Endocrine Abstracts

The human adrenal gland develops from around 4 weeks post conception and undergoes rapid growth and differentiation in early fetal life. At birth, the adrenal gland consists of a mature adult type cortex capable of mineralocorticoid and glucocorticoid production, as well as a fetal zone that involutes in the first few months. Disruption of the HPA axis development can cause adrenal hypoplasia. This is classically broken down into secondary causes (ACTH insufficiency); ACTH-resistance like conditions (sometimes called familial glucocorticoid deficiency (FGD)); and defects in adrenal development itself (primary adrenal hypoplasia). Advances in molecular biology have played an important role in defining some of these conditions, leading to better understanding of phenotype and clinical evolution. The best example of this is X-linked adrenal hypoplasia, which was first reported to be due to defects in DAX1/NR0B1 20 years ago. This condition classically presents with salt-losing adrenal failure and hypogonadotropic hypogonadism, but a much greater range of presentations and features have now been described. More recently, IMAGe syndrome (Intrauterine growth restriction, Metaphyseal dysplasia, Adrenal hypoplasia and Genital anomalies) has been shown to be due to activation of the cell-cycle regulator CDKN1C, a factor where loss of function causes Beckwith–Wiedemann syndrome and hyperinsulinism. Diabetes has recently been reported in CDKN1C activation. Finally, the range of ACTH resistance-like conditions has expanded rapidly (MRAP, NNT, and MCM4), some of which have unique associated features. Establishing a specific diagnosis can be important for identifying associated features, tailoring treatment to an individual, establishing long-term prognosis, and identifying other family members at risk of adrenal insufficiency. As many of these conditions have overlapping clinical and biochemical features, genetic approaches to diagnosis are proving invaluable in many cases.