Original Article

Aldosterone Synthesis in Salt-Wasting Congenital Adrenal Hyperplasia with Complete Absence of Adrenal 21-Hydroxylase

Phyllis W. Speiser, M.D., Levon Agdere, M.D., Hajime Ueshiba, M.D., Perrin C. White, M.D., and Maria I. New, M.D.

N Engl J Med 1991; 324:145-149January 17, 1991

Abstract

Abstract

Background.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a disorder of cortisol and aldosterone biosynthesis that results from mutations in the CYP21 gene encoding the adrenal 21-hydroxylase P-450c21. It can cause severe salt wasting in newborns that requires long-term treatment with glucocorticoids and mineralocorticoids. We describe a spontaneous partial recovery from this disorder in a 19-year-old woman who had discontinued treatment.

Full Text of Background....

Methods.

We measured plasma and urinary levels of adrenal hormones, plasma renin activity, and sodium balance longitudinally in the patient and four other patients in whom adrenal hyperplasia had been diagnosed in infancy and in whom DNA analysis had predicted a complete absence of functional P-450c21. The ratio of plasma renin activity to urinary aldosterone was used as a measure of the response of the adrenal zona glomerulosa. Two patients underwent intravenous infusion of [3H]progesterone for the measurement of extraadrenal production of 21-hydroxylated precursors of aldosterone.

Full Text of Methods....

Results.

The patient who had discontinued her medication excreted a normal amount of aldosterone (20.0 nmol per square meter of body-surface area per day) while following a diet low in sodium. Her ratio of plasma renin activity to urinary aldosterone-18-glucuronide excretion was 1.7 after three days of sodium restriction, as compared with a ratio of 4.7 at the age of nine years (normal range, 0.03 to 0.1). The percentage of extraadrenal conversion of progesterone to deoxycorticosterone was low. The four other patients had variable responses to sodium restriction after the neonatal period (range for plasma renin activity:urinary aldosterone-18-glucuronide, 1.9 to 19.4).

Full Text of Results....

Conclusions.

Although patients with salt-wasting 21-hydroxylase deficiency have functionally equivalent mutations in their CYP21 genes, they may vary from one another and over time in their ability to produce mineralocorticoids. This variation may be attributable to another adrenal enzyme with 21-hydroxylase activity. (N Engl J Med 1991; 324:145–9.)

Full Text of Conclusions....

Read the Full Article...

Article Activity

24 articles have cited this article

Article

PATIENTS with congenital adrenal hyperplasia due to 21-hydroxylase deficiency cannot adequately synthesize cortisol, and more than two thirds of them have a parallel block in aldosterone biosynthesis.1 Inefficient cortisol synthesis results in excessive production of adrenal androgens, which do not require 21-hydroxylation for their synthesis, and consequent signs of androgen excess such as ambiguous genitalia in females and abnormal somatic growth in both sexes. Inadequate synthesis of aldosterone leads to inappropriate salt wasting with the risk of vascular collapse and death if not treated.

The molecular genetic basis of this disorder has been extensively characterized.2 , 3 The CYP21 gene (previously termed CYP21B) encodes a microsomal cytochrome P-450 responsible for steroid 21-hydroxylation. All mutations identified to date in the CYP21 gene have been either deletions or transfers of deleterious sequences from the adjacent pseudogene CYP21P (previously termed CYP21A) to the active gene CYP21 (gene conversion).4 , 5

Clinical wisdom suggests that the phenotypic severity of the disease is directly related to the degree of enzyme deficiency. This idea is supported by in vitro studies of gene expression, which suggest that the phenotypic form of the disease may be related to the degree of enzymatic compromise conferred by a given mutation.6 , 7 The shortcomings of this idea include the lack of any consistently used definition of the clinical manifestations of the salt-wasting form as distinguished from the simple-virilization form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the occurrence of discordance within families for the expression of salt wasting,8 9 10 11 and variation in the phenotype over time.9 , 10 , 12 13 14

The present study was initiated when a 19-year-old woman with severe salt-wasting 21-hydroxylase deficiency presented for reevaluation after a 4-year hiatus in medical care, including a 1 1/2-year period during which she took no glucocorticoids or mineralocorticoids. In the light of molecular genetic studies in this patient that had demonstrated homozygous deletion of the CYP21 gene,15 her ability to survive without cortisol treatment seemed paradoxical. We therefore performed hormonal studies in her and four other patients in whom the following criteria were met: the patient had had a salt-wasting crisis when a newborn; longitudinal clinical, hormonal, and metabolic data were available; and there was a complete absence of a functional P-450c21 enzyme as predicted by molecular genetic analysis. Our object was to examine over time the correlation between clinical and hormonal status and genotype in classic salt-wasting 21-hydroxylase deficiency.

Methods

The patients were studied as described below in the Children's Clinical Research Center at the New York Hospital—Cornell Medical Center. The study protocol was approved by the institutional review committee, and the patients or their parents gave informed consent.

Patient 1

A girl weighing 2.5 kg was born to a 32-year-old woman (gravida 8, para 4) after a normal gestation. Her genitalia were noted to be ambiguous at birth. At 6 days of life the infant began to vomit and have diarrheal stools; at 14 days she was admitted to another hospital because of severe dehydration and hypotension with hyponatremia and hyperkalemia (Table 1Table 1Biochemical Profiles of Five Patients with Salt-Wasting Congenital Adrenal Hyperplasia (21-Hydroxylase Deficiency).). The urinary 17-ketosteroid excretion rate was 260 μmol per day (normal mean ±SD, 5.6±4.2). The patient received glucocorticoid and mineralocorticoid therapy. Her family history was notable in that three older sisters with similar clinical features had died 10 days to 2 months after birth.

Pubarche occurred at the age of 7 1/2 years and menarche at 10 years, indicating adequate suppression of adrenal androgen secretion. At the ages of 9 years and 12 years16 the ratio of plasma renin activity to the 24-hour urinary aldosterone-18-glucuronide excretion rate (corrected for body-surface area) was abnormally elevated during periods in which the production of 21-hydroxylase precursors was completely suppressed with dexamethasone. At the time of the first measurements the sodium balance was marginal (ratio of sodium output to sodium intake, 1.5) although the patient was taking 0.1 to 0.2 mg of fludrocortisone daily and her dietary sodium intake was 75 mmol per day.

At the age of 15 years the patient was lost to medical care, and at 18 she stopped taking her medication. When 19 years old, she presented for reevaluation, with hirsutism and secondary amenorrhea. Physical examination revealed that she had stunted growth, virilization, and a deep voice. The height was 138.7 cm, and the weight 37.5 kg. The blood pressure was 106/60 mm Hg and did not change when the patient stood erect; there were no other signs of dehydration. There were excessive amounts of coarse dark hair on the face, chest, and lower abdomen and many facial comedones. An examination of the genital region showed evidence of a clitoral recession; the vaginal orifice, despite reconstruction and dilation, was constricted.

CT imaging of the abdomen revealed nodular adrenal hyperplasia and small bilateral ovarian cysts. The morning serum 17-hydroxyprogesterone concentration was 363 nmol per liter, the morning progesterone concentration 81 nmol per liter, and the urinary 17-ketosteroid excretion rate 270 μmol per day — all markedly elevated levels. The serum cortisol concentration was low (50 nmol per liter) at the end of a six-hour infusion of corticotropin. The serum levels of electrolytes and urea nitrogen were normal. When the patient followed a diet with ad libitum sodium intake, the plasma renin activity was 15.8 ng per liter per second (normal range, 0.1 to 1) and the urinary aldosterone-18-glucuronide excretion rate was 24.2 nmol per square meter of body-surface area per day (normal range, 14 to 42).

Patients 2 through 5

Four other patients also had severe 21-hydroxylase deficiency. All had hypotension and hypovolemia during the neonatal period (Table 1), and the diagnosis of the deficiency had been confirmed by the observation of markedly elevated levels of urinary 17-ketosteroid, pregnanetriol excretion, or both (data not shown). Aldosterone deficiency was later documented under conditions of maximal stimulation of the renin—angiotensin axis during adequate suppression of precursors of 21-hydroxylase, which might act as mineralocorticoid antagonists.

Hormonal Assays

Serum concentrations of adrenocortical hormones were measured by radioimmunoassay.17 18 19 Urinary aldosterone was measured as the acid-hydrolyzable conjugate aldosterone-18-glucuronide,20 a urinary metabolite of aldosterone whose concentration represents a constant percentage of secreted aldosterone.21 , 22 Plasma renin activity was determined according to the method of Sealey and Laragh with modifications.23 The ratio of plasma renin activity to daily urinary aldosterone excretion was used as an index of the efficiency of the adrenal zona glomerulosa in synthesizing aldosterone.

Measurement of Extraadrenal 21-Hydroxylase Activity

Extraadrenal 21-hydroxylase activity24 was determined in Patient 1 (19 years old) and Patient 2 (20 years old) by measuring the conversion of [³H]progesterone to [³H]deoxycorticosterone.25 A priming dose of [³H]progesterone (15 μCi) was administered intravenously over a 30-minute period and then followed by a constant infusion (20 μCi) lasting 100 minutes. Seventy, 80, and 90 minutes after the start of the constant infusion, blood samples were drawn from the contralateral arm without the use of a tourniquet. The [³H]progesterone concentration in these three blood samples was constant (data not shown). Urine was collected for three days from the beginning of the infusion of Radio-labeled steroid; the level of recovery of radioactivity was above 90 percent.

[³H]Progesterone and [³H]deoxycorticosterone were purified from plasma, and [³H]tetrahydrodeoxycorticosterone from urine, with a previously described Chromatographic method.24 , 26 The percentage of progesterone converted to deoxycorticosterone was calculated by dividing the number of counts per minute of [³H]tetrahydrodeoxycorticosterone per liter of urine (corrected for recovery) by the quantity of [³H]progesterone infused (normal mean ±SD, 1.3±0.4 percent27).

HLA Typing and Molecular Genetic Studies

The HLA serotypes of the five patients have been reported previously,28 as have the preparation of DNA, Southern blot hybridization, in-gel oligonucleotide hybridization, and interpretation of the results (Patient 1 was reported on as Patient A² and as the subject with HLA-B47;5115; Patient 2 as Patient G²; Patient 3 as Patient C [index patient]29; Patient 4 as Patient I² and Patient D29; and Patient 5 as Patient K2 and Patient O29).

Results

Patient 1 had homozygous deletion of the gene encoding 21-hydroxylase, CYP21.2 Patients 2 through 5 each had a heterozygous deletion of CYP21; the second chromosome in each patient had a mutation that rendered the gene product entirely inactive. Patient 2 had the 8-bp (base pair) deletion in exon 3 that is predicted to cause a frame shift producing a nonsense codon downstream and consequent premature termination of translation.30 , 31 Patients 3, 4, and 5 had the Gln-318 mutation (CAG to TAG) that is also predicted to terminate translation before synthesis of the putative heme-binding site.29 Three of five chromosomes with deletions of CYP21 carried genes encoding the HLA antigens B47 and DR7. The three chromosomes with the Gln-318 mutation carried genes encoding three different sets of HLA antigens.

In Patient 1 (19 years old; Fig. 1Figure 1Results of Metabolic-Balance Studies in Patient 1 before and during Sodium Restriction at the Age of 19 Years. and Table 1), the ratio of plasma renin activity to urinary aldosterone-18-glucuronide excretion as adjusted for body-surface area was 1.7 after three days of sodium deprivation and 3.5 after four days of deprivation. Sodium balance was nearly achieved after three days of sodium restriction (24-hour urinary sodium excretion, 33 mmol; oral intake, 10 mmol), and body weight reached a plateau. In contrast, when the patient was nine years old, the plasma renin activity:aldosterone-18-glucuronide excretion ratio was 4.7 while the sodium intake was 75 mmol per day, and sodium balance was still slightly negative, even with mineralocorticoid treatment (Table 1). The ratio for the conversion of [3H]progesterone to [3H]deoxycorticosterone was 0.28 percent (normal, 1.3±0.2 percent).

The results in the four other patients are also shown in Table 1. Their ratio of plasma renin activity to aldosterone-18-glucuronide excretion, as adjusted for changes in body-surface area from childhood through young adulthood, was markedly elevated, ranging from 1.9 to 19.4 under conditions of moderate-to-severe sodium restriction. Patient 2, who had the lowest ratio, had a persistently negative sodium balance and mild hyponatremia. (His ratio for the conversion of [3H]progesterone to [3H]deoxycorticosterone was 0.98 percent.) Symptomatic hyponatremia (serum sodium concentration, 123 nmol per liter) developed in Patient 5 after only two days of sodium restriction. In none of the four patients was the 24-hour urinary aldosterone excretion rate greater than 13.9 nmol per square meter per day, even when their levels of plasma renin activity were markedly elevated.

Although Patients 3, 4, and 5 had the same mutations, they had variable responses to sodium deprivation. Patients 4 and 5 had relatively more severe aldosterone deficiency, with plasma renin activity:urinary aldosterone-18-glucuronide ratios of 19.4 and 11.3, respectively, whereas Patient 3 had a ratio of 5.8 under similar study conditions.

Discussion

We correlated clinical, biochemical, and molecular genetic findings in five patients who had severe salt-wasting 21-hydroxylase deficiency in infancy. All but one patient had persistent impairment of aldosterone synthesis associated with a homozygous deletion or equivalently severe mutations in CYP21. The findings that one patient had amelioration of aldosterone deficiency with age and that three patients with identical genotypes had variable responses to sodium deprivation (Patients 3 through 5) indicate that other factors contribute to the clinical picture in this form of congenital adrenal hyperplasia. It is not clear why one patient had so much improvement in aldosterone biosynthesis as she grew older. In principle, this improvement could be explained by an increase in the synthesis or the activity of a partially active mutant P-450c21 enzyme. Alternatively, it could be explained by activation of another adrenal or extraadrenal "rescue" enzyme, distinct from P-450c21, with 21-hydroxylase activity. Human P-450c21 is not expressed in extraadrenal tissues32 and thus cannot mediate the extraadrenal 21-hydroxylation that occurs in normal persons.24

In the presence of CYP21 mutations that partially impair 21-hydroxylase function, a marked increase in plasma renin activity could lead to some aldosterone synthesis and therefore to sodium balance. Patient 1, however, had a homozygous deletion of the CYP21 genes, and the four other patients had mutations that resulted in termination of translation before the putative heme-binding site of P-450c21, without which any cytochrome P-450—dependent enzyme remains completely inactive. The net functional effect in these four patients was equivalent to a homozygous deletion of CYP21, yet each of them was capable of producing some aldosterone.

Extraadrenal 21-hydroxylation as a source of substrate for adrenal aldosterone synthesis is unlikely in view of the normal-to-low ratio for conversion of progesterone to deoxycorticosterone in Patients 1 and 2. The possibility of extraadrenal 21-hydroxylation becomes even lower if one considers that Patient 1 was able to excrete 20.0 nmol of aldosterone-18-glucuronide per square meter per day after three days of sodium deprivation, when circulating deoxycorticosterone was undetectable. This young woman had been amenorrheic for several years and had radiographic and laparoscopic findings consistent with polycystic ovary disease. Although the gonads are capable of 21-hydroxylation, no difference in the conversion ratio of progesterone to deoxycorticosterone has been found in men or women,27 and aldosterone cannot be synthesized by the ovaries.

Thus, one must postulate the existence of another adrenal enzyme that has at least some 21-hydroxylase activity. None of the three other adrenal cytochrome P-450 enzymes involved in steroidogenesis is known to have 21-hydroxylase activity. Human homologues of another cytochrome P-450 enzyme, the rabbit-liver form I (P450IIC) — known to have 21-hydroxylase activity33 , 34 — have been cloned,35 , 36 but 21-hydroxylase activity has not been demonstrated in preparations of human liver microsomes. It is possible that some factor present in vivo in microsomes and necessary for enzyme activity is lost in the in vitro preparation. Expression of these enzymes has not yet been detected in human adrenal glands.

The most notable difference between the patient in whom sodium homeostasis recovered and the other patients was her extreme noncompliance, in that she discontinued both glucocorticoid and mineralocorticoid therapy 1 1/2 years before presenting for medical reevaluation. It is conceivable that very high levels of 21-hydroxylase precursors, or their metabolic byproducts, induced expression of a "rescue" enzyme as discussed above. There is evidence that both estrogen37 and progesterone38 have roles as inducers of extraadrenal 21-hydroxylase. In fact, the latter may be part of a feedback loop to counterbalance the natriuretic effect of progesterone during the luteal phase of the menstrual cycle in normal women.27

In conclusion, the phenotypic spectrum of congenital adrenal hyperplasia due to 21-hydroxylase deficiency is not entirely explained by specific mutations found in the CYP21 gene. The unusual phenomenon of recovery from salt wasting may be determined by the activity of an adrenal enzyme other than P-450c21.

Supported by grants (HD-00072, RR-47, RR-06020–01, AM-97029, and DK-37867) from the National Institutes of Health, by the Horace Goldsmith Foundation, and by the Harold and Juliet Kalikow Foundation.

Presented in part at a meeting of the Society for Pediatric Research, Anaheim, Calif., April 1987, and reported in abstract form (Pediatr Res 1987; 21: Suppl:254A).

We are indebted to the staff of the Children's Clinical Research Center and its Core Laboratory for assistance in performing these studies and hormone assays; to Drs. Bo Dupont and Soo Young Yang for the HLA serotyping; to Mrs. Vita Amendolagine and Mr. Christopher Crawford for assistance in the preparation of the manuscript; and to Drs. Joseph M. Gertner, Abraham G. White, and Grace M. Tannin for critically reading the manuscript.

Source Information

From the Department of Pediatrics, New York Hospital-Cornell Medical Center, 525 E. 68th St., New York, NY 10021, where reprint requests should be addressed to Dr. Speiser.

References

References

1. 1

   White PC, New MI, Dupont B. Congenital adrenal hyperplasia . N Engl J Med 1987; 316:1519–24, 1580–6.
   Full Text | Web of Science | Medline

2. 2

   White PC, Vitek A, Dupont B, New MI. Characterization of frequent deletions causing steroid 21-hydroxylase deficiency . Proc Natl Acad Sci U S A 1988; 85:4436–40.
   CrossRef | Web of Science | Medline

3. 3

   Morel Y, Andre J, Uring-Lambert B, et al. Rearrangements and point mutations of P450c21 genes are distinguished by five restriction endonuclease haplotypes identified by a new probing strategy in 57 families with congenital adrenal hyperplasia . J Clin Invest 1989; 83:527–36.
   CrossRef | Web of Science | Medline

4. 4

   White PC. Analysis of mutations causing steroid 21-hydroxylase deficiency . Endocr Res 1989; 15:239–56.
   CrossRef | Web of Science | Medline

5. 5

   Strachan T. Molecular pathology of congenital adrenal hyperplasia . Clin Endocrinol (Oxf) 1990; 32:373–93.
   CrossRef | Web of Science | Medline

6. 6

   Chiou S-H, Hu M-C, Chung B-C. A missense mutation at Ile172→Asn or Arg356→Trp causes steroid 21-hydroxylase deficiency . J Biol Chem 1990; 265:3549–52.
   Web of Science | Medline

7. 7

   Tusie-Luna M-T, Traktman P, White PC. Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus . J Biol Chem 1990; 265:20916–22.
   Web of Science | Medline

8. 8

   Rosenbloom AL, Smith DW. Varying expression for salt losing in related patients with congenital adrenal hyperplasia . Pediatrics 1966; 38:215–9.
   Web of Science | Medline

9. 9

   Stoner E, DiMartino-Nardi J, Kuhnle U, Levine LS, Oberfield SE, New MI. Is salt-wasting in congenital adrenal hyperplasia due to the same gene as the fasciculata defect? Clin Endocrinol (Oxf) 1986; 24:9–20.
   CrossRef | Web of Science | Medline

10. 10

    Morel Y, David M, Forest MGH, et al. Gene conversions and rearrangements cause discordance between inheritance of forms of 21-hydroxylase deficiency and HLA types . J Clin Endocrinol Metab 1989; 68:592–9.
    CrossRef | Web of Science | Medline

11. 11

    Sinnott PJ, Dyer PA, Price DA, Harris R, Strachan T. 21-Hydroxylase deficiency families with HLA identical affected and unaffected sibs . J Med Genet 1989; 26:10–7.
    CrossRef | Web of Science | Medline

12. 12

    Amor M, Parker KL, Globerman H, New MI, White PC. Mutation of the CYP21B gene (ILE-172→ASN) causes steroid 21-hydroxylase deficiency . Proc Natl Acad Sci U S A 1988; 85:1600–4.
    CrossRef | Web of Science | Medline

13. 13

    Prader A. Vollkommen Männliche aussere Genitalentwicklung und Salzverlustsyndrom bei Mädchen mit kongenitalem adrenogenitalem Syndrom . Helv Paediatr Acta 1958; 13:5–14.
    Medline

14. 14

    Homer JM, Hintz RL, Luetscher JA. The role of renin and angiotensin in salt-losing 21-hydroxylase-deficient congenital adrenal hyperplasia . J Clin Endocrinol Metab 1979; 48:776–83.
    CrossRef | Web of Science | Medline

15. 15

    White PC, New MI, Dupont B. HLA-linked congenital adrenal hyperplasia results from a defective gene encoding a cytochrome P-450 specific for steroid 21-hydroxylation . Proc Natl Acad Sci U S A 1984; 81:7505–9.
    CrossRef | Web of Science | Medline

16. 16

    Kuhnle U, Chow D, Rapaport R, Pang S, Levine LS, New MI. The 21-hydroxylase activity in the glomerulosa and fasciculata of the adrenal cortex in congenital adrenal hyperplasia . J Clin Endocrinol Metab 1981; 52:534–44.
    CrossRef | Web of Science | Medline

17. 17

    Pang S, Hotchkiss J, Drash AL, Levine LS, New MI. Microfilter paper method for 17α-hydroxyprogesterone radioimmunoassay: its application for rapid screening for congenital adrenal hyperplasia . J Clin Endocrinol Metab 1977; 45:1003–8.
    CrossRef | Web of Science | Medline

18. 18

    Korth-Schutz S, Virdis R, Saenger P, Chow DM, Levine LS, New MI. Serum androgens as a continuing index of adequacy of treatment of congenital adrenal hyperplasia . J Clin Endocrinol Metab 1978; 46:452–8.
    CrossRef | Web of Science | Medline

19. 19

    Rauh W, Levine LS, Gottesdiener K, New MI. Mineralocorticoids, salt balance and blood pressure after prolonged ACTH administration in juvenile hypertension . Klin Wochenschr 1978; 56:Suppl I:161–7.
    CrossRef | Medline

20. 20

    Chakmakjian ZH, Pryor WW, Abraham GE. A radioimmunoassay for serum and urine aldosterone by celite column chromatography . Anal Lett 1974;7:97–108.
    CrossRef | Web of Science

21. 21

    Luetscher JA, Dowdy AJ, Callaghan AM, Cohn AP. Studies of secretion and metabolism of aldosterone and cortisol . Trans Assoc Am Physicians 1962; 75:293–300.
    Medline

22. 22

    New MI, Miller B, Peterson RE. Aldosterone excretion in normal children and in children with adrenal hyperplasia . J Clin Invest 1966; 45:412–28.
    CrossRef | Web of Science | Medline

23. 23

    Preibisz JJ, Sealey JE, Aceto RM, Laragh JH. Plasma renin activity measurements: an update . Cardiovasc Rev Rep 1982; 3:787–804.
    

24. 24

    Winkel CA, Milewich L, Parker CR Jr, Gant NF, Simpson ER, MacDonald PC. Conversion of plasma progesterone to deoxycorticosterone in men, nonpregnant and pregnant women, and adrenalectomized subjects: evidence for steroid 21-hydroxylase activity in nonadrenal tissues . J Clin Invest 1980; 66:803–12.
    CrossRef | Web of Science | Medline

25. 25

    Antonipillai I, Moghissi E, Frasier SD, Horton R. The origin of plasma deoxycorticosterone in the syndrome of congenital adrenal hyperplasia and in acute states of adrenocorticotropin excess . J Clin Endocrinol Metab 1983; 57:580–4.
    CrossRef | Web of Science | Medline

26. 26

    New MI, Seaman MP. Secretion rates of cortisol and aldosterone precursors in various forms of congenital adrenal hyperplasia . J Clin Endocrinol Metab 1970; 30:361–71.
    CrossRef | Web of Science | Medline

27. 27

    Antonipillai I, Moghissi E, Hawks D, Schneider T, Horton R. The origin of plasma deoxycorticosterone in men and in women during the menstrual cycle . J Clin Endocrinol Metab 1983; 56:93–8.
    CrossRef | Web of Science | Medline

28. 28

    Dupont B, Virdis R, Lerner AJ, Nelson C, Pollack MS, New MI. Distinct HLA-B antigen associations for the salt-wasting and simple virilizing forms of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. In: Albert ED, Baur MP, Mayr WR, eds. Histocompatibility testing 1984. Berlin, Germany: Springer-Verlag, 1984:660.
    

29. 29

    Globerman H, Amor M, Parker KL, New MI, White PC. Nonsense mutation causing steroid 21-hydroxylase deficiency . J Clin Invest 1988; 82:139–44.
    CrossRef | Web of Science | Medline

30. 30

    White PC, New MI, Dupont B. Structure of human steroid 21-hydroxylase genes . Proc Natl Acad Sci U S A 1986; 83:5111–5.
    CrossRef | Web of Science | Medline

31. 31

    Higashi Y, Yoshioka H, Yamane M, Gotoh O, Fujii-Kuriyama Y. Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: a pseudogene and a genuine gene . Proc Natl Acad Sci U S A 1986; 83:2841–5.
    CrossRef | Web of Science | Medline

32. 32

    Mellon SH, Miller WL. Extraadrenal steroid 21-hydroxylation is not mediated by P450c21 . J Clin Invest 1989; 84:1497–502.
    CrossRef | Web of Science | Medline

33. 33

    Dieter HH, Muller-Eberhard U, Johnson EF. Identification of rabbit microsomal cytochrome P-450 isozyme, form I, as a hepatic progesterone 21-hydroxylase . Biochem Biophys Res Commun 1982; 105:515–20.
    CrossRef | Web of Science | Medline

34. 34

    Johnson EF, Finlayson M, Hujsak CM, Pendurthi UR, Tukey RH. Genetic contributions to the variation among rabbits of liver microsomal deoxycorticosterone synthesis . Arch Biochem Biophys 1989; 273:273–80.
    CrossRef | Web of Science | Medline

35. 35

    Tukey RH, Okino S, Barnes H, Griffin KJ, Johnson EF. Multiple gene-like sequences related to the rabbit hepatic progesterone 21-hydroxylase cytochrome P-450 1 . J Biol Chem 1985; 260:13347–54.
    Web of Science | Medline

36. 36

    Okino ST, Quattrochi LC, Pendurthi UR, McBride OW, Tukey RH. Characterization of multiple human cytochrome P-450 1 cDNAs: the chromosomal localization of the gene and evidence for alternate RNA splicing . J Biol Chem 1987; 262:16072–9.
    Web of Science | Medline

37. Erratum, J Biol Chem 1988; 263:2576.
    Web of Science

38. 37

    MacDonald PC, Cutrer S, MacDonald SC, Casey ML, Parker CR Jr. Regulation of extraadrenal steroid 21-hydroxylase activity: increased conversion of plasma progesterone to deoxycorticosterone during estrogen treatment of women pregnant with a dead fetus . J Clin Invest 1982; 69:469–78.
    CrossRef | Web of Science | Medline

39. 38

    Winkel CA, Casey ML, Worley RJ, Madden JD, MacDonald PC. Extraadrenal steroid 21-hydroxylase activity in a woman with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency . J Clin Endocrinol Metab 1983; 56:104–7.
    CrossRef | Web of Science | Medline

Citing Articles (24)

Citing Articles

1. 1

   Henrik Falhammar, Marja Thorén. (2012) Clinical outcomes in the management of congenital adrenal hyperplasia. Endocrine
   CrossRef

2. 2

   Saroj Nimkarn, Karen Lin-Su, Maria I. New. (2011) Steroid 21 Hydroxylase Deficiency Congenital Adrenal Hyperplasia. Pediatric Clinics of North America 58:5, 1281-1300
   CrossRef

3. 3

   Christine M Trapp, Phyllis W Speiser, Sharon E Oberfield. (2011) Congenital adrenal hyperplasia: an update in children. Current Opinion in Endocrinology, Diabetes and Obesity 18:3, 166-170
   CrossRef

4. 4

   Richard J Auchus. (2010) Congenital adrenal hyperplasia in adults. Current Opinion in Endocrinology, Diabetes and Obesity 17:3, 210-216
   CrossRef

5. 5

   Richard J. Auchus, Alice Y. Chang. (2010) 46,XX DSD: the masculinised female. Best Practice & Research Clinical Endocrinology & Metabolism 24:2, 219-242
   CrossRef

6. 6

   Saroj Nimkarn, Karen Lin-Su, Maria I. New. (2009) Steroid 21 Hydroxylase Deficiency Congenital Adrenal Hyperplasia. Endocrinology & Metabolism Clinics of North America 38:4, 699-718
   CrossRef

7. 7

   2009. Adrenal Gland. , 277-316.
   CrossRef

8. 8

   Pedro Iglesias, Pilar Tajada, Isabel Martínez, Juan J. Díez. (2009) Hiperplasia suprarrenal congénita con síndrome pierde sal asociada a hiperaldosteronismo hiperreninémico. Medicina Clínica 132:2, 80-81
   CrossRef

9. 9

   MARIA I. NEW. (2004) An Update of Congenital Adrenal Hyperplasia. Annals of the New York Academy of Sciences 1038:1, 14-43
   CrossRef

10. 10

    Perrin C. White, Phyllis W. Speiser. (2002) Long-term consequences of childhood-onset congenital adrenal hyperplasia. Best Practice & Research Clinical Endocrinology & Metabolism 16:2, 273-288
    CrossRef

11. 11

    Lu Yu, Damian G. Romero, Celso E. Gomez-Sanchez, Elise P. Gomez-Sanchez. (2002) Steroidogenic enzyme gene expression in the human brain. Molecular and Cellular Endocrinology 190:1-2, 9-17
    CrossRef

12. 12

    Daniela Rogoff, Celso E. Gomez-Sanchez, Mark F. Foecking, Jacobo Wortsman, Andrzej Slominski. (2001) Steroidogenesis in the human skin: 21-hydroxylation in cultured keratinocytes. The Journal of Steroid Biochemistry and Molecular Biology 78:1, 77-81
    CrossRef

13. 13

    Perrin C. White. (2001) Congenital adrenal hyperplasias. Best Practice & Research Clinical Endocrinology & Metabolism 15:1, 17-41
    CrossRef

14. 14

    Phyllis W. Speiser. (2001) CONGENITAL ADRENAL HYPERPLASIA OWING TO 21-HYDROXYLASE DEFICIENCY. Endocrinology & Metabolism Clinics of North America 30:1, 31-59
    CrossRef

15. 15

    Phyllis W. Speiser. (2001) Molecular Diagnosis of CYP21 Mutations in Congenital Adrenal Hyperplasia. American Journal of PharmacoGenomics 1:2, 101-110
    CrossRef

16. 16

    Paul F. J. Koppens, Theo Hoogenboezem, Stenvert L. S. Drop, Sabine M. P. F. de Muinck Keizer-Schrama, Herman J. Degenhart. (1998) Aldosterone production despite absence or defectiveness of the CYP21 genes in two patients with salt-losing congenital adrenal hyperplasia caused by steroid 21-hydroxylase deficiency. Clinical Endocrinology 49:6, 815-822
    CrossRef

17. 17

    C. Krüger, K. Höper, R. Weissörtel, J. Hensen, H. G. Dörr. (1996) Value of direct measurement of active renin concentrations in congenital adrenal hyperplasia due to 21-hydroxylase deficiency. European Journal of Pediatrics 155:10, 858-861
    CrossRef

18. 18

    William H. Hoffman, Myung Y. Shln, Patricia A. Donohoue, Sandra W. Helman, Stephanle L. Brown, George Rosculet, Virendra B. Mahesh. (1996) Phenotypic evolution of classic 21-hydroxylase deficiency. Clinical Endocrinology 45:1, 103-109
    CrossRef

19. 19

    Brenda Kohn, Darren Day, Ramin Alemzadeh, Devi Enerio, Sanjivan V. Patel, Joseph V. Pelczar, Phyllis W. Speiser. (1995) Splicing mutation inCYP21 associated with delayed presentation of salt-wasting congenital adrenal hyperplasia. American Journal of Medical Genetics 57:3, 450-454
    CrossRef

20. 20

    Y. J. LIM, J. A. BATCH, G. L. WARNE. (1995) Adrenal 21-hydroxylase deficiency in childhood: 25 years' experience. Journal of Paediatrics and Child Health 31:3, 222-227
    CrossRef

21. 21

    Epstein, Franklin H., , White, Perrin C.. (1994) Disorders of Aldosterone Biosynthesis and Action. New England Journal of Medicine 331:4, 250-258
    Full Text

22. 22

    Maria I. New. (1994) 21-hydroxylase deficiency congenital adrenal hyperplasia. The Journal of Steroid Biochemistry and Molecular Biology 48:1, 15-22
    CrossRef

23. 23

    Synthia H. Mellon, Christian F. Deschepper. (1993) Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Research 629:2, 283-292
    CrossRef

24. 24

    Ariel Rösler, Esther Leiberman, Tirza Cohen. (1992) High frequency of congenital adrenal hyperplasia (classic 11β-hydroxylase deficiency) among Jews from Morocco. American Journal of Medical Genetics 42:6, 827-834
    CrossRef