earlier than indicated using adult reference ranges. The findings indicate that plasma free metanephrines provide a sensitive tool for detection of pheochromocytoma in children. Age appropriate reference ranges should be used and gender differences should be considered.

Congenital adrenal hyperplasia describes a group of inherited autosomal recessive disorders characterized by an enzymatic defect in cortisol biosynthesis, compensatory increases in corticotropin secretion, and adrenocortical hyperplasia. 21-Hydroxylase deficiency is responsible for more than 95% of cases and is one of the most common known autosomal recessive disorders. The classic or severe type presents in the newborn period or early childhood with virilization and adrenal insufficiency, with or without salt loss; the mild or nonclassic form presents in late childhood or early adulthood with mild hyperandrogenism and is an important cause of masculinization and infertility in women. This wide range of phenotypic expression is mostly explained by genetic variation, although genotype-phenotype discrepancies have been described. Reproductive, metabolic, and other comorbid conditions, including risk for tumors, are currently under investigation in both forms of the disease. A high proportion of patients with adrenal incidentalomas may be homozygous or heterozygous for 21-hydroxylase deficiency. Women with congenital adrenal hyperplasia often develop the polycystic ovary syndrome. Ectopic adrenal rest tissue is often found in the testes of men with congenital adrenal hyperplasia; characteristic clinical and radiologic findings help differentiate this tissue from other tumors. Levels of corticotropin-releasing hormone are elevated in patients with depression and anxiety and are expected to be elevated in patients with congenital adrenal hyperplasia; it is unknown whether patients with 21-hydroxylase deficiency have an increased incidence of these psychiatric disorders. Abnormalities in both the structure and function of the adrenal medulla have been shown in patients with classic congenital adrenal hyperplasia, and the degree of adrenomedullary impairment may be a biomarker of disease severity. The 21-hydroxylase-deficient mouse has provided a useful model with which to examine disease mechanisms and test new therapeutic interventions in classic disease, including gene therapy. Treatment of this condition is intended to reduce excessive corticotropin secretion and replace both glucocorticoids and mineralocorticoids. However, clinical management is often complicated by inadequately treated hyperandrogenism, iatrogenic hypercortisolism, or both. New treatment approaches currently under investigation include combination therapy to block androgen action and inhibit estrogen production, and bilateral adrenalectomy in the most severely affected patients. Other approaches, which are in a preclinical stage of investigation, include treatment with a corticotropin-releasing hormone antagonist and gene therapy.

Long thought to be two separate syndromes, Ehlers-Danlos syndrome hypermobility type (EDS-HT) and benign joint hypermobility syndrome (BJHS) appear on close examination to represent the same syndrome, with virtually identical clinical manifestations. While both EDS-HT and BJHS were long thought to lack the genetic loci of other connective tissue disorders, including all other types of EDS, researchers have discovered a genetic locus that accounts for manifestations of both EDS-HT and BJHS in a small population of patients. However, given the modest sample size of these studies and the strong correlation between serum levels of tenascin-X with clinical symptoms of both EDS-HT and BJHS, strong evidence exists for the origins of both types of hypermobility originating in haploinsufficiency or deficiency of the gene TNXB, responsible for tenascin-X.

Congenital adrenal hyperplasia (CAH) owing to 21-hydroxylase deficiency is a common disorder, and is characterised by a defect in cortisol biosynthesis with or without a defect in aldosterone synthesis and androgen excess. The classic form, also known as the severe form, occurs in 1 : 15 000 births worldwide, while the nonclassic or mild form occurs in approximately 1 : 1000 births worldwide and is much more common (up to 1 : 20) in certain ethnic groups. In classic 21-hydroxylase deficiency, glucocorticoids are given in doses sufficient to suppress adrenal androgen secretion, and mineralocorticoids are given to normalise electrolytes and plasma renin activity. The management of CAH may be complicated by iatrogenic Cushing’s syndrome, inadequately treated hyperandrogenism, or both. Prenatal treatment may decrease virilisation of the affected female foetus, but the efficacy and safety of treating CAH prenatally remains to be fully defined. Close clinical monitoring of growth and development is essential to optimise treatment outcome. New treatment approaches are currently under investigation in the most severely affected patients, while nonclassic CAH does not always require treatment.

During the past 50 years since the discovery of cortisone therapy as an effective treatment for CAH, many advances have been made in the management of 21-hydroxylase deficiency. Despite these advances, the clinical management of patients with CAH is often complicated by abnormal growth and development, iatrogenic Cushing's syndrome, inadequately treated hyperandrogenism, and infertility. New treatment approaches to classic CAH represent potential solutions to these unresolved issues. At the National Institutes of Health, a long-term randomized clinical trial is investigating a new treatment regimen: a reduced hydrocortisone dose, an antiandrogen, and an aromatase inhibitor. Peripheral blockade of androgens may also be helpful in the adult woman with CAH and PCOS. Other promising new treatment approaches include LHRH agonist-induced pubertal delay with or without growth hormone therapy, alternative glucocorticoid preparations or dose schedules, CRH antagonist treatment, and gene therapy. The applicability and success of these new approaches await the results of current research.

In July 1998, Cortef oral suspension (Pharmacia & Upjohn) was reformulated changing the suspending agent tragacanth to xanthan gum. We subsequently observed suboptimal control of hormone levels in a group of children with classic congenital adrenal hyperplasia, despite increasing doses of Cortef suspension and stringent instructions to parents regarding shaking of the bottles of medication. Nineteen children receiving Cortef and fludrocortisone therapy were changed to hydrocortisone tablets and fludrocortisone, with a 10 percent reduction in hydrocortisone dose. A significant decrease in 17-hydroxyprogesterone (235 +/- 120 vs. 27 +/- 7 nmol/L; p

Glucocorticoids are essential for the normal development and functioning of the adrenal medulla. Whether adrenomedullary structure and function are normal in patients with congenital adrenal hyperplasia is not known.We measured plasma and urinary catecholamines and plasma metanephrines in 38 children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (25 children with the salt-wasting form and 13 with the simple virilizing form), 39 age-matched normal subjects, and 20 patients who had undergone bilateral adrenalectomy. Adrenal specimens obtained from three other patients with 21-hydroxylase deficiency who had undergone bilateral adrenalectomy and specimens obtained at autopsy from eight other patients were examined histologically.Plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were 40 to 80 percent lower in the patients with congenital adrenal hyperplasia than in the normal subjects (P0.05), and the values were lowest in the patients with the most severe deficits in cortisol production. Urinary epinephrine excretion and plasma epinephrine concentrations were at or below the limit of detection of the assay in 8 (21 percent) of the patients with congenital adrenal hyperplasia and in 19 (95 percent) of the patients who had undergone adrenalectomy. In the group of patients with congenital adrenal hyperplasia, plasma epinephrine and metanephrine concentrations and urinary epinephrine excretion were approximately 50 percent lower in those who had been hospitalized for adrenal crises than in those who had not. In three patients with congenital adrenal hyperplasia who had undergone bilateral adrenalectomy, the formation of the adrenal medulla was incomplete, and electron-microscopical studies revealed a depletion of secretory vesicles in chromaffin cells.Congenital adrenal hyperplasia compromises both the development and the functioning of the adrenomedullary system.

Treatment outcome in congenital adrenal hyperplasia is often sub-optimal due to hyperandrogenism, treatment-induced hypercortisolism, or both. We previously reported better control of linear growth, weight gain, and bone maturation in a short term cross-over study of a new four-drug treatment regimen containing an antiandrogen (flutamide), an inhibitor of androgen to estrogen conversion (testolactone), reduced hydrocortisone dose, and fludrocortisone, compared to the effects of a control regimen of hydrocortisone and fludrocortisone. Twenty-eight children have completed 2 yr of follow-up in a subsequent long term randomized parallel study comparing these two treatment regimens. During 2 yr of therapy, compared to children receiving hydrocortisone, and fludrocortisone treatment, children receiving flutamide, testolactone, reduced hydrocortisone dose (average of 8.7 +/- 0.6 mg/m2 x day), and fludrocortisone had significantly (P < or = 0.05) higher plasma 17-hydroxyprogesterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone levels. Despite elevated androgen levels, children receiving the new treatment regimen had normal linear growth rate (at 2 yr, 0.1 +/- 0.5 SD units), and bone maturation (at 2 yr, 0.7 +/- 0.3 yr bone age/yr chronological age). No significant adverse effects were observed after 2 yr. We conclude that the regimen of flutamide, testolactone, reduced hydrocortisone dose, and fludrocortisone provides effective control of congenital adrenal hyperplasia with reduced risk of glucocorticoid excess. A long term study of this new regimen is ongoing.

The second most common cause of congenital adrenal hyperplasia is 11 beta-hydroxylase deficiency, an autosomal recessive disorder. We performed genetic analysis of CYP11B1, the gene encoding steroid 11 beta-hydroxylase, in three patients with classic 11 beta-hydroxylase deficiency. Herein we describe the first splice donor site mutation, a new nonsense mutation, and a new missense mutation in this disorder. An African-American patient was found to be a compound heterozygote for a codon 318 + 1G --A substitution at the 5'-splice donor site of intron 5, in combination with Q356X, a nonsense mutation previously reported in an African-American patient. A Caucasian patient was found to be a compound heterozygote with a novel missense mutation, T318R, in combination with a previously reported 28-bp deletion in exon 2. A different mutation at codon 318 (T318M) has been described previously. A Caucasian patient was heterozygous for a novel nonsense mutation (Q19X) in exon 2. The second mutation was not identified in this patient. Multiple apparent polymorphisms were also observed. Two of these polymorphisms in CYP11B1 represent sequences from CYP11B2, suggesting that gene conversion may have occurred. In summary, we have identified three novel mutations and two previously reported mutations in CYP11B1 patients with 11 beta-hydroxylase deficiency. Our data suggest the presence of a mutational hot spot at codon 318 of CYP11B1, and the possibility of a founder effect in frequently identified mutations.

Pyoderma gangrenosum (PG) may occur as a purely cutaneous disorder, but is usually seen in adults with inflammatory bowel disease 1-3 or malignancy.a, 5 Although PG has been described in children with no underlying systemic disease, 6, 7 it has never been reported in association with Iracheitis. We describe a 9-month-old boy with PG in whom respiratory failure developed as a result of a noninfectious necrotizing tracheitis.

To the Editor: Congenital adrenal hyperplasia due to 21-hydroxylase deficiency results in deficient production of cortisol and aldosterone, chronic stimulation of the adrenal cortex by corticotropi...

Congenital adrenal hyperplasia describes a group of inherited autosomal recessive disorders characterized by an enzymatic defect in cortisol biosynthesis, compensatory increases in corticotropin secretion, and adrenocortical hyperplasia. 21-Hydroxylase deficiency is responsible for more than 95% of cases and is one of the most common known autosomal recessive disorders. The classic or severe type presents in the newborn period or early childhood with virilization and adrenal insufficiency, with or without salt loss; the mild or nonclassic form presents in late childhood or early adulthood with mild hyperandrogenism and is an important cause of masculinization and infertility in women. This wide range of phenotypic expression is mostly explained by genetic variation, although genotype-phenotype discrepancies have been described. Reproductive, metabolic, and other comorbid conditions, including risk for tumors, are currently under investigation in both forms of the disease. A high proportion of patients with adrenal incidentalomas may be homozygous or heterozygous for 21-hydroxylase deficiency. Women with congenital adrenal hyperplasia often develop the polycystic ovary syndrome. Ectopic adrenal rest tissue is often found in the testes of men with congenital adrenal hyperplasia; characteristic clinical and radiologic findings help differentiate this tissue from other tumors. Levels of corticotropin-releasing hormone are elevated in patients with depression and anxiety and are expected to be elevated in patients with congenital adrenal hyperplasia; it is unknown whether patients with 21-hydroxylase deficiency have an increased incidence of these psychiatric disorders. Abnormalities in both the structure and function of the adrenal medulla have been shown in patients with classic congenital adrenal hyperplasia, and the degree of adrenomedullary impairment may be a biomarker of disease severity. The 21-hydroxylase-deficient mouse has provided a useful model with which to examine disease mechanisms and test new therapeutic interventions in classic disease, including gene therapy. Treatment of this condition is intended to reduce excessive corticotropin secretion and replace both glucocorticoids and mineralocorticoids. However, clinical management is often complicated by inadequately treated hyperandrogenism, iatrogenic hypercortisolism, or both. New treatment approaches currently under investigation include combination therapy to block androgen action and inhibit estrogen production, and bilateral adrenalectomy in the most severely affected patients. Other approaches, which are in a preclinical stage of investigation, include treatment with a corticotropin-releasing hormone antagonist and gene therapy.

SELECTED CASE A female patient, now 7 years 6 months old, had developed pubic hair at approximately 2 years of age. At 4 years of age she developed acne and was taken to a pediatrician. Findings on physical examination included a height of 109 cm (95th percentile), a weight of 17 kg (75th percentile), Tanner I breasts, Tanner II pubic hair, clitoromegaly (clitoral index of 49 mm 2 ; normal, 1 2 ), posterior labial fusion, and acne. The bone age was advanced (6 years 10 months). Serum levels were as follows: 17-hydroxyprogesterone, 380 nmol/L (normal

In a sample of 301 men, aged 54-62 years, who were employed in the telephone industry in New Jersey, and who were followed prospectively from 1963/1964 to 1984, 65 of 148 deaths were manifested by the abrupt occurrence of fatal ventricular arrhythmias. On multivariate analysis, the factors present at the initial examination that were significantly related to the subsequent occurrence of arrhythmic deaths were: abnormal patterns of QRS conduction; the level of blood pressure; the number of cigarettes currently being smoked; chronic myocardial ischemia; chronic airway disease; and failure to engage in any exercise or heavy physical activity. Among 28 other potential risk factors representing myocardial disorders, ventricular dysrhythmias, other disorders of cardiac rate, rhythm, conduction, and repolarization, and non-cardiac risk factors (including cholesterol level, serum uric acid level, diabetes mellitus, alcohol intake, general arteriosclerosis, other non-cardiac disease, and social, behavioral, and attitudinal variables), none significantly added to risk for arrhythmic death. The risk factors related to the subsequent occurrence of other deaths, manifested by the gradual development of circulatory failure, were significantly different from the risk factors related to arrhythmic deaths.