OVERVIEW

What is 21-Hydroxylase Deficiency?

21-Hydroxylase deficiency is a genetic disorder caused by congenital gene defects that reduce the activity of the enzyme 21-hydroxylase, affecting a pair of organs called the adrenal glands and leading to congenital adrenal hyperplasia.

The adrenal glands are located above the kidneys, resembling small caps on top of them—hence their name. These glands primarily produce and secrete three crucial hormones:

• Aldosterone, also known as a mineralocorticoid, regulates the body's salt and fluid balance.
• Cortisol, also called a glucocorticoid, controls the metabolism of sugars and fats and helps the body adapt to environmental changes in stressful situations.
• Androgens, or male hormones, are present in both males and females.

21-Hydroxylase deficiency leads to reduced synthesis of cortisol and aldosterone while increasing androgen production, which can result in male pseudo-precocious puberty or virilization in females.

Due to the lack of cortisol, the pituitary gland in the brain intensively signals the release of adrenocorticotropic hormone (ACTH) to stimulate the adrenal glands to produce more cortisol. However, the issue is not that the adrenal glands are inactive but rather that the "worker" in the production line—21-hydroxylase—is defective.

Under prolonged ACTH stimulation, the adrenal glands gradually enlarge and become hyperplastic, ultimately leading to congenital adrenal hyperplasia—the final outcome of 21-hydroxylase deficiency.

Is 21-Hydroxylase Deficiency Common?

21-Hydroxylase deficiency is a rare genetic disorder.

Global data show that it occurs in about 1 in 15,000 live births. Prevalence varies by ethnicity and region, with the lowest rate among Chinese (1 in 28,000 live births), followed by Caucasians (1 in 5,000–23,000). The Yupik people of Alaska have the highest incidence, with 1 in 280 live births affected.

Are 21-Hydroxylase Deficiency and Congenital Adrenal Hyperplasia the Same Condition?

Congenital adrenal hyperplasia encompasses several enzyme deficiencies, including 21-hydroxylase deficiency, 11β-hydroxylase deficiency, 3β-hydroxysteroid dehydrogenase deficiency, and 17α-hydroxylase deficiency. Among these, 21-hydroxylase deficiency is the most common, accounting for over 90% of cases.

What Are the Types of 21-Hydroxylase Deficiency?

Based on the degree of enzyme deficiency, 21-hydroxylase deficiency is classified into classic and non-classic forms:

• Non-classic 21-Hydroxylase Deficiency: More prevalent than the classic form, it retains 20%–50% of enzyme activity, allowing sufficient production of glucocorticoids and mineralocorticoids for daily physiological needs. Symptoms are milder, without salt-wasting (e.g., low sodium levels).
• Classic 21-Hydroxylase Deficiency: Enzyme activity is only 0%–2%, severely disrupting the production of all three key adrenal hormones. Symptoms are severe, appearing prenatally or shortly after birth, including cortisol deficiency (e.g., poor feeding, lethargy, vomiting, diarrhea, dehydration, low blood pressure, hypoglycemia, weight loss), salt-wasting (low sodium, high potassium), and ambiguous genitalia or virilization in female newborns.

SYMPTOMS

What are the common manifestations of 21-hydroxylase deficiency?

• Symptoms of cortisol deficiency: Refusal to eat, lethargy, vomiting, diarrhea, dehydration, low blood pressure, low blood sugar, failure to gain weight or slow growth.
• Manifestations of salt-wasting due to mineralocorticoid deficiency: Low blood sodium, elevated blood potassium, etc.
• Signs of androgen excess: Particularly in affected girls, whose excessive androgen production may cause their external genitalia to resemble those of boys at birth.
• Short stature: Untreated children of either sex may experience early puberty, potentially leading to premature growth cessation and short stature.

What are the manifestations of non-classic 21-hydroxylase deficiency?

• Children: Post-neonatal androgen excess without cortisol deficiency symptoms. Possible features include premature pubic hair development, acne, accelerated growth (tall childhood stature), but early puberty may cause premature epiphyseal closure and adult short stature (though not universal).
• Females: Nearly all girls under 10 exhibit premature pubic hair; adolescents/adults may show hirsutism, irregular/absent menstruation, acne, infertility, clitoromegaly, or hair loss.
• Males: Premature pubic hair in childhood; acne/infertility post-puberty; adult short stature.
• Adrenal masses: CT may reveal unilateral/bilateral adrenal adenomas.

What are the manifestations of classic 21-hydroxylase deficiency?

Symptom severity varies with residual enzyme activity. Hormonal deficiency manifestations include:

• Cortisol deficiency symptoms: As above (refusal to eat, lethargy, etc.).
• Salt-wasting from mineralocorticoid deficiency: Low sodium, high potassium.
• Androgen excess:
  • Infants/children: Ambiguous genitalia; newborn girls may have clitoromegaly, labial fusion, urogenital sinus, or rarely, unassignable sex at birth.
  • Affected males may show subtle abnormalities like hyperpigmented scrotum/enlarged penis.
  • Precocious puberty with potential adult short stature.
  • Behavioral masculinization (aggressiveness) in girls.
  • Fertility: High female infertility rates; possible male subfertility.
• Possible adrenal/pituitary tumors, insulin resistance, or hyperleptinemia.

Where does 21-hydroxylase deficiency primarily occur?

The disorder affects the adrenal glands.

CAUSES

What causes 21-hydroxylase deficiency?

21-hydroxylase deficiency is a genetic disorder caused by gene mutations. Humans have two 21-hydroxylase genes: one is an active "true" gene, while the other is an inactive "pseudo" gene.

The "pseudo" gene often interferes disruptively. When this "pseudo" gene gets involved, it can cause problems, leading to mutations that affect 21-hydroxylase activity to varying degrees. As a result, adrenal hormone synthesis is disrupted, and the disease develops.

Who is most commonly affected by 21-hydroxylase deficiency?

Individuals with a family history of 21-hydroxylase deficiency have a higher risk of developing the condition.

Is 21-hydroxylase deficiency contagious?

21-hydroxylase deficiency is a congenital genetic disorder and is not contagious.

Is 21-hydroxylase deficiency hereditary?

21-hydroxylase deficiency is a genetic disorder that follows an autosomal recessive inheritance pattern.

DIAGNOSIS

How is 21-hydroxylase deficiency diagnosed?

When diagnosing 21-hydroxylase deficiency, doctors primarily rely on measuring blood 17-hydroxyprogesterone levels.

What tests are needed for 21-hydroxylase deficiency?

Generally, the following tests are required: 17-hydroxyprogesterone, adrenocorticotropic hormone (ACTH), cortisol, renin, sex hormones, blood gas analysis, blood electrolytes, and imaging studies:

• 17-hydroxyprogesterone: Mainly used to confirm the diagnosis.
• ACTH, cortisol, renin, sex hormones: Primarily assist in diagnosis.
• Blood gas analysis: Determines whether acidosis is present.
• Blood electrolytes: Checks for low sodium, high potassium, etc.
• Imaging studies: Adrenal CT, pituitary MRI, etc., to aid in diagnosis.

TREATMENT

Which department should I visit for 21-hydroxylase deficiency?

Pediatrics, Endocrinology.

Can 21-hydroxylase deficiency resolve on its own?

21-hydroxylase deficiency is a congenital genetic disorder and cannot resolve on its own.

How is 21-hydroxylase deficiency treated?

The main treatment methods for 21-hydroxylase deficiency are medication and surgery:

• Medication involves taking tablets to compensate for the adrenal glands' inability to produce sufficient hormones for daily needs:
• Glucocorticoid therapy: The goal is to supplement the deficient amount while minimizing side effects (iatrogenic Cushing's syndrome). For example, dexamethasone 0.25–0.75 mg taken at bedtime is the preferred option for adults and older adolescents with fully closed epiphyses. Newborns often use hydrocortisone, with a typical starting dose of 20–30 mg per square meter of body surface area per day (7.5 mg), divided into 3 doses. Children commonly take hydrocortisone at 10–15 mg per square meter of body surface area per day, divided into 3 doses.
• Mineralocorticoid therapy: Such as fludrocortisone, adjusted to normalize blood sodium and potassium levels. Salt tablets or saline solutions may be added if necessary.
• Surgery primarily addresses abnormal external genitalia, mainly for girls.

What are the common side effects of medications for 21-hydroxylase deficiency?

Glucocorticoid use may lead to Cushing's syndrome, including weight gain, moon face, thin limbs, and skin striae; premature epiphyseal closure and short stature; gastrointestinal bleeding; osteoporosis and fractures; and increased susceptibility to infections.

Can 21-hydroxylase deficiency be cured?

21-hydroxylase deficiency cannot be cured.

DIET & LIFESTYLE

What should patients with 21-hydroxylase deficiency pay attention to in daily life?

21-hydroxylase deficiency is a lifelong condition, requiring lifelong medication. Treatment is effective, and most children can lead relatively normal lives.

Special attention should be paid to the possibility of a serious condition called "adrenal crisis." This is particularly likely when the child is ill—especially with vomiting, fever, or infection—when medication is stopped, or during surgery.

Symptoms such as refusal to eat, vomiting, abdominal pain, weakness, fever, confusion, or coma may indicate an adrenal crisis. In such cases, immediate emergency care is needed to actively prevent and manage the crisis.

Does 21-hydroxylase deficiency require follow-up examinations? How often?

Regular follow-up examinations are necessary for 21-hydroxylase deficiency. In the first 3 months after birth, treatment response should be assessed monthly. During the neonatal and infant periods, assessments should be conducted every 3 months, and later every 3 to 6 months.

Evaluations primarily include monitoring growth rate, blood pressure, bone growth, and measuring serum 17-hydroxyprogesterone, androstenedione, and plasma renin activity.

Does 21-hydroxylase deficiency affect fertility?

21-hydroxylase deficiency may impact fertility. Female patients have higher rates of infertility and an increased risk of miscarriage, while male fertility may also be impaired.

PREVENTION

Can 21-hydroxylase deficiency be prevented? How to prevent it?

Preconception genetic screening and prenatal diagnosis are methods to prevent this condition.

How can patients with 21-hydroxylase deficiency prevent complications?

Newborn screening, early diagnosis for suspected cases, and active treatment are effective ways to prevent complications.