Congenital Adrenal Hyperplasia: 11β-Hydroxylase Deficiency

 

 Buy Article Permissions and Reprints

ABSTRACT

The most potent corticosteroids are 11β-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11β-hydroxylase activity, catalyzing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11β-hydroxylase (P450c11), is expressed in high levels in the zona fasciculata and is regulated by adrenocorticotropic hormone (ACTH). CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. The substrate for P450c11 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11β-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension and is autosomal recessively inherited. Classical and nonclassical forms of 11β-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11β-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). Molecular genetic studies of the CYP11B1 gene in 11β-hydroxylase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. Molecular genetic studies have practical importance for the prenatal diagnosis of virilizing CAH forms.

REFERENCES

• 1 Eberlein W R, Bongiovanni A M. Plasma and urinary corticosteroids in the hypertensive form of congenital adrenal hyperplasia.  J Biol Chem . 1956;  223 85-94
  PubMedGoogle Scholar
• 2 Miller W L. Molecular biology of steroid hormone biosynthesis.  Endocr Rev . 1988;  9 295-318
  CrossrefPubMedGoogle Scholar
• 3 Curnow K M, Tusie-Luna M T, Pascoe L. The product of the CYP11B2 gene is required for aldosterone biosynthesis in the human adrenal cortex.  Mol Endocrinol . 1991;  5 1513-1522
  PubMedGoogle Scholar
• 4 Kawamoto T, Mitsuuchi Y, Toda K. Role of steroid 11β-hydroxylase and steroid 18-hydroxylase in the biosynthesis of glucocorticoids and mineralocorticoids in humans.  Proc Natl Acad Sci U S A . 1992;  89 1458-1462
  PubMedGoogle Scholar
• 5 White P C, Curnow K M, Pascoe L. Disorders of steroid 11β-hydroxylase isozymes.  Endocr Rev . 1994;  15 421-438
  CrossrefPubMedGoogle Scholar
• 6 Mornet E, Dupont J, Vitek A, White P C. Characterization of two genes encoding human steroid 11β-hydroxylase (P-45011b).  J Biol Chem . 1989;  264 20961-20967
  CrossrefPubMedGoogle Scholar
• 7 Chua S C, Szabo P, Vitek A. Cloning of cDNA encoding steroid 11β-hydroxylase (P450c11).  Proc Natl Acad Sci U S A . 1987;  84 7193-7197
  PubMedGoogle Scholar
• 8 Taymans S E, Pack S, Pak E. Human CYP11B2 (aldosterone synthase) maps to chromosome 8q24.3  J Clin Endocrinol Metab . 1998;  83 1033-1036
  CrossrefPubMedGoogle Scholar
• 9 Nelson D R, Kamataki T, Waxman D J. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature.  DNA Cell Biol . 1993;  12 1-51
  CrossrefPubMedGoogle Scholar
• 10 Kawamoto T, Mitsuuchi Y, Toda K. Cloning of cDNA and genomic DNA for human cytochrome P-45011β.  FEBS Lett . 1990;  269 345-349
  CrossrefPubMedGoogle Scholar
• 11 Lala D S, Rice D A, Parker K L. Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I.  Mol Endocrinol . 1992;  6 1249-1258
  CrossrefPubMedGoogle Scholar
• 12 Pang S Y, Wallace M A, Hofman L. Worldwide experience in newborn screening for classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.  Pediatrics . 1988;  81 866-874
  PubMedGoogle Scholar
• 13 Zachmann M, Tassinari D, Prader A. Clinical and biochemical variability of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency: a study of 25 patients.  J Clin Endocrinol Metab . 1983;  56 222-229
  CrossrefPubMedGoogle Scholar
• 14 Rösler A, Leiberman E, Cohen T. High frequency of congenital adrenal hyperplasia (classic 11β-hydroxylase deficiency) among Jews from Morocco.  Am J Med Genet . 1992;  42 827-834
  CrossrefPubMedGoogle Scholar
• 15 Hochberg Z, Schechter J, Benderly A, Leiberman E, Rösler A. Growth and pubertal development in patients with congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.  Am J Dis Child . 1985;  139 771-776
  PubMedGoogle Scholar
• 16 Carmina E, Malizia G, Pagano M, Janni A. Prevalence of late-onset 11β-hydroxylase deficiency in hirsute patients.  J Endocrinol Invest . 1988;  11 595-598
  PubMedGoogle Scholar
• 17 Azziz R, Boots L R, Parker C R, Bradley E, Zacur H A. 11β-hydroxylase deficiency in hyperandrogenism.  Fertil Steril . 1991;  55 733-741
  PubMedGoogle Scholar
• 18 Joehrer K, Geley S, Strasser-Wozak E MC. CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11β-hydroxylase deficiency.  Hum Mol Genet . 1997;  6 1829-1834
  CrossrefPubMedGoogle Scholar
• 19 Rösler A, Leiberman E, Sack J. Clinical variability of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.  Horm Res . 1982;  16 133-141
  PubMedGoogle Scholar
• 20 Hague W M, Honour J W. Malignant hypertension in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.  Clin Endocrinol (Oxf) . 1983;  18 505-510
  PubMedGoogle Scholar
• 21 Zadik Z, Kahana L, Kaufmann H, Benderly A, Hochberg Z. Salt loss in hypertensive form of congenital adrenal hyperplasia (11β-hydroxylase deficiency).  J Clin Endocrinol Metab . 1984;  58 384-387
  PubMedGoogle Scholar
• 22 Hochberg Z, Benderly A, Kahana L, Zadik Z. Requirement of mineralocorticoid in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.  J Clin Endocrinol Metab . 1986;  63 36-40
  PubMedGoogle Scholar
• 23 Levine L S, Rauh W, Gottesdiener K. New studies of the 11β-hydroxylase and 18-hydroxylase enzymes in the hypertensive form of congenital adrenal hyperplasia.  J Clin Endocrinol Metab . 1980;  50 258-263
  PubMedGoogle Scholar
• 24 Pang S, Levine L S, Lorenzen F. Hormonal studies in obligate heterozygotes and siblings of patients with 11β-hydroxylase deficiency congenital adrenal hyperplasia.  J Clin Endocrinol Metab . 1980;  50 586-589
  PubMedGoogle Scholar
• 25 Rösler A, Cohen H. Absence of steroid biosynthetic defects in heterozygote individuals for classic 11β-hydroxylase deficiency due to a R448H mutation in the CYP11B1 gene.  J Clin Endocrinol Metab . 1995;  80 3771-3773
  CrossrefPubMedGoogle Scholar
• 26 Peter M, Sippell W G. Evidence for endocrinological abnormalities in heterozygotes for adrenal 11β-hydroxylase deficiency of a family with the R448H mutation in the CYP11B1 gene.  J Clin Endocrinol Metab . 1997;  82 3506-3508
  CrossrefPubMedGoogle Scholar
• 27 Wudy S A, Homoki J, Wachter U A, Teller W M. Diagnosis of congenital adrenogenital hyperplasia due to 11β-hydroxylase deficiency by gas chromatographic and mass spectrometric analysis of urinary steroids.  Dtsch Med Wochenschr . 1997;  122 3-11
  PubMedGoogle Scholar
• 28 Honour J W, Anderson J M, Shackleton C H. Difficulties in the diagnosis of congenital adrenal hyperplasia in early infancy: the 11β-hydroxylase defect.  Acta Endocrinol (Copenh) . 1983;  103 101-109
  PubMedGoogle Scholar
• 29 Rösler A, Weshler N, Leiberman E. 11β-hydroxylase deficiency congenital adrenal hyperplasia: update of prenatal diagnosis.  J Clin Endocrinol Metab . 1988;  66 830-838
  PubMedGoogle Scholar
• 30 Schumbert Z, Rosemann A, Landa H, Rösler A. 11-Deoxycortisol in amniotic fluid: prenatal diagnosis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.  Clin Endocrinol (Oxf) . 1980;  12 257-260
  PubMedGoogle Scholar
• 31 Sippell W G, Müller-Holve W, Dörr H G, Bidlingmaier F KD. Concentrations of aldosterone, corticosterone, 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, cortisol, and cortisone determined simultaneously in human amniotic fluid throughout gestation.  J Clin Endocrinol Metab . 1981;  52 385-392
  PubMedGoogle Scholar
• 32 Cerame B I, Newfield R S, Pascoe L. Prenatal diagnosis and treatment of 11β-hydroxylase deficiency congenital adrenal hyperplasia resulting in normal female genitalia.  J Clin Endocrinol Metab . 1999;  84 3129-3134
  CrossrefPubMedGoogle Scholar
• 33 Curnow K M, Slutsker L, Vitek J. Mutations in the CYP11B1 gene causing congenital adrenal hyperplasia and hypertension cluster in exons 6, 7, and 8.  Proc Natl Acad Sci U S A . 1993;  90 4552-4556
  PubMedGoogle Scholar
• 34 Geley S, Kapelari K, Joehrer K. CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency.  J Clin Endocrinol Metab . 1996;  81 2896-2901
  CrossrefPubMedGoogle Scholar
• 35 Forest M G, Morel Y, David M. Prenatal treatment of congenital adrenal hyperplasia.  TEM . 1998;  9 284-289
  PubMedGoogle Scholar
• 36 White P C, Dupont J, New M I. A mutation in CYP11B1 (Arg-448→His) associated with steroid 11β-hydroxylase deficiency in Jews of Moroccan origin.  J Clin Invest . 1991;  87 1664-1667
  CrossrefPubMedGoogle Scholar
• 37 Helmberg A, Ausserer B, Kofler R. Frame shift by insertion of 2 basepairs in codon 394 of CYP11B1 causes congenital adrenal hyperplasia due to steroid 11 beta-hydroxylase deficiency.  J Clin Endocrinol Metab . 1992;  75 1278-1281
  CrossrefPubMedGoogle Scholar
• 38 Naiki Y, Kawamoto T, Mitsuuchi Y. A nonsense mutation (TGG [Trp116] → TAG [Stop]) in CYP11B1 causes steroid 11β-hydroxylase deficiency.  J Clin Endocrinol Metab . 1993;  77 1677-1682
  CrossrefPubMedGoogle Scholar
• 39 Skinner C A, Rumsby G. Steroid 11β-hydroxylase deficiency caused by a five base pair duplication in the CYP11B1 gene.  Hum Mol Genet . 1994;  3 377-378
  PubMedGoogle Scholar
• 40 Yang L X, Toda K, Miyahara K. Classic steroid 11β-hydroxylase deficiency caused by a C → G transversion in exon 7 of CYP11B1.  Biochem Biophys Res Commun . 1995;  216 723-728
  CrossrefPubMedGoogle Scholar
• 41 Skinner C A, Rumsby G, Honour J W. Single strand conformation polymorphism (SSCP) analysis for the detection of mutations in the CYP11B1 gene.  J Clin Endocrinol Metab . 1996;  81 2389-2393
  CrossrefPubMedGoogle Scholar
• 42 Nakagawa Y, Yamada M, Ogawa H, Igarashi Y. Missense mutation in CYP11B1 (CGA[Arg-384] → GGA[Gly]) causes steroid 11β-hydroxylase deficiency.  Eur J Endocrinol . 1995;  132 286-289
  PubMedGoogle Scholar
• 43 Merke D P, Tajima T, Chhabra A. Novel CYP11B1 mutations in congenital adrenal hyperplasia due to steroid 11β-hydroxylase deficiency.  Clin Endocrinol Metab . 1998;  83 270-273
  PubMedGoogle Scholar
• 44 Viemann M, Peter M, Schwarz H P, Sólyom J, Sippell W G. CYP11B1 gene mutations in patients with 11β-hydroxylase deficiency.  Horm Res . 1998;  50(S3) 108
  PubMedGoogle Scholar
• 45 Chabre O, Portrat-Doyen S, Chaffanjon P. Bilateral laparoscopic adrenalectomy for congenital adrenal hyperplasia with severe hypertension, resulting from two novel mutations in splice donor sites of CYP11B1 J Clin Endocrinol Metab .  2000;  85 4060-4068
  PubMedGoogle Scholar
• 46 Portrat S, Mulatero P, Curnow K M. Deletion hybrid genes, due to unequal crossing over between CYP11B1 (11β-hydroxylase) and CYP11B2 (aldosterone synthase) cause steroid 11β-hydroxylase deficiency and congenital adrenal hyperplasia.  J Clin Endocrinol Metab . 2001;  86 3197-3201
  CrossrefPubMedGoogle Scholar
• 47 Hampf M, Dao N T, Hoan N T, Bernhardt R. Unequal crossing-over between aldosterone synthase and 11β-hydroxylase genes causes congenital adrenal hyperplasia.  J Clin Endocrinol Metab . 2001;  86 4445-4452
  CrossrefPubMedGoogle Scholar