ESPE Abstracts

Introduction: Adrenal insufficiency is a rare, but potentially fatal medical condition, most frequently congenital in children. Rapid and accurate diagnosis is imperative for effective treatment. A growing number of causative gene mutations in overlapping clinical phenotypes and different syndromes which share adrenal insufficiency as one of the main characteristics were published recently.

Case Presentation: An infant (born at term, uneventful pregnancy, BW 3.795uh, BL 52 cm) was admitted in the Clinic of Nephrology at 7 months due to acute renal failure (GFR - 53 ml/min/1.73m2, elevated BUN, compensated metabolic acidosis, dyselectrolytemia, vomiting). Improved renal function after therapy, pathological profile of organic acids and suspicion of a congenital metabolic disease (24h-urine & DBS). No cortisol deficiency. Normal 17-OHP in DBS at birth. Following a new infection (1 month after dismission), severe deterioration (dehydration, metabolic acidosis, hyperkalemia, hyponatremia, hypoglycemia, start of hyperpigmentation, muscular hypotonia, no appetite, apathy). Gradual decrease of cortisol, aldosterone, increase of ACTH, until a clear clinical and hormonal constellation for primary adrenal failure became evident. During the first 3 months very high needs in respect of the hormonal and salt substitution were evident. The patient was referred for genetic testing as a rare complex disease was suspected.

Material and Methods: DNA was extracted from peripheral blood. Whole-genome sequencing data was generated by BGI (Poland) on a BGISEQ-500 next-generation sequencer using the DNBSEQ technology for library preparation. The average coverage surpassed the clinical standard of 30X. Targeted bioinformatic analysis was performed first applying an Organic aciduria gene panel consisting of 161 genes and then expanding the analysis with a genome-wide scan for pathogenic/likely pathogenic variants.

Results: Expanding the analysis beyond the Organic aciduria gene panel we detected two pathogenic variants in the AIRE gene associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). After an in-depth interpretation of the findings consulting different databases and a multidisciplinary discussion for clinical correlation a final genetic diagnosis of APECED was established.

Conclusion: We report on a patient with unusual early, fast progressing adrenal insufficiency, which developed after acute renal failure. The molecular genetic landscape of primary adrenal insufficiency, after excluding congenital adrenal hyperplasia, represents a real challenge. A gene panel approach based on certain aspects of the clinical synopsis could sometimes be inaccurate. Whole-genome sequencing combined with a broader genome-wide variant filtering strategy and guided by close interdisciplinary discussion with the referring doctors could allow for a timely diagnosis, personalized treatment (endocrine and non-endocrine) and follow-up.