Abstract
Primary adrenocortical insufficiency (PAI) is an important cause of morbidity in neonates. The most common cause of PAI in neonates is congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD). Other rarer monogenic cases, for example, adrenal hypoplasia congenita (AHC) or familial glucocorticoid deficiency, also simulate clinical manifestation of 21-OHD, leading to misdiagnosis. The therapies and prognosis of these monogenic cases of PAI are entirely different. This study aimed to compare the differences of clinical data and identify genetic etiologies of PAI cases in the neonatal period. All 7 neonates initially presented with hyperpigmentation, hyponatremia, hyperkalemia, and high serum adrenocorticotropic hormone levels. Only CAH patients showed hyperandrogenism and remarkably elevated serum 17-hydroxyprogesterone levels. All the pathogenic mutations found in CYP21A2 were well known, except c.1069C>T (exon 8). The male patient with AHC had a novel hemizygous deletion of exon 2 in DAX1. The other one with familial glucocorticoid deficiency type 1 had two novel heterozygous mutations in the gene coding melanocortin 2 receptor, c.701C>T (exon 2) and c.119delT (exon 2). Glucocorticoid and/or mineralocorticoid replacement therapy depends on the cause of PAI. Genetic testing can be performed as a alternative diagnostic approach to provide information about therapy, prognosis, and genetic counseling.
Highlights
The clinical feature of primary adrenocortical insufficiency (PAI) depends on the class of deficient hormone including glucocorticoid, mineralocorticoid, and adrenal androgens, and the extent of hormone deficiency
The most common cause of PAI in the neonatal period is congenital adrenal hyperplasia (CAH), which occurs in approximately 1 of 14,200 live births [1, 2]. 21-hydroxylase deficiency (21-OHD) caused by mutations in the CYP21A2 gene represents 95–99% of cases of CAH [3]. 21-OHD results in the defective conversion of 17hydroxyprogesterone (17-OHP) to 11-deoxycortisol, which leads to impaired synthesis of cortisol and aldosterone, and increased secretion of adrenocorticotropic hormone (ACTH)
Five patients were diagnosed with CAH, one patient was diagnosed with adrenal hypoplasia congenita (AHC), and the other one was diagnosed with familial glucocorticoid deficiency type 1 (FGD1)
Summary
The clinical feature of primary adrenocortical insufficiency (PAI) depends on the class of deficient hormone including glucocorticoid, mineralocorticoid, and adrenal androgens, and the extent of hormone deficiency. As a consequence of cortisol deficiency, the production of pro-opiomelanocortin is increased, which is the prohormone of adrenocorticotropic hormone (ACTH) and melanocyte-stimulating hormone. The elevated melanocyte-stimulating hormone results in increased melanin synthesis, causing hyperpigmentation. The Primary Adrenocortical Insufficiency in Newborns above clinical findings of neonates with PAI are non-specific, misdiagnosis and delayed diagnosis are likely to result in potentially life-threatening adrenal crisis. Except for clinical findings caused by glucocorticoid and/or mineralocorticoid deficiency, the increasing androgens may cause clitoridauxe and virilization in female neonates, and hyperpigmentation of scrotum and enlarged phallus in male neonate. Even when the detectable enzyme activity is as low as 1–2 percent, the patient could present with the form of simple virilizing [4]
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