ESPE2021 ePoster Category 1 Adrenal A (10 abstracts)
Adrenocortical hormone profiles do not predict the molecular etiology in non-CAH primary adrenal insufficiency
Tuba Seven Menevse 1 , Yasemin Kendir Demirkol 2 , Busra Gurpinar Tosun 1 , Elvan Bayramoglu 3 , Melek Yildiz 4 , Sezer Acar 5 , Seda Erisen Karaca 6 , Zerrin Orbak 7 , Asan Onder 8 , Elif Sobu 9 , Ahmet Anik 10 , Zeynep Atay 11 , Fuat Bugrul 12 , Korcan Demir 13 , Durmus Dogan 14 , Hamdi Cihan Emeksiz 8 , Heves Kirmizibekmez 15 , Nurhan Ozcan Murat 16 , Akan Yaman 17 , Serap Turan 1 , Abdullah Bereket 1 & Tulay Guran 1
1Department of Pediatric Endocrinology and Diabetes, Marmara University, School of Medicine, Istanbul, Turkey; 2Department of Pediatric Genetics, Umraniye Research and Training Hospital, University of Health Sciences, Istanbul, Turkey; 3Department of Pediatric Endocrinology, Haseki Training and Research Hospital, Istanbul, Turkey; 4Department of Pediatric Endocrinology and Diabetes, Kanuni Sultan Suleyman Research and Training Hospital, University of Health Sciences, Istanbul, Turkey; 5Department of Pediatric Endocrinology and Diabetes, Behcet Uz Education and Research Hospital, Izmir, Turkey; 6Department of Pediatrics, Duzce University, School of Medicine, Bolu, Turkey; 7Department of Pediatric Endocrinology and Diabetes, Ataturk University, School of Medicine, Erzurum, Turkey; 8Department of Pediatric Endocrinology and Diabetes, Istanbul Medeniyet University Prof. Dr. Suleyman Yalcin City Hospital, Istanbul, Turkey; 9Department of Pediatric Endocrinology, Kartal Training and Research Hospital, Istanbul, Turkey; 10Department of Pediatric Endocrinology, Aydin Adnan Menderes University, School of Medicine, Aydin, Turkey; 11Department of Pediatric Endocrinology and Diabetes, Kosuyolu İstanbul Medipol Hospital, Istanbul, Turkey; 12Department of Pediatric Endocrinology and Diabetes, Selcuk University, School of Medicine, Konya, Turkey; 13Department of Pediatric Endocrinology and Diabetes, Dokuz Eylul University, School of Medicine, Izmir, Turkey; 14Department of Pediatric Endocrinology and Diabetes, Onsekiz Mart University, School of Medicine, Canakkale, Turkey; 15Department of Pediatric Endocrinology and Diabetes, Umraniye Research and Training Hospital, University of Health Sciences, Istanbul, Turkey; 16Department of Pediatric Endocrinology and Diabetes, Derince Research and Training Hospital, Kocaeli, Turkey; 17Department of Pediatrics, Gungoren Hospital, Istanbul, Turkey
Background: Primary adrenal insufficiency other than congenital adrenal hyperplasia (non-CAH PAI) is very uncommon in children but associated with a variety of molecular defects. Biosynthesis of adrenocortical hormones is reduced although the relation of steroid profiles with underlying molecular etiology is not yet studied.
Objective: Investigation of clinical and steroid hormone profiles of a multicenter cohort of children with non-CAH PAI.
Design: Patients with CAH, adrenoleukodystrophy, autoimmune adrenal insufficiency or obvious syndromic PAI on clinical and biochemical assessment were excluded. Genetic analysis was performed using either targeted gene panel or whole-exome sequencing. Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls.
Setting: Sixteen tertiary pediatric endocrinology clinics.
Patients: Forty-one children (19 females, median age: 3 months, range: 0-8 years) with non-CAH PAI of unknown etiology.
Results: A genetic diagnosis was obtained in 29 (68%) patients by targeted gene panel. Further molecular diagnosis could not be achieved by WES. The range of etiologies was: MC2R (n = 6), StAR (n = 6), NNT (n = 3), NR0B1 (n = 3), CYP11A1 (n = 2), MRAP (n = 2), SGPL1 (n = 2), ABCD1 (n = 1), AIRE (n = 1), AAAS (n = 1), HSD3B2 (n = 1). Steroid profiling demonstrated low levels in all adrenocortical steroid hormones irrespective of age and not varied among the genetic etiologies except two patients with new-onset symptoms of PAI due to homozygous c.518T>A(p.Leu173Gln) SGPL1, and hemizygous c.1772G>T(p.Arg591Leu) ABCD1 defects, and another patient with non-classic non-CAH PAI due to homozygous c.1351C>T (p.Arg451Trp) variant in CYP11A1. Compared to age-matched healthy control group in whom steroid hormone concentrations are physiologically low, the patient group had even lower steroid concentrations, most significantly in cortisone, cortisol, and corticosterone (P < 0.0001, area under the ROC curve: 0.96, 0.88, 0.87, respectively). Plasma cortisol<4 ng/ml, cortisone<11 ng/ml, and corticosterone<0.11 ng/ml had >95% specificity to segregate non-CAH PAI patients compared to control groups.
Conclusion: Adrenocortical hormone profiles are highly sensitive for the diagnosis of non-CAH PAI, while, in contrast to CAH, they are unlikely to point out a specific molecular diagnosis. Targeted gene panel sequencing is an undisputed optimal approach in the molecular diagnosis of non-CAH PAI with low cost and high efficacy, while little additional benefit is expected from whole-exome sequencing. Further progress can be made, mainly by more collaboration and exchanging knowledge for delineation of rare causes of primary adrenal insufficiency.
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