A high rate of novel CYP11B1 mutations in Saudi Arabia
Introduction
Congenital adrenal hyperplasia (CAH) is a group of hereditary disorders due to enzymatic deficiency in the adrenal steroid synthesis pathway [1]. The most common type is 21-hydroxylase deficiency which occurs in about 1:14,000 of normal population [1], [2]. It is due to mutations in the CYP21A2 gene leading to variable deficiency of 21-hydroxylase activity with correspondingly variable clinical and biochemical features [3]. Deficiency of this enzyme has a major impact on glucocorticoid and mineralocorticoid synthesis and on adrenal androgen production with consequent effects on hemodynamic stability, electrolyte balance, and sexual differentiation.
11β-hydroxylase catalyzes the conversion of 11 deoxycortisol and deoxcorticosterone (DOC) to cortisol and corticosterone, respectively [4], [5]. Deficiency of this enzyme has similar effects to those of 21-hydroxylase except that patients with 11β-hydroxylase deficiency do not usually manifest salt losing adrenal crisis due to accumulation of DOC proximal to the enzymatic defect [6]. In fact, these patients may develop hypertension (HTN) and hypokalemia secondary to the mineralocorticoid activity of DOC [7], [8]. 11β-hydroxylase deficiency (11β-OHD) is usually due to mutations in the gene CYP11B1 [4]. Although there are ethnic differences in its prevalence, it has generally been considered the second most common form of CAH [6], [7]. However, it is much less common than CYP21A2 deficiency occurring only in about 5% of cases of CAH [1].
In Saudi Arabia, there is a high rate of consanguineous marriages and autosomal recessive genetic diseases are quite common [9], [10], [11]. The genetic defects and clinical spectrum of hereditary diseases are often unique. CYP11B1 deficiency has been reported to be more common in Saudi Arabia than the reported prevalence from other societies [12], [13]. However, there are no previous studies of the molecular basis of this disorder and its genotype phenotype pattern in detail. Therefore, the aims of this study were to characterize the molecular genetics of patients/families with 11 β-OHD in our population and to describe theier clinical, biochemical and management patterns. Our study revealed that most mutations (5 out of 6 mutations) are novel suggesting a unique genetic background of CYP11B1 deficiency in Saudi Arabia. We have characterized the functional aspects of these mutations and studied the clinical phenotype. This showed only a modest genotype/phenotype correlation.
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Patients and methods
We studied 16 cases of CYP11B1 deficiency from 8 unrelated families (Table 1). In 46,XX subjects, the clinical presentation varied from clitromegaly only to complete ambiguous genitalia with normal uteri and ovaries (Table 1). There was no clear correlation between the severity of the biochemical profiles and the clinical phenotype (Table 1, Table 2). However, many patients had biochemical testing while they were on glucocorticoid therapy and that may have altered the real levels of adrenal
Results
Mutational analysis and sex of rearing (Table 3 and the Supplementary materials)
Family A (Patients A1-A4): Three siblings with 46,XX presented at variable ages (2–16 years) with ambiguous genitalia, HTN and hypokalemia. Their 46,XY sibling had accelerated growth and HTN but normal male genitalia. Mutational analysis of all siblings revealed an insertion mutation (Codon 18, c.53_54insT) leading to frameshift and truncation at codon 39 (Fig. 1). One 46,XX sibling chose to be raised as a female
Discussion
In this report, we described 16 cases of CYP11B1 deficiency from 8 unrelated families and characterized their molecular genetics (Table 3). Several novel mutations were identified and functionally characterized. The cases illustrate the heterogeneous clinical and biochemical presentations and the complex gender identity and gender assignment decisions in this disorder. Overall, 46,XX patients presented with variable degree of ambiguity of the external genitalia ranging from clitromegaly only to
Disclosure summary
None of the authors have a conflict of interest that is relevant to the subject matter or materials included in this Work.
Conflict of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Acknowledgements
This work was supported by a grant 13-MED1154-20 from King Abdulaziz City for Science and Technology for Ali. S. Alzahrani and Grant R01GM086596 from the National Institute of General Medical Sciences for Richard J. Auchus.
References (25)
- et al.
Congenital adrenal hyperplasia
Lancet (Lond. Engl.)
(2005) - et al.
Consanguinity in Saudi Arabia: a unique opportunity for pediatric kidney research
Am. J. Kidney Dis.
(2014) - et al.
A prevalent and three novel mutations in CYP11B1 gene identified in Chinese patients with 11-beta hydroxylase deficiency
J. Steroid Biochem. Mol. Biol.
(2013) - et al.
Mutations in critical domains confer the human mTOR gene strong tumorigenicity
J. Biol. Chem.
(2013) - et al.
Divergent gender identity in three siblings with 46, XX karyotype and severely virilizing congenital adrenal hyperplasia caused by a novel CYP11B1 mutation, Endocrine Practice
Off. J. Am. Coll. Endocrinol. Am. Assoc. Clin. Endocrinol.
(2014) - et al.
Characterization of two genes encoding human steroid 11 beta-hydroxylase (P-450(11) beta)
J. Biol. Chem.
(1989) - et al.
Phenotypic, metabolic, and molecular genetic characterization of six patients with congenital adrenal hyperplasia caused by novel mutations in the CYP11B1 gene
J. Steroid Biochem. Mol. Biol.
(2016) - et al.
The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders
Endocr. Rev.
(2011) - et al.
Biochemical and genetic diagnosis of 21-hydroxylase deficiency
Endocrine
(2015) - et al.
CYP11B1 mutations causing congenital adrenal hyperplasia due to 11 beta-hydroxylase deficiency
J. Clin. Endocrinol. Metab.
(1996)