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  • Küçük Resim Yok
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    Adrenocortical hormone profiles do not predict the molecular etiology in non-CAH primary adrenal insufficiency
    (Karger, 2021) Seven Menevşe, Tuba; Kendir Demirkol, Yasemin; Gürpınar Tosun, Büşra; Bayramoğlu, Elvan; Yıldız, Melek; Acar, Sezer; Erişen Karaca, Seda; Orbak, Zerrin; Önder, Asan; Söbü, Elif; Anık, Ahmet; Atay, Zeynep; Buğrul, Fuat; Demir, Korcan; Doğan, Durmuş; Emeksiz, Hamdi Cihan; Kırmızıbekmez, Heves; Özcan Murat, Nurhan; Yaman, Akan; Turan, Serap; Bereket, Abdullah; Güran, Tülay
    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.
  • Küçük Resim Yok
    Öğe
    Steroid hormone profiles and molecular diagnostic tools in pediatric patients with non-CAH primary adrenal insufficiency
    (National Library of Medicine's (NLM) Medline, 2022) Seven Menevşe, Tuba; Kendir Demirkol, Yasemin; Gürpınar Tosun, Büşra; Bayramoğlu, Elvan; Yıldız, Melek; Acar, Sezer; Erişen Karaca, Seda; Orbak, Zerrin; Önder, Asan; Söbü, Elif; Anık, Ahmet; Atay, Zeynep; Buğrul, Fuat; Buluş, Ayşe Derya; Demir, Korcan; Doğan, Durmuş; Emeksiz, Hamdi Cihan; Kırmızıbekmez, Heves; Özcan Murat, Nurhan; Yaman, Akan; Turan, Serap; Bereket, Abdullah; Güran, Tülay
    CONTEXT: There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. OBJECTIVE: This work aimed to investigate the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. METHODS: Pediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targeted-gene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. This study comprised 18 pediatric endocrinology clinics with 41 patients (17 girls, median age: 3 mo, range: 0-8 y) with non-CAH PAI of unknown etiology. RESULTS: A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to a healthy control group, patients showed lower steroid concentrations, most statistically significantly in cortisone, cortisol, and corticosterone (P?