Abstract
BackgroundPrimary adrenal insufficiency (PAI) is a rare but life-threatening condition. Differential diagnosis of numerous causes of PAI requires a thorough understanding of the condition.MethodsTo describe the genetic composition and presentations of PAI. The following data were collected retrospectively from 111 patients with non-21OHD with defined genetic diagnoses: demographic information, onset age, clinical manifestations, laboratory findings and genetic results. Patients were divided into four groups based on the underlying pathogenesis: (1) impaired steroidogenesis, (2) adrenal hypoplasia, (3) resistance to adrenocorticotropic hormone (ACTH) and (4) adrenal destruction. The age of onset was compared within the groups.ResultsMutations in the following genes were identified:NR0B1(n=39),STAR(n=33),CYP11B1(n=12),ABCD1(n=8),CYP17A1(n=5),HSD3B2(n=4),POR(n=4),MRAP(n=2),MC2R(n=1),CYP11A1(n=1),LIPA(n=1) andSAMD9(n=1). Frequent clinical manifestations included hyperpigmentation (73.0%), dehydration (49.5%), vomiting (37.8%) and abnormal external genitalia (23.4%). Patients with adrenal hypoplasia typically presented manifestations earlier than those with adrenal destruction but later than those with impaired steroidogenesis (both p<0.01). The elevated ACTH (92.6%) and decreased cortisol (73.5%) were the most common laboratory findings. We generated a differential diagnosis flowchart for PAI using the following clinical features: 17-hydroxyprogesterone, very-long-chain fatty acid, external genitalia, hypertension and skeletal malformation. This flowchart identified 84.8% of patients with PAI before next-generation DNA sequencing.ConclusionsSTARandNR0B1were the most frequently mutated genes in patients with non-21OHD PAI. Age of onset and clinical characteristics were dependent on aetiology. Combining clinical features and molecular tests facilitates accurate diagnosis.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Shanghai
National Key R&D Program of China
Shanghai Healthcare Commission Project
Clinical Research Center For Primary Adrenal Insufficiency, Pediatric College, Shanghai Jiao Tong University School of Medicine
Subject
Genetics (clinical),Genetics