Congenital Adrenal Hyperplasia
Introduction to Congenital Adrenal Hyperplasia (CAH)
Congenital Adrenal Hyperplasia (CAH) is a group of inherited autosomal recessive disorders characterized by impaired cortisol synthesis in the adrenal cortex. This deficiency leads to excessive production of adrenocorticotropic hormone (ACTH), resulting in adrenal hyperplasia and accumulation of cortisol precursors. The most common form of CAH, accounting for about 95% of cases, is due to 21-hydroxylase deficiency.
CAH can be classified into two main types:
- Classic CAH: More severe form, presenting in infancy or early childhood
- Non-classic CAH: Milder form, often presenting later in childhood or adulthood
The incidence of classic CAH is approximately 1 in 10,000 to 1 in 15,000 live births, while non-classic CAH is more common, affecting about 1 in 1,000 individuals.
Pathophysiology of CAH
The pathophysiology of CAH primarily involves defects in enzymes required for cortisol synthesis. The most common enzymatic defect is in 21-hydroxylase, encoded by the CYP21A2 gene. Other less common enzyme deficiencies include:
- 11β-hydroxylase deficiency
- 3β-hydroxysteroid dehydrogenase deficiency
- 17α-hydroxylase deficiency
- P450 oxidoreductase deficiency
In 21-hydroxylase deficiency:
- Cortisol production is impaired, leading to increased ACTH secretion from the pituitary gland.
- Excessive ACTH stimulates adrenal hyperplasia and increased production of cortisol precursors.
- These precursors are shunted into the androgen synthesis pathway, resulting in excess androgen production.
- In severe cases, aldosterone production may also be affected, leading to salt-wasting.
The severity of the enzyme deficiency determines the clinical presentation and classification of CAH.
Clinical Presentation of CAH
The clinical presentation of CAH varies depending on the type and severity of the enzyme deficiency:
Classic CAH
Salt-wasting form (75% of classic CAH cases):
- Severe cortisol and aldosterone deficiency
- Presents in neonatal period with:
- Failure to thrive
- Vomiting
- Dehydration
- Hyponatremia
- Hyperkalemia
- Metabolic acidosis
- Virilization of external genitalia in females (ambiguous genitalia)
- Normal male genitalia at birth, but early signs of puberty
Simple virilizing form (25% of classic CAH cases):
- Adequate aldosterone production
- Presents with:
- Virilization in females
- Early puberty in males
- Accelerated growth and bone maturation
Non-classic CAH
- Milder enzyme deficiency
- Presents later in childhood or adulthood with:
- Premature pubarche
- Hirsutism
- Acne
- Menstrual irregularities
- Infertility
Diagnosis of CAH
The diagnosis of CAH involves a combination of clinical presentation, biochemical tests, and genetic analysis:
Newborn Screening
- Measurement of 17-hydroxyprogesterone (17-OHP) levels in dried blood spots
- Positive screens require confirmatory testing
Biochemical Tests
- Elevated serum 17-OHP levels (primary diagnostic test)
- ACTH stimulation test to assess adrenal function
- Elevated androgens (testosterone, androstenedione)
- Plasma renin activity and aldosterone levels (for salt-wasting assessment)
Genetic Testing
- CYP21A2 gene sequencing for confirmation and genetic counseling
- Identification of specific mutations can help predict disease severity
Imaging Studies
- Pelvic ultrasound or MRI to assess internal genitalia in females
- Bone age assessment (typically advanced in untreated CAH)
Prenatal diagnosis is possible through chorionic villus sampling or amniocentesis in families with a known history of CAH.
Treatment of CAH
The primary goals of CAH treatment are to replace deficient hormones, suppress excess androgen production, and promote normal growth and development:
Hormone Replacement Therapy
- Glucocorticoids:
- Hydrocortisone is preferred in children
- Prednisone or dexamethasone may be used in adults
- Dose adjusted based on clinical response and hormone levels
- Mineralocorticoids:
- Fludrocortisone for salt-wasting CAH
- Sodium chloride supplementation in infants
Surgical Management
- Feminizing genitoplasty for severely virilized females
- Timing and extent of surgery are controversial and require careful consideration
Monitoring and Follow-up
- Regular assessment of growth, pubertal development, and bone age
- Periodic measurement of 17-OHP, androgens, and electrolytes
- Adjustment of medication doses to optimize control
Stress Dose Management
- Increased glucocorticoid doses during illness, surgery, or significant stress
- Patient and family education on stress dosing is crucial
Adjunctive Therapies
- GnRH analogs to delay puberty in cases of advanced bone age
- Growth hormone therapy in selected cases of significant height deficit
Treatment is lifelong and requires a multidisciplinary approach involving endocrinologists, urologists, gynecologists, and mental health professionals.
Complications of CAH
Patients with CAH may experience various complications, both from the disease itself and from long-term treatment:
Disease-related Complications
- Adrenal crisis: Life-threatening complication of cortisol deficiency
- Short stature due to advanced bone age
- Infertility or reduced fertility
- Polycystic ovarian syndrome (PCOS)-like symptoms in females
- Testicular adrenal rest tumors (TARTs) in males
- Psychological and social issues related to genital ambiguity or gender identity
Treatment-related Complications
- Iatrogenic Cushing's syndrome from excessive glucocorticoid treatment
- Growth suppression
- Osteoporosis
- Obesity and metabolic syndrome
- Hypertension
Long-term Health Concerns
- Increased risk of cardiovascular disease
- Impaired quality of life
- Potential for adrenal tumors
Regular monitoring and careful balance of treatment are essential to minimize these complications and optimize long-term outcomes for patients with CAH.
21-Hydroxylase Deficiency
21-Hydroxylase deficiency is the most common form of CAH, accounting for about 95% of all cases.
Pathophysiology
- Caused by mutations in the CYP21A2 gene
- Impaired conversion of 17-hydroxyprogesterone to 11-deoxycortisol
- Results in cortisol deficiency and androgen excess
- Can also affect aldosterone production in severe cases
Clinical Presentation
Classic Form
- Salt-wasting (75% of classic cases):
- Severe cortisol and aldosterone deficiency
- Neonatal crisis with hyponatremia, hyperkalemia, and shock
- Virilization of female genitalia
- Simple virilizing (25% of classic cases):
- Cortisol deficiency with sufficient aldosterone
- Prenatal virilization in females
- Rapid growth and precocious puberty in both sexes
Non-classic Form
- Milder enzyme deficiency
- Late-onset symptoms: hirsutism, acne, menstrual irregularities
- May be asymptomatic
Diagnosis
- Elevated 17-hydroxyprogesterone levels
- ACTH stimulation test for borderline cases
- Genetic testing for CYP21A2 mutations
Treatment
- Glucocorticoid replacement (e.g., hydrocortisone)
- Mineralocorticoid replacement (fludrocortisone) for salt-wasting form
- Sodium chloride supplementation in infants with salt-wasting CAH
- Surgical correction of virilized genitalia in severely affected females
Long-term Management
- Regular monitoring of growth, puberty, and bone age
- Adjustment of medication doses based on clinical and biochemical parameters
- Stress dose management for illness or surgery
- Psychological support and genetic counseling
11β-Hydroxylase Deficiency
11β-Hydroxylase deficiency is the second most common form of CAH, accounting for about 5-8% of cases.
Pathophysiology
- Caused by mutations in the CYP11B1 gene
- Impaired conversion of 11-deoxycortisol to cortisol
- Results in cortisol deficiency and androgen excess
- Accumulation of deoxycorticosterone (DOC) leading to hypertension
Clinical Presentation
- Virilization of external genitalia in females
- Precocious puberty in males
- Hypertension (a distinguishing feature from 21-hydroxylase deficiency)
- Accelerated growth and advanced bone age
- Potential salt-wasting crisis in severe cases (rare)
Diagnosis
- Elevated 11-deoxycortisol and 11-deoxycorticosterone levels
- Elevated androgens (testosterone, androstenedione)
- Suppressed plasma renin activity
- Genetic testing for CYP11B1 mutations
Treatment
- Glucocorticoid replacement to suppress ACTH and androgen production
- Antihypertensive medications if needed
- Surgical correction of virilized genitalia in severely affected females
- Careful monitoring of growth and development
Long-term Management
- Regular monitoring of blood pressure
- Adjustment of glucocorticoid doses to minimize side effects
- Monitoring for potential complications (e.g., testicular adrenal rest tumors in males)
- Psychological support and genetic counseling
3β-Hydroxysteroid Dehydrogenase Deficiency
3β-Hydroxysteroid Dehydrogenase (3β-HSD) deficiency is a rare form of CAH, affecting both adrenal and gonadal steroidogenesis.
Pathophysiology
- Caused by mutations in the HSD3B2 gene
- Impaired conversion of Δ5 to Δ4 steroids
- Affects cortisol, aldosterone, and sex steroid production
Clinical Presentation
Severe (Classic) Form
- Salt-wasting crisis in neonates
- Ambiguous genitalia in both males and females
- Undervirilization of male genitalia
- Mild clitoromegaly in females
Moderate and Mild Forms
- Variable degrees of androgen insufficiency
- Premature pubarche
- Menstrual irregularities in females
- Gynecomastia in males
Diagnosis
- Elevated Δ5 steroids (pregnenolone, 17-hydroxypregnenolone, DHEA)
- Increased ratio of Δ5 to Δ4 steroids
- ACTH stimulation test
- Genetic testing for HSD3B2 mutations
Treatment
- Glucocorticoid replacement
- Mineralocorticoid replacement in salt-wasting cases
- Sex hormone replacement at puberty
- Surgical management of genital ambiguity if needed
Long-term Management
- Regular monitoring of adrenal and gonadal function
- Assessment of growth and pubertal development
- Fertility considerations and potential assisted reproductive technologies
- Psychological support and genetic counseling
17α-Hydroxylase Deficiency
17α-Hydroxylase deficiency is a rare form of CAH that affects both adrenal and gonadal steroidogenesis.
Pathophysiology
- Caused by mutations in the CYP17A1 gene
- Impaired 17α-hydroxylation and 17,20-lyase activities
- Decreased production of cortisol and sex steroids
- Increased production of mineralocorticoid precursors
Clinical Presentation
- 46,XY individuals:
- Female external genitalia (complete sex reversal)
- Absence of secondary sexual characteristics at puberty
- 46,XX individuals:
- Normal female external genitalia
- Primary amenorrhea and lack of pubertal development
- Hypertension and hypokalemia (due to mineralocorticoid excess)
- Tall stature (due to delayed epiphyseal closure)
Diagnosis
- Elevated progesterone and mineralocorticoid precursors
- Low levels of cortisol, androgens, and estrogens
- Suppressed plasma renin activity
- Genetic testing for CYP17A1 mutations
Treatment
- Glucocorticoid replacement (to suppress ACTH and mineralocorticoid precursors)
- Sex hormone replacement (estrogen in females, testosterone in males)
- Management of hypertension if present
- Gonadectomy consideration in 46,XY individuals raised as females
Long-term Management
- Regular monitoring of blood pressure and electrolytes
- Bone density assessment and management
- Fertility considerations and counseling
- Psychological support and gender identity considerations
P450 Oxidoreductase Deficiency
P450 Oxidoreductase (POR) Deficiency is a rare and complex form of CAH that affects multiple steroidogenic enzymes.
Pathophysiology
- Caused by mutations in the POR gene
- POR is an electron donor for multiple cytochrome P450 enzymes
- Affects activities of 21-hydroxylase, 17α-hydroxylase, and aromatase
- Results in combined enzyme deficiencies
Clinical Presentation
- Variable phenotype due to multiple enzyme impairments
- Skeletal malformations (Antley-Bixler syndrome features in severe cases)
- Genital ambiguity in both sexes:
- Undervirilization in males
- Virilization in females (but can regress postnatally)
- Potential for adrenal insufficiency
- Maternal virilization during pregnancy
Diagnosis
- Complex steroid profile with elevated 17-hydroxyprogesterone and progesterone
- Low sex steroids
- Impaired response to ACTH stimulation
- Genetic testing for POR mutations
Treatment
- Glucocorticoid replacement if adrenal insufficiency is present
- Sex hormone replacement at puberty
- Surgical management of genital ambiguity and skeletal abnormalities
- Multidisciplinary approach involving endocrinology, genetics, and orthopedics
Long-term Management
- Regular monitoring of adrenal and gonadal function
- Assessment of growth and skeletal development
- Fertility considerations and potential assisted reproductive technologies
- Psychological support and genetic counseling
StAR Protein Deficiency (Lipoid CAH)
StAR (Steroidogenic Acute Regulatory) protein deficiency, also known as lipoid CAH, is the most severe form of CAH, affecting the initial step of steroidogenesis.
Pathophysiology
- Caused by mutations in the STAR gene
- Impaired transport of cholesterol into mitochondria
- Affects all steroid hormone production
- Accumulation of lipid droplets in steroidogenic tissues
Clinical Presentation
- Severe salt-wasting crisis in early infancy
- Complete lack of steroidogenesis
- 46,XY individuals:
- Female external genitalia (complete sex reversal)
- Müllerian structures absent due to AMH production by Sertoli cells
- 46,XX individuals:
- Normal female external genitalia
- Lack of pubertal development
- Hyperpigmentation due to elevated ACTH
Diagnosis
- Extremely low levels of all steroid hormones
- Elevated ACTH and plasma renin activity
- Severe electrolyte imbalances (hyponatremia, hyperkalemia)
- Adrenal imaging may show enlarged adrenal glands with lipid accumulation
- Genetic testing for STAR mutations
Treatment
- Immediate and lifelong glucocorticoid replacement
- Mineralocorticoid replacement (fludrocortisone)
- Salt supplementation, especially in infancy
- Sex hormone replacement at the time of puberty:
- Estrogen for 46,XX individuals and 46,XY individuals raised as females
- Testosterone for 46,XY individuals raised as males (rare)
- Stress dose management for illness or surgery
Long-term Management
- Regular monitoring of electrolytes and hormone replacement adequacy
- Careful attention to growth and development
- Bone density assessment and management
- Fertility considerations:
- 46,XX individuals may have preserved ovarian function but usually require assisted reproductive technologies
- 46,XY individuals are typically infertile
- Psychological support and gender identity counseling
- Genetic counseling for family members
Prognosis
- With early diagnosis and proper treatment, patients can have a good quality of life
- Lifetime risk of adrenal crisis necessitates vigilant management
- Long-term outcomes depend on adherence to treatment and management of potential complications
- Fertility challenges may have significant psychological impact
Research Directions
- Gene therapy approaches to restore StAR function
- Development of novel steroid replacement strategies
- Improvement of fertility preservation and assisted reproductive techniques
- Long-term outcome studies to optimize management protocols
