What is the treatment for Non-Classical Congenital Adrenal Hyperplasia (NCAH)?

Non-Classical Congenital Adrenal Hyperplasia (NCAH)

Overview and Pathophysiology

NCAH is a milder autosomal recessive variant of 21-hydroxylase deficiency characterized by 20-50% residual enzyme activity (versus 0-5% in classic CAH), resulting in impaired cortisol biosynthesis with compensatory adrenal androgen excess but no life-threatening salt-wasting. 1, 2

• The disorder is caused by mutations in the CYP21A2 gene, with approximately two-thirds of patients being compound heterozygotes carrying both severe and mild mutations on different alleles 2
• Prevalence varies dramatically by ethnicity: 3.7% in Ashkenazi Jews, 0.1-0.2% in general Caucasian populations, with an overall worldwide prevalence of 4.2% among women presenting with androgen excess symptoms 1, 3

Clinical Presentation

In Females

• Hirsutism (60-80%), acne (30%), androgenic alopecia (2-8%), and menstrual irregularities (56%) dominate the clinical picture, frequently mimicking PCOS and leading to delayed diagnosis 1
• Rare manifestations include clitoromegaly (6-20%) and premature pubarche 1
• Fertility may be impaired due to androgen excess, dysovulation, and progesterone-mediated implantation issues 1

In Males

• NCAH remains largely asymptomatic in males and is typically diagnosed only through familial genetic screening or incidental fertility evaluations 1
• Uncommon presentations include premature pubarche, tall stature, gynecomastia, or testicular adrenal rest tumors (TARTs) 1
• Male fertility does not appear significantly impaired 1

In Children

• Accelerated growth velocity and advanced bone age may occur 2, 4
• Premature adrenarche can be an early manifestation 2

Diagnosis

Screening should utilize basal 17-hydroxyprogesterone (17-OHP) ≥2 ng/ml (6 nmol/l) as the threshold, with definitive diagnosis requiring 17-OHP ≥10 ng/ml (30 nmol/l) either basally or after cosyntropin stimulation 3

• The American Academy of Dermatology guidelines recommend screening for NCAH in patients with acne plus additional signs of androgen excess through 17-OHP measurement 5
• Molecular genetic analysis of CYP21A2 should be offered to all diagnosed patients for confirmation and genetic counseling, as patients frequently carry alleles that may result in classic CAH in their offspring 3
• Endocrinologic evaluation is warranted in prepubertal children with acne plus early-onset body odor, axillary/pubic hair, accelerated growth, advanced bone age, or genital maturation 5
• In postpubertal females, testing is indicated with infrequent menses, hirsutism, androgenetic alopecia, infertility, polycystic ovaries, clitoromegaly, or truncal obesity 5

Treatment Approach

General Principles

Treatment must be reserved for symptomatic patients only, as asymptomatic individuals do not require therapy 1, 4

Pediatric Patients

• Glucocorticoid replacement therapy should be considered for children with accelerated growth velocity or advanced bone age to normalize linear growth and achieve "on-time" puberty 2, 4

Adult Women

For menstrual irregularities, hirsutism, and cutaneous symptoms, oral contraceptive pills and/or antiandrogens (cyproterone acetate, spironolactone) are preferred over glucocorticoids due to superior efficacy and avoidance of adrenal suppression and metabolic complications 1, 3

• Glucocorticoid therapy may benefit women actively seeking fertility, as it reduces adrenal androgen excess and improves ovulation 3, 2
• Some women may require ovulation induction or assisted reproductive technology to achieve pregnancy 3
• Patients with NCAH have higher miscarriage risk and may benefit from glucocorticoid treatment during pregnancy 3

Adult Men

• Treatment is generally not required in asymptomatic males 1

Metabolic and Long-Term Considerations

• Conflicting evidence suggests possible associations with mild insulin resistance, obesity, and increased cardiovascular risk, particularly in women 1
• Bone mineral density appears normal or increased in NCAH, possibly due to prolonged androgen exposure, though fracture risk remains uncertain 1
• Close monitoring for complications of glucocorticoid therapy should include bone mineral density assessment every 3-5 years if glucocorticoids are used 6

Critical Pitfalls

• Many affected women are misdiagnosed with PCOS, delaying appropriate management and genetic counseling 1
• Glucocorticoids pose risks of iatrogenic Cushing's syndrome and adrenal suppression; treatment should not be initiated merely to normalize hormone levels in asymptomatic patients 2, 4
• All diagnosed patients require genetic counseling regarding the risk of classic CAH in offspring 3