ESPE2024 Rapid Free Communications Adrenals and HPA Axis 2 (6 abstracts)
Rare Genetic Etiology of Primary Adrenal Insufficiency in Children; Clinical and Genetic Characterization of a Large Sudanese Cohort
Salwa Musa 1,2 , Mohamed Abdullah 2,3 , Samar Hassan 2 , Luqman Fauzi 4 , Younus Qamar 4 , Charlotte Hall 4 , Saptarshi Maitra 4 , Avinaash Maharaj 4 , Lucia Mariela Marroquin Ramirez 4 , Jordan Read 4 , Li F Chan 4 , Louise A Metherell 4 & Chris J Smith 4
1Department of Paediatrics and Child Health Faculty of Medicine, Al-Neelain University, Khartoum, Sudan. 2Department of Paediatric Endocrinology and Diabetes, Gaafar Ibn Auf Paediatric Tertiary Hospital., Khartoum, Sudan. 3Department of Paediatrics, Faculty of Medicine, University of Khartoum., Khartoum, Sudan. 4Centre of Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom, London, United Kingdom
Background: Studies of Primary Adrenal Insufficiency (PAI) from Africa are scanty while in Sudan, congenital adrenal hyperplasia (CAH) followed by Triple A syndrome are the commonest reported genetic etiologies in children. Diagnosis is challenging, especially in resource limited settings where presentation can mimic common childhood diseases and facilities for biochemical and genetic testing are restricted.
Patients & Methods: 48 patients from 43 families (31M:17F) with clinical presentation of PAI, paired with biochemical finding of low cortisol ± (high ACTH and/or negative response to short Synacthen stimulation) were included. Individuals with clear clinical signs and/or biochemical diagnosis of CAH (CYP21A2) or Triple A syndrome (AAAS) were excluded. In affected individuals, commonly mutated genes/exons were sequenced: MC2R, MRAP, CYP11A1 and STAR, followed by whole exome sequencing (WES) in mutation-negative individuals and family members (where available). WES results and segregation within families were confirmed by Sanger sequencing. in vitro splicing assays were employed to investigate potential splice defects.
Results: Hyperpigmentation was the commonest presenting symptom in 47/48 of patients while adrenal crisis was the leading cause of admission in 36. 18 families documented a family history of similar condition while 12 families had sibling death(s) with the same condition indicating challenging diagnosis. Genetic etiology was identified in 26/43 families, of which, 4 were novel. 21 families had a gene defect consistent with non-autoimmune PAI; ABCD1 (n = 7), NNT (n = 5) including a novel, synonymous splice-causing variant seen in more than one family, and CYP11A1 (n = 3). Further identified mutations include HSD3B2, MC2R, MRAP, NR0B1, STAR and a CYP11B1-B2 fusion event (n = 1 for each). AIRE mutations were found in 3 families, indicating an autoimmune origin. A further 9 patients from 8 families had diabetes, hypocalcemia and/or mucocutaneous candidiasis, suggesting autoimmune etiology. In three families the PAI resolved, in two of which we identified ARSA mutations fitting a diagnosis of Metachromatic Leukodystrophy (MLD) which was not previously reported or may have been a transient occurrence. The remaining six families had clinically and biochemically confirmed PAI with no autoimmune features where a genetic diagnosis remains to be found.
Conclusion: The landscape of gene defects in Sudan is different from that in Europe, with fewer MRAP/MC2R and more ABCD1/NNT mutations, including NNT and AIRE founder mutations. Diagnosis is challenging especially in limited resources; thus, genetic diagnosis is crucial for family counselling and optimal treatment plan. WES revealed itself as a useful frontline tool for the differential diagnosis of individuals presenting with adrenal insufficiency in this population, permitting personalized approach.
Article tools
My recent searches
My recently viewed abstracts
Authors
ESPE Abstracts
© Bioscientifica 2024 |
Privacy policy |
Cookie settings
BiosciAbstracts
Bioscientifica Abstracts is the gateway to a series of products that provide a permanent, citable record of abstracts for biomedical and life science conferences.
Find out more