CONGENITAL ADRENAL HYPERPLASIA WITH PSEUDOHERMAPHRODISM AND SYMPTOMS OF ADDISON'S DISEASE*

Abstract Context Mortality and infection-related hospital admissions are increased in patients with primary adrenal insufficiency (PAI). However, the risk of primary care–managed infections in patients with PAI is unknown. Objective To estimate infection risk in PAI due to Addison’s disease (AD) and congenital adrenal hyperplasia (CAH) in a primary care setting. Design Retrospective cohort study using UK data collected from 1995 to 2018. Main outcome measures Incidence of lower respiratory tract infections (LRTIs), urinary tract infections (UTIs), gastrointestinal infections (GIIs), and prescription counts of antimicrobials in adult PAI patients compared to unexposed controls. Results A diagnosis of PAI was established in 1580 AD patients (mean age 51.7 years) and 602 CAH patients (mean age 35.4 years). All AD patients and 42% of CAH patients were prescribed glucocorticoids, most frequently hydrocortisone in AD (82%) and prednisolone in CAH (50%). AD and CAH patients exposed to glucocorticoids, but not CAH patients without glucocorticoid treatment, had a significantly increased risk of LRTIs (adjusted incidence rate ratio AD 2.11 [95% confidence interval (CI) 1.64–2.69], CAH 3.23 [95% CI 1.21–8.61]), UTIs (AD 1.51 [95% CI 1.29–1.77], CAH 2.20 [95% CI 1.43–3.34]), and GIIs (AD 3.80 [95% CI 2.99–4.84], CAH 1.93 [95% CI 1.06–3.52]). This was mirrored by increased prescription of antibiotics (AD 1.73 [95% CI 1.69–1.77], CAH 1.77 [95% CI 1.66–1.89]) and antifungals (AD 1.89 [95% CI 1.74–2.05], CAH 1.91 [95% CI 1.50–2.43]). Conclusions There is an increased risk of infections and antimicrobial use in PAI in the primary care setting at least partially linked to glucocorticoid treatment. Future studies will need to address whether more physiological glucocorticoid replacement modes could reduce this risk.

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CYP21A2 polymorphisms in patients with autoimmune Addison's disease, and linkage disequilibrium to HLA risk alleles

Acta Endocrinologica ◽

10.1530/eje-14-0432 ◽

2014 ◽

Vol 171 (6) ◽

pp. 743-750 ◽

Cited By ~ 6

Author(s):

Ingeborg Brønstad ◽

Beate Skinningsrud ◽

Eirik Bratland ◽

Kristian Løvås ◽

Dag Undlien ◽

...

Keyword(s):

Linkage Disequilibrium ◽

Genetic Variants ◽

Direct Sequencing ◽

Addison’S Disease ◽

Addison's Disease ◽

Nucleotide Polymorphisms ◽

Adrenal Hyperplasia ◽

Single Nucleotide ◽

Risk Alleles ◽

Chromosome 6P21.3

ObjectiveSteroid 21-hydroxylase, encoded by CYP21A2, is the major autoantigen in autoimmune Addison's disease (AAD). CYP21A2 is located in the region of the HLA complex on chromosome 6p21.3, which harbours several risk alleles for AAD. The objective was to investigate whether CYP21A2 gene variants confer risk of AAD independently of other risk alleles in the HLA loci.DesignDNA samples from 381 Norwegian patients with AAD and 340 healthy controls (HC) previously genotyped for the HLA-A, -B, -DRB1, and -DQB1 and MICA loci were used for genotyping of CYP21A2.MethodsGenotyping of CYP21A2 was carried out by direct sequencing. Linkage of CYP21A2 to the HLA loci was assessed using UNPHASED version 3.0.10 and PHASE version 2.1.ResultsHeterozygotes of the single-nucleotide polymorphisms (SNPs) rs397515394, rs6467, rs6474, rs76565726 and rs6473 were detected significantly more frequently in AAD patients compared with HC (P<0.005), but all SNPs were in a linkage disequilibrium (LD) with high-risk HLA–DRB1 haplotypes. rs6472C protected against AAD (odds ratio=0.15, 95% CI (0.08–0.30), P=3.8×10−10). This SNP was not in an LD with HLA loci (P=0.02), but did not increase protection when considering the effect of HLA–DRB1 alleles. Mutations causing congenital adrenal hyperplasia were found in heterozygosity in <1.5% of the cases in both groups.ConclusionGenetic variants of CYP21A2 associated to AAD are in LD with the main AAD risk locus HLA-DRB1, and CYP21A2 does not constitute an independent susceptibility locus.

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