Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management.
Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology.
Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded.
Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics.
Patients: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study.
Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c. IVS3ds + 1delG in MRAP. Several important clinical and molecular insights emerged.
Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.
C1 [Guran, Tulay; Aycan, Zehra; Bereket, Abdullah; Turan, Serap] Marmara Univ, Dept Pediat Endocrinol & Diabet, Fevzi Cakmak Mh Mimar Sinan Cd 41, TR-34899 Istanbul, Turkey.
[Guran, Tulay] Univ Birmingham, Inst Metab & Syst Res, Birmingham B15 2TT, W Midlands, England.
[Buonocore, Federica; Suntharalingham, Jenifer P.; Achermann, John C.] UCL, Inst Child Hlth, Dept Genet & Genom Med, London WC1N 1EH, England.
[Saka, Nurcin; Bas, Firdevs; Aydin, Banu Kucukemre; Abali, Zehra Yavas] Istanbul Univ, Istanbul Fac Med, Dept Pediat Endocrinol & Diabet, TR-34452 Istanbul, Turkey.
[Ozbek, Mehmet Nuri; Demirbilek, Huseyin] Diyarbakir Childrens Hosp, Clin Pediat Endocrinol, TR-21100 Diyarbakir, Turkey.
[Aycan, Zehra; Agladioglu, Sebahat Yilmaz] Childrens Hlth & Dis Training & Res Hosp, Dr Sami Ulus Obstet & Gynecol, Clin Pediat Endocrinol, TR-06100 Ankara, Turkey.
[Darcan, Sukran; Ozen, Samim] Ege Univ, Dept Pediat Endocrinol & Diabet, TR-35040 Izmir, Turkey.
[Bideci, Aysun; Doger, Esra] Gazi Univ, Dept Pediat Endocrinol & Diabet, TR-06550 Ankara, Turkey.
[Guven, Ayla; Yildiz, Metin] Goztepe Educ & Res Hosp, Pediat Endocrinol Clin, TR-34810 Istanbul, Turkey.
[Guven, Ayla] Amasya Univ, Fac Med, Dept Pediat, TR-05189 Amasya, Turkey.
[Demir, Korcan] Dr Behcet Uz Childrens Hosp, Pediat Endocrinol Clin, Izmir, Turkey.
[Akinci, Aysehan] Inonu Univ, Dept Pediat Endocrinol & Diabetes, Malatya, Turkey.
[Buyukinan, Muammer] Konya Training & Res Hosp, Clin Pediat Endocrinol, TR-42100 Konya, Turkey.
[Tarim, Omer] Uludag Univ, Dept Pediat Endocrinol & Diabet, TR-16059 Bursa, Turkey.
[Catli, Gonul] Eylul Univ, Dept Pediat Endocrinol & Diabet, TR-35210 Izmir, Turkey.
[Yuksel, Bilgin] Cukurova Univ, Dept Pediat Endocrinol & Diabet, TR-01330 Adana, Turkey.
[Akcay, Teoman] Kanuni Sultan Suleyman Educ & Res Hosp, Clin Pediat Endocrinol, TR-34303 Istanbul, Turkey.
[Ucar, Ahmet] Sanliurfa Childrens Hosp, Pediat Endocrinol Clin, TR-63300 Sanliurfa, Turkey.
[Isik, Emregul] Gaziantep Childrens Hosp, Pediat Endocrinol Clin, TR-27010 Gaziantep, Turkey.
[Ozhan, Bayram] Pamukkale Univ, Fac Med, Dept Pediat Endocrinol & Diabet, TR-20160 Denizli, Turkey.
[Bolu, Semih] Duzce Univ, Fac Med, Dept Pediat Endocrinol & Diabet, TR-81620 Duzce, Turkey.
[Ozgen, Ilker Tolga] Bezm I Alem Vakif Univ, Dept Pediat Endocrinol & Diabet, TR-34093 Istanbul, Turkey.