We discuss (a) the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain-of-function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed-onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine-1-phosphate lyase-1 (SGPL1).
Moreover, six of 10 patients had a blunted cortisol response after ACTH stimulation, thus confirming the diagnosis of primary adrenal insufficiency (PAI).
Subsequent endocrine assessment with a synthetic adrenocorticotropin hormone (ACTH) stimulation test and measurement of ACTH levels revealed primary adrenal insufficiency also known as Morbus Addison.
The diagnostic process of primary adrenal insufficiency includes demonstration of low cortisol concentrations along with high plasma ACTH and identifying the cause of the disorder.
In addition to the patient's clinical symptoms and laboratory results, the results from ACTH and corticotropin-releasing hormone stimulation tests were used to make a diagnosis of primary adrenal insufficiency.
X-linked congenital adrenal hypoplasia (X-linked AHC) is characterized by acute onset of primary adrenal insufficiency in infancy or early childhood and hypogonadotropic hypogonadism (HH) at puberty.
The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels.
Congenital adrenal hyperplasia accounts for most cases of PAI in childhood, followed by abnormalities in the development of the adrenal gland, resistance to adrenocorticotropin hormone action and adrenal destruction.
Mutations in the DAX1 locus cause X-linked adrenal hypoplasia congenita (AHC) and hypogonadotropic hypogonadism (HH), which manifest with primary adrenal insufficiency and incomplete or absent sexual maturation, respectively.
These data indicate that molecular analysis of the DAX1 (NR0B1) gene is important for the diagnosis and genetic counseling of children with primary adrenal insufficiency.
Plasma cortisol, 17OH-progesterone, DHEA-S, androstendione and aldosterone were low, while ACTH and plasma renin activity were elevated, consistent with the diagnosis of primary adrenal insufficiency.
DAX1/NR0B1 mutations cause primary adrenal insufficiency in early childhood and hypogonadotropic hypogonadism (HHG), leading to absent or incomplete sexual maturation.
On laboratory testing, severely depressed concentrations of morning cortisol, along with highly elevated values of adrenocorticotropic hormone (ACTH) revealed primary adrenal insufficiency as the primary cause of the patient's symptomatology.
These data indicate that molecular analysis of the DAX1 (NR0B1) gene is important for the diagnosis and genetic counseling of children with primary adrenal insufficiency.
The continuous molecular genetic analysis of male patients with primary adrenal insufficiency revealed 13 novel mutations within the coding region of the NR0B1 gene which are predicted to inactivate the DAX1 function.
These findings further emphasize the variable clinical presentation in children with DAX1 gene mutations and indicate the value of genetic testing in boys with primary adrenal insufficiency.
These studies reveal the variable clinical presentation of DAX-1 mutations and emphasize the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked AHC.
The syndrome of familial adrenocorticotropin (ACTH) unresponsiveness is a rare form of primary adrenal insufficiency, usually without mineralocorticoid deficiency.