Overview
Definition:
Congenital Adrenal Hyperplasia (CAH) is a group of inherited genetic disorders that affect the adrenal glands
These glands produce hormones, including cortisol and androgens
In CAH, enzyme deficiencies lead to reduced production of cortisol and aldosterone, and an overproduction of androgens, causing various clinical manifestations from birth.
Epidemiology:
The overall incidence of classic CAH is approximately 1 in 10,000 to 20,000 live births, with variations depending on the specific enzyme deficiency and population
Non-classic CAH is more common, with an estimated prevalence of 1 in 1,000 to 2,000
Newborn screening programs aim to identify affected infants early.
Clinical Significance:
CAH is a critical diagnosis due to the risk of adrenal crisis, a life-threatening condition characterized by hypotension, hypoglycemia, and electrolyte imbalances
Early identification and management are vital to prevent mortality and long-term morbidities, including precocious puberty, infertility, and ambiguous genitalia.
Clinical Presentation
Infants With Positive Newborn Screen:
A positive newborn screen for CAH typically indicates elevated levels of 17-hydroxyprogesterone (17-OHP)
Depending on the specific CAH type and severity, infants may present with ambiguous genitalia in females (virilization), salt-wasting crisis (vomiting, poor feeding, dehydration, shock), or simple virilizing forms with rapid growth and early pubarche.
Newborn Screening Markers:
Commonly screened for are 17-hydroxyprogesterone (17-OHP)
Elevated 17-OHP is the primary indicator for CAH screening, particularly for 21-hydroxylase deficiency, the most common form
Other markers may be included in broader panels or for specific enzyme deficiencies.
Signs Of Adrenal Crisis:
Lethargy
Poor feeding
Vomiting
Dehydration
Hypotension
Hypoglycemia
Hyponatremia
Hyperkalemia
Shock
These signs usually appear within the first few weeks of life in salt-wasting forms.
Diagnostic Approach
History Taking:
Detailed family history of CAH, consanguinity, or unexplained infant deaths
Maternal history of virilization during pregnancy (if applicable)
Detailed birth history and immediate postnatal period
Any signs of dehydration, poor feeding, or lethargy in the infant
For older infants/children, history of precocious puberty or growth acceleration.
Physical Examination:
Assessment of external genitalia for virilization (ambiguous genitalia in females, phallic enlargement in males)
Evaluation for signs of dehydration, shock, and electrolyte imbalance
Measurement of weight, length, and head circumference for growth assessment
Examination for salt-wasting symptoms like poor skin turgor and lethargy
Examination for signs of adrenal insufficiency.
Confirmatory Investigations:
Serum 17-hydroxyprogesterone (17-OHP) levels: The key confirmatory test
Levels vary with gestational age and time of collection
A single elevated value may require repeat testing
In salt-wasting CAH, concurrently measure electrolytes (Na, K), renin activity, and aldosterone
For suspected 11-beta-hydroxylase deficiency, check 11-deoxycorticosterone and androstenedione
For 3-beta-hydroxysteroid dehydrogenase deficiency, check DHEA and pregnenolone
Genetic testing: Confirms the specific enzyme deficiency and mutation
Hormonal profile: Cortisol, ACTH, and other adrenal steroids as indicated.
Differential Diagnosis:
Other causes of ambiguous genitalia in newborns include Swyer syndrome, complete androgen insensitivity syndrome, ovotesticular DSD, and other rare enzyme deficiencies
Other causes of adrenal insufficiency in neonates include sepsis, primary adrenal hypoplasia, and congenital hypopituitarism
Other causes of electrolyte imbalance include severe gastroenteritis, renal disorders.
Management
Immediate Management Of Positive Screen:
Prompt communication with parents about the need for urgent follow-up
Arrange for immediate blood collection for confirmatory hormonal assays
If clinical suspicion is high or infant is symptomatic, initiate empiric treatment with hydrocortisone to prevent adrenal crisis while awaiting results
Refer to pediatric endocrinology urgently.
Medical Management:
Glucocorticoid replacement therapy: Hydrocortisone is the preferred drug in infants and children for its short half-life and mineralocorticoid activity
Dosage typically starts at 10-20 mg/m²/day divided into 2-3 doses
Fludrocortisone: For salt-wasting forms, to replace aldosterone deficiency
Dosage typically 0.05-0.1 mg/day, adjusted based on renin activity, blood pressure, and electrolytes
Sodium supplementation: May be needed in salt-wasting forms, particularly during illness.
Surgical Management:
Female infants with virilized genitalia may require genitoplasty
The timing and extent of surgical intervention are controversial and depend on the degree of virilization and the goals of care, often managed by a multidisciplinary team including pediatric endocrinologists, surgeons, and geneticists
Management decisions are individualized.
Supportive Care And Monitoring:
Education for parents on CAH, medication administration, stress dosing, and recognizing signs of adrenal crisis
Regular monitoring of growth, weight, bone age, hormone levels (17-OHP, androstenedione, renin activity), electrolytes, and blood pressure
Close follow-up with pediatric endocrinology is essential.
Complications
Early Complications:
Adrenal crisis: Life-threatening
Can present with hypoglycemia, hyponatremia, hyperkalemia, dehydration, shock, and death
Ambiguous genitalia: Psychological and social impact
Inadequate glucocorticoid replacement leading to growth acceleration and bone age advancement.
Late Complications:
Short stature: Due to early bone age advancement or inadequate glucocorticoid therapy
Infertility: In both males and females
Ovarian hyperstimulation, polycystic ovarian syndrome (PCOS)-like features in females
Testicular adrenal rests in males
Osteoporosis
Obesity
Hypertension
Psychosexual issues related to ambiguous genitalia and androgen excess.
Prevention Strategies:
Strict adherence to glucocorticoid and mineralocorticoid therapy
Education on stress dosing during illness or injury
Regular monitoring of hormonal levels and growth parameters
Early and appropriate surgical management for virilized genitalia
Genetic counseling for families.
Prognosis
Factors Affecting Prognosis:
Severity of enzyme deficiency
Age at diagnosis and initiation of treatment
Adherence to therapy
Development of adrenal crisis
Management of ambiguous genitalia
Individual genetic makeup.
Outcomes:
With timely diagnosis and appropriate management, most individuals with CAH can achieve normal growth and development, puberty, and reproductive potential
However, lifelong monitoring and management are required
Adrenal crisis remains a significant risk if treatment is interrupted or inadequate.
Follow Up:
Lifelong follow-up with a pediatric endocrinologist is mandatory
This includes regular assessment of growth, pubertal development, hormonal status, bone age, and adherence to medication
Transition to adult endocrinology care is crucial
Genetic counseling and carrier screening for family members are recommended.
Key Points
Exam Focus:
The primary enzyme deficiency in classic CAH is 21-hydroxylase deficiency
Salt-wasting CAH presents with adrenal insufficiency and virilization (females)
Newborn screening for CAH relies on elevated 17-OHP
Hydrocortisone is the drug of choice for glucocorticoid replacement in children
Stress dosing of glucocorticoids is critical to prevent adrenal crisis.
Clinical Pearls:
Always consider CAH in a neonate with ambiguous genitalia or unexplained dehydration and shock
Remember to check electrolytes and renin activity in suspected salt-wasting CAH
Empiric hydrocortisone treatment may be life-saving while awaiting confirmatory tests if suspicion is high.
Common Mistakes:
Delaying confirmatory testing and treatment in a symptomatic infant with a positive screen
Inadequate stress dosing of steroids during illness
Misinterpreting elevated 17-OHP in premature infants or stressed newborns without considering the clinical context
Underestimating the psychosocial impact of ambiguous genitalia.