A Novel Mutation in theCYP11B1Gene Causes Steroid 11β-Hydroxylase Deficient Congenital Adrenal Hyperplasia with Reversible Cardiomyopathy

Mohammad A Alqahtani,Saleh M Al-Qahtani,Abdullah A Alhayani,Brain F Meyer,Minjing Zou,Yufei Shi,Ali M Alsuheel,Hessa M Gilban,Ayed A Shati

doi:10.1155/2015/595164

Abstract

Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency is the second most common form of CAH, resulting from a mutation in the CYP11B1 gene. Steroid 11β-hydroxylase deficiency results in excessive mineralcorticoids and androgen production leading to hypertension, precocious puberty with acne, enlarged penis, and hyperpigmentation of scrotum of genetically male infants. In the present study, we reported 3 male cases from a Saudi family who presented with penile enlargement, progressive darkness of skin, hypertension, and cardiomyopathy. The elder patient died due to heart failure and his younger brothers were treated with hydrocortisone and antihypertensive medications. Six months following treatment, cardiomyopathy disappeared with normal blood pressure and improvement in the skin pigmentation. The underlying molecular defect was investigated by PCR-sequencing analysis of all coding exons and intron-exon boundary of the CYP11B1 gene. A novel biallelic mutation c.780 G>A in exon 4 of the CYP11B1 gene was found in the patients. The mutation created a premature stop codon at amino acid 260 (p.W260∗), resulting in a truncated protein devoid of 11β-hydroxylase activity. Interestingly, a somatic mutation at the same codon (c.779 G>A, p.W260∗) was reported in a patient with papillary thyroid cancer (COSMIC database). In conclusion, we have identified a novel nonsense mutation in the CYP11B1 gene that causes classic steroid 11β-hydroxylase deficient CAH. Cardiomyopathy and cardiac failure can be reversed by early diagnosis and treatment.

Highlights

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by inactivating mutations in genes involved in the cortisol biosynthesis
We have presented three cases of classic steroid 11β-hydroxylase deficiency from nonconsanguineous parents
Their diagnosis was initially missed at the local hospital and the patients developed dilated cardiomyopathy due to hypertension

Summary

Introduction

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by inactivating mutations in genes involved in the cortisol biosynthesis. More than 90% of CAH cases are due to steroid 21-hydroxylase deficiency. Steroid 11β-hydroxylase is encoded by CYP11B1 and its deficiency is the second most common cause of CAH. Mutations in the CYP11B1 gene cause an impairment of these two reactions, resulting in excessive DOC accumulation and androgen production. Despite failure of aldosterone production, overproduction of DOC, a less potent mineralocorticoid, can bind and activate the mineralocorticoid receptor to cause salt retention and hypertension in about two-thirds of patients [1]. The CYP11B1 gene is localized on chromosome 8q21, approximately 40 kb from the paralog CYP11B2 gene which encodes aldosterone synthase [7]. We reported three additional cases and characterized the underlying genetic defect with discovery of a novel mutation in the CYP11B1 gene

Subjects and Methods

Results

Discussion