An Aldosterone Biosynthetic Defect in a Salt-Losing Disorder

Ulick, Stanley; Gautier, E; Vetter, K; Markello, James R.; Yaffe, Sumner J.; Lowe, Charles U.

doi:10.1210/jcem-24-7-669

Cited by 131 publications

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“…Precedence for such an abnormality can be found in patients with an aldosterone biosynthetic defect, with Na loss, with extensively increased secretion of 18-OH-B, and with slight increases in B secretion. Treatment with DOC and a high Na diet reduce the secretory rates of 18-OH-B and corticosterone in these patients (34).…”

Section: Miscellaneous Measurementsmentioning

confidence: 89%

17-hydroxylation deficiency in man.

Biglieri¹,

Herron²,

Brust³

1966

J. Clin. Invest.

532

154

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The biosynthesis of steroid hormones 1 requires a number of hydroxylating enzymes. Deficiency of these enzymes is demonstrated by increased or decreased amounts of certain steroid metabolites in blood and urine and is best exemplified by the deficiency of 11,8-hydroxylase (1) and 21-hydroxylase (2) in patients with congenital adrenal hyperplasia. 17a-Hydroxylase activity is present in these disorders because of the increases in secretion of androgens and excretion of pregnanetriol. In addition, a lack of 3-hydroxysteroid dehydrogenase has also been described (3). 17-Hydroxylation is essential not only to the biosynthesis of cortisol but also to the formation of * Submitted for publication July 19, 1966; accepted September 7, 1966 androstenedione = 4-androsten-3,17-dione; compound S= li-deoxycortisol = 4-pregnen-17a,21-diol-3,20-dione; dehydroepiandrosterone = 5-androsten -3,8 -ol -17 -one; dexamethasone = 1,4-pregnandien-9-fluoro-16a-methyl-1 ll,17a, 21-triol-3,20-dione; etiocholanolone = 5,B-androstan-3a-ol-17-one; pregnanediol = 5,8-pregnan-3a,20a-diol; pregnanetriol = 5p6-pregnan-3a,11a,20a-triol; stilbestrol = diethylstilbestrol = aca'diethyl-4,4'stilbenediol; tetrahydroaldosterone = TH aldosterone = 5,8-pregnan-3a,11p,21-trihydroxy-20 keto-18-ol; tetrahydrocortisol = THF = 5fi-pregnan-3a,1llf,17a,21-tetrol-20-one; tetrahydrocortisone = THE = 5fi-pregnan-3a,17a,21-triol-11,20-dione; tetrahydrodeoxycorticosterone = THDOC = 5#-pregnan-3a, 21-diol-20-one; tetrahydro-ll-deoxycortisol = 5,0-pregnan3a,17a,21-triol-20-one; and tetrahydro-18-OH-dehydrocorticosterone = TH-18-OH compound A = 5#-pregnan3a,18,21-trihydroxy-11,20-dione.gonadal hormones (4, 5), the androgenic steroids, androstenedione, testosterone, and, eventually, estrogens (6). Deficiency of this enzyme system should be manifested clinically in both adrenal and gonadal abnormalities if the enzyme is similar in both glands. Furthermore, it is reasonable to assume that lack of 1 7-hydroxylated steroids would allow uninhibited release of adrenocorticotropin. In such a circumstance in which cortisol secretion is absent, prolonged survival would not be anticipated because mineralocorticoids would be the only adrenal steroids produced. We will describe and discuss a patient with deficiency in 17a-hydroxylase activity with possibly a second defect in production of aldosterone. MethodsCase report The female patient M. H. was the product of a full-term normal pregnancy and weighed 7 pounds at birth. Several severe episodes of bronchitis occurred before 5 years of age. The patient was hospitalized for an influenza-like syndrome when she was 5 years old; the mother (29 years) and one sibling (11 months) died from "influenza" at this time. From 5 to 10 years of age the patient was absent from school about one-third of the time because of infections of the upper respiratory tract. She was hospitalized at age 9 for severe upper respiratory infection, high fever, and unconsciousness. Intravenous glucose therapy promptly restored consciousness, and hypoglycemia was d...

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Section: Miscellaneous Measurementsmentioning

confidence: 89%

17-hydroxylation deficiency in man.

Biglieri¹,

Herron²,

Brust³

1966

J. Clin. Invest.

532

154

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“…Ceci suppose la double intervention enzymatique d'une 18-hydroxylase puis d'une 18-OH-dehydrogenase [12]. A ces deux etapes enzymatiques correspondent deux types d'hypoaldosteronisme congenital: defaut en 18 hydroxylation d^crit par VISSER et al [6,22], defaut en 18-OH-dehydrogenase des observations de ULICK et al [18] et DAVID et al [5]. Notre observation appartient a ce dernier groupe.…”

Section: Discussionunclassified

“…L'elimination urinaire de 150 /j,g de TH DOC par 24 heures ne peut etre interpretee avec certitude faute de valeurs temoins. II est possible qu'une augmentation de la secretion de DOC intervienne aussi [18].…”

Section: Discussionunclassified

Hypoaldostéronisme congénital familial par défaut de la 18-OH-déhydrogénase: Etude hormonale avant et après guérison du syndrome de perte de sel

et al. 1968

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ExtractIn one case studied from the neonatal period through a follow-up period at almost five years of age, a salt-losing syndrome could be related to a defect in 18-OH-dehydrogenase.In the intial course of the disease, treatment with desoxycorticosterone acetate controlled the saltlosing tendency. At that time, the rate of aldosterone secretion was less than 10 ,ag/day and that of urinary tetrahydroaldosterone was less than S^g/day. In contrast, the rate of corticosterone secretion was 5400 / «g/day and the F:B ratio was 0.8. Urinary 18 hydroxytetrahydro A (18 OH-THA) was increased to 128^g/24 h. There was no cortisol insufficiency; secretion rate was 20 mg m 2 /day and plasma ACTH 0.24 mU/100 ml plasma. At 20 months of age, treatment was stopped because of hypernatremia. From that time on, the child was clinically normal and received no salt supplement.The hormonal results were as follows: At 22 months of age, the secretion rate of aldosterone was less than 5 /tg/day and of corticosterone was 8600 / «g/day on the sixth day of a well-tolerated salt suppression test. 18 OH-THA was 116,ag/day; the F:B ratio for urinary metabolites was low, 0.9.At 3 years and 7 months of age, excretion of urinary tetrahydroaldosterone was 10 ^g/day, 18 OH-THA was in the normal range, and the F:B ratio remained low, 0.6 (normal salt intake).At 4 years and six months of age, secretion rate was 19 ,wg/day and the 18 hydrocorticosterone secretion rate was 470 ,«g/day (ratio 18 OH-B: aldosterone 24.7). Plasma renin activity was 88.8 ng/l/min.The brother of the propositus was observed when 6 years of age. Urinary tetrahydrosterone was 27 ,«g/day, 18 OH-THA was 75 / Mg/day, and the urinary F:B ratio was 0.7 while receiving a normal salt intake.The spontaneous clinical improvement of subjects with the salt-losing syndrome is possibly related to the appearance of a certain amount of aldosterone, an increase in secretion of corticosterone, and modification in salt content of a normal diet during this period. SpeculationA salt-losing syndrome due to 18-OH-dehydrogenase deficiency, probably familial, improved spontaneously. Long-term studies showed persistence of the biosynthetic defect. The data presented raise questions concerning clinical recovery that could be correlated with steroid administration and, possibly, with modifications in sodium homeostasis at that period of life.

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“…Visser & Cost (3) were the first to describe a patient with deficient 18-hydroxylation of corticosterone (4). Subsequently, Ulick et al (5) and Rappaport et al (6) described two patients with deficient 18-OHdehydrogenase. The two biochemically different forms of selective aldosterone deficiency are termed corticosterone methyl oxidase (CMO) deficiency type I and type II (7).…”

Section: Introductionmentioning

confidence: 99%

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

Peter

Bünger

Drop

et al. 1998

European Journal of Endocrinology

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We performed a molecular genetic study in two patients with congenital hypoaldosteronism. An original study of these patients was published in this Journal in 1982. Both index cases, a girl (patient 1) and a boy (patient 2), presented with salt-wasting and failure to thrive in the neonatal period. Parents of patient 1 were not related, whereas the parents of patient 2 were cousins. Endocrine studies had shown a defect in 18-oxidation of 18-OH-corticosterone in patient 1 and a defect in the 18-hydroxylation of corticosterone in patient 2. Plasma aldosterone was decreased in both patients, whereas 18-OH-corticosterone was elevated in patient 1 and decreased in patient 2. Plasma corticosterone and 11-deoxycorticosterone were elevated in both patients, whereas cortisol and its precursors were in the normal range. According to the nomenclature proposed by Ulick, the defects are termed corticosterone methyl oxidase (CMO) deficiency type II in patient 1, and type I in patient 2 respectively. Genetic defects in the gene CYP11B2 encoding aldosterone synthase have been described in a few cases. In patient 1, we identified only one heterozygous amino acid substitution (V386A) in exon 7, which has no deleterious effect on the enzyme activity. In patient 2 and his older brother, we identified a homozygous single base exchange (G to T) in codon 255 (GAG), causing a premature stop codon E255X (TAG). The mutant enzyme has lost the five terminal exons containing the haem binding site, and is thus a loss of function enzyme. This is only the second report of a patient with CMO deficiency type II without a mutation in the exons and exon-intron boundaries, whereas the biochemical phenotype of the two brothers with CMO deficiency type I can be explained by the patient's genotype.

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An Aldosterone Biosynthetic Defect in a Salt-Losing Disorder

Cited by 131 publications

References 0 publications

17-hydroxylation deficiency in man.

17-hydroxylation deficiency in man.

Hypoaldostéronisme congénital familial par défaut de la 18-OH-déhydrogénase: Etude hormonale avant et après guérison du syndrome de perte de sel

Molecular genetic study in two patients with congenital hypoaldosteronism (types I and II) in relation to previously published hormonal studies

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