Update on the Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia due to 11β-Hydroxylase Deficiency

Motaghedi, Roja; Betensky, Brian P.; Slowinska, Bozena; Cerame, Barbara; Cabrer, Maria; New, Maria I.; Wilson, Robert

doi:10.1515/jpem.2005.18.2.133

Cited by 17 publications

(7 citation statements)

References 20 publications

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“…We found that 41 compound heterozygotes or homozygotes for select missense or nonsense mutations-namely P49L, R141Q, W260X, G267S, L299P, T318M, T318R, A331V, Q356X, A368D, R374Q, V441G, G444D, G446V, and R448H-present with moderate to severe classic CAH because of 11β-hydroxylase, confirming prior results (3,(14)(15)(16)(17)(22)(23)(24). These patients were mainly from Croatia, Tunisia, Africa, Turkey, and Saudi Arabia.…”

Section: Discussionsupporting

confidence: 88%

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Khattab

Haider

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.steroid hormones | missense mutations | classic CAH | ambiguous genitalia C ongenital adrenal hyperplasia (CAH) is a Mendelian disorder transmitted as an autosomal recessive trait. The most prevalent form of CAH arises from steroid 21-hydroxylase enzyme deficiency, accounting for ∼90-95% of all cases (1, 2). In contrast, CAH caused by steroid 11β-hydroxylase deficiency is considerably rare, with a prevalence of 5-8% (3), from which we estimate an overall frequency of 1 in 100,000 live births.Two homologous enzymes, 11β-hydroxylase and aldosterone synthase, are encoded by the CYP11B1 and CYP11B2 genes, respectively. The two genes are 40-kb apart, each comprising nine exons and mapped to chromosome 8q21-22 (3, 4) (Fig. 1A). In contrast to CYP21A2 and its CYP21A1P pseudogene, CYP11B1 and CYP11B2 are both active and do not have a pseudogene. The two encoded homologs, however, have distinct functions in cortisol and aldosterone synthesis, respectively (3). In the zona fasciculata, 11β-hydroxylase converts 11-deoxycortisol and 11-deoxycorticosterone to cortisol and corticosterone, respectively, and is regulated by adrenocorticotropic hormone secreted by the pituitary. In contrast, in the zona glomerulosa aldosterone synthase converts corticosterone to aldosterone with the intermediate production of 18-hydroxycorticosterone. These latter conversions are controlled mainly by the renin angiotensin II system and serum potassium concentration (3).Deficiency of 11β-hydroxylase prevents the conversion of 11-deoxycortisol to cortisol and 11-deoxycorticosterone to corticosterone. This results in high levels of 11-deoxycortisol and 11-deoxycorticosterone, respectively, which are shunted into the androgen synthesis pathway, resulting in high levels of the androgenic steroid, androstenedione. Female newborns are thus profoundly virilized and exhibit significant masculinization of the ex...

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Section: Discussionsupporting

confidence: 88%

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Khattab

Haider

Kumar

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Tunisians often carry the two mutations, G379 V and Q356X [ 24 ], of which Q356X is also common among sub-Saharan Africans and African-Americans [ 2 , 3 , 24 – 26 ]. The T318 M mutation is most common among Yemenis [ 2 , 27 , 28 ], and some new mutations such as c.53_54insT, G206 V, W260X, R448P, and H465L are often found in Saudi Arabs [ 29 – 31 ]. The R454C mutation has only been reported among the Chinese [ 8 , 10 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Non-classical 11β-hydroxylase deficiency caused by compound heterozygous mutations: a case study and literature review

Wang

Tong

et al. 2018

J Ovarian Res

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Background11β-hydroxylase deficiency (11OHD) is extremely rare, and reports of non-classical 11OHD are even rarer. Non-classical 11OHD usually presents as premature adrenarche, hyperandrogenism, menstrual disorders, and hypertension. Because the symptoms of non-classical 11OHD are mild, delayed diagnosis or misdiagnosis as polycystic ovary syndrome or primary hypertension is common.Case presentationThis paper introduces a case of a young female patient presenting hypertension and menstrual disorders. Laboratory examination revealed increased androgen levels, mild adrenal hyperplasia, mild left ventricular hypertrophy, and mild sclerosis of the lower limb arteries. 11OHD was confirmed by genetic testing, and the patient was found to carry compound heterozygous mutations in CYP11B1 (c.583 T > C and c.1358G > A). The mutation Y195H is located in exon 3 and has not been reported previously. In silico studies indicated that this mutation may cause reduced enzymatic activity. After treatment with hydrocortisone and spironolactone, blood pressure was brought under good control, and menstruation returned to normal. We also conducted a retrospective review of previously reported cases in the literature (over 170 cases since 1991).ConclusionsEarly diagnosis of non-classical 11OHD is difficult because its symptoms are mild. The possibility of this disease should be considered in patients with early-onset hypertension, menstrual disorders, and hyperandrogenism to provide early treatment and prevent organ damage due to hypertension and hyperandrogenism. CYP11B1 mutations are known to be race-specific and are concentrated in exons 3 and 8, of which mutations in the former are mostly associated with non-classical 11OHD, whereas mutations in the latter are mostly found in classical 11OHD, characterized by severe loss of enzymatic activity.

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“…The one, p.R448H, is most frequently found in almost all affected alleles (23 alleles) of Moroccan Jews [5,13] but also in Caucasian patients (7 alleles) [35,36]; the other, p.R448C, is rare (2 alleles) [5,35]. Another mutation, p.G444D, modifies a Gly conserved in CYP11B1 species and steroidogenic cytochromes but not other cytochromes, and decreases 11β-hydroxylase activity [37]. Finally, our third new mutation, p.A259D, changes Ala259 conserved only in mitochondrial enzymes and located in the helix G according to our modeling.…”

Section: Discussionmentioning

confidence: 99%

Three Novel <i>CYP11B1</i> Mutations in Congenital Adrenal Hyperplasia due to Steroid 11Beta-Hydroxylase Deficiency in a Moroccan Population

Chabraoui¹,

Abid²,

Menassa

et al. 2010

Horm Res Paediatr

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Background/Aims: Steroid 11β-hydroxylase deficiency (11OHD), the second cause of congenital adrenal hyperplasia (CAH), accounts only for 5% of all CAH. To date, only 51 different mutations have been reported with poor clinical and biological data. Most of them could be considered as private mutations except one, p.R448H, identified especially in Moroccan Jews but also in Caucasian patients. As two other CYP11B1 mutations have a high incidence in Tunisian patients, we report from another Maghreb population the clinical, follow-up and molecular genetics of 5 Moroccan patients with classical 11OHD. Methods: Patients belonging to 3 families were recruited on clinical data. The diagnosis was confirmed by 11-deoxycortisol determination. Sequencing of the CYP11B1 gene and molecular modeling were performed. Results: Clinical, hormonal and follow-up data were consistent with a severe form of 11OHD. Gender reassignment and evolution of hypertension were discussed. Three novel mutations, p.Ala259Asp, p.Gly446Val and IVS5+2T>G were identified. As each patient was homozygous for one mutation, we could deduce from their phenotype and our modeling studies that the p.Gly446Val mutation was more severe than p.Ala259Asp. Conclusion: This study shows a good correlation between phenotype and genotype. Each CYP11B1 mutation is new and private, contrasting with the high incidence of two Tunisian mutations.

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Update on the Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia due to 11β-Hydroxylase Deficiency

Cited by 17 publications

References 20 publications

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency

Non-classical 11β-hydroxylase deficiency caused by compound heterozygous mutations: a case study and literature review

Three Novel <i>CYP11B1</i> Mutations in Congenital Adrenal Hyperplasia due to Steroid 11Beta-Hydroxylase Deficiency in a Moroccan Population

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