Background: Primary Adrenal Insufficiency (PAI) is a rare life-threatening disorder. Data on etiology and outcome of PAI in childhood are scanty, with the exception of Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD). The aim of our study is to evaluate etiology, morbidity and long-term outcome of PAI in a large cohort of children and characterize clinical presentation in subjects with PAI not due to 21OHD CAH.
Material and methods: 802 children followed in 8 tertiary centers were retrospectively included.
Results: 85% of patients (n=682) had 21OHD CAH and were not reviewed further. Different etiologies were found in 15% subjects (n=120): 37.5% had autoimmune PAI (10% isolated; 20.8% Autoimmune Polyendocrinopathy Syndrome type 1; 6.7% Autoimmune Polyendocrinopathy Syndrome type 2); 25% had steroid biosynthetic defects: 11-hydroxylase deficiency (n=3), 3β-hydroxysteroiddehydrogenase deficiency (n=6), 17α-hydroxylase deficiency (n=1), X-linked Adrenal Hypoplasia Congenita due to DAX1 mutations(n=13), Familial Glucocorticoid Deficiency due to mutation in MC2R (n=4) or MRAP (n=1) and Glycerol Kinase Deficiency (n=2). 20.8% (n=25) had adrenoleukodystrophy; 6.7% (n=8) had rare syndromes (TripleA, Pearson); 2.5% (n=3) had a history of infection or hemorrhage. Finally in 7.5% of patients (n=9) no defined etiology was found. Mean age at diagnosis was 6.7±5.2 yrs; time between onset and diagnosis ranged from 0 to 56 months. Common signs/symptoms were fatigue (76.7%), hyperpigmentation (48.3%), dehydration (31.7%), neurologic signs (32.5%) and hypotension (29.2%); most common biochemical finding was increased ACTH (89.2%), followed by hypocortisolism (64.2%) and hyponatremia (50%) whereas hyperkalemia and hypoglycemia were found in 28.3% and 25.8% of subjects, respectively. Overall mortality was <1%.
Conclusion: In our large cohort of pediatric patients with PAI, the most common cause of adrenal insufficiency is CAH due to 21OHD. Among patients with non 21OHD PAI we found that the second most frequent cause was autoimmunitiy, mostly represented by congenital autoimmune polyendocrine syndromes. Other causes were in order represented by rare steroid biosynthetic defects, adrenoleukodystrophy and rare congenital syndromes. 7.5% of our patients still remain without a definite diagnosis. With the exception of hyperpigmentation, which occurs late in the majority of cases, signs and symptoms at presentation of PAI in our cohort were highly aspecific leading to significant delay in diagnosis in particular in older children.
18 - 21 May 2019
European Society of Endocrinology