Inherited congenital adrenal hyperplasia in the rabbit: absent cholesterol side-chain cleavage cytochrome P450 gene expression.

We investigated adrenal steroidogenic enzymes, their activity and mRNA expression, and in vitro biosynthesis of an enzyme in rabbits with congenital adrenal hyperplasia (CAH; weight: CAH, 19 +/- 5 mg/adrenal; normal, 2.7 +/- 1.0 mg/adrenal). Serum pregnenolone (delta 5-P) levels in CAH newborn rabbits (12-36 h) were normal (mean/range, 438/51-2191 ng/dl), but corticosterone levels were low [0.05 +/- 0.05 microgram/dl; P less than 0.001 vs. normal (0.66 +/- 0.57)]. Serum Na+ levels in CAH newborn rabbits were in the normal range (143 +/- 30 meq/liter), but K+ levels were elevated [7 +/- 1.1 meq/liter; P less than 0.05 vs. normal (5.9 +/- 0.6 meq/liter)]. Minced normal adrenal tissue incubated with [3H] cholesterol (30-100 pmol/flask) and ACTH (100 mU/flask) produced [3H]delta 5-P (newborn, 21 and 45 fmol/100 mg; adult, 3 and 5 fmol/100 mg) and [3H]corticosterone (newborn, 23 fmol/100 mg; adult, 11.3 fmol/100 mg), but CAH adrenals produced no product (less than 1.3 fmol/100 mg). Adrenal mitochondria from normal newborn rabbits produced delta 5-P (4.4-7 nmol/mg protein), but CAH adrenals did not, while CAH adrenal mitochondria demonstrated over 4 times greater 11 beta-hydroxylase activity. A Western blot of adrenal homogenate from normal newborn rabbits revealed a cholesterol side-chain cleavage cytochrome P450 (P450scc)-immunoreactive species (mol wt, 53 x 10(3), but this species was absent in CAH adrenals; CAH adrenals had a normal adrenodoxin and intensified 17 alpha-hydroxylase cytochrome P450 (P450(17)alpha) band compared to normal adrenals. In vitro translation of RNA in a cell-free rabbit reticulocyte lysate system containing [35S] methionine yielded a precursor P450scc protein (mol wt, 58.5 x 10(3)) with normal adrenal RNA, but not with CAH adrenal RNA. P450scc mRNA was detected in all normal adrenals, but was not detected in all CAH adrenals. 21-Hydroxylase cytochrome P450 mRNA expression was detected at a similar level in both normal and CAH adrenals. We conclude that CAH in the rabbit is caused by inherited absent P450scc gene expression. The clinical, pathological, and biochemical manifestations of P450scc deficiency in the rabbit are nearly identical to the human disorder. Increased 11 beta-hydroxylase activity and increased P450(17)alpha on Western blot of CAH adrenals indicate altered gene expression of other steroidogenic enzymes due to CAH. Further molecular analysis of the P450scc gene in this animal CAH model will facilitate understanding of P450scc deficiency CAH.     

P450 oxidoreductase deficiency: a new disorder of steroidogenesis affecting all microsomal P450 enzymes

Combined partial deficiency of 17alpha-hydroxylase and 21-hydroxylase activities was first described in 1985; however the genes for P450c17 and P450c21 in these patients lack mutations. In 1986 we postulated that this disorder might be due to mutations in P450 oxidoreductase (POR), the flavoprotein that donates electron to these and all other microsomal P450 enzymes, but this hypothesis was not tested until the POR gene sequence became available through the genome database. We found five POR missense mutations in our first four patients. In vitro assays of the activities of these mutations showed that the standard assay of POR activity, reduction of cytochrome c, correlated poorly with the patients' phenotypes, but that assays of POR-supported 17alpha-hydroxylase and 17,20 lyase activities correlated well. POR deficiency is a new disorder of adrenal and gonadal steroidogenesis that affects all microsomal cytochrome P450 enzymes, hence may have important implications for genetic differences in drug metabolism.     

Congenital adrenal hyperplasia and P450 oxidoreductase deficiency

Congenital adrenal hyperplasia (CAH) comprises a group of autosomal recessive disorders, which are usually due to inactivating mutations in single enzymes involved in adrenal steroid biosynthesis. The characteristics of the biochemical and clinical phenotype depend on the specific enzymatic defect. In 21-hydroxylase and 11beta-hydroxylase deficiency only adrenal steroidogenesis is affected, whereas a defect in 3beta-hydroxysteroid dehydrogenase or 17alpha-hydroxylase also involves gonadal steroid biosynthesis. Recently, mutations in the electron donor enzyme P450 oxidoreductase were identified as the cause of CAH with apparent combined 17alpha-hydroxylase and 21-hydroxylase deficiency, thereby illustrating the impact of redox regulation enzymes on steroidogenesis. P450 oxidoreductase deficiency (ORD) has a complex phenotype including two unique features not observed in any other CAH variant, skeletal malformations and severe genital ambiguity in both sexes. Despite invariably low circulating androgens, females with ORD may present with virilized genitalia and mothers may suffer from virilization during pregnancy. This apparently contradictory finding may be explained by the existence of an alternative pathway in human androgen biosynthesis, with important implications for physiology and pathophysiology. This review discusses the biochemical and clinical presentation and the genetic and functional basis of the currently known CAH variants, with a specific focus on ORD.     

Long term outcome in adult males with classic congenital adrenal hyperplasia.

The effects of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency on final height and fertility were evaluated in 30 affected males, aged 17-43 yr. The mean adult height of these patients was 165.64 +/- 8.4 cm (mean +/- SD), with a mean SD score of -1.65 +/- 1.2 cm. The difference between the mean final height SD score and mean target height SD score was -1.67 +/- 1.0 cm. All patients had short stature and did not reach their estimated target heights. There was no difference in height SD score between the salt-wasting and simple virilizing CAH patients. No correlation between the final height and degree of hormonal control or bone age advancement was observed. Of the 30 subjects, 18 had testicular sonograms. Abnormal sonogram findings of testicular adrenal rests were present in 9 patients (group 1), whereas sonogram without adrenal rests comprised the remaining 9 patients (group 2). In group 1, 8 of 9 patients and in group 2, 4 of 9 patients were salt-wasters; the remainder were simple virilizers. In group 1, 7 of 9 patients had semen analysis, and all were judged infertile. Of the 6 patients in group 2 who had semen analysis, 1 was azoospermic, and the remainder were normal. During optimal adrenal hormone suppression, gonadotropins at baseline and after GnRH stimulation were significantly higher in group 1 than in group 2, reflecting the loss of Leydig cell function to secrete testosterone. In conclusion, adult males affected with CAH due to 21-hydroxylase deficiency do not achieve the height predicted from parental heights. The presence of adrenal rests within the testes of adult males with classic CAH are more frequent in the salt-wasting form and are associated with a higher risk for infertility.     

21-羟化酶缺陷型先天性肾上腺皮质增生症治疗现状

21-羟化酶缺陷型先天性肾上腺皮质增生症是一类常见的人类常染色体隐性遗传病.患儿可具有失盐、脱水、两性畸形、假性性甲熟及肾上腺危象等临床征象,如何治疗该病一直为学者们所关注.近年来,在产前及出生后药物治疗领域,一些新兴药物及治疗方案在减轻患儿代谢紊乱,改善患儿身高等方面显示出了良好疗效.此外,针对该遗传性疾病的基因治疗...     

Prenatal dexamethasone treatment does not prevent alterations of the hypothalamic pituitary adrenal axis in steroid 21-hydroxylase deficient mice.

A major difficulty in the clinical management of congenital adrenal hyperplasia (CAH) is adjustment of glucocorticoid doses to suppress ACTH and androgens without causing iatrogenic hypercortisolism. The possibility that structural alterations of the adrenal or a dysfunction of the hypothalamic pituitary adrenal (HPA) axis caused by glucocorticoid deficiency during fetal life contribute to this problem was studied in 21-hydroxylase deficient mice caused by deletion of the cytochrome P-450 21-hydroxylase gene. Homozygotes showed about 200-fold elevations in plasma progesterone, hyperplastic adrenal cortices lacking zonation, and structural alterations of adrenocortical mitochondria. Histochemical studies showed increases in hypothalamic CRH messenger RNA (mRNA) and immunoreactive (ir) CRH, and pituitary POMC mRNA in homozygous mice. VP mRNA levels in PVN perikarya were normal, but irVP in parvicellular terminals of the median eminence was increased in homozygotes. Prenatal dexamethasone treatment (0.5 to 2 microg/day) prevented the increases in CRH mRNA, whereas dexamethasone only partially decreased POMC mRNA levels, and had no effect on serum progesterone levels. The data suggest that intrauterine glucocorticoid deficiency in CAH causes hyperactivity of the hypothalamic-pituitary-corticotroph axis and insensitivity to glucocorticoid feedback. These studies in 21-hydroxylase deficient mice may provide new insights on the mechanism, clinical manifestations and management of some types of human CAH.     

Treatment with growth hormone and luteinizing hormone releasing hormone analog improves final adult height in children with congenital adrenal hyperplasia

Final adult height is often compromised in children with congenital adrenal hyperplasia (CAH). This study examines the impact of GH and LHRH analog (LHRHa) on final adult height in patients with CAH due to 21-hydroxylase deficiency. Fourteen patients with CAH (eight males, six females) predicted to be more than 1.0 sd below their midparental target height received GH and LHRHa until final height. Each patient was matched at the start of GH therapy to a CAH patient treated only with glucocorticoids according to type of CAH, sex, and chronological age. Mean age, bone age, height, height prediction, and target height were the same in both groups at the beginning of GH therapy. Mean duration of GH treatment was 4.4 +/- 1.5 yr. Mean duration of LHRHa therapy was 4.2 +/- 2.0 yr. In the treatment group, final height sd score of -0.4 + 0.8 was significantly greater than both the initial prediction of -1.5 +/- 0.9 (P < 0.0001) and the final height sd score of the untreated group of -1.4 +/- 1.1 (P = 0.01). Our results indicate that the combination of GH and LHRHa improves final adult height in patients with CAH.     

Congenital adrenal hyperplasia: transition from chil dhood to adulthood.

Congenital adrenal hyperplasia (CAH) is a group of disorders caused by inborn errors of steroid metabolism. The most common form owing to 21-hydroxylase deficiency (CAH-21OHD) is present in about 1:10,000- 1:15,000 live births worldwide. In its classic salt-wasting form (-66-75% of cases) patients may suffer potentially lethal adrenal insufficiency. Non-salt-wasting forms of CAH-21 OHD are recognized by genital ambiguity in affected females, and by signs of androgen excess in later childhood in males. Non-classic CAH-21 OHD may be detected in up to 1-3% of certain populations, and is often mistaken for idiopathic precocious pubarche in children or polycystic ovary syndrome in young women. This chapter will address issues relating to transition of CAH care from the pediatric to the adult endocrinologist.     

Fractures and bone mineral density in adult women with 21-hydroxylase deficiency

CONTEXT: Patients with classical congenital adrenal hyperplasia (CAH) receive lifelong, often supraphysiological, glucocorticoid therapy. Pharmacological doses of glucocorticoids are an established risk factor for osteoporosis. OBJECTIVE: Our objective was to evaluate bone mineral density (BMD), fracture prevalence, and markers of bone metabolism in adult females with CAH. DESIGN: This was a cross-sectional observational study. SETTING: Tertiary care referral centers were used in this study. PARTICIPANTS: We studied 61 women, aged 18-63 yr, with genetically verified CAH due to 21-hydroxylase deficiency. They were patients with salt wasting (n = 27), simple virilizing (n = 28), and nonclassical 21-hydroxylase deficiency (n = 6). A total of 61 age-matched women were controls. MAIN OUTCOME MEASURES: History of fractures was recorded. Total body, lumbar spine, and femoral neck BMD were measured by dual-energy x-ray absorptiometry. The World Health Organization criteria for osteopenia and osteoporosis were used. Serum marker of bone resorption, beta-C telopeptide was studied. RESULTS: The mean glucocorticoid dose in hydrocortisone equivalents was 16.9 +/- 0.9 mg/m2. Patients had lower BMD than controls at all measured sites (P < 0.001). In patients younger than 30 yr old, 48% were osteopenic vs. 12% in controls (P < 0.009). In patients 30 yr or older, 73% were osteopenic or osteoporotic vs. 21% in controls (P < 0.001). BMD was similar in the two classical forms and had no obvious relationship to genotypes. beta-C-telopeptide was decreased in older patients. More fractures were reported in patients than controls (P < 0.001). The number of vertebrae and wrist fractures almost reached significance (P = 0.058). CONCLUSIONS: Women with CAH have low BMD and increased fracture risk. BMD should be monitored, adequate prophylaxis and treatment instituted, and glucocorticoid doses optimized from puberty.     

Cryptic 21-hydroxylase deficiency in families of patients with classical congenital adrenal hyperplasia

Serum androgens and 17-hydroxyprogesterone concentrations and HLA genotypes were determined in 124 families of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH). In 8 pedigrees, we discovered 16 pubertal or postpubertal family members of either sex who had biochemical evidence of 21-hydroxylase deficiency but were without clinical symptoms of excess virilism, amenorrhea, or infertility. We designated these family members as individuals with cryptic 21-hydroxylase deficiency. Within each generation, the family members with cryptic 21-hydroxylase deficiency were HLA identical. It is proposed that these family members are genetic compounds, having 21-hydroxylase deficiency as a result of two recessive gene defects: 1) a severe 21-hydroxylase gene defect present in the index case with classical CAH (21-OHCAH) and 2) a mild 21-hydroxylase gene defect (21-OHCRYPTIC). Thus, the CAH genotype in the family members with cryptic 21-hydroxylase deficiency is 21-OHCAH/21-OHCRYPTIC. Lod score analysis for linkage between the cryptogenic 21-OH trait and HLA gave a combined Lod score for males and females of theta = 0.00 of 3.409. Close genetic linkage between HLA and 21-OHCRYPTIC was thus established. This study provides support for the previously reported heterogeneity of 21-hydroxylase deficiency which may result from allelic variability at the locus for steroid 21-hydroxylase.     

Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency

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, <18.5 pg/ml: SW, 92%). The plasma free metanephrine concentration correlated with the expected 21-hydroxylase activity based on genotype, and there was a significant trend for free metanephrine concentrations across the three genotype groups (P < 0.0001). Our findings indicate that measurement of adrenomedullary function, best assessed by the free metanephrine concentration, is a useful biomarker of disease severity in 21-hydroxylase deficiency. Molecular genotype and plasma free metanephrine concentration predict phenotype with similar accuracy. Both methods are more accurate in the most severe forms of the disease.     

Three novel point mutations of the CYP21 gene detected in classical forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH) [OMIM 201 910] is a group of autosomal recessive disorders most commonly due to 21-hydroxylase deficiency and presenting with a wide range of clinical manifestations. A limited number of inactivating pseudogene-derived mutations account for the majority of 21-hydroxylase gene ( CYP21) mutations, additional rare mutations can be found in single families and small populations. We found three novel CYP21 mutations in CAH patients suffering from the classical form of the disease, of which one is a frameshift mutation (1353-1354insA) leading to a premature termination codon (K277K, Q228A...E294X), one results in a premature stop codon (2551C>T, R444X), and one is a missense mutation (2609T>C; P463L). The frameshift and premature stop mutations can be predicted to result in a CYP21 protein without any residual enzyme activity. To determine the functional consequences of the P463L mutation, the IN VITRO enzyme activity was studied in COS-7 cells and revealed a reduced 21-hydroxylase activity of 2.6+/-0.8 (SD)% for the conversion of 17-hydroxyprogesterone (17OHP) to 11-deoxycortisol and of 3.0+/-0.5 % for the conversion of progesterone to 11-deoxycorticosterone (DOC). We conclude that functional analyses of unknown mutations provide information on the disease severity and should be always performed when novel CYP21 mutations are detected. Knowledge of the residual 21-hydroxylase function improves both genetic counselling and individual clinical management in CAH patients.     

Congenital adrenal hyperplasia caused by 21-hydroxylase deficiency. Its molecular basis and its remaining therapeutic problems

This article discusses congenital adrenal hyperplasia (CAH) caused by a deficiency of 21-hydroxylase, which represents 90% of all cases of CAH. As in other genetic disorders of metabolism, the symptoms of CAH are related to both the decrease of the final products of metabolism and the accumulation of precursors that are not normally secreted or that are secreted in only very small amounts. The biochemistry, pathophysiology, treatment, genetics, and long-term follow-up (including fertility and sexual orientation) of both the simple virilizing form and the salt-losing form of 21-hydroxylase deficiency are presented, as well as the possibility of prenatal treatment.     

P450XXI (steroid 21-hydroxylase) gene deletions are not found in family studies of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia (CAH) is a common genetic disorder due to defective 21-hydroxylation of steroid hormones. The human P450XXIA2 gene encodes cytochrome P450c21 [steroid 21-monooxygenase (steroid 21-hydroxylase), EC 1.14.99.10], which mediates 21-hydroxylation. The P450XXIA2 gene may be distinguished from the duplicated P450XXIA1 pseudogene by cleavage with the restriction endonuclease Taq I, with the XXIA2 gene characterized by a 3.7-kilobase (kb) fragment and the XXIA1 pseudogene characterized by a 3.2-kb fragment. Restriction endonuclease mapping by several laboratories has suggested that deletion of the P450XXIA2 gene occurs in about 25% of patients with CAH, as their genomic DNA lacks detectable 3.7-kb Taq I fragments. We have cloned human P450c21 cDNA and used it to study genomic DNA prepared from 51 persons in 10 families, each of which includes 2 or more persons with CAH. After Taq I digestion, apparent deletions are seen in 7 of the 20 alleles of the probands; using EcoRI, apparent deletions are seen in 9 of the 20 alleles. However, the apparently deleted alleles seen with Taq I do not coincide with those seen with EcoRI. Furthermore, studies with Bgl II, EcoRI, Kpn I, and Xba I yield normal patterns with at least two enzymes in all cases. Since all probands yielded normal patterns with at least two of the five enzymes used, we conclude that the P450XXIA2 gene "deletions" widely reported in CAH patients probably represent gene conversions, unequal crossovers, or polymorphisms rather than simple gene deletions.     

Pituitary-adrenal responses to corticotropin-releasing hormone in different degrees of adrenal 21-hydroxylase deficiency.

21-Hydroxylase congenital adrenal hyperplasia (21-OHCAH) involves a primary defect of the adrenal gland and a secondary involvement of ACTH secretion. The responses of the pituitary-adrenal axis to ovine CRH (oCRH, 1 micrograms/kg) were examined in subjects with different degrees of 21-OH deficiency. We studied 43 subjects: 7 classical and 6 nonclassical (NC) 21-OHCAH patients, 15 heterozygotes (HT) and 15 control subjects. Baseline plasma ACTH levels were higher in classical CAH than in NC-CAH, HT, and control subjects (mean +/- SEM, 66 +/- 14, 6 +/- 1.6, 4 +/- 0.5, and 5 +/- 0.5 pmol/L, respectively). The mean plasma ACTH response to oCRH in NC-CAH (17 +/- 3 pmol/L) was higher than in controls and HT (9 +/- 0.8 and 11 +/- 1.5 pmol/L). The highest ACTH responses to oCRH were obtained for classical CAH patients (126 +/- 29 pmol/L). Plasma cortisol rose after oCRH in control, HT, and NC-CAH patients but did not change in classical CAH. After oCRH, plasma 17-hydroxyprogesterone (17-OHP) were 4 +/- 0.5, 8 +/- 1.6, 93 +/- 28, and 359 +/- 110 nmol/L for controls, HT, NC-CAH, and classical patients, respectively. There was a significant correlation (r = 0.70) between 17-OHP and the ACTH responses to oCRH. The 17-OHP responses to oCRH were also correlated (r = 0.94) with the 17-OHP responses to the synthetic ACTH test. We conclude that the release of endogenous ACTH by oCRH result in graded 17-OHP responses on 21-OH deficiency. The present study also suggests that different degrees of adrenal biosynthetic defect may result in graded ACTH responses to oCRH.     

Molecular genetic analysis of Tunisian patients with a classic form of 21-hydroxylase deficiency: identification of four novel mutations and high prevalence of Q318X mutation

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders mainly due to defects in the steroid 21-hydroxylase (CYP21) gene. To determine the mutational spectrum in the Tunisian CAH population, the CYP21 active gene was analyzed in 51 unrelated patients using our cascade strategy (digestion by restriction enzyme, sequencing). All patients had a classical form of 21-hydroxylase deficiency. Mutations were detected in over 94% of the chromosomes examined. The most frequent mutation in the Tunisian CAH population was found to be Q318X, with large prevalence (35.3%), in contrast to 0.5-13.8% described in other series. Incidence of other mutations does not differ, as previously described: large deletions (19.6%), mutation in intron 2 (17.6%), and I172N (10.8%). Four novel mutations were found in four patients with the salt-wasting form. These four novel mutations include three point mutations that have not been reported to occur in the CYP21P pseudogene: R483W, W19X, 2669insC, and one small conversion of DNA sequence from exon 5 to exon 8. Our results have shown a good genotype/phenotype correlation in the case of most mutations. This is the first report of screening for mutations of 21-hydroxylase gene in the Tunisian population and even in the Arab population.     

Cardiovascular risk factors and ultrasound evaluation of intima-media thickness at common carotids, carotid bulbs, and femoral and abdominal aorta arteries in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a tendency for obesity, high insulin, and high 24-h blood pressure levels has been reported in children and adolescents. Increased intima-media thickness (IMT) is considered a measure of subclinical atherosclerosis and a predictor of myocardial infarction and stroke. OBJECTIVE: The objective of the study was to evaluate glucose metabolism, lipid profile, IMT of the abdominal aorta, right and left common carotids, carotid bulbs, and common femoral arteries in adult CAH patients. Subjects: Nineteen (10 females, nine males; 28 +/- 3.5 yr) patients (12 salt wasting and seven simple virilizing) and 19 (10 females, nine males) healthy subjects matched for anthropometric parameters (age, sex, body mass index, smoking habit, waist to hip ratio, and blood pressure). METHODS: Glucose metabolism was studied using the oral glucose tolerance test and the homeostasis model assessment-insulin resistance. The echo-Doppler was used for arterial ultrasound. 17-Hydroxyprogesterone, androstenedione, testosterone, ACTH, plasma renin activity, total and high-density lipoprotein cholesterol, and triglycerides were measured. RESULTS: CAH patients had significantly higher fasting plasma insulin (11.6 +/- 6.20 microU/ml vs 5.18 +/- 2.4 microU/ml; P < 0.0001) and homeostasis model assessment-insulin resistance than controls (2.46 +/- 1.92 vs 1.12 +/- 0.58; P = 0.0033). IMT of the studied arteries was higher in CAH patients than controls. There was no correlation between IMT and cumulative glucocorticoid doses and androgen levels. CONCLUSION: A reduced insulin sensitivity and increased IMT were demonstrated in adults with CAH, who consequently need a follow-up for cardiovascular risk.     

Attenuated forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency

A variety of mild forms of congenital adrenal hyperplasia (CAH) due to partial 21-hydroxylase deficiency have recently been described. We report two families in whom members presented with CAH with various degrees of enzyme deficiency. In family A, two children had the classical salt-losing CAH. Their male sibling and mother presented a very mild asymptomatic form of CAH, characterized by elevated basal plasma levels of 17-hydroxyprogesterone (17-OHP) and exaggerated responses of progesterone and 17-OHP to ACTH stimulation. The Hormonal profile and HLA types of these two individuals suggested allelic compounds, having one mutant gene for classical CAH and another for a mild form. In family B, the proband presented an attenuated form of CAH, manifested by amenorrhea and hirsutism, elevated basal levels of plasma 17-OHP and androgens, as well as markedly increased ACTH response. Two of her four siblings had the same ad HLA type, elevated basal plasma 17-OHP levels, and increased ACTH response. Their father, their paternal aunt, and their paternal uncle had the ab HLA type and normal basal plasma 17-OHP but markedly increased ACTH response. The haplotypes a, b, and d were considered to be linked to a mutation resulting in mild 21-hydroxylase deficiency, the homozygotes with ab HLA type having a milder form of CAH than the homozygotes with the ad HLA type. The wide spectrum of clinical and hormonal characteristics among homozygotes for the 21-hydroxylase deficiency trait suggests that their is a continuum of degree of enzyme deficiency. Furthermore, it suggests that most nonclassical subjects are allelic compounds for variable degrees of severity in the mutation at the 21-hydroxylase locus. More specifically, the study of families A and B shows that the so-called cryptic and attenuated forms of CAH have the same pathophysiological basis.     

IS SALT-WASTING IN CONGENITAL ADRENAL HYPERPLASIA DUE TO THE SAME GENE AS THE FASCICULATA DEFECT?

Clinical studies in patients with 21-hydroxylase deficiency congenital adrenal hyperplasia (CAH) were designed to ascertain the genetics of the salt-wasting component of the disorder. The gene controlling aldosterone biosynthesis may not be the same gene that controls 21-hydroxylase in the adrenal zona fasciculata. This we infer from the following clinical observations: (1) concordance for salt-wasting is not observed in all HLA-identical sibs with CAH; (2) the defect in aldosterone biosynthesis does not persist throughout life as does the fasciculata defect; (3) there is a significantly increased gene frequency of B40 and Bw47 in salt-wasting CAH; (4) obligate heterozygote parents of patients with salt-wasting CAH do not express a partial defect in aldosterone biosynthesis, as they do in the fasciculata. These observations cast doubt on the accepted concept of the autosomal recessive transmission of the glomerulosa 21-hydroxylase deficiency.     

Extensive clinical experience: nonclassical 21-hydroxylase deficiency

CONTEXT: Nonclassical congenital adrenal hyperplasia (CAH) owing to steroid 21-hydroxylase deficiency (NC21OHD) is the most frequent of all autosomal recessive genetic diseases, occurring in one in 100 persons in the heterogeneous New York City population. NC21OHD occurs with increased frequency in certain ethnic groups, such as Ashkenazi Jews, in whom one in 27 express the disease. NC21OHD is underdiagnosed in both male and female patients with hyperandrogenic symptoms because hormonal abnormalities in NC21OHD are only mild to moderate, not severe as in the classical form of CAH. Unlike classical CAH, NC21OHD is not associated with ambiguous genitalia of the newborn female. MAIN OUTCOME MEASURES: The hyperandrogenic symptoms include advanced bone age, early pubic hair, precocious puberty, tall stature, and early arrest of growth in children; infertility, cystic acne, and short stature in both adult males and females; hirsutism, frontal balding, polycystic ovaries, and irregular menstrual periods in females; and testicular adrenal rest tissue in males. CONCLUSIONS: The signs and symptoms of hyperandrogenism are reversed with dexamethasone treatment.