Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a collection of autosomal recessive disorders marked by disrupted cortisol production. It arises from a deficiency in one of the five enzymes necessary for synthesis of cortisol in the adrenal cortex. These disorders often involve abnormal production of hormones like glucocorticoids, mineralocorticoids, or sex steroids, potentially affecting the development of primary or secondary sex characteristics in some affected infants, children, or adults. It is among the most prevalent autosomal recessive disorders in humans.

Types

CAH manifests in different forms. Each form's clinical presentation varies significantly based on the specific enzyme defect, precursor retention, and product deficiency. Classical forms are evident in infancy, while nonclassical forms emerge in late childhood. Classic CAH can be further divided into salt-wasting and simple-virilizing forms, depending on the presence or absence of mineralocorticoid deficiency. However, this classification is often clinically insignificant since all patients experience some salt loss, and symptoms may overlap.

Classic

Salt-wasting

In 75% of severe enzyme deficiency cases, inadequate aldosterone production can cause salt wasting, growth failure, and potentially life-threatening hypovolemia and shock. A missed diagnosis of salt-loss CAH is linked to increased risk of early neonatal morbidity and mortality.

Simple-virilizing

The primary feature of CAH in newborn females is abnormal external genitalia development, with varying degrees of virilization. Clinical practice guidelines recommend CAH evaluation for newborns with bilateral inaccessible gonads. If virilizing CAH is not identified and treated, both boys and girls may experience rapid postnatal growth and virilization.

Nonclassic

Besides the salt-wasting and simple-virilizing forms diagnosed in infancy, there is a mild or "nonclassic" form, characterized by varying degrees of postnatal androgen excess, sometimes asymptomatic. The nonclassic form may become apparent in late childhood, leading to signs of hyperandrogenism such as accelerated growth, acne, hirsutism, premature pubarche, menstrual irregularities, and secondary polycystic ovary syndrome. In adult males, early balding and infertility may indicate the diagnosis. The nonclassic form involves mild subclinical impairment of cortisol synthesis, with usually normal serum cortisol levels.

Signs and Symptoms

The symptoms of CAH differ based on the type of CAH and the patient's gender. Possible symptoms include:

Due to insufficient mineralocorticoids:

• Vomiting caused by salt-wasting, which can lead to dehydration and potentially death

  
  

Due to excessive androgens:

• Severe virilization may result in clitoromegaly (enlarged clitoris) resembling a phallic structure.

  
  

• Ambiguous genitalia can occur in some infants, making it challenging to initially determine the external genitalia as "male" or "female".

  
  

• Early appearance of pubic hair and rapid growth during childhood.

  
  

• Precocious puberty or absence of puberty development (sexual infantilism: absent or delayed puberty)

  
  

• Excessive facial hair, virilization, and/or menstrual irregularity during adolescence

  
  

• Infertility due to anovulation

  
  

• Shallow vagina

  
  

Due to insufficient androgens and estrogens:

• Undervirilization in XY males can lead to an apparent vulva.

  
  

• Ambiguous genitalia in XY males with 3β-hydroxysteroid dehydrogenase deficiency (3β-HSD2D).

  
  

• In females, hypogonadism may result in sexual infantilism or atypical pubertal development, infertility, and other reproductive system issues.

Genetics

CAH arises from mutations in genes that code for enzymes involved in the biochemical processes of producing mineralocorticoids, glucocorticoids, or sex steroids from cholesterol within the adrenal glands (steroidogenesis).

Each CAH type is linked to a particular defective gene. The most prevalent form (95% of cases) involves the gene for 21-hydroxylase, located at 6p21.3 within the HLA complex; 21-hydroxylase deficiency is due to a specific mutation with two closely similar copies in sequence, comprising an active gene (CYP21A2) and an inactive pseudogene (CYP21A1P). Mutant alleles result from recombination between the active and pseudogenes (gene conversion). Approximately 5% of CAH cases are caused by defects in the gene for 11β-hydroxylase, leading to 11β-hydroxylase deficiency. Other, rarer CAH forms are due to mutations in genes such as HSD3B2 (3β-hydroxysteroid dehydrogenase 2), CYP17A1 (17α-hydroxylase/17,20-lyase), CYP11A1 (P450scc; cholesterol side-chain cleavage enzyme), STAR (steroidogenic acute regulatory protein; StAR), CYB5A (cytochrome b5), and CYPOR (cytochrome P450 oxidoreductase; POR).

Expressivity

Additional variability is introduced by the level of enzyme inefficiency caused by the specific alleles present in each patient. Some alleles lead to more severe enzyme inefficiency. Generally, severe inefficiency results in changes in the fetus and issues during prenatal or perinatal life. Milder inefficiency is often linked to excessive or deficient sex hormone effects during childhood or adolescence, while the mildest CAH forms affect ovulation and fertility in adults.

Diagnosis

Clinical evaluation

Female infants with classic CAH exhibit ambiguous genitalia due to high androgen exposure in utero. CAH caused by 21-hydroxylase deficiency is the leading cause of ambiguous genitalia in genotypically normal female infants (46XX). Less severely affected females may show early pubarche. Young women might experience symptoms of polycystic ovarian syndrome (oligomenorrhea, polycystic ovaries, hirsutism).

Males with classic CAH typically show no signs at birth. Some may display hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone, and potential penile enlargement. The diagnosis age for males with CAH varies based on the severity of aldosterone deficiency. Boys with salt-wasting disease present early with hyponatremia and hypovolemia symptoms. Boys without salt-wasting present later with virilization signs.

In less common forms of CAH, males are undermasculinized, and females usually show no signs or symptoms at birth.

Laboratory studies

Genetic analysis can confirm a CAH diagnosis, but it's not necessary when classic clinical and laboratory findings are present.

In classic 21-hydroxylase deficiency, laboratory tests reveal:

• Hypoglycemia (due to hypocortisolism) - Cortisol functions to increase blood glucose levels through mechanisms such as (a) stimulating gluconeogenesis in the liver, (b) promoting glycogenolysis, and (c) preventing glucose from leaving the bloodstream by downregulating GLUT-4 receptors. When cortisol is deficient, these processes are effectively reversed. Although compensatory mechanisms exist to mitigate hypocortisolism's impact, they are limited, resulting in hypoglycemia.

  
  

• Hyponatremia (due to hypoaldosteronism) - Aldosterone, the end product of the renin-angiotensin-aldosterone system, regulates blood pressure by increasing sodium retention in exchange for potassium. A lack of aldosterone leads to hyperkalemia and hyponatremia. This distinguishes it from 11-hydroxylase deficiency, where excess 11-deoxycorticosterone, with weak mineralocorticoid activity, retains sodium at potassium's expense, preventing salt wasting and causing hypertension/water retention and sometimes hypokalemia.

  
  

• Hyperkalemia (due to hypoaldosteronism)

  
  

• Elevated 17α-hydroxyprogesterone

Classic 21-hydroxylase deficiency typically results in 17α-hydroxyprogesterone blood levels >242 nmol/L. For comparison, a full-term infant at three days of age should have <3 nmol/L. Neonatal screening programs often have specific reference ranges by weight and gestational age, as high levels may occur in premature infants without CAH. Salt-wasting patients usually have higher 17α-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17α-hydroxyprogesterone may not be elevated in a random blood sample but will rise during a corticotropin stimulation test.

Classification

Cortisol, an adrenal steroid hormone, is essential for normal endocrine function, with production beginning in the second month of fetal life. Poor cortisol production is a hallmark of most CAH forms. Inefficient cortisol production results in rising ACTH levels, as cortisol inhibits ACTH production. Increased ACTH stimulation causes overgrowth (hyperplasia) and overactivity of the adrenal cortex's steroid-producing cells. The defects causing adrenal hyperplasia are congenital (present at birth).

Cortisol deficiency in CAH is usually partial and not the most serious issue. Cortisol synthesis shares steps with mineralocorticoid synthesis like aldosterone, androgens like testosterone, and estrogens like estradiol. Excessive or deficient production of these hormones causes the most significant problems in CAH. Specific enzyme inefficiencies are linked to characteristic patterns of mineralocorticoid or sex steroid over- or underproduction.

Since the 1960s, most endocrinologists have used traditional names for CAH forms, which correspond to deficient enzyme activity. In the 1980s, as enzyme structures and genes were identified, most enzymes were found to be cytochrome P450 oxidases and renamed accordingly. Some reactions involve multiple enzymes, while a single enzyme may mediate multiple reactions. Variation exists in different tissues and mammalian species.

In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed CAH cases. Unless another specific enzyme is mentioned, "CAH" usually refers to 21-hydroxylase deficiency. (The terms "salt-wasting CAH" and "simple virilizing CAH" typically refer to subtypes of this condition.) CAH due to deficiencies in enzymes other than 21-hydroxylase presents similar management challenges as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency.

Common medical term	%	OMIM	Enzyme(s)	Locus	Substrate(s)	Product(s)	Mineralocorticoids	Androgens
21-Hydroxylase CAH	95%	201910	P450c21	6p21.3	17-OH-Progesterone→ Progesterone→	11-Deoxycortisol DOC	↓	↑
11β-Hydroxylase CAH	5%	202010	P450c11β	8q21-22	11-Deoxycortisol→ DOC→	Cortisol Corticosterone	↑	↑
3β-HSD CAH	Very rare	201810	3βHSD2	1p13	Pregnenolone→ 17-OH-Pregnenolone→ DHEA→	Progesterone 17-OH-Progesterone Androstenedione	↓	↓
17α-Hydroxylase CAH	Very rare	202110	CYP17A1	10q24.3	Pregnenolone→ Progesterone→ 17-OH-Pregnenolone→	17-OH-Pregnenolone 17-OH-Progesterone DHEA	↑	↓
Lipoid CAH (20,22-desmolase)	Very rare	201710	StAR P450scc	8p11.2 15q23-q24	Transport of cholesterol Cholesterol→	Into mitochondria Pregnenolone	↓	↓

Screening

In the United States and over 40 other countries, newborns are routinely screened for 21-hydroxylase CAH at birth. This screening identifies elevated levels of 17α-hydroxyprogesterone (17-OHP). High levels of 17-OHP allow for early detection of CAH, enabling newborns to begin medication early and lead relatively normal lives.

However, the screening process has a high rate of false positives. In one study, CAH screening showed the lowest positive predictive value (111 true-positive cases out of 20,647 abnormal screening results over two years, or 0.53%, compared to 6.36% for biotinidase deficiency, 1.84% for congenital hypothyroidism, 0.56% for classic galactosemia, and 2.9% for phenylketonuria). This suggests that 200 unaffected newborns required clinical and laboratory follow-up for each true case of CAH.

In 2020, Wael AbdAlmageed from the USC Information Sciences Institute and Mimi Kim from USC's Keck School Of Medicine conducted a joint study using deep learning technology to examine the facial morphology and features of CAH patients compared to controls. In this cross-sectional study of 102 CAH patients and 144 control participants, deep learning methods achieved a mean area under the receiver operating characteristic curve of 92% for predicting CAH from facial images. Facial features differentiated CAH patients from controls, with analyses showing the nose and upper face as most contributory. These findings indicate that facial morphologic features, as analyzed by deep neural networks, can serve as a phenotypic biomarker for predicting CAH.

Treatment

The clinical manifestations of each CAH form are distinct and largely depend on the specific enzyme defects, precursor retention, and defective products. The therapeutic objective of CAH is to replenish deficient adrenal hormones and suppress excess precursors.

Treatment for all forms of CAH may include:

1. Administering sufficient glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids

   
   

2. Providing replacement mineralocorticoid and additional salt if there is a deficiency

   
   

3. Supplying replacement testosterone or estrogens during puberty if deficient

   
   

4. Additional treatments to optimize growth by delaying puberty or bone maturation

   
   

If CAH is due to a 21-hydroxylase enzyme deficiency, treatment aims to normalize androstenedione levels, while normalization of 17α-hydroxyprogesterone indicates overtreatment. Monitoring involves measuring androstenedione and 17α-hydroxyprogesterone levels in blood or saliva.

Crinecerfont (Crenessity) received approval for medical use in the United States in December 2024.