An Update of Congenital Adrenal Hyperplasia

Abstract

Congenital adrenal hyperplasia (CAH) is a family of autosomal recessive disorders caused by mutations that encode for enzymes involved in one of the various steps of adrenal steroid synthesis. These defects result in the absence or the decreased synthesis of cortisol from its cholesterol precursor. The anterior pituitary secretes excess adrenocorticotrophic hormone (ACTH) via feedback regulation by cortisol, which results in overstimulation of the adrenals and causes hyperplasia. Symptoms due to CAH can vary from mild to severe depending on the degree of ensymatic defect. In the classical form of CAH, there is a severe enzymatic defect owing to mutations in the CYP21 gene. Classically affected female fetuses undergo virilization of the genitalia prenatally and present with genital ambiguity at birth; however, prenatal treatment of CAH with dexamethasone to prevent ambiguity has been successfully utilized for over a decade. In the less severe, late-onset form of CAH, prenatal virilization does not occur. The milder enzyme deficiency was termed nonclassical 21-hydroxylase deficiency (NC21OHD) in 1979 and was later found to be the most common autosomal recessive disorder in humans. Disease frequency of NC21OHD varies between ethnic groups with the highest ethnic-specific disease frequency in Ashkenazi Jews at 1/27. NC21OHD is diagnosed by serum elevations of 17-OHP that plot on a nomogram between the range for unaffected individuals and levels observed for classical CAH and is typically confirmed with molecular genetic analysis. Similar to classical CAH, nonclassical 21-hydroxylase deficiency may cause premature development of pubic hair, advanced bone age, accelerated linear growth velocity and diminished final height in both males and females. Severe cystic acne has also been attributed to nonclassical CAH. Women may present with symptoms of androgen excess, including hirsutism, temporal baldness, and infertility. Menarche in females may be normal or delayed and secondary amenorrhea is a frequent occurrence. Polycystic ovary syndrome may also be seen in these patients. In males, early beard growth, acne, and growth spurt may prompt the diagnosis of NC21OHD. Although many males appear to be asymptomatic, they may present with oligozoospermia or diminished fertility. Individuals presenting to dermatology and infertility clinics with symptoms of hyperandrogenemia are rarely screened for NC21OHD. However, with hormonal and molecular genetic screening, previously undiagnosed patients may be identified and can therefore receive glucocorticoid treatment, which has been shown to reverse symptoms within 3 months.

How Many Deaths Can Be Prevented by Newborn Screening for Congenital Adrenal Hyperplasia?

“…For example, it has been suggested that early detection and treatment could potentially normalize linear growth and adult height, which are altered in both classical CAH and non-classical 21-hydroxylase deficiency [55]. Although hormone replacement therapy and early diagnosis have been linked to increased adult height, this has not yet been established as a benefit of earlier detection [56].…”

Prenatal Diagnosis and Treatment of Congenital Adrenal Hyperplasia

“…This interaction induces clitoral enlargement, promotes fusion of the labial folds, and causes rostral migration of the urethral/vaginal perineal orifice. Therefore, affected females are born with virilized external genitalia including clitoromegaly and labial fusion [7]. However, internal female genitalia (uterus, fallopian tubes and ovaries) are normal as females cannot produce müllerian-inhibiting hormone since they do not have testicular Sertoli cells.…”

Classical Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency in Croatia between 1995 and 2006

“…Mild 21-OHD results in the nonclassical form, characterized by hyperandrogenism presenting later in childhood or in early adulthood. Early recognition of CAH might prevent a life-threatening adrenal crisis, enable correct gender assignment at birth and prevent postnatal virilization, growth acceleration and premature pubarche [1]. A large proportion of patients with the classical form of CAH are recognized clinically soon after birth, but in a certain number of patients, especially males, diagnosis is missed.…”