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.