High frequency of congenital adrenal hyperplasia (classic 11β‐hydroxylase deficiency) among Jews from Morocco

Rösler, Ariel; Leiberman, Esther; Cohen, Tirza

doi:10.1002/ajmg.1320420617

Cited by 141 publications

(91 citation statements)

References 17 publications

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“…In our cohort, most such 46, XX females, misassigned to the male gender at birth, were reared as males, although some were subsequently reassigned to the female gender. Fourth, 21-hydroxylase deficiency is not associated with hypertension, whereas 59% of 11β-hydroxylasedeficient patients in whom blood pressures were measured were hypertensive (26,27). Correlations between 11-deoxycorticosterone and hypertension were nonetheless poor.…”

Section: Mutationmentioning

confidence: 94%

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.

112

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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: Mutationmentioning

confidence: 94%

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.

112

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“…A deficiency in 21-hydroxylase causes an increase in the hormone 17-hydroxyprogesterone, as well as excess testosterone The next most common form of CAH is 11-β-hydroxylase deficiency (1 in 100,000) [22]. Like 21 hydroxylase deficiency, 11-β-hydroxylase deficiency presents in newborn girls with ambiguous genitalia.…”

Section: Congenital Adrenal Hyperplasiamentioning

confidence: 99%

“…The next most common form of CAH is 11-β-hydroxylase deficiency (1 in 100,000) [22]. Like 21 hydroxylase deficiency, 11-β-hydroxylase deficiency presents in newborn girls with ambiguous genitalia.…”

Section: Congenital Adrenal Hyperplasiamentioning

confidence: 99%

Steroid hormones: relevance and measurement in the clinical laboratory

Holst

Soldin

Guo

et al. 2004

Clinics in Laboratory Medicine

138

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The steroid hormones are synthesized in the adrenal cortex, the gonads, and the placenta; are all derived from cholesterol and many are of clinical importance. Steroid hormones are synthesized in the mitochondria and smooth endoplasmic reticulum. Because they are lipophilic, they cannot be stored in vesicles from which they would diffuse easily and are therefore synthesized when needed as precursors. Upon stimulation of the parent cell, steroid hormone precursors are converted to active hormones and diffuse out of the parent cell by simple diffusion as their intracellular concentration rises.Because all steroid hormones are derived from cholesterol, they are not soluble in plasma and other body fluids. As a result, steroids are bound to transport proteins that increase their half-life and insure ubiquitous distribution. The protein-bound steroids are in equilibrium with a small fraction of free steroids, which are 'active.' Steroids can act quickly, by binding to cell surface receptors, or slowly, by binding to cytoplasmic or nucleic receptors and ultimately activate gene transcription.The adrenal glands are composed of the adrenal medulla and the adrenal cortex. The adrenal cortex is divided into three major anatomic zones: the zona glomerulosa, which produces aldosterone; and the zonae fasciculata and reticularis, which together produce cortisol and adrenal androgens. The medulla synthesizes catecholamines. More than 30 steroids are produced in the adrenal cortex; they can be divided into three functional categories: mineralocorticoids, glucocorticoids, and androgens.The steroids that are made almost exclusively in the adrenal glands are cortisol, 11-deoxycortisol, aldosterone, corticosterone, and 11-deoxycorti-costerone. Most other steroid hormones, including the estrogens, are made by the adrenal glands and the gonads [ MineralocorticoidsThe mineralocorticoids are formed in the zona glomerulosa. The main function of the mineralocorticoids is to promote tubular reabsorption of sodium and secretion of potassium and hydrogen ions at the collecting tubule, distal tubule, and collecting ducts [2]. When sodium is reabsorbed, water is absorbed simultaneously. The absorption of sodium and water increases fluid volume and arterial pressure.Aldosterone is the most potent mineralocorticoid and accounts for about 90% of the total mineralocorticoid activity. Mineralocorticoid potency in descending order is: aldosterone, 11-deoxycorticosterone, 18-oxocortisol, corticosterone, and cortisol [1]. Although cortisol has mainly glucocorticoid activity, it also has some mineralocorticoid activity. Cortisol has 1/400 of the potency of aldosterone, but its concentration is about 80 times greater than that of aldosterone [4]. The adrenal production of cortisol is approximately 25 mg/day and that of aldosterone is 100μg/day. Corticosterone has mainly glucocorticoid activity and some mineralocorticoid activity.Aldosterone secretion is regulated primarily by the renin-angiotensin system; it also is stimulated by increased serum potas...

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“…Entretanto a hipertensão arterial pode ou não estar presente e é observada em 30-60% dos casos (42,43). A hipertensão, muitas vezes, só se manifesta nas fases mais tardias da infância ou adolescência e é atribuída ao excesso de DOC.…”

Section: Hiperplasia Congênita De Adrenal Por Deficiência De 11β-hidrunclassified

Bases Moleculares da Hiperplasia Adrenal Congênita

Mello

Bachega

Costa-Santos

et al. 2002

Arq Bras Endocrinol Metab

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RESUMOHiperplasia adrenal congênita (HAC) é uma doença autossômica recessiva decorrente da alteração de enzimas que participam da síntese do cortisol. As manifestações podem ser causadas pela deficiência do cortisol e, em alguns casos, aldosterona e pelo acúmulo de precursores. O objetivo desta revisão é apresentar os mecanismos moleculares dos principais defeitos enzimáticos envolvidos na etiopatogênese da HAC. A deficiência da 21-hidroxilase (21OH) ocorre em 95% dos casos de HAC. Existem dois genes que codificam o P450c21: um ativo, CYP21, e um pseudogene CYP21P. Ambos são altamente homólogos (98%), o que favorece o emparelhamento desigual dos cromossomos homólogos durante a meiose, levando a duplicações e/ou deleções ou conversões desses genes. Adicionalmente, foram também descritas mutações de ponto, muitas delas presentes no pseudogene sugerindo microconversões. Mutações no gene CYP11B1 causam HAC por deficiência da 11β-hidroxilase, forma esta que corresponde a 5% dos casos. Algumas mutações são recorrentes, situando-se principalmente entre os exons 6-8 que representaria uma área hot-spot no gene CYP11B1. A deficiência de 17-hidroxilase é causada por mutações no gene CYP17, que codificam uma proteína alterada, levando a deficiência total ou parcial de 17-hidroxilação e 17,20-liase ou deficiência isolada de 17,20-liase. Finalmente, deficiência de 3β-HSD é causada por mutações no gene HSD3B2, que codifica a enzima 3β-HSD tipo II e estas mutações têm sido associadas tanto com a forma clássica como com a forma não clássica da deficiência da 3β-HSD. Congenital adrenal hiperplasia (CAH) is a recessive autossomic disease caused by inherited defects in cortisol biosynthesis. The manifestations are caused both by the deficient synthesis of cortisol, and sometimes of aldosterone, and by accumulation of the precursor steroids. The objective of this review is to present the molecular mechanisms of the main enzymatic defects involved in the etiopathogenesis of CAH. Deficiency of 21-hydroxylase (21OH) accounts for more than 95% of all cases of CAH. The human genome contains two CYP genes: one active, CYP21, and a pseudogene, CYP21P. Both are highly homologous (98%), facilitating recombination events during meiosis, leading to duplication and/or deletion or conversion of these genes. Additionally, point mutations have also been described. Deficiency of 11β-hydroxylase (11βOH) is caused by mutations in the CYP11B1 gene, and accounts for 5% of all cases. Some mutations are recurrent, and mainly located on exons 6-8, which is considered a hot-spot area in CYP11B1 gene. Deficiency of 17α-hydroxylase (17OH) is caused by mutations in the CYP17 gene, producing a truncated or impaired protein. These mutations have been described in patients with combined defi-

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High frequency of congenital adrenal hyperplasia (classic 11β‐hydroxylase deficiency) among Jews from Morocco

Cited by 141 publications

References 17 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

Steroid hormones: relevance and measurement in the clinical laboratory

Bases Moleculares da Hiperplasia Adrenal Congênita

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