Abnormal steroidogenesis in three patients with Antley-Bixler syndrome: apparent decreased activity of 17alpha-hydroxylase, 17,20-lyase and 21-hydroxylase.

BACKGROUND: Antley-Bixler syndrome (ABS) is characterized mainly by abnormal skeletal morphogenesis such as craniosynostosis and radiohumeral synostosis, and by ambiguous genitalia in some cases. The mechanisms resulting in these deformities have not been determined. METHODS: The adrenal and gonadal function of three Japanese ABS patients were evaluated. Patient 1 (17-year-old-male) had bilateral cryptoorchidism, delayed puberty and symptoms of glucocorticoid deficiency. Patient 2 (14-year-old male) and patient 3 (4-year-old female) presented with emaciation. Additionally, patient 3 had partial labial fusion and common urogenital sinus. In each patient, blood sampling for steroid analysis before and after rapid adrenocorticotropic hormone (ACTH) stimulation was carried out. Additionally, urinary steroids were quantified. Molecular analysis of CYP17 and CYP21A2 were also performed. RESULTS: All patients showed elevated basal 17alpha-deoxysteroid levels. Although the 17alpha-deoxysteroid levels further increased after rapid ACTH stimulation, 17alpha-hydroxysteroids including cortisol did not respond, suggesting impaired 17alpha-hydroxylation. Patient 1 and patient 2 showed low adrenal androgen blood levels both before and after rapid ACTH stimulation. Patient 3 showed lower than normal excretions of urinary androgens. Additionally, a prolonged ACTH stimulation in patient 3 failed to elicit significant increase of adrenal androgens. These findings suggested impaired 17,20-lyase activity. In contrast to attenuated 17alpha-hydroxycorticosteroids, notably cortisol, elevated 17alpha-hydroxyprogesterone (17OHP) levels were observed, not only in pubertal patients (1 and 2) but also in prepubertal patient 3, indicating impaired 21-hydroxylation. This assumption was supported by increased urinary 21-deoxycortisol metabolite excretion in patients 2 and 3. With the exception of a heterozygous mutation of CYP17 in one of the patients, other mutations of this gene or CYP21A2 were identified in any of the patients. CONCLUSION: Combined decreased 17alpha-hydroxylation, 17,20-lyase activity and 21-hydroxylation was detected in three ABS patients. Considering that the enzymes responsible are all cytochrome P450 enzymes and that another cytochrome P450 enzyme, lanosterol 14alpha-demethylase, has recently been shown to be impaired in an ABS patient, we speculate that dysfunction of a system which commonly regulates cytochrome P 450 activity may be responsible for the ABS phenotype.

[Dysfunction of the aldosterone synthesis pathway as a marker of malignity in symptomatic and asymptomatic adrenal masses]. / Du dysfonctionnement de la voie de synthèse de l'aldostérone comme marqueur de malignité des masses surrénaliennes symptomatiques et asymptomatiques.

Fundamental research performed in the author's laboratory led to the understanding of mechanisms of the mineralocorticoid biosynthetic pathway. Sensitive assays were then developed to allow measurement of the different mineralocorticoid metabolites in several biological fluids. Using these methods biological markers that contribute to the differential diagnosis between benign and malignant adrenal tumors were identified. In the present paper we report that the exploration of the entire mineralocorticoid pathway in the plasma of patients during basal state and after stimulation and/or inhibition test is a powerful tool to predict or validate diagnosis of adrenal malignancy. Moreover, mineralocorticoid exploration can help differentiate between two different types of malignancy, ie malignant cortical adrenaloma and metastases of other cancer. The biochemical mechanisms leading to the atypical mineralocorticoid metabolism in the case of malignant cortical adrenaloma are now under study.

[Corticosteroid biosynthesis in various water-salt dietary regimens]. / Biosintez kortikosteroidnykh gormonov nadpochechnikami pri razlichnykh vodno-solevykh rezhimakh pitaniia.

The production of desoxycorticosterone, 18-hydroxy-desoxycorticosterone and corticosterone by the mouse adrenals increases in vitro whereas 18-hydroxy-corticosterone and/or aldosterone production falls to an uncertain level when the salt consumption rises from about 0.07 to 50 mekv per animal a day under conditions of water consumption ad libitum. Specific activity values of 3H-corticosteroids, being formed by the adrenal cortex capsule from 3H-progesterone, added to the incubated culture, decrease. Aldosterone production by the adrenals remains unchanged under conditions of sodium load with the limited water consumption. It is suggested that the stimulating effect of endogenous ACTH on the adrenal cortex is potentiated because of the increased salt consumption.

[Reactivity of the adrenal cortex and the renin-angiotensin system in young rats with spontaneous hypertension]. / Reaktivnost' kory nadpochechnikov i sistemy renin-angiotenzin u molodykh krys so spontannoi gipertoniei.

Corticosteroid biosynthesis from 14C-progesterone by the adrenal glands in vitro, 14C-aldosterone metabolism by the liver, plasma aldosterone content, and also angiotensin I concentration and blood plasma renin activity were studied in Okamoto rats with spontaneous hypertension and in Wistar rats with normal blood pressure, 4--5 weeks of age. Acute immobilization stress induced in rats with normal blood pressure caused activation of the adrenal cortex glucocorticoid function without increase of aldosterone biosynthesis or of its blood content, whereas in rats with hypertension the same stress led to adrenal cortex mineralocorticoid function activation and to the sharp blood plasma aldosterone elevation. In rats with normal blood pressure there is a reduction of renin activity and an increase in the angiotensin I content during stress, whereas in rats with hypertension the activity of the renin-angiotensin system remains unchanged. An increase in the mineralocorticoid concentration in rats with spontaneous hypertension can play an important role under these conditions in the elevation of arterial pressure.

[Relationship between the hypophyseal-adrenal and the genital systems in silver-black foxes]. / O vzaimodeistvii mezhdu gipofizarno-nadpochechnikovoi i polovoi sistemoi u serebristo-chernykh lisits.

Interaction between the hypophysial-adrenal system (HAS) and the hypophysis-gonad system was studied. For this purpose the foxes were subjected to total gonadectomy 8 months before they were sacrificed. Functional activity of the HAS was judged by the hypophysis ACTH content, corticosteroid production by the adrenal cortex in vitro, and by the glucocorticoid concentration in the peripheral blood. Castration of male foxes foxes failed to influence the activity of various HAS links. Gonadectomy of females was accompanied by changes in the activity of individual HAS links in different direction--some reduction of ACTH in the hypophysis, a sharp and significant fall of the peripheral blood glucocorticoid level and a marked significant elevation of hydrococortisone production in the adrenal cortex in vitro.

[Paths of corticosteroid biosynthesis in the adrenal glands of rhesus monkeys]. / Puti biosinteza kortikosteroidov v nadpochechnikakh Macaca rhesus.

In experiments in vitro corticosteroid formation from radioactive cholesterol in tha adrenal glands of monkeys (Macaca rhesus) was studied. A conclusion was drawn that pregnenolone and its hydroxy-derivatives were of the leading significance in the cortizol and corticosterone synthesis in the adrenal glands of monkeys. Progesteron was produced in insignificant amounts and was almost unutilized for steroidogenesis. The formation of 17.21-dioxypregnenolone was revealed; its role in the capacity of cortizol precursor was proved; 17-oryprogesteron was found to be of no great significance in cortizol synthesis; 21-oxypregnenolone, but not progesteron proved to serve as the principal intermediate product in corticosterone formation.