Abstract
Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency is a rare autosomal recessive genetic disorder. It is caused by reduced or absent activity of 11β-hydroxylase (CYP11B1) enzyme and the resultant defects in adrenal steroidogenesis. The most common clinical features of 11 beta-hydroxylase deficiency are ambiguous genitalia, accelerated skeletal maturation and resultant short stature, peripheral precocious puberty and hyporeninemic hypokalemic hypertension. The biochemical diagnosis is based on raised serum 11-deoxycortisol and 11-deoxycorticosterone levels together with increased adrenal androgens. More than 100 mutations in CYP11B1 gene have been reported to date. The level of in-vivo activity of CYP11B1 relates to the degree of severity of 11 beta-hydroxylase deficiency. Clinical management of 11 beta-hydroxylase deficiency can pose a challenge to maintain adequate glucocorticoid dosing to suppress adrenal androgen excess while avoiding glucocorticoid-induced side effects. The long-term outcomes of clinical and surgical management are not well studied. This review article aims to collate the current available data about 11 beta-hydroxylase deficiency and its management.
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P.W. Speiser, R. Azziz, L.S. Baskin, L. Ghizzoni, T.W. Hensle, D.P. Merke, H.F. Meyer-Bahlburg, W.L. Miller, V.M. Montori, S.E. Oberfield, M. Ritzen, P.C. White, S. Endocrine, Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 95(9), 4133–4160 (2010). doi:10.1210/jc.2009-2631
H. Falhammar, M. Thoren, Clinical outcomes in the management of congenital adrenal hyperplasia. Endocrine. 41(3), 355–373 (2012). doi:10.1007/s12020-011-9591-x
L.d Crecchio, Sopra un caso di apparenzi virili in una donna. Morgagni 7, 154–188 (1865)
L. Wilkins, R.A. Lewis, R. Klein, E. Rosemberg, The suppression of androgen secretion by cortisone in a case of congenital adrenal hyperplasia. Bull. Johns. Hopkins. Hosp. 86(4), 249–252 (1950)
T.H. Shepard, S.W. Clausen, Case of adrenogenital syndrome with hypertension treated with cortisone. Pediatrics. 8(6), 805–811 (1951)
L. Wilkins, J.F. Crigler Jr., S.H. Silverman, L.I. Gardner, C.J. Migeon, Further studies on the treatment of congenital adrenal hyperplasia with cortisone. III. The control of hypertension with cortisone, with a discussion of variations in the type of congenital adrenal hyperplasia and report of a case with probable defect of carbohydrate-regulating hormones. J. Clin. Endocrinol. Metab. 12(8), 1015–1030 (1952). doi:10.1210/jcem-12-8-1015
A.M. Bongiovanni, W.R. Eberlein, Plasma and urinary corticosteroids in the hypertensive form of congenital adrenal hyperplasia. J. Biol. Chem. 223(1), 85–94 (1956)
P.C. White, P.W. Speiser, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr. Rev. 21(3), 245–291 (2000). doi:10.1210/edrv.21.3.0398
D.P. Merke, S.R. Bornstein, Congenital adrenal hyperplasia. Lancet. 365(9477), 2125–2136 (2005). doi:10.1016/S0140-6736(05)66736-0
M. Zachmann, D. Tassinari, A. Prader, Clinical and biochemical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. A study of 25 patients. J. Clin. Endocrinol. Metab. 56(2), 222–229 (1983). doi:10.1210/jcem-56-2-222
S. Nimkarn, M.I. New, Steroid 11beta- hydroxylase deficiency congenital adrenal hyperplasia. Trends. Endocrinol. Metab. 19(3), 96–99 (2008). doi:10.1016/j.tem.2008.01.002
W. Arlt, D.S. Willis, S.H. Wild, N. Krone, E.J. Doherty, S. Hahner, T.S. Han, P.V. Carroll, G.S. Conway, D.A. Rees, R.H. Stimson, B.R. Walker, J.M. Connell, R.J. Ross; United Kingdom Congenital Adrenal Hyperplasia Adult Study, E., Health status of adults with congenital adrenal hyperplasia: a cohort study of 203 patients. J. Clin. Endocrinol. Metab. 95(11), 5110–5121 (2010). doi:10.1210/jc.2010-0917
S. Gidlof, H. Falhammar, A. Thilen, U. von Dobeln, M. Ritzen, A. Wedell, A. Nordenstrom, One hundred years of congenital adrenal hyperplasia in Sweden: a retrospective, population-based cohort study. Lancet Diabetes Endocrinol. 1(1), 35–42 (2013). doi:10.1016/S2213-8587(13)70007-X
H. Falhammar, A. Nordenstrom, Nonclassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency: clinical presentation, diagnosis, treatment, and outcome. Endocrine 50(1), 32–50 (2015). doi:10.1007/s12020-015-0656-0
A. Rosler, E. Leiberman, T. Cohen, High frequency of congenital adrenal hyperplasia (classic 11 beta-hydroxylase deficiency) among Jews from Morocco. Am. J. Med. Genet. 42(6), 827–834 (1992). doi:10.1002/ajmg.1320420617
P.C. White, Steroid 11 beta-hydroxylase deficiency and related disorders. Endocrinol. Metab. Clin. North. Am. 30(1), 61–79 (2001). vi
P.W. Speiser, P.C. White, Congenital adrenal hyperplasia. N. Engl. J. Med. 349(8), 776–788 (2003). doi:10.1056/NEJMra021561
M.I. New, M.P. Seaman, Secretion rates of cortisol and aldosterone precursors in various forms of congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 30(3), 361–371 (1970). doi:10.1210/jcem-30-3-361
N. Krone, W. Arlt, Genetics of congenital adrenal hyperplasia. Best. Pract. Res. Clin. Endocrinol. Metab. 23(2), 181–192 (2009). doi:10.1016/j.beem.2008.10.014
L. Schiffer, S. Anderko, F. Hannemann, A. Eiden-Plach, R. Bernhardt, The CYP11B subfamily. J. Steroid. Biochem. Mol. Biol. 151, 38–51 (2015). doi:10.1016/j.jsbmb.2014.10.011
H. Selye, H. Stone, Hormonally induced transformation of adrenal into myeloid tissue. Am. J. Pathol. 26(2), 211–233 (1950)
S. Jaresch, E. Kornely, H.K. Kley, R. Schlaghecke, Adrenal incidentaloma and patients with homozygous or heterozygous congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 74(3), 685–689 (1992). doi:10.1210/jcem.74.3.1311000
H. Falhammar, Non-functioning adrenal incidentalomas caused by 21-hydroxylase deficiency or carrier status? Endocrine. 47(1), 308–314 (2014). doi:10.1007/s12020-013-0162-1
E. Charmandari, G. Eisenhofer, S.L. Mehlinger, A. Carlson, R. Wesley, M.F. Keil, G.P. Chrousos, M.I. New, D.P. Merke, Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 87(7), 3031–3037 (2002). doi:10.1210/jcem.87.7.8664
H. Falhammar, H. Filipsson Nystrom, A. Wedell, M. Thoren, Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur. J. Endocrinol. 164(2), 285–293 (2011). doi:EJE-10-0877 [pii] 10.1530/EJE-10-0877
G.P. Finkielstain, M.S. Kim, N. Sinaii, M. Nishitani, C. Van Ryzin, S.C. Hill, J.C. Reynolds, R.M. Hanna, D.P. Merke, Clinical characteristics of a cohort of 244 patients with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 97(12), 4429–4438 (2012). doi:10.1210/jc.2012-2102
F. Tutunculer, N. Saka, S.C. Arkaya, S. Abbasoglu, F. Bas, Evaluation of adrenomedullary function in patients with congenital adrenal hyperplasia. Horm. Res. 72(6), 331–336 (2009). doi:10.1159/000249160
A. Rosler, E. Leiberman, J. Sack, H. Landau, A. Benderly, S.W. Moses, T. Cohen, Clinical variability of congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Horm. Res. 16(3), 133–141 (1982)
N.A. al-Jurayyan, Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency in Saudi Arabia: clinical and biochemical characteristics. Acta. Paediatr. 84(6), 651–654 (1995)
C.P. Burren, J. Montalto, A.B. Yong, J.A. Batch, CYP11 beta 1 (11-beta-hydroxylase) deficiency in congenital adrenal hyperplasia. J. Paediatr. Child. Health. 32(5), 433–438 (1996)
S. Riedl, H.H. Nguyen, S. Clausmeyer, E. Schulze, F. Waldhauser, R. Bernhardt, A homozygous L299P mutation in the CYP11B1 gene leads to complete virilization in 46,XX individuals with 11-beta-hydroxylase deficiency. Horm. Res. 70(3), 145–149 (2008). doi:10.1159/000137659
S. Parajes, L. Loidi, N. Reisch, V. Dhir, I.T. Rose, R. Hampel, M. Quinkler, G.S. Conway, L. Castro-Feijoo, D. Araujo-Vilar, M. Pombo, F. Dominguez, E.L. Williams, T.R. Cole, J.M. Kirk, E. Kaminsky, G. Rumsby, W. Arlt, N. Krone, Functional consequences of seven novel mutations in the CYP11B1 gene: four mutations associated with nonclassic and three mutations causing classic 11{beta}-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 95(2), 779–788 (2010). doi:10.1210/jc.2009-0651
A. Nordenskjold, G. Holmdahl, L. Frisen, H. Falhammar, H. Filipsson, M. Thoren, P.O. Janson, K. Hagenfeldt, Type of mutation and surgical procedure affect long-term quality of life for women with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 93(2), 380–386 (2008). doi:jc.2007-0556 [pii] 10.1210/jc.2007-0556
A.S. Oberman, E. Flatau, R. Luboshitzky, Bilateral testicular adrenal rests in a patient with 11-hydroxylase deficient congenital adrenal hyperplasia. J. Urol. 149(2), 350–352 (1993)
P.C. White, K.M. Curnow, L. Pascoe, Disorders of steroid 11 beta-hydroxylase isozymes. Endocr. Rev. 15(4), 421–438 (1994). doi:10.1210/edrv-15-4-421
V. Harde, M. Muller, W.G. Sippell, T. Schwarz, R. Folster-Holst, [Acne infantum as presenting symptom of congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency]. J. Dtsch. Dermatol. Ges. 4(8), 654–657 (2006). doi:10.1111/j.1610-0387.2006.06016.x
Z. Hochberg, J. Schechter, A. Benderly, E. Leiberman, A. Rosler, Growth and pubertal development in patients with congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Am. J. Dis. Child. 139(8), 771–776 (1985)
N. Reisch, W. Hogler, S. Parajes, I.T. Rose, V. Dhir, J. Gotzinger, W. Arlt, N. Krone, A diagnosis not to be missed: nonclassic steroid 11beta-hydroxylase deficiency presenting with premature adrenarche and hirsutism. J. Clin. Endocrinol. Metab. 98(10), E1620–1625 (2013). doi:10.1210/jc.2013-1306
M. Mimouni, H. Kaufman, A. Roitman, C. Morag, N. Sadan, Hypertension in a neonate with 11 beta-hydroxylase deficiency. Eur. J. Pediatr. 143(3), 231–233 (1985)
M. John, S.K. Menon, N.S. Shah, P.S. Menon, Congenital adrenal hyperplasia 11beta-hydroxylase deficiency: two cases managed with bilateral adrenalectomy. Singapore Med. J. 50(2), e68–70 (2009)
A. Sathya, R. Ganesan, A. Kumar, Congenital adrenal hyperplasia masquerading as periodic paralysis in an adolescent girl. Singapore Med. J. 53(7), e148–149 (2012)
H. Falhammar, M. Thoren, J. Calissendorff, Thyrotoxic periodic paralysis: clinical and molecular aspects. Endocrine 43(2), 274–284 (2013). doi:10.1007/s12020-012-9777-x
Z. Zadik, L. Kahana, H. Kaufman, A. Benderli, Z. Hochberg, Salt loss in hypertensive form of congenital adrenal hyperplasia (11-beta-hydroxylase deficiency). J. Clin. Endocrinol. Metab. 58(2), 384–387 (1984). doi:10.1210/jcem-58-2-384
Z. Hochberg, A. Benderly, Z. Zadik, Salt loss in congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Arch. Dis. Child. 59(11), 1092–1094 (1984)
Y. Liel, Acute adrenal crisis complicating hypertensive congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Clin. Genet. 43(2), 92–93 (1993)
B. Ezquieta, C. Luzuriaga, Neonatal salt-wasting and 11 beta-hydroxylase deficiency in a child carrying a homozygous deletion hybrid CYP11B2 (aldosterone synthase)-CYP11B1 (11 beta-hydroxylase). Clin. Genet. 66(3), 229–235 (2004). doi:10.1111/j.1399-0004.2004.00291.x
H. Falhammar, M. Thoren, K. Hagenfeldt, A 31-year-old woman with infertility and polycystic ovaries diagnosed with non-classic congenital adrenal hyperplasia due to a novel CYP21 mutation. J. Endocrinol. Invest. 31(2), 176–180 (2008). doi:10.1007/BF03345586
M. Pall, R. Azziz, J. Beires, D. Pignatelli, The phenotype of hirsute women: a comparison of polycystic ovary syndrome and 21-hydroxylase-deficient nonclassic adrenal hyperplasia. Fertil. Steril. 94(2), 684–689 (2010). doi:10.1016/j.fertnstert.2009.06.025
R. Azziz, E. Carmina, D. Dewailly, E. Diamanti-Kandarakis, H.F. Escobar-Morreale, W. Futterweit, O.E. Janssen, R.S. Legro, R.J. Norman, A.E. Taylor, S.F. Witchel, Task Force on the Phenotype of the Polycystic Ovary Syndrome of The Androgen, E., Society, P., The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report. Fertil. Steril. 91(2), 456–488 (2009). doi:10.1016/j.fertnstert.2008.06.035
M.I. New, F. Lorenzen, A.J. Lerner, B. Kohn, S.E. Oberfield, M.S. Pollack, B. Dupont, E. Stoner, D.J. Levy, S. Pang, L.S. Levine, Genotyping steroid 21-hydroxylase deficiency: hormonal reference data. J. Clin. Endocrinol. Metab. 57(2), 320–326 (1983). doi:10.1210/jcem-57-2-320
I.A. Hughes, O. Arisaka, L.A. Perry, J.W. Honour, Early diagnosis of 11 beta-hydroxylase deficiency in two siblings confirmed by analysis of a novel steroid metabolite in newborn urine. Acta. Endocrinol. 111(3), 349–354 (1986)
K. Lange-Kubini, M. Zachmann, B. Kempken, T. Torresani, 15 beta-hydroxylated steroids may be diagnostically misleading in confirming congenital adrenal hyperplasia suspected by a newborn screening programme. Eur. J. Pediatr. 155(11), 928–931 (1996)
F. Mantero, G. Opocher, D. Armanini, S. Filipponi, 11 Beta-hydroxylase deficiency. J. Endocrinol. Invest. 18(7), 545–549 (1995)
R. Azziz, L.R. Boots, C.R. Parker Jr., E. Bradley Jr., H.A. Zacur, 11 beta-hydroxylase deficiency in hyperandrogenism. Fertil. Steril. 55(4), 733–741 (1991)
F. Kelestimur, Y. Sahin, D. Ayata, A. Tutus, The prevalence of non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency among hirsute women in a Turkish population. Clin. Endocrinol. 45(4), 381–384 (1996)
Y. Sahin, F. Kelestimur, The frequency of late-onset 21-hydroxylase and 11 beta-hydroxylase deficiency in women with polycystic ovary syndrome. Eur. J. Endocrinol. 137(6), 670–674 (1997)
M. Peter, W.G. Sippell, Evidence for endocrinological abnormalities in heterozygotes for adrenal 11 beta-hydroxylase deficiency of a family with the R448H mutation in the CYP11B1 gene. J. Clin. Endocrinol. Metab. 82(10), 3506–3508 (1997). doi:10.1210/jcem.82.10.4051
S. Pang, L.S. Levine, F. Lorenzen, D. Chow, M. Pollack, B. Dupont, M. Genel, M.I. New, Hormonal studies in obligate heterozygotes and siblings of patients with 11 beta-hydroxylase deficiency congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 50(3), 586–589 (1980). doi:10.1210/jcem-50-3-586
A. Rosler, H. Cohen, Absence of steroid biosynthetic defects in heterozygote individuals for classic 11 beta-hydroxylase deficiency due to a R448H mutation in the CYP11B1 gene. J. Clin. Endocrinol. Metab. 80(12), 3771–3773 (1995). doi:10.1210/jcem.80.12.8530633
E. Mornet, J. Dupont, A. Vitek, P.C. White, Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta. J. Biol. Chem. 264(35), 20961–20967 (1989)
K.M. Curnow, L. Slutsker, J. Vitek, T. Cole, P.W. Speiser, M.I. New, P.C. White, L. Pascoe, 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. 90(10), 4552–4556 (1993)
N. Kandemir, D.Y. Yilmaz, E.N. Gonc, A. Ozon, A. Alikasifoglu, A. Dursun, R.K. Ozgul, Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-beta hydroxylase deficiency. J. Steroid. Biochem. Mol. Biol. (2016). 10.1016/j.jsbmb.2016.03.006
A. Wedell, A. Thilen, E.M. Ritzen, B. Stengler, H. Luthman, Mutational spectrum of the steroid 21-hydroxylase gene in Sweden: implications for genetic diagnosis and association with disease manifestation. J. Clin. Endocrinol. Metab. 78(5), 1145–1152 (1994). doi:10.1210/jcem.78.5.8175971
J. Jaaskelainen, A. Levo, R. Voutilainen, J. Partanen, Population-wide evaluation of disease manifestation in relation to molecular genotype in steroid 21-hydroxylase (CYP21) deficiency: good correlation in a well defined population. J. Clin. Endocrinol. Metab. 82(10), 3293–3297 (1997). doi:10.1210/jcem.82.10.4271
H. Falhammar, A. Wedell, A. Nordenstrom, Biochemical and genetic diagnosis of 21-hydroxylase deficiency. Endocrine. 50(2), 306–314 (2015). doi:10.1007/s12020-015-0731-6
R. Marino, P. Ramirez, J. Galeano, N. Perez Garrido, C. Rocco, M. Ciaccio, D.M. Warman, G. Guercio, E. Chaler, M. Maceiras, I. Bergada, M. Gryngarten, V. Balbi, E. Pardes, M.A. Rivarola, A. Belgorosky, Steroid 21-hydroxylase gene mutational spectrum in 454 Argentinean patients: genotype-phenotype correlation in a large cohort of patients with congenital adrenal hyperplasia. Clin. Endocrinol. 75(4), 427–435 (2011). doi:10.1111/j.1365-2265.2011.04123.x
M.I. New, M. Abraham, B. Gonzalez, M. Dumic, M. Razzaghy-Azar, D. Chitayat, L. Sun, M. Zaidi, R.C. Wilson, T. Yuen, Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. Proc. Natl. Acad. Sci. U. S. A. 110(7), 2611–2616 (2013). doi:10.1073/pnas.1300057110
H. Falhammar, H. Filipsson, G. Holmdahl, P.O. Janson, A. Nordenskjold, K. Hagenfeldt, M. Thoren, Fractures and bone mineral density in adult women with 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 92(12), 4643–4649 (2007). doi:jc.2007-0744 [pii] 10.1210/jc.2007-0744
K. Hagenfeldt, P.O. Janson, G. Holmdahl, H. Falhammar, H. Filipsson, L. Frisen, M. Thoren, A. Nordenskjold, Fertility and pregnancy outcome in women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Hum. Reprod. 23(7), 1607–1613 (2008). doi:den118 [pii] 10.1093/humrep/den118
H. Falhammar, H. Filipsson, G. Holmdahl, P.O. Janson, A. Nordenskjold, K. Hagenfeldt, M. Thoren, Increased liver enzymes in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Endocr. J. 56(4), 601–608 (2009)
L. Frisen, A. Nordenstrom, H. Falhammar, H. Filipsson, G. Holmdahl, P.O. Janson, M. Thoren, K. Hagenfeldt, A. Moller, A. Nordenskjold, Gender role behavior, sexuality, and psychosocial adaptation in women with congenital adrenal hyperplasia due to CYP21A2 deficiency. J. Clin. Endocrinol. Metab. 94(9), 3432–3439 (2009). doi:10.1210/jc.2009-0636
A. Nordenstrom, L. Frisen, H. Falhammar, H. Filipsson, G. Holmdahl, P.O. Janson, M. Thoren, K. Hagenfeldt, A. Nordenskjold, Sexual function and surgical outcome in women with congenital adrenal hyperplasia due to CYP21A2 deficiency: clinical perspective and the patients’ perception. J. Clin. Endocrinol. Metab. 95(8), 3633–3640 (2010). doi:jc.2009-2639 [pii] 10.1210/jc.2009-2639
H. Falhammar, H.F. Nystrom, U. Ekstrom, S. Granberg, A. Wedell, M. Thoren, Fertility, sexuality and testicular adrenal rest tumors in adult males with congenital adrenal hyperplasia. Eur. J. Endocrinol. 166(3), 441–449 (2012). doi:10.1530/EJE-11-0828
H. Falhammar, H. Filipsson Nystrom, A. Wedell, K. Brismar, M. Thoren, Bone mineral density, bone markers, and fractures in adult males with congenital adrenal hyperplasia. Eur. J. Endocrinol. 168(3), 331–341 (2013). doi:10.1530/EJE-12-0865
U. Nygren, H.F. Nystrom, H. Falhammar, K. Hagenfeldt, A. Nordenskjold, M. Sodersten, Voice problems due to virilization in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin. Endocrinol. 79(6), 859–866 (2013). doi:10.1111/cen.12226
A. Strandqvist, H. Falhammar, P. Lichtenstein, A.L. Hirschberg, A. Wedell, C. Norrby, A. Nordenskjold, L. Frisen, A. Nordenstrom, Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia: epidemiological studies in a nonbiased national cohort in Sweden. J. Clin. Endocrinol. Metab. 99(4), 1425–1432 (2014). doi:10.1210/jc.2013-3326
H. Falhammar, A. Butwicka, M. Landen, P. Lichtenstein, A. Nordenskjold, A. Nordenstrom, L. Frisen, Increased psychiatric morbidity in men with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 99(3), E554–560 (2014). doi:10.1210/jc.2013-3707
H. Falhammar, H.F. Nystrom, M. Thoren, Quality of life, social situation, and sexual satisfaction, in adult males with congenital adrenal hyperplasia. Endocrine. 47(1), 299–307 (2014). doi:10.1007/s12020-013-0161-2
H. Engberg, A. Butwicka, A. Nordenstrom, A.L. Hirschberg, H. Falhammar, P. Lichtenstein, A. Nordenskjold, L. Frisen, M. Landen, Congenital adrenal hyperplasia and risk for psychiatric disorders in girls and women born between 1915 and 2010: a total population study. Psychoneuroendocrinology. 60, 195–205 (2015). doi:10.1016/j.psyneuen.2015.06.017
H. Falhammar, L. Frisen, A.L. Hirschberg, C. Norrby, C. Almqvist, A. Nordenskjold, A. Nordenstrom, Increased cardiovascular and metabolic morbidity in patients with 21-hydroxylase deficiency: a Swedish population-based national cohort study. J. Clin. Endocrinol. Metab. 100(9), 3520–3528 (2015). doi:10.1210/JC.2015-2093
P.C. White, J. Dupont, M.I. New, E. Leiberman, Z. Hochberg, A. Rosler, A mutation in CYP11B1 (Arg-448----His) associated with steroid 11 beta-hydroxylase deficiency in Jews of Moroccan origin. J. Clin. Invest. 87(5), 1664–1667 (1991). doi:10.1172/JCI115182
K. Matsubara, N. Kataoka, S. Ogita, S. Sano, T. Ogata, M. Fukami, N. Katsumata, Uniparental disomy of chromosome 8 leading to homozygosity of a CYP11B1 mutation in a patient with congenital adrenal hyperplasia: implication for a rare etiology of an autosomal recessive disorder. Endocr. J. 61(6), 629–633 (2014)
K. Joehrer, S. Geley, E.M. Strasser-Wozak, R. Azziz, H.A. Wollmann, K. Schmitt, R. Kofler, P.C. White, CYP11B1 mutations causing non-classic adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Hum. Mol. Genet. 6(11), 1829–1834 (1997)
S. Menabo, S. Polat, L. Baldazzi, A.E. Kulle, P.M. Holterhus, J. Grotzinger, F. Fanelli, A. Balsamo, F.G. Riepe, Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency: functional consequences of four CYP11B1 mutations. Eur. J. Hum. Genet. 22(5), 610–616 (2014). doi:10.1038/ejhg.2013.197
S. Polat, A. Kulle, Z. Karaca, I. Akkurt, S. Kurtoglu, F. Kelestimur, J. Grotzinger, P.M. Holterhus, F.G. Riepe, Characterisation of three novel CYP11B1 mutations in classic and non-classic 11beta-hydroxylase deficiency. Eur. J. Endocrinol. 170(5), 697–706 (2014). doi:10.1530/EJE-13-0737
C. Brautbar, A. Rosler, H. Landau, I. Cohen, D. Nelken, T. Cohen, C. Levine, J. Sack, A. Benderli, S. Moses, E. Lieberman, B. Dupont, L.S. Levine, M.I. New, No linkage between HLA and congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. N. Engl. J. Med. 300(4), 205–206 (1979)
F. Mantero, C. Scaroni, P. Masarotto, C.V. Pasini, HLA and hormonal data for identification of heterozygotes in 11 beta- and 17 alpha-hydroxylase deficiency syndromes. Clin. Exp. Pharmacol. Physiol. 9(3), 265–269 (1982)
V. Tonetto-Fernandes, S.H. Lemos-Marini, H. Kuperman, L.M. Ribeiro-Neto, I.T. Verreschi, C.E. Kater, Serum 21-Deoxycortisol, 17-Hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and hormonal correlations and identification of patients with 11beta-hydroxylase deficiency among a large group with alleged 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 91(6), 2179–2184 (2006). doi:10.1210/jc.2005-1890
N. Kandemir, N. Yordam, Congenital adrenal hyperplasia in Turkey: a review of 273 patients. Acta. Paediatr. 86(1), 22–25 (1997)
E. Carmina, G. Malizia, M. Pagano, A. Janni, Prevalence of late-onset 11 beta-hydroxylase deficiency in hirsute patients. J. Endocrinol. Invest. 11(8), 595–598 (1988)
T. Eldar-Geva, A. Hurwitz, P. Vecsei, Z. Palti, A. Milwidsky, A. Rosler, Secondary biosynthetic defects in women with late-onset congenital adrenal hyperplasia. N. Engl. J. Med. 323(13), 855–863 (1990). doi:10.1056/NEJM199009273231302
R.D. Brown, R. Gaunt, E. Gisoldi, N. Smith, The role of deoxycorticosterone in adrenal regeneration hypertension. Endocrinology 91(4), 921–924 (1972). doi:10.1210/endo-91-4-921
G.P. Vinson, The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function. J. Endocrinol. 211(1), 3–16 (2011). doi:10.1530/JOE-11-0178
A. Glenthoj, M.D. Nielsen, J. Starup, Congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency: final diagnosis in adult age in three patients. Acta. Endocrinol. 93(1), 94–99 (1980)
W.M. Hague, J.W. Honour, Malignant hypertension in congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. Clin. Endocrinol. 18(5), 505–510 (1983)
O. Chabre, S. Portrat-Doyen, P. Chaffanjon, J. Vivier, P. Liakos, F. Labat-Moleur, E. Chambaz, Y. Morel, G. Defaye, 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. 85(11), 4060–4068 (2000). doi:10.1210/jcem.85.11.6897
E. Melcescu, J. Phillips, G. Moll, J.S. Subauste, C.A. Koch, 11Beta-hydroxylase deficiency and other syndromes of mineralocorticoid excess as a rare cause of endocrine hypertension. Horm. Metab. Res. 44(12), 867–878 (2012). doi:10.1055/s-0032-1321851
R.M. Williams, A. Deeb, K.K. Ong, W. Bich, P.R. Murgatroyd, I.A. Hughes, C.L. Acerini, Insulin sensitivity and body composition in children with classical and nonclassical congenital adrenal hyperplasia. Clin. Endocrinol. 72(2), 155–160 (2010). doi:10.1111/j.1365-2265.2009.03587.x
C.F. Mooij, J.M. Kroese, F.C. Sweep, A.R. Hermus, C.J. Tack, Adult patients with congenital adrenal hyperplasia have elevated blood pressure but otherwise a normal cardiovascular risk profile. PLoS. One. 6(9), e24204 (2011). doi:10.1371/journal.pone.0024204
H. Falhammar, H. Filipsson, G. Holmdahl, P.O. Janson, A. Nordenskjold, K. Hagenfeldt, M. Thoren, Metabolic profile and body composition in adult women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 92(1), 110–116 (2007). doi:jc.2006-1350 [pii] 10.1210/jc.2006-1350
P. Sartorato, E. Zulian, S. Benedini, B. Mariniello, F. Schiavi, F. Bilora, G. Pozzan, N. Greggio, A. Pagnan, F. Mantero, C. Scaroni, 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. J. Clin. Endocrinol. Metab. 92(3), 1015–1018 (2007). doi:10.1210/jc.2006-1711
C. Bouvattier, L. Esterle, P. Renoult-Pierre, A.B. de la Perriere, F. Illouz, V. Kerlan, V. Pascal-Vigneron, D. Drui, S. Christin-Maitre, F. Galland, T. Brue, Y. Reznik, F. Schillo, D. Pinsard, X. Piguel, G. Chabrier, B. Decoudier, P. Emy, I. Tauveron, M.L. Raffin-Sanson, J. Bertherat, J.M. Kuhn, P. Caron, M. Cartigny, O. Chabre, D. Dewailly, Y. Morel, P. Touraine, V. Tardy-Guidollet, J. Young, Clinical outcome, hormonal status, gonadotrope axis, and testicular function in 219 adult men born with classic 21-hydroxylase deficiency. A French national Survey. J. Clin. Endocrinol. Metab. 100(6), 2303–2313 (2015). doi:10.1210/jc.2014-4124
G. Jermendy, I. Szabolcs, G. Szilagyi, L. Domotor, P. Karpati, Diabetes mellitus associated with late onset congenital adrenal hyperplasia: coincidence or causality? Diabet. Med. 8(5), 489–491 (1991)
J. Helleday, B. Siwers, E.M. Ritzen, K. Carlstrom, Subnormal androgen and elevated progesterone levels in women treated for congenital virilizing 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 76(4), 933–936 (1993). doi:10.1210/jcem.76.4.8473408
R.E. Cornean, P.C. Hindmarsh, C.G. Brook, Obesity in 21-hydroxylase deficient patients. Arch. Dis. Child. 78(3), 261–263 (1998)
K. Hagenfeldt, E. Martin Ritzen, H. Ringertz, J. Helleday, K. Carlstrom, Bone mass and body composition of adult women with congenital virilizing 21-hydroxylase deficiency after glucocorticoid treatment since infancy. Eur. J. Endocrinol. 143(5), 667–671 (2000)
C. Paganini, G. Radetti, C. Livieri, V. Braga, D. Migliavacca, S. Adami, Height, bone mineral density and bone markers in congenital adrenal hyperplasia. Horm. Res. 54(4), 164–168 (2000). doi:53253
N.M. Stikkelbroeck, W.J. Oyen, G.J. van der Wilt, A.R. Hermus, B.J. Otten, Normal bone mineral density and lean body mass, but increased fat mass, in young adult patients with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 88(3), 1036–1042 (2003). doi:10.1210/jc.2002-021074
J.A. King, A.B. Wisniewski, B.J. Bankowski, K.A. Carson, H.A. Zacur, C.J. Migeon, Long-term corticosteroid replacement and bone mineral density in adult women with classical congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 91(3), 865–869 (2006). doi:10.1210/jc.2005-0745
T.M. Volkl, D. Simm, C. Beier, H.G. Dorr, Obesity among children and adolescents with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Pediatrics. 117(1), e98–105 (2006). doi:10.1542/peds.2005-1005
A. Bachelot, G. Plu-Bureau, E. Thibaud, K. Laborde, G. Pinto, D. Samara, C. Nihoul-Fekete, F. Kuttenn, M. Polak, P. Touraine, Long-term outcome of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Horm. Res. 67(6), 268–276 (2007). doi:10.1159/000098017
T.M. Volkl, D. Simm, A. Korner, W. Rascher, W. Kiess, J. Kratzsch, H.G. Dorr, Does an altered leptin axis play a role in obesity among children and adolescents with classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency? Eur. J. Endocrinol. 160(2), 239–247 (2009). doi:10.1530/EJE-08-0770
H.J. Zhang, J. Yang, M.N. Zhang, C.Q. Liu, M. Xu, X.J. Li, S.Y. Yang, X.Y. Li, Metabolic disorders in newly diagnosed young adult female patients with simple virilizing 21-hydroxylase deficiency. Endocrine. 38(2), 260–265 (2010). doi:10.1007/s12020-010-9382-9
S. Bjornsdottir, M. Saaf, S. Bensing, O. Kampe, K. Michaelsson, J.F. Ludvigsson, Risk of hip fracture in Addison’s disease: a population-based cohort study. J. Intern. Med. 270(2), 187–195 (2011). doi:10.1111/j.1365-2796.2011.02352.x
F.J. Cameron, B. Kaymakci, E.A. Byrt, P.R. Ebeling, G.L. Warne, J.D. Wark, Bone mineral density and body composition in congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 80(7), 2238–2243 (1995). doi:10.1210/jcem.80.7.7608286
M. Gussinye, A. Carrascosa, N. Potau, M. Enrubia, E. Vicens-Calvet, L. Ibanez, D. Yeste, Bone mineral density in prepubertal and in adolescent and young adult patients with the salt-wasting form of congenital adrenal hyperplasia. Pediatrics. 100(4), 671–674 (1997)
H. Falhammar, L. Frisen, C. Norrby, A.L. Hirschberg, C. Almqvist, A. Nordenskjold, A. Nordenstrom, Increased mortality in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 99(12), E2715–2721 (2014). doi:10.1210/jc.2014-2957
R.L. Rushworth, H. Falhammar, C.F. Munns, A.M. Maguire, D.J. Torpy, Hospital admission patterns in children with CAH: admission rates and adrenal crises decline with age. Int. J. Endocrinol. 2016, 5748264 (2016). doi:10.1155/2016/5748264
K. Muthusamy, M.B. Elamin, G. Smushkin, M.H. Murad, J.F. Lampropulos, K.B. Elamin, N.O. Abu Elnour, J.F. Gallegos-Orozco, M.M. Fatourechi, N. Agrwal, M.A. Lane, F.N. Albuquerque, P.J. Erwin, V.M. Montori, Clinical review: adult height in patients with congenital adrenal hyperplasia: a systematic review and metaanalysis. J. Clin. Endocrinol. Metab. 95(9), 4161–4172 (2010). doi:10.1210/jc.2009-2616
E.A. Eugster, L.A. Dimeglio, J.C. Wright, G.R. Freidenberg, R. Seshadri, O.H. Pescovitz, Height outcome in congenital adrenal hyperplasia caused by 21-hydroxylase deficiency: a meta-analysis. J. Pediatr. 138(1), 26–32 (2001). doi:10.1067/mpd.2001.110527
C.G. Bergstrand, Growth in congenital adrenal hyperplasia. Acta. Paediatr. Scand. 55(5), 463–472 (1966)
R.T. Kirkland, B.S. Keenan, J.H. Holcombe, J.L. Kirkland, G.W. Clayton, The effect of therapy on mature height in congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 47(6), 1320–1324 (1978). doi:10.1210/jcem-47-6-1320
M.D. Urban, P.A. Lee, C.J. Migeon, Adult height and fertility in men with congenital virilizing adrenal hyperplasia. N. Engl. J. Med. 299(25), 1392–1396 (1978). doi:10.1056/NEJM197812212992505
J. DiMartino-Nardi, E. Stoner, A. O’Connell, M.I. New, The effect of treatment of final height in classical congenital adrenal hyperplasia (CAH). Acta. Endocrinol. Suppl. 279, 305–314 (1986)
A. Balsamo, A. Cicognani, L. Baldazzi, M. Barbaro, F. Baronio, M. Gennari, M. Bal, A. Cassio, K. Kontaxaki, E. Cacciari, CYP21 genotype, adult height, and pubertal development in 55 patients treated for 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 88(12), 5680–5688 (2003). doi:10.1210/jc.2003-030123
J. Jaaskelainen, R. Voutilainen, Bone mineral density in relation to glucocorticoid substitution therapy in adult patients with 21-hydroxylase deficiency. Clin. Endocrinol. 45(6), 707–713 (1996)
Z. Chakhtoura, A. Bachelot, D. Samara-Boustani, J.C. Ruiz, B. Donadille, J. Dulon, S. Christin-Maitre, C. Bouvattier, M.C. Raux-Demay, P. Bouchard, J.C. Carel, J. Leger, F. Kuttenn, M. Polak, P. Touraine, Centre des Maladies Endocriniennes Rares de la, C., Association, S., Impact of total cumulative glucocorticoid dose on bone mineral density in patients with 21-hydroxylase deficiency. Eur. J. Endocrinol. 158(6), 879–887 (2008). doi:10.1530/EJE-07-0887
D. El-Maouche, S. Collier, M. Prasad, J.C. Reynolds, D.P. Merke, Cortical bone mineral density in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Clin. Endocrinol. (Oxf). 82(3), 330–337 (2015). doi:10.1111/cen.12507
H.L. Claahsen-van der Grinten, B.J. Otten, M.M. Stikkelbroeck, F.C. Sweep, A.R. Hermus, Testicular adrenal rest tumours in congenital adrenal hyperplasia. Best. Pract. Res. Clin. Endocrinol. Metab. 23(2), 209–220 (2009). doi:10.1016/j.beem.2008.09.007
M.A. Rich, M.A. Keating, Leydig cell tumors and tumors associated with congenital adrenal hyperplasia. Urol. Clin. North. Am. 27(3), 519–528 (2000). x
H.L. Claahsen-van der Grinten, B.J. Otten, A.R. Hermus, F.C. Sweep, C.A. Hulsbergen-van de Kaa, Testicular adrenal rest tumors in patients with congenital adrenal hyperplasia can cause severe testicular damage. Fertil. Steril. 89(3), 597–601 (2008). doi:10.1016/j.fertnstert.2007.03.051
R.V. Clark, B.D. Albertson, A. Munabi, F. Cassorla, G. Aguilera, D.W. Warren, R.J. Sherins, D.L. Loriaux, Steroidogenic enzyme activities, morphology, and receptor studies of a testicular adrenal rest in a patient with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 70(5), 1408–1413 (1990). doi:10.1210/jcem-70-5-1408
J. Blumberg-Tick, P. Boudou, K. Nahoul, G. Schaison, Testicular tumors in congenital adrenal hyperplasia: steroid measurements from adrenal and spermatic veins. J. Clin. Endocrinol. Metab. 73(5), 1129–1133 (1991). doi:10.1210/jcem-73-5-1129
M.E. Combes-Moukhovsky, M.L. Kottler, P. Valensi, P. Boudou, M. Sibony, J.R. Attali, Gonadal and adrenal catheterization during adrenal suppression and gonadal stimulation in a patient with bilateral testicular tumors and congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 79(5), 1390–1394 (1994). doi:10.1210/jcem.79.5.7962333
J.P. Bercovici, J. Fiet, L. Gibault, A. Volant, J.H. Abalain, H.H. Floch, E. Sonnet, G. Fournier, Testicular adrenal rest tumours in salt wasting congenital adrenal hyperplasia (in vivo and in vitro studies). J. Steroid. Biochem. Mol. Biol. 93(1), 67–72 (2005). doi:10.1016/j.jsbmb.2004.10.023
H.L. Claahsen-van der Grinten, B.J. Otten, F.C. Sweep, P.N. Span, H.A. Ross, E.J. Meuleman, A.R. Hermus, Testicular tumors in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency show functional features of adrenocortical tissue. J. Clin. Endocrinol. Metab. 92(9), 3674–3680 (2007). doi:10.1210/jc.2007-0337
G.J. Hamwi, G. Gwinup, J.H. Mostow, P.K. Besch, Activation of testicular adrenal rest tissue by prolonged excessive acth production. J. Clin. Endocrinol. Metab. 23, 861–869 (1963). doi:10.1210/jcem-23-9-861
A.C. Bonaccorsi, I. Adler, J.G. Figueiredo, Male infertility due to congenital adrenal hyperplasia: testicular biopsy findings, hormonal evaluation, and therapeutic results in three patients. Fertil. Steril. 47(4), 664–670 (1987)
N.M. Stikkelbroeck, A.R. Hermus, H.M. Suliman, G.J. Jager, B.J. Otten, Asymptomatic testicular adrenal rest tumours in adolescent and adult males with congenital adrenal hyperplasia: basal and follow-up investigation after 2.6 years. J. Pediatr. Endocrinol. Metab. 17(4), 645–653 (2004)
N. Reisch, M. Scherr, L. Flade, M. Bidlingmaier, H.P. Schwarz, U. Muller-Lisse, M. Reincke, M. Quinkler, F. Beuschlein, Total adrenal volume but not testicular adrenal rest tumor volume is associated with hormonal control in patients with 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 95(5), 2065–2072 (2010). doi:10.1210/jc.2009-1929
N.M. Stikkelbroeck, B.J. Otten, A. Pasic, G.J. Jager, C.G. Sweep, K. Noordam, A.R. Hermus, High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 86(12), 5721–5728 (2001). doi:10.1210/jcem.86.12.8090
H.L. Claahsen-van der Grinten, F.C. Sweep, J.G. Blickman, A.R. Hermus, B.J. Otten, Prevalence of testicular adrenal rest tumours in male children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Eur. J. Endocrinol. 157(3), 339–344 (2007). doi:10.1530/EJE-07-0201
A. Martinez-Aguayo, A. Rocha, N. Rojas, C. Garcia, R. Parra, M. Lagos, L. Valdivia, H. Poggi, A. Cattani, Chilean Collaborative Testicular Adrenal Rest Tumor Study, G., Testicular adrenal rest tumors and Leydig and Sertoli cell function in boys with classical congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 92(12), 4583–4589 (2007). doi:10.1210/jc.2007-0383
U. Willi, M. Atares, A. Prader, M. Zachmann, Testicular adrenal-like tissue (TALT) in congenital adrenal hyperplasia: detection by ultrasonography. Pediatr. Radiol. 21(4), 284–287 (1991)
Z. Aycan, V.N. Bas, S. Cetinkaya, S. Yilmaz Agladioglu, T. Tiryaki, Prevalence and long-term follow-up outcomes of testicular adrenal rest tumours in children and adolescent males with congenital adrenal hyperplasia. Clin. Endocrinol. 78(5), 667–672 (2013). doi:10.1111/cen.12033
M. Kaynar, M.G. Sonmez, Y. Unlu, T. Karatag, E. Tekinarslan, A. Sumer, Testicular adrenal rest tumor in 11-Beta-hydroxylase deficiency driven congenital adrenal hyperplasia. Korean J. Urol. 55(4), 292–294 (2014). doi:10.4111/kju.2014.55.4.292
I. Karnak, M.E. Senocak, S. Gogus, N. Buyukpamukcu, A. Hicsonmez, Testicular enlargement in patients with 11-hydroxylase deficiency. J. Pediatr. Surg. 32(5), 756–758 (1997)
G.I. Bayhan, S. Cetinkaya, H.G. Cinar, Z. Aycan, Testicular adrenal rest tumor in a patient with 11beta-hydroxylase deficient congenital adrenal hyperplasia. J. Pediatr. Endocrinol. Metab. 23(7), 729–732 (2010)
T. Unuvar, K. Demir, A. Abaci, A. Atas, H. Cakmakci, E. Bober, A 2-year-old boy with a testicular mass. Diagnosis: testicular tumor of adrenogenital syndrome due to 11-beta-hydroxylase deficiency. Pediatr. Ann. 39(8), 471–474 (2010). doi:10.3928/00904481-20100726-04
B.R. Walker, S.J. Skoog, B.H. Winslow, D.A. Canning, E.S. Tank, Testis sparing surgery for steroid unresponsive testicular tumors of the adrenogenital syndrome. J. Urol. 157(4), 1460–1463 (1997)
T. Tiryaki, Z. Aycan, S. Hucumenoglu, H. Atayurt, Testis sparing surgery for steroid unresponsive testicular tumors of the congenital adrenal hyperplasia. Pediatr. Surg. Int. 21(10), 853–855 (2005). doi:10.1007/s00383-005-1547-x
I. Nermoen, J. Rorvik, S.H. Holmedal, D.L. Hykkerud, K.J. Fougner, J. Svartberg, E.S. Husebye, K. Lovas, High frequency of adrenal myelolipomas and testicular adrenal rest tumours in adult Norwegian patients with classical congenital adrenal hyperplasia because of 21-hydroxylase deficiency. Clin. Endocrinol. 75(6), 753–759 (2011). doi:10.1111/j.1365-2265.2011.04151.x
H. Falhammar, D.J. Torpy, Congenital adrenal hyperplasia due to 21-hydroxylase deficiency presenting as adrenal incidentaloma: a systematic review and meta-analysis. Endocr. Pract. 22(6), 736–752 (2016). doi:10.4158/EP151085.RA
S.M. Baumgartner-Parzer, S. Pauschenwein, W. Waldhausl, K. Polzler, P. Nowotny, H. Vierhapper, Increased prevalence of heterozygous 21-OH germline mutations in patients with adrenal incidentalomas. Clin. Endocrinol. (Oxf). 56(6), 811–816 (2002)
H. Falhammar, M. Thoren, An 88-year-old woman diagnosed with adrenal tumor and congenital adrenal hyperplasia: connection or coincidence? J. Endocrinol. Invest. 28(5), 449–453 (2005)
J. Patrova, I. Jarocka, H. Wahrenberg, H. Falhammar, Clinical outcomes in adrenal incidentaloma: experience from one center. Endocr. Pract. 21(8), 870–877 (2015). doi:10.4158/EP15618.OR
H. Falhammar, D.J. Torpy, A 42-year-old man presented with adrenal incidentaloma due to non-classic congenital adrenal hyperplasia with a novel CYP21A2 mutation. Intern. Med. J. 46(9), 1115–1116 (2016). doi:10.1111/imj.13177
H.G. Doerr, W.G. Sippell, S.L. Drop, F. Bidlingmaier, D. Knorr, Evidence of 11 beta-hydroxylase deficiency in childhood adrenocortical tumors. The plasma corticosterone/11-deoxycorticosterone ratio as a possible marker for malignancy. Cancer 60(7), 1625–1629 (1987)
E.A. Werder, R. Voutilainen, M. Zachmann, Virilizing adrenal tumour mimicking congenital adrenal hyperplasia with P450c11 (11 beta-hydroxylase) deficiency. Eur. J. Pediatr. 153(6), 411–415 (1994)
M. Reincke, M. Peter, W.G. Sippell, B. Allolio, Impairment of 11 beta-hydroxylase but not 21-hydroxylase in adrenal ‘incidentalomas’. Eur. J. Endocrinol. 136(2), 196–200 (1997)
C. Dall’Asta, L. Barbetta, R. Libe, E. Passini, B. Ambrosi, Coexistence of 21-hydroxylase and 11 beta-hydroxylase deficiency in adrenal incidentalomas and in subclinical Cushing’s syndrome. Horm. Res. 57(5–6), 192–196 (2002). doi:58381
M. Kacem, M. Said, L. Achour, F. Hadj Youssef, S. Ben Kacem, S. Mahjoub, M. Elmay, Large bilateral adrenal incidentalomas complicating untreated 11B hydroxylase deficiency in the third decade of life. A case report. Ann. Endocrinol. 61(5), 418–421 (2000)
Y. Touitou, P. Lecomte, A. Auzeby, A. Bogdan, Y. Besnier, Evidence of 11 beta-hydroxylase deficiency in a patient with cortical adrenal adenoma. Horm. Metab. Res. 21(5), 272–274 (1989). doi:10.1055/s-2007-1009210
N. Reisch, L. Flade, M. Scherr, M. Rottenkolber, F. Pedrosa Gil, M. Bidlingmaier, H. Wolff, H.P. Schwarz, M. Quinkler, F. Beuschlein, M. Reincke, High prevalence of reduced fecundity in men with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 94(5), 1665–1670 (2009). doi:10.1210/jc.2008-1414
P.J. Simm, M.R. Zacharin, Successful pregnancy in a patient with severe 11-beta-hydroxylase deficiency and novel mutations in CYP11B1 gene. Horm. Res. 68(6), 294–297 (2007). doi:10.1159/000107651
M.E. Toaff, R. Toaff, R. Chayen, Congenital adrenal hyperplasia caused by 11 beta-hydroxylase deficiency with onset of symptoms after one spontaneous pregnancy. Am. J. Obstet. Gynecol. 121(2), 202–204 (1975)
R.M. Mulaikal, C.J. Migeon, J.A. Rock, Fertility rates in female patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N. Engl. J. Med. 316(4), 178–182 (1987). doi:10.1056/NEJM198701223160402
J. Jaaskelainen, M. Hippelainen, O. Kiekara, R. Voutilainen, Child rate, pregnancy outcome and ovarian function in females with classical 21-hydroxylase deficiency. Acta. Obstet. Gynecol. Scand. 79(8), 687–692 (2000)
N. Krone, I. Wachter, M. Stefanidou, A.A. Roscher, H.P. Schwarz, Mothers with congenital adrenal hyperplasia and their children: outcome of pregnancy, birth and childhood. Clin. Endocrinol. 55(4), 523–529 (2001)
B.J. Otten, M.M. Stikkelbroeck, H.L. Claahsen-van der Grinten, A.R. Hermus, Puberty and fertility in congenital adrenal hyperplasia. Endocr. Dev. 8, 54–66 (2005). doi:10.1159/000084093
F. Gastaud, C. Bouvattier, L. Duranteau, R. Brauner, E. Thibaud, F. Kutten, P. Bougneres, Impaired sexual and reproductive outcomes in women with classical forms of congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 92(4), 1391–1396 (2007). doi:10.1210/jc.2006-1757
J.C. Lo, M.M. Grumbach, Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol. Metab. Clin. North. Am. 30(1), 207–229 (2001)
A. Casteras, P. De Silva, G. Rumsby, G.S. Conway, Reassessing fecundity in women with classical congenital adrenal hyperplasia (CAH): normal pregnancy rate but reduced fertility rate. Clin. Endocrinol. 70(6), 833–837 (2009). doi:10.1111/j.1365-2265.2009.03563.x
M. Bouchard, M.G. Forest, M. David, H. Dechaud, J.G. Juif, [Familial congenital adrenal hyperplasia caused by 11 beta-hydroxylase. Failure of prevention of sexual ambiguity and prenatal diagnosis]. Pediatrie. 44(8), 637–640 (1989)
S. Geley, K. Kapelari, K. Johrer, M. Peter, J. Glatzl, H. Vierhapper, S. Schwarz, A. Helmberg, W.G. Sippell, P.C. White, R. Kofler, CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 81(8), 2896–2901 (1996). doi:10.1210/jcem.81.8.8768848
B.I. Cerame, R.S. Newfield, R.C. Wilson, M.I. New, Prenatal diagnosis and treatment of 11beta-hydroxylase deficiency congenital adrenal hyperplasia. Diagnosis and treatment of unborn child, ed. by M.I. New (Idelson-Gnocchi Ltd., Reddick, FL, 1999), pp. 175–178
N.K. Maclaren, C.J. Migeon, S. Raiti, Gynecomastia with congenital virilizing adrenal hyperplasia (11-beta-hydroxylase deficiency). J. Pediatr. 86(4), 579–581 (1975)
M. Zachmann, A. Prader, Letter: Gynecomastia with congenital virilizing adrenal hyperplasia (11beta-hydroxylase deficiency). J. Pediatr. 87(5), 839–840 (1975)
Z. Zadik, A. Pertzelan, H. Kaufman, S. Levin, Z. Laron, Gynaecomastia in two prepubertal boys with congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Helv. Paediatr. Acta. 34(2), 185–187 (1979)
Z. Hochberg, L. Even, Z. Zadik, Mineralocorticoids in the mechanism of gynecomastia in adrenal hyperplasia caused by 11 beta-hydroxylase deficiency. J. Pediatr. 118(2), 258–260 (1991)
K.M. Ajlouni, M.A. Arnaout, Y. Qoussous, Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency with skeletal abnormalities. J. Endocrinol. Invest. 19(5), 316–319 (1996)
H. Haibach, M.J. Rosenholtz, Prepubertal gynecomastia with lobules and acini: a case report and review of the literature. Am. J. Clin. Pathol. 80(2), 252–255 (1983)
A. Rosler, E. Leiberman, Enzymatic defects in steroidogenesis: 11beta hydroxylase deficiency CAH in Pediatric and adolescent endocrinology, ed. by M.I. New, L.S. Levine (Karger, Basel, 1984), pp. 47–64
E. Khorasani, R. Vakili, Congenital Adrenal Hyperplasia and Schmid Metaphyseal Chondrodysplasia in a Child. Iran J. Med. Sci. 41(1), 64–66 (2016)
M. Peter, Congenital adrenal hyperplasia:11b-hydroxylase deficiency. Semin. Reprod. Med. 20(3), 249–254 (2002)
D.P. Merke, Approach to the adult with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 93(3), 653–660 (2008). doi:10.1210/jc.2007-2417
K. Liivak, V. Tillmann, 24-hour blood pressure profiles in children with congenital adrenal hyperplasia on two different hydrocortisone treatment regimens. J. Pediatr. Endocrinol. Metab. 22(6), 511–517 (2009)
A. Nordenstrom, C. Marcus, M. Axelson, A. Wedell, E.M. Ritzen, Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11beta-hydroxysteroid dehydrogenase reductase activity. J. Clin. Endocrinol. Metab. 84(4), 1210–1213 (1999). doi:10.1210/jcem.84.4.5584
M. Quinkler, R. Miodini Nilsen, K. Zopf, M. Ventz, M. Oksnes, Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. Eur. J. Endocrinol. 172(5), 619–626 (2015). doi:10.1530/EJE-14-1114
A. Bajpai, M. Kabra, P.S. Menon, Combination growth hormone and gonadotropin releasing hormone analog therapy in 11beta-hydroxylase deficiency. J. Pediatr. Endocrinol. Metab. 19(6), 855–857 (2006)
L.J. Chalmers, L. Casas, M.I. New, P.R. Blackett, Prolongation of growth by treatment of 11-hydroxylase deficiency with depot-leuprolide, growth hormone, and hydrocortisone. J. Pediatr. Endocrinol. Metab. 19(10), 1251–1255 (2006)
M. Orio Hernandez, J. Yebra Yebra, C. Bezanilla Lopez, R. Gracia Bouthelier, [11beta-hydroxylase deficiency: improvement of final height with growth hormone and gonadotropin-releasing hormone analog]. An. Pediatr. 67(2), 153–156 (2007)
M.A. Nour, D. Pacaud, Height augmentation in 11beta-hydroxylase deficiency congenital adrenal hyperplasia. Int. J. Pediatr. Endocrinol. 2015(1), 12 (2015). doi:10.1186/s13633-015-0008-0
D.I. Shulman, G.L. Francis, M.R. Palmert, E.A. Eugster, Lawson Wilkins Pediatric Endocrine Society, D., Therapeutics, C., Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development. Pediatrics. 121(4), e975–983 (2008). doi:10.1542/peds.2007-2081
L. Laue, D.P. Merke, J.V. Jones, K.M. Barnes, S. Hill, G.B. Cutler Jr., A preliminary study of flutamide, testolactone, and reduced hydrocortisone dose in the treatment of congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 81(10), 3535–3539 (1996). doi:10.1210/jcem.81.10.8855797
D.P. Merke, M.F. Keil, J.V. Jones, J. Fields, S. Hill, G.B. Cutler Jr., Flutamide, testolactone, and reduced hydrocortisone dose maintain normal growth velocity and bone maturation despite elevated androgen levels in children with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 85(3), 1114–1120 (2000). doi:10.1210/jcem.85.3.6462
K. Lin-Su, M.G. Vogiatzi, I. Marshall, M.D. Harbison, M.C. Macapagal, B. Betensky, S. Tansil, M.I. New, Treatment with growth hormone and luteinizing hormone releasing hormone analog improves final adult height in children with congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 90(6), 3318–3325 (2005). doi:10.1210/jc.2004-2128
J.J. Van Wyk, D.F. Gunther, E.M. Ritzen, A. Wedell, G.B. Cutler Jr., C.J. Migeon, M.I. New, The use of adrenalectomy as a treatment for congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 81(9), 3180–3190 (1996). doi:10.1210/jcem.81.9.8784066
R.L. Meyers, J.R. Grua, Bilateral laparoscopic adrenalectomy: a new treatment for difficult cases of congenital adrenal hyperplasia. J. Pediatr. Surg. 35(11), 1586–1590 (2000). doi:10.1053/jpsu.2000.18321
S.A. Warinner, D. Zimmerman, G.B. Thompson, C.S. Grant, Study of three patients with congenital adrenal hyperplasia treated by bilateral adrenalectomy. World. J. Surg. 24(11), 1347–1352 (2000)
P.E. Clayton, W.L. Miller, E.M. Ritzen, S. Oberfield, W.G. Sippell, P.W. Speiser, Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric endocrine society and the European society for Paediatric endocrinology. J. Clin. Endocrinol. Metab. 87(9), 4048–4053 (2002). doi:10.1210/jc.2002-020611. JOINT LWPES/ESPE CAH WORKING GROUP
D.P. Merke, S.R. Bornstein, N.A. Avila, G.P. Chrousos, NIH conference. Future directions in the study and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Ann. Intern. Med. 136(4), 320–334 (2002)
J.J. Van Wyk, E.M. Ritzen, The role of bilateral adrenalectomy in the treatment of congenital adrenal hyperplasia. J. Clin. Endocrinol. Metab. 88(7), 2993–2998 (2003). doi:10.1210/jc.2002-022026
C.M. Ogilvie, G. Rumsby, T. Kurzawinski, G.S. Conway, Outcome of bilateral adrenalectomy in congenital adrenal hyperplasia: one unit’s experience. Eur. J. Endocrinol. 154(3), 405–408 (2006). doi:10.1530/eje.1.02096
J. Nasir, C. Royston, C. Walton, M.C. White, 11 beta-hydroxylase deficiency: management of a difficult case by laparoscopic bilateral adrenalectomy. Clin. Endocrinol. 45(2), 225–228 (1996)
M. Kacem, A. Moussa, I. Khochtali, R. Nabouli, Y. Morel, A. Zakhama, Bilateral adrenalectomy for severe hypertension in congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency: long term follow-up. Ann. Endocrinol. 70(2), 113–118 (2009). doi:10.1016/j.ando.2008.12.005
J. Solyom, K. Racz, F. Peter, J. Homoki, W.G. Sippell, M. Peter, Clinical, hormonal and molecular genetic characterization of Hungarian patients with 11-hydroxylase deficiency. Int. J. Disabil. Hum. Dev 2, 37–44 (2001)
M. Zhang, Y. Liu, S. Sun, H. Zhang, W. Wang, G. Ning, X. Li, A prevalent and three novel mutations in CYP11B1 gene identified in Chinese patients with 11-beta hydroxylase deficiency. J. Steroid. Biochem. Mol. Biol. 133, 25–29 (2013). doi:10.1016/j.jsbmb.2012.08.011
M. Kharrat, S. Trabelsi, M. Chaabouni, F. Maazoul, L. Kraoua, L. Ben Jemaa, N. Gandoura, S. Barsaoui, Y. Morel, R. M’Rad, H. Chaabouni, Only two mutations detected in 15 Tunisian patients with 11beta-hydroxylase deficiency: the p.Q356X and the novel p.G379V. Clin. Genet. 78(4), 398–401 (2010). doi:10.1111/j.1399-0004.2010.01403.x
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Dr Krupali Bulsari has not received funding or research grant for this study. Associate Prof Henrik Falhammar has received support from the Magnus Bergvall Foundation, Karolinska Institutet and the Stockholm County Council.
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Bulsari, K., Falhammar, H. Clinical perspectives in congenital adrenal hyperplasia due to 11β-hydroxylase deficiency. Endocrine 55, 19–36 (2017). https://doi.org/10.1007/s12020-016-1189-x
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DOI: https://doi.org/10.1007/s12020-016-1189-x