DISCUSSION
Classic congenital adrenal hyperplasia (CAH) is generally caused by mutations in the CYP21A2 gene (resulting in 21α-hydroxylase deficiency) and has a prevalence of 1:15,000 [7]. The mode of inheritance is mainly autosomal recessive [8]. The patients deficient in 21𝛼-hydroxylase present with signs of cortisol deficiency along with aldosterone deficiency in life-threatening situations. Insufficiency of adrenal hormones disturbs the balance of the hypothalamus-pituitary-adrenal (HPA) axis and impairs the negative feedback system leading to an increase in ACTH secretion from the pituitary gland. The stimulant effect of ACTH on the steroidogenesis pathway, in turn, leads to hyperplasia of both the adrenal glands with increased production of androgens. The intensity of clinical manifestations depends on the site and severity of the defect in the biosynthesis pathway [8]. In this variety, there is an accumulation of 17-OH-progesterone in the serum, which is further redirected to form adrenal androgens [8]. In about one-third of the cases, this defect is severe and presents at birth with features of glucocorticoid and mineralocorticoid deficiency and elevated androgens. The remaining two-third of the cases have adequate secretion of mineralocorticoids but there may be features of cortisol insufficiency and/or ACTH and androgen excess. Sometimes mild enzyme defects may be present that are not apparent until adult life, when females may present with amenorrhea and/or hirsutism, which is referred to as Late-onset CAH [8].
With the increasing concern on inherited defects, screening for CAH has been a part of the routine neonatal check-up in many parts of the world. In Sweden and Norway, the test is performed by measuring 17 hydroxyprogesterone (17-OHP) in blood using a filter paper no earlier than 48 hours after the birth. The other screening methods are radioimmunoassay employed in the US, enzyme-linked immunosorbent assay in Japan, and time-resolved fluoroimmunoassay in Europe. Preterm newborns have a higher 17-OHP concentration in serum than babies born at term. Thus, cut-off levels are based on gestational age in Japan and Europe, and birth weight in the US [9]. Screening aims to determine the sex, improve the outcomes and prevent neonatal deaths [10]. During the prenatal period methods like amniocentesis and chorionic villous sampling (CVS) can be utilized to screen the fetus for genetic defects. The lack of adequate screening in this part of the world led to the severe clinical presentation in this child with typical signs of salt loss and hypoglycemia. It has been shown that these findings can have a negative influence on the child’s cognitive performance. The long-term consequences of the salt-wasting crisis at birth are hard to predict, but early diagnosis and avoiding hypo-cortisolism in the neonatal period has proved to improve prognosis and lead to a favorable cognitive development as well [7].
The management of this disorder is a constant balancing act. Although the prenatal administration of synthetic glucocorticoid (dexamethasone) to pregnant females with a previous history of a child with CAH has been shown to ameliorate virilization of external genitalia in the affected female fetus, uncertainties exist in terms of long-term efficacy and safety profile of this measure or its use in male fetuses. Adding to the concern is the fact that the dose of dexamethasone that the fetus is exposed to is estimated to be 60 times the normal fetal cortisol level [12]. The management involves the lifelong substitution of cortisol but due to the inability to match the exact circadian rhythm of the hormones, it carries a risk of both under and over-treatment. Our patient improved significantly with the appropriate dose and treatment with normalization of the electrolytes and adequate weight gain. But a careful approach was warranted as the receptors for both glucocorticoids and mineralocorticoids are overly expressed in parts of the brain like the hippocampus, amygdala, and prefrontal cortex and excess replacement may disturb the cognitive and affective functions in patients receiving overtreatment [7]. Ideally, there should be a balance between the substitution and suppression of glucocorticoids and mineralocorticoids. Needless to say, patients with Classic CAH on replacement therapy require added care and monitoring especially during the critical stages of any illness. Administration of stress doses of hydrocortisone acutely during sickness undoubtedly plays a very crucial role but may still be unable to control hypoglycemia. Although our patient showed significant improvement in the glucose levels with the treatment, as per the guidelines, additional glucose supplementation is essential in preventing a hypoglycemic crisis, especially in the pediatric population [11].
The potentially fatal presentation of the patient at the time of arrival to the hospital could have been prevented, had the child been screened for the disorder at birth. This case, therefore, highlights the significance of neonatal screening for CAH at birth for better outcomes in patients. The newborn screening for CAH has already been a routine part of the neonatal screening protocol for most countries [12] and calls for an urgent need in low and middle-income countries as well.