Congenital Adrenal Hyperplasia: Symptoms, Types, Causes and Treatment

Congenital adrenal hyperplasia (CAH) is a group of inherited disorders that disrupt the body’s ability to produce certain hormones, mainly cortisol and, in some cases, aldosterone. This imbalance can cause a range of symptoms, from mild to life-threatening, and has diverse impacts on growth, development, and overall health. Understanding CAH requires exploring its symptoms, the different types, underlying causes, and modern approaches to treatment. Let’s dive in.

Symptoms of Congenital Adrenal Hyperplasia

CAH can affect people from birth or develop later in childhood or adolescence. The symptoms depend on the severity of the enzyme deficiency and the specific type of CAH, but all forms stem from disruptions in adrenal hormone production. Early recognition and understanding of these symptoms are crucial for timely intervention and optimal health outcomes.

Main Symptom	Age of Onset	Typical Impact	Source(s)
Virilization	Birth	Ambiguous genitalia (females)	1 5 8
Salt Wasting	Infancy	Dehydration, shock	5 8
Precocious Puberty	Childhood	Early puberty, rapid growth	5 13
Hirsutism/Acne	Adolescence/Adult	Excess hair, skin changes	5 1
Infertility	Adulthood	Reproductive challenges	1 15
Hypertension	Childhood	High blood pressure	2 4

Table 1: Key Symptoms

Overview of Symptom Patterns

CAH’s most visible hallmark is virilization — the development of male physical characteristics in genetic females. This is most dramatic in classic CAH detected at birth, but milder forms may not appear until later. Salt-wasting crises, which can be fatal if untreated, are seen in more severe forms. In childhood, children may grow rapidly and enter puberty earlier than their peers. Adolescents and adults often struggle with excess androgen symptoms like hirsutism, acne, and, in women, menstrual irregularities or infertility.

Symptom Details

Virilization and Ambiguous Genitalia

• Classic CAH, especially due to 21-hydroxylase deficiency, often causes female infants to be born with ambiguous genitalia due to excess androgens in utero. Males typically look normal at birth but may develop signs of early puberty later 1 5 8.
• 11β-hydroxylase deficiency can cause profound virilization in female newborns 2.

Salt-Wasting Crisis

• Infants lacking both cortisol and aldosterone can’t retain sodium, leading to dehydration, vomiting, and potentially fatal shock (Addisonian crisis) if not treated quickly 5 8.
• Salt-wasting forms are most often linked with classic 21-hydroxylase and some 3β-hydroxysteroid dehydrogenase deficiencies 5 6.

Androgen Excess in Later Childhood and Adolescence

• Untreated or poorly controlled CAH results in rapid growth and early puberty (precocious puberty), but final adult height may be compromised due to early closure of growth plates 5 13.
• Girls may develop hirsutism, acne, and irregular periods; boys may show signs of early puberty, such as deepened voice and pubic hair 1 5.

Other Chronic Manifestations

• Infertility can occur, especially in women with poorly controlled CAH or those with long-term androgen excess 1 15.
• Hypertension is particularly notable in 11β-hydroxylase deficiency and, less commonly, in other forms 2 4.

Types of Congenital Adrenal Hyperplasia

CAH is not a single disease, but a spectrum of disorders, each defined by which enzyme in the adrenal steroid pathway is deficient. The severity and symptoms depend on the specific enzyme affected and the degree of its impairment.

Type (Deficiency)	Frequency	Main Features	Source(s)
21-Hydroxylase Deficiency	>90% cases	Virilization, salt wasting	1 4 5 7 8
11β-Hydroxylase Deficiency	5–8% cases	Virilization, hypertension	2 4
3β-Hydroxysteroid Dehydrogenase Deficiency	<0.5% cases	Salt wasting, ambiguous genitalia	4 6 9
17α-Hydroxylase Deficiency	Rare	Hypertension, sexual infantilism	4 9
P450 Oxidoreductase Deficiency	Very rare	Skeletal anomalies, ambiguous genitalia	9

Table 2: Major CAH Types

The Major Forms Explained

21-Hydroxylase Deficiency (CYP21A2)

• Most common (90–95%) form of CAH 1 4 5 7 8
• Ranges from severe "classic" (with or without salt wasting) to "non-classic" (mild), which may only cause symptoms in adolescence or adulthood 1 5
• Classic forms present early with virilization and, in some cases, salt-wasting crisis

11β-Hydroxylase Deficiency (CYP11B1)

• Accounts for 5–8% of CAH cases 2 4
• Characterized by androgen excess (virilization) and hypertension due to accumulation of deoxycorticosterone, a mineralocorticoid 2
• More common in certain populations with high rates of consanguinity 2

3β-Hydroxysteroid Dehydrogenase Deficiency (HSD3B2)

• Very rare, less than 0.5% of CAH cases 4 6 9
• Affects both adrenal and gonadal steroid production, leading to ambiguous genitalia in both sexes and salt-wasting in severe forms 6 9
• Non-classic forms are controversial and not well established 6

17α-Hydroxylase and P450 Oxidoreductase Deficiencies

• Extremely rare 4 9
• 17α-hydroxylase deficiency leads to sexual infantilism and hypertension due to lack of sex steroids and excess mineralocorticoids 4 9
• P450 oxidoreductase deficiency presents with unique skeletal malformations and severe genital ambiguity in both sexes 9

Causes of Congenital Adrenal Hyperplasia

CAH is rooted in genetics, specifically mutations in genes encoding enzymes responsible for steroid hormone biosynthesis. The adrenal cortex relies on a finely tuned pathway to produce cortisol, aldosterone, and sex steroids. Disruption at any step can tilt the hormonal balance, leading to the symptoms seen in CAH.

Cause	Main Gene(s) Involved	Effect on Hormones	Source(s)
21-hydroxylase deficiency	CYP21A2	↓Cortisol, ↓Aldosterone, ↑Androgens	8 9 11
11β-hydroxylase deficiency	CYP11B1	↓Cortisol, ↑Androgens, ↑Mineralocorticoids	2 9
3β-hydroxysteroid dehydrogenase deficiency	HSD3B2	↓Cortisol, ↓Aldosterone, ↓Sex steroids	6 9
17α-hydroxylase deficiency	CYP17A1	↓Cortisol, ↓Sex steroids, ↑Mineralocorticoids	9
P450 oxidoreductase deficiency	POR	Combined deficits, unique features	9

Table 3: Genetic Causes of CAH

How Genetic Mutations Cause CAH

Inherited Enzyme Deficiencies

• CAH is inherited in an autosomal recessive manner: two faulty gene copies (one from each parent) are required for the condition to manifest 9 11.
• The specific gene mutated determines which enzyme is deficient and, therefore, which hormones are under- or overproduced 8 9.

Pathway Disruption and Hormone Imbalance

• 21-hydroxylase deficiency (CYP21A2 gene): Most common. Leads to decreased cortisol and aldosterone, triggering overproduction of ACTH and, consequently, excess androgen synthesis 8 9 11.
  • Most mutations are gene conversions or deletions due to the presence of a closely related pseudogene (CYP21P) 8.
• 11β-hydroxylase deficiency (CYP11B1 gene): Results in reduced cortisol but excess 11-deoxycorticosterone, causing hypertension and androgen excess 2 9.
• Other rare enzyme defects: Affect both adrenal and gonadal steroid synthesis, causing a broader range of hormonal deficiencies and clinical effects 6 9.

Genotype-Phenotype Correlation

• The severity of symptoms correlates with how much enzyme activity is lost. Complete loss = classic, severe disease; partial loss = milder, non-classic forms 8 11.
• Genetic testing (genotyping) helps confirm diagnosis, predict severity, and guide genetic counseling 11.

Treatment of Congenital Adrenal Hyperplasia

Managing CAH is a lifelong process that aims to replace deficient hormones, control excess androgens, and prevent crises and long-term complications. Treatment is tailored to the type and severity of CAH, patient age, and specific health needs.

Treatment	Purpose	Special Considerations	Source(s)
Glucocorticoids	Replace cortisol, suppress androgens	Dose must be individualized	1 5 8 15
Mineralocorticoids	Replace aldosterone (salt-wasting forms)	Salt supplementation may be needed	5 6 8
Stress dosing	Prevent adrenal crisis during illness	Higher doses during stress	5 13 15
Surgical intervention	Correct genital ambiguity (females)	Multidisciplinary approach	1 5
Fertility/Adolescent care	Preserve reproductive health	Menstrual regulation, tumor monitoring	1 5
Experimental therapies	Improve hormone replacement and control	Gene/cell therapy, adjunct agents	15

Table 4: Major Treatment Approaches

Standard Medical Management

Glucocorticoid Replacement

• Cornerstone of therapy: Hydrocortisone in children; longer-acting steroids in adults 1 5 8 15
• Suppresses excess ACTH, reducing androgen overproduction
• Dosing is carefully balanced: too little = poor control; too much = iatrogenic Cushing’s syndrome (weight gain, growth suppression) 1 15

Mineralocorticoid Replacement and Salt Supplementation

• For patients with salt-wasting forms, fludrocortisone replaces aldosterone and salt tablets may be needed, especially in infants 5 6 8
• Regular monitoring of blood pressure and electrolytes is essential

Stress Dosing and Emergency Care

• During illness, surgery, or trauma, patients require increased glucocorticoid doses to prevent life-threatening adrenal crisis 5 13 15
• Families and caregivers are educated on recognizing adrenal crisis and administering emergency injections

Surgical and Supportive Interventions

Genital Surgery

• For females with ambiguous genitalia, surgical correction may be considered, ideally with input from multidisciplinary teams and with regard for future sexual and reproductive health 1 5

Reproductive and Long-term Health

• Teens and adults may need care for menstrual irregularities, fertility challenges, and to monitor for adrenal rest tumors (especially in males) 1 5 15
• Bone health and metabolic monitoring are also important, as both disease and treatment can affect these systems 1 15

Advanced and Experimental Therapies

Prenatal Treatment

• Some centers have offered prenatal dexamethasone to pregnant women at risk of having affected infants to minimize virilization in females 12 14
• This approach is experimental, has safety concerns, and is only considered in specialized settings with informed consent 14

New Horizons

• Novel glucocorticoid formulations that mimic natural circadian rhythms, adjunct agents to suppress androgen excess, and even gene or cell-based therapies are under study, aiming for better disease control with fewer side effects 15
• Biomarkers such as 11-oxygenated androgens are emerging for better disease monitoring 15

Conclusion

Congenital adrenal hyperplasia is a complex, lifelong condition that affects people in many ways, from birth through adulthood. Advances in understanding, diagnosis, and treatment have greatly improved outcomes, but challenges remain.

Key takeaways:

• CAH includes several types, most commonly due to 21-hydroxylase deficiency, each with distinct symptoms and risks 1 4 5 8.
• Symptoms range from ambiguous genitalia and salt-wasting crises in newborns to androgen excess, infertility, and metabolic complications later in life 1 5 13.
• CAH is caused by inherited defects in genes coding for adrenal steroidogenic enzymes, with severity determined by the degree of enzyme loss 8 9 11.
• Treatment is lifelong and centers on hormone replacement, crisis prevention, and addressing long-term health risks, with new therapies on the horizon 1 5 8 15.
• Early detection and multidisciplinary care are essential to optimize growth, development, and quality of life for those with CAH.

By understanding the nuances of CAH, affected individuals, families, and healthcare teams can work together to navigate its challenges and make the most of emerging therapies and ongoing research.