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

Abstract

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.

Overview of Monogenic Forms of Hypertension Combined With Hypokalemia

“…11β-OHD is the second major subtype of CAH, accounting for 0.2–8% of all CAH cases while 21-hydroxysteroid deficiency is the most common subtype of CAH ( 39 , 40 ). Mutation in CYP11B1 , encoding steroid 11β-hydroxylase (11β-OH), results in a series of pathophysiological changes, and the mutation has a significant racial specificity ( 41 ). Deficiency of 11β-OH leads to impaired conversion of 11-deoxycortisol and 11-deoxycorticosterone to cortisol and corticosterone, respectively, resulting in an elevated ACTH level and superfluous adrenal androgens.…”

“…Firstly, some mutations which result in partial activity defects of relevant enzymes are possibly responsible for some mild phenotypes, which may be misdiagnosed easily ( 38 , 85 ). For instance, patients with the mutations in exon 3 of gene CYP11B1 tend to present as a non-classic phenotype, similar to polycystic ovary syndrome ( 41 ). Second, the overlap of germline and somatic mutations may be one of the causes of phenotypic variability.…”

46,XX DSD due to Androgen Excess in Monogenic Disorders of Steroidogenesis: Genetic, Biochemical, and Clinical Features

“…The CYP11B1 gene is located on the long arm of chromosome 8 (8q21–q22), and it is in very close proximity to the highly homologous CYP11B2 gene, which encodes for aldosterone synthase. About 130 mutations of the CYP11B1 gene have been described and are localized all over the gene, with a minor presence in exons 1 and 9 [128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150]. Figure 5 summarizes the majority of allelic variants that have been described so far in the literature for females (62 patients) together with their influence on genital phenotype (see also Table S2).…”

“…A recent review [147] reported that the R448H mutation and eight other mutations (Q356X, G379V, T318M, c.53_54 insT, R454C, R448P, and R148X) are the most frequently found and account for approximately 40% of all cases. CYP11B1 mutations show significant ethnic specificity, and an updated description of their characteristics can be found in the studies of Khattab et al [146] and Wang et al [147].…”

“…A recent review [147] reported that the R448H mutation and eight other mutations (Q356X, G379V, T318M, c.53_54 insT, R454C, R448P, and R148X) are the most frequently found and account for approximately 40% of all cases. CYP11B1 mutations show significant ethnic specificity, and an updated description of their characteristics can be found in the studies of Khattab et al [146] and Wang et al [147]. Recombination events between the two homologous genes have been reported where the CYP11B1 gene is under the control of the CYP11B2 promoter such that it responds to angiotensin II and not to ACTH, resulting clinically in classical 11-OHD [151,152].…”