Adrenocortical hormone profiles do not predict the molecular etiology in non-CAH primary adrenal insufficiency
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Tarih
2021
Dergi Başlığı
Dergi ISSN
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Erişim Hakkı
info:eu-repo/semantics/closedAccess
Özet
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.
Açıklama
Anahtar Kelimeler
Primary Adrenal Insufficiency, Molecular Etiology, Hormone Profiles
Kaynak
Hormone Research in Paediatrics
WoS Q Değeri
Q2
Scopus Q Değeri
Cilt
94
Sayı
SUPPL 1
Künye
Seven Menevşe, T., Kendir Demirkol, Y., Gürpınar Tosun, B., Bayramoğlu, E., Yıldız, M., Acar, S. ... Güran, T. (2021). Adrenocortical hormone profiles do not predict the molecular etiology in non-CAH primary adrenal insufficiency. Hormone Research in Paediatrics (64-65. ss.).
