Case Presentation

A 2-week-old female newborn is brought to the emergency department with poor feeding, vomiting, and lethargy. The parents report that the baby has been increasingly difficult to wake for feedings over the past 24 hours.

Physical Examination

• Weight: 2.8 kg (birth weight was 3.2 kg)
• Temperature: 38.2°C
• Heart rate: 180 bpm
• Respiratory rate: 60 breaths/min
• Blood pressure: 65/40 mmHg
• Skin: Hyperpigmentation noted, especially in the genital area and nipples
• Genitalia: Ambiguous with clitoromegaly

Laboratory Findings

• Serum sodium: 124 mEq/L (low)
• Serum potassium: 6.8 mEq/L (high)
• Blood glucose: 48 mg/dL (low)
• 17-hydroxyprogesterone: 22,000 ng/dL (markedly elevated)

Diagnosis and Management

Based on the clinical presentation, physical examination, and laboratory findings, a diagnosis of salt-wasting congenital adrenal hyperplasia is made. The patient is immediately started on intravenous hydrocortisone and fludrocortisone, along with fluid resuscitation and glucose administration. Genetic testing confirms a mutation in the CYP21A2 gene, consistent with 21-hydroxylase deficiency.

Varieties of Clinical Presentations

1. Classic Salt-Wasting CAH

   • Severe aldosterone deficiency
   • Presents in early infancy with salt-wasting crisis
   • Hyponatremia, hyperkalemia, metabolic acidosis
   • Dehydration, shock, and potentially death if untreated
   • Ambiguous genitalia in females, normal-appearing male genitalia with hyperpigmentation

2. Classic Simple Virilizing CAH

   • Sufficient aldosterone production to prevent salt-wasting
   • Prenatal virilization of female genitalia
   • Rapid postnatal growth and pseudoprecocious puberty in both sexes
   • Advanced bone age

3. Non-classic CAH (Late-onset CAH)

   • Milder enzyme deficiency
   • Symptoms may appear in late childhood, adolescence, or adulthood
   • Premature pubarche, hirsutism, acne, menstrual irregularities
   • Infertility or subfertility

4. CAH-X Syndrome

   • CAH with a contiguous gene deletion affecting CYP21A2 and TNXB genes
   • Features of CAH plus connective tissue abnormalities (joint hypermobility, skin hyperextensibility)

5. Prenatal-onset Growth Restriction

   • Rare presentation in severe cases
   • Intrauterine growth restriction due to cortisol deficiency
   • Can be associated with salt-wasting crisis after birth

6. Asymptomatic CAH

   • Detected through newborn screening
   • No clinical signs at birth
   • May develop symptoms later if untreated

7. CAH with Atypical Genital Development in Males

   • Varying degrees of undervirilization in genetically male infants
   • Can include cryptorchidism, hypospadias, or micropenis

1. Q: What is the most common enzyme deficiency in CAH?

   A: The most common enzyme deficiency in CAH is 21-hydroxylase deficiency, accounting for about 90-95% of all cases. It is caused by mutations in the CYP21A2 gene.

2. Q: How does 21-hydroxylase deficiency affect steroid hormone production?

   A: 21-hydroxylase deficiency leads to decreased production of cortisol and aldosterone. This results in increased ACTH production, which causes accumulation of steroid precursors that are shunted into the androgen pathway, leading to excess androgen production.

3. Q: What are the typical electrolyte abnormalities seen in salt-wasting CAH?

   A: Salt-wasting CAH typically presents with hyponatremia (low sodium), hyperkalemia (high potassium), and metabolic acidosis due to aldosterone deficiency.

4. Q: How does CAH affect genital development in female fetuses?

   A: Excess androgens produced in CAH can cause virilization of female external genitalia, resulting in various degrees of clitoromegaly, labial fusion, and formation of a urogenital sinus. Internal female reproductive organs (uterus, fallopian tubes, ovaries) develop normally.

5. Q: What is the gold standard test for diagnosing 21-hydroxylase deficiency?

   A: The gold standard test is measurement of 17-hydroxyprogesterone (17-OHP) levels, either baseline or after ACTH stimulation. Genetic testing for mutations in the CYP21A2 gene can confirm the diagnosis.

6. Q: What is the rationale behind newborn screening for CAH?

   A: Newborn screening for CAH aims to identify infants with the salt-wasting form before they develop potentially life-threatening adrenal crises. It also helps in early diagnosis and treatment of simple virilizing forms.

7. Q: How is a salt-wasting crisis managed in an infant with CAH?

   A: Management includes immediate administration of intravenous fluids, glucose, and sodium chloride to correct dehydration and electrolyte imbalances. Intravenous hydrocortisone is given to replace cortisol. Fludrocortisone is added for mineralocorticoid replacement once the patient is stabilized.

8. Q: What is the difference between classic and non-classic CAH?

   A: Classic CAH is more severe, presenting in infancy or early childhood with salt-wasting and/or virilization. Non-classic CAH is milder, often presenting later in childhood or adulthood with signs of androgen excess but without salt-wasting.

9. Q: How does CAH affect growth and final height?

   A: Untreated or poorly controlled CAH can lead to accelerated growth and bone maturation in childhood due to excess androgens, potentially resulting in early epiphyseal fusion and reduced final adult height.

10. Q: What are the long-term complications of CAH?

    A: Long-term complications can include infertility, osteoporosis, obesity, metabolic syndrome, testicular adrenal rest tumors in males, and psychological/psychosexual issues, especially in females with virilization.

11. Q: How is CAH treated in the long term?

    A: Long-term treatment involves lifelong glucocorticoid replacement (e.g., hydrocortisone) and, in salt-wasting forms, mineralocorticoid replacement (fludrocortisone). Doses are carefully adjusted to control symptoms and normalize hormone levels while minimizing side effects.

12. Q: What is the role of prenatal treatment in CAH?

    A: Prenatal treatment with dexamethasone in pregnancies at risk for CAH aims to reduce virilization of female fetuses. However, it remains controversial due to potential risks and the need to treat unaffected fetuses until genetic diagnosis is possible.

13. Q: How does stress dosing work in patients with CAH?

    A: Patients with CAH need increased glucocorticoid doses during times of physical stress (illness, surgery, injury) to mimic the body's normal stress response. This typically involves doubling or tripling the usual oral dose or using intravenous hydrocortisone in severe cases.

14. Q: What are testicular adrenal rest tumors (TARTs) and how are they managed in CAH?

    A: TARTs are benign tumors in the testes of males with CAH, caused by growth of adrenal tissue. They can lead to infertility if untreated. Management includes optimizing glucocorticoid therapy and, in some cases, surgical intervention.

15. Q: How does CAH affect fertility in females?

    A: Fertility can be reduced in females with CAH due to various factors including anovulation, polycystic ovarian syndrome-like features, vaginal stenosis, and psychosexual issues. Proper hormonal control and, in some cases, surgical correction can improve fertility outcomes.

16. Q: What is the inheritance pattern of CAH?

    A: CAH is inherited in an autosomal recessive pattern. Both parents must be carriers of a mutated gene for a child to be affected. There is a 25% chance of CAH in each pregnancy when both parents are carriers.

17. Q: How does 11β-hydroxylase deficiency differ from 21-hydroxylase deficiency?

    A: 11β-hydroxylase deficiency, the second most common form of CAH, leads to virilization and hypertension due to accumulation of 11-deoxycorticosterone (a potent mineralocorticoid). Unlike 21-hydroxylase deficiency, it does not cause salt-wasting.

18. Q: What is the significance of 17-hydroxyprogesterone (17-OHP) measurement in CAH?

    A: 17-OHP is the substrate for 21-hydroxylase. In 21-hydroxylase deficiency, 17-OHP levels are markedly elevated, making it a key diagnostic marker. It's used in both newborn screening and for monitoring treatment effectiveness.

19. Q: How does congenital lipoid adrenal hyperplasia differ from other forms of CAH?

    A: Congenital lipoid adrenal hyperplasia is the most severe form of CAH, caused by mutations in the STAR gene. It affects both adrenal and gonadal steroidogenesis, leading to deficiencies in all steroid hormones, including androgens.

20. Q: What are the challenges in managing adolescent patients with CAH?

    A: Challenges include balancing hormone replacement to optimize growth and pubertal development, managing psychosexual issues, ensuring treatment adherence, and transitioning care from pediatric to adult services.

21. Q: How is adrenal crisis prevented in patients with CAH?

    A: Adrenal crisis prevention involves regular medication adherence, stress dosing during illnesses or surgeries, patient and family education about crisis symptoms, and providing emergency hydrocortisone injections for home use.

22. Q: What is the role of adrenal androgens in bone health in CAH patients?

    A: Adrenal androgens contribute to bone mineralization. Overzealous suppression of adrenal androgens with high-dose glucocorticoids can lead to osteoporosis, emphasizing the need for careful dose titration in CAH management.

23. Q: How does CAH affect the hypothalamic-pituitary-gonadal axis?

    A: Excess adrenal androgens can suppress gonadotropin secretion, leading to hypogonadotropic hypogonadism. This can cause delayed puberty in undertreated patients or precocious puberty in poorly controlled cases.

24. Q: What are the principles of glucocorticoid dose adjustment in growing children with CAH?

    A: Glucocorticoid dosing in children aims to suppress excess androgen production while allowing normal growth. Doses are typically adjusted based on clinical features, growth velocity, bone age advancement, and hormone levels (17-OHP, androstenedione).

25. Q: How does CAH-X syndrome differ from classic CAH, and what are its implications?

    A: CAH-X syndrome involves a contiguous gene deletion affecting both CYP21A2 and TNXB genes. In addition to CAH symptoms, patients exhibit connective tissue abnormalities similar to Ehlers-Danlos syndrome, requiring multidisciplinary management.