Clinical and Molecular Analysis of Four Patients With 11β-Hydroxylase Deficiency.

Qiaoli Zhou,Ziyang Zhu,Qianqi Liu,Wei Gu,Zhanjun Jia,Chunli Wang,Bixia Zheng,Dandan Wang

doi:10.3389/fped.2020.00410

Abstract

Objective: 11β-hydroxylase deficiency (11βOHD) is a rare autosomal recessive disorder caused by mutations in the CYP11B1 gene. It is characterized by virilization, hypertension, and significant final height impairment. In this study, we aim to investigate the clinical and molecular characteristics of four unrelated Chinese patients with 11βOHD disorder.Methods: The clinical information of four 11βOHD patients were carefully reviewed. Genetic analysis was performed using next-generation sequencing (NGS) based panel analysis. NGS coverage depth was analyzed to detect exonic copy-number variants (CNVs) on patient 1. Quantitative PCR (qPCR) was subsequently performed to confirm the CNVs detected from the NGS coverage depth analysis.Results: The mean age of the patients at diagnosis was 4.7 years (range, 2.0–9.3 years). Two genetically female patients (patients 1 and 2) with 11βOHD presented severe virilization of external genitalia and were raised as males. Two genetically male patients (patients 3 and 4) presented precocious puberty. Additionally, patients 1, 3, and 4 presented with hypertension. In patient 4, unilateral adrenal mass was detected and removed at the age of 9 years. Interestingly, the height of patient 4 (174.4 cm, +6.7 SD) wasn't impaired and reached his mid-parental height (173 cm). Three novel variants in the CYP11B1 gene (c.1150_1153del, c.217C>T, and c.400G>C) were identified by NGS. Various bioinformatics tools revealed potential pathogenic effects for the novel variants, and evolutionary-conservation revealed that the novel missense variant affected an amino acid that is highly conserved among species. Furthermore, NGS coverage depth analysis and qPCR identified a novel heterozygous deletion of exons 1–6 in patient 1.Conclusion: Our study expands the spectrum of mutations of the CYP11B1 gene in Chinese population. In addition, We reported the first case of a patient with classical 11βOHD disorder, whose final height wasn't compromised.

Highlights

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by defects in various enzymes that are involved in the synthesis of cortisol from cholesterol by the adrenal cortex [1]
The CYP11B1 gene includes 9 exons and encodes a 503 amino acid protein which belongs to the cytochrome P450 system
All patients were born to nonconsanguineous parents at full-term gestation

Summary

Introduction

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders caused by defects in various enzymes that are involved in the synthesis of cortisol from cholesterol by the adrenal cortex [1]. Variants that lead to deactivated CYP11B1 can abolish or reduce the activity of the 11β-hydroxylase which converts 11-deoxycortisol to cortisol and 11-deoxycorticosterone (DOC) to corticosterone in the mitochondria of the adrenal cortex. Reduced activity of 11βhydroxylase leads to decreased cortisol secretion, accumulation of glucocorticoid and mineralocorticoid precursors, and excessive adrenal androgen biosynthesis. The excess androgens result in varying degrees of enlargement of the clitoris, fusion of the labioscrotal folds, and the vaginal and urogenital confluence. Both girls and boys with classical 11βOHD undergo rapid postnatal growth with sexual precocity and skeletal maturation, leading to short stature in adulthood [10, 11]. We performed a genetic and phenotypic analysis of four Chinese patients with 11βOHD, including two 46,XX females misassigned to the male gender at birth and reared as males, and two 46,XY males

Objectives

Methods

Results

Discussion

Conclusion