Congenital Adrenal Hyperplasia, Non-Classical Form

Introduction

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is a milder and later onset form of a genetic condition known as congenital adrenal hyperplasia. Some people affected by the condition have no associated signs and symptoms while others experience symptoms of androgen (male hormone) excess. Women with NCAH are generally born with normal female genitalia. Later in life, signs and symptoms of the condition can vary but may include hirsutism, frontal baldness, delayed menarche (first period), menstrual irregularities, and infertility. Little has been published about males with NCAH. They may have early beard growth and relatively small testes. Typically, they have normal sperm counts. NCAH is caused by changes (mutations) in the CYP21A2 gene and is inherited in an autosomal recessive manner. Treatment is only necessary in people who are symptomatic and may include a glucocorticoid called dexamethasone.

Associated Anatomy

The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which produces steroid hormones and an inner medulla. The adrenal cortex itself is divided into three zones: the zona glomerulosa, the zona fasciculata and the zona reticularis.

The adrenal cortex produces three main types of steroid hormones: mineralocorticoids, glucocorticoids, and androgens. Mineralocorticoids (such as aldosterone) produced in the zona glomerulosa help in the regulation of blood pressure and electrolyte balance. The glucocorticoids cortisol and cortisone are synthesized in the zona fasciculata; their functions include the regulation of metabolism and immune system suppression. The innermost layer of the cortex, the zona reticularis, produces androgens that are converted to fully functional sex hormones in the gonads and other target organs. The production of steroid hormones is called steroidogenesis, and involves a number of reactions and processes that take place in cortical cells. The medulla produces the catecholamine, adrenaline and noradrenaline, which function to produce a rapid response throughout the body in stress situations.

A number of endocrine diseases involve dysfunctions of the adrenal gland. Overproduction of cortisol leads to Cushing’s syndrome, whereas insufficient production is associated with Addison’s disease. Congenital adrenal hyperplasia is a genetic disease produced by dysregulation of endocrine control mechanisms. A variety of tumors can arise from adrenal tissue and are commonly found in medical imaging when searching for other diseases.

Causes

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is caused by changes (mutations) in the CYP21A2 gene. This gene provides instructions for making an enzyme called 21-hydroxylase, which is found in the adrenal glands. The adrenal glands are cone-shaped organs that sit on top of the kidneys and are responsible for releasing various types of hormones that the body needs to function. Mutations in CYP21A2 lead to deficient levels of 21-hydroxylase which cause low levels of hormones such as cortisol and/or aldosterone and an overproduction of androgens (male hormones such as testosterone). Cortisol is a hormone that affects energy levels, blood sugar levels, blood pressure, and the body’s response to stress, illness, and injury. Aldosterone helps the body maintain the proper level of sodium (salt) and water and helps maintain blood pressure. Irregular levels of these hormones lead to the signs and symptoms ofNCAH.

The amount of functional 21-hydroxylase enzyme determines the severity of the disorder. People with NCAH have CYP21A2 mutations that result in the production of reduced amounts of the enzyme, but more enzyme than the classic form of congenital adrenal hyperplasia.

Differential Diagnosis

Differential diagnosis of NCAH should be made for following conditions:

  • 3-Beta-Hydroxysteroid Dehydrogenase Deficiency
  • 5-Alpha-Reductase Deficiency
  • Adrenal Hypoplasia
  • Androgen Insensitivity Syndrome
  • Bilateral adrenal hemorrhage
  • Congenital Adrenal Hyperplasia
  • Defects in testosterone synthesis
  • Denys-Drash Syndrome
  • Disorders of Sex Development
  • Familial Glucocorticoid Deficiency
  • Fluid, Electrolyte, and Nutrition Management of the Newborn
  • Gender Identity
  • Hyperkalemia in Emergency Medicine
  • Hyponatremia in Emergency Medicine
  • Mixed gonadal dysgenesis
  • Nutritional Considerations in Failure to Thrive
  • Obstructive uropathy
  • Pediatric Adrenal Insufficiency (Addison Disease)
  • Pediatric Cryptorchidism Surgery
  • Pediatric Hypertrophic Pyloric Stenosis
  • Pediatric Hypokalemia
  • Polycystic Ovarian Syndrome
  • Pseudohypoparathyroidism
  • Renal Disease and Pregnancy
  • Sexual Orientation
  • Sinonasal Manifestations of Cystic Fibrosis
  • Small-Bowel Obstruction Imaging
  • WAGR Syndrome

Drugs

Hydrocortisone (A-Hydrocort, Cortef, Hydrocort)

Same as cortisol, which is the primary steroid hormone secreted by adrenal zona fasciculata and reticularis. DOC in children due to short half-life and decreased potential for growth suppression. Mineralocorticoid effect at large doses.

Fludrocortisone acetate (Florinef)

Synthetic steroid with predominantly mineralocorticoid activity. Acts on renal tubule to promote sodium retention in exchange for potassium or hydrogen ion and thus maintain intravascular and extracellular volume. For patients who require parenteral mineralocorticoid therapy, high-dose hydrocortisone must be used. Available only as tab; may be crushed for infants and children.

Epidemiology

Approximately 1 in 10 to 15,000 people in the United States has congenital adrenal hyperplasia due to classic 21-hydroxylase deficiency. The prevalence is higher is other parts of the world.

Pathophysiology

In broad terms, the virilizing forms (simple virilizing, salt-wasting, and nonclassic) of CAH are characterized by mutations that significantly impair cortisol biosynthesis and lead to the accumulation of steroid intermediates proximal to the deficient enzyme. The resulting loss of cortisol negative feedback inhibition leads to increased hypothalamic corticotrophin releasing hormone (CRH) and pituitary adrenocorticotrophic hormone (ACTH) secretion. With decreased P450c21 activity, conversions of 17-hydroxyprogesterone (17-OHP) to 11-deoxycortisol, and progesterone (P4) to deoxycorticosterone, are impaired. Elevated 17-OHP, P4, and androstenedione concentrations are typically found. The excessive ACTH stimulation also results in fasciculata-reticularis zone hypertrophy, resulting in the adrenal hyperplasia typical of the syndrome, and possibly increased adrenocortical nodularity. Individuals with NCAH generally have adequate mineralocorticoid secretion.

Unfortunately, the pathophysiology of NCAH (and CAH) is more complicated than this description would suggest. For example, patients with NCAH usually have no evidence of ACTH or CRH excess. In fact, some have an over-responsive glucocorticoid response to ACTH stimulation, possibly reflective of subtle adrenal hyperplasia. Another mechanism resulting in excessive adrenal androgen secretion especially in NCAH results from the alteration in enzyme kinetics due to the CYP21A2 missense mutations. The mutated enzyme protein is synthesized, but is less efficient than the wild type. The net result is an increased precursor to product ratio, independent of ACTH levels. Hence, P4 and 17-OHP levels in these patients may remain above normal even in the presence of excessive glucocorticoid administration. In addition, genetic variations at other loci may influence steroid metabolism and steroid responsiveness.

Alterations in ovarian and gonadotropic function, with the appearance of a polycystic ovary-like phenotype, also contribute to the androgen excess of these patients. Functional ovarian abnormalities in patients with CAH and/or NCAH may relate to a number of etiologies, including disruption of the hypothalamic-pituitary-ovarian (HPO) axis by persistently elevated progesterones (e.g. P4 and/or 17-OHP) or androgens, and/or a direct glucocorticoid effect. Androgen excess impairs hypothalamic sensitivity to progesterone resulting in a persistently rapid GnRH pulse frequency which favors LH hypersecretion. This LH hypersecretion initiates and maintains a vicious cycle in which excessive ovarian androgen secretion intensifies the consequences of the excessive adrenal androgen production. In fact, women with NCAH demonstrate higher LH concentrations than normal women. Prenatal programming of the hypothalamus due to excessive in utero androgen exposure may contribute to LH hypersecretion and reproductive dysfunction among women with classical forms of CAH. However, in utero exposure to excessive androgens is unlikely to play a major role in the pathophysiology among women with NCAH.

Finally, while the 17,20-lyase activity of P450c17 towards Δ4 substrates (conversion of 17-OHP to androstenedione) is not significant in humans, it is possible that patients with CAH and NCAH may experience increased androgen excess due to a backdoor or alternative pathway converting either P4 or 17-OHP to more potent androgens such as dihydrotestosterone (DHT). Enzymes involved in this alternative pathway include 5α-reductases and 3α-hydroxysteroid dehydrogenases. The ovarian expression of 5α-reductase may contribute to excessive ovarian androgen secretion in NCAH as well as PCOS.

Overall, a more thorough understanding of the pathophysiologic mechanisms underlying the symptomatology of NCAH will improve our ability to select effective therapeutic regimens and choose reliable markers indicative of therapeutic success. For example, available data would suggest that the measurement of P4 or 17-OHP may not be the most accurate marker of therapeutic efficacy, and suppression of excessive androgen secretion from both ovaries and adrenals may be necessary for optimum steroidogenic control.

Possible Complications

There are three forms of 21-hydroxylase deficiency: the classic salt wasting form, the simple virilizing form, and the non-classic form. Most patients with 21-hydroxylase deficiency will have the classic salt-wasting form or the simple virilizing form.

Infants with the severe classic salt wasting form develop symptoms within the first few weeks of life. These include:

  • Salt wasting crisis
    • low sodium levels (hyponatremia)
    • high potassium levels (hyperkalemia)
    • high levels of renin in the blood (hyperreninemia)
    • low blood volume (hypovolemic shock)
  • Ambiguous genitalia in female newborns babies (genitalia that is not typical female nor male appearing), with normal internal feminine reproductive organs (ovaries, uterus, and fallopian tubes); male babies usually have normal genitalia but may have small testes and an enlarged penis.

Salt wasting crises can be life-threatening and require immediate treatment.

Infants with the classic simple virilizing form may have:

  • Ambiguous external genitalia in female babies with normal internal reproductive organs; males are born with normal genitalia and may have small testes and an enlarged penis

Later in life both males and females with both classic forms of 21-hydroxylase deficiency may have:

  • Puberty starting in childhood (precocious puberty)
  • Excessive hair growth
  • Acne
  • Shorter than average adult height
  • Reduced fertility
  • Irregular periods (females)
  • Testicular enlargement and testicular tumors (males)

Females with the non-classic type of 21-hydroxylase deficiency have normal female genitalia, but when they get older, symptoms may include excessive hair growth (hirsutism), male pattern baldness, irregular periods and reduced fertility. Males with the non-classic type may have early beard growth, an enlarged penis, and small testes. The non-classical form is not considered a rare disease and some people with this form of 21-hydroxylase deficiency may not experience any signs or symptoms.

Possible Treatment

In some cases, people affected by non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) may not require any treatment. Many are asymptomatic throughout their lives, although symptoms may develop during puberty, after puberty, or post partum. If symptoms are present, a glucocorticoid called dexamethasone is often recommended. Dexamethasone can treat irregular menstruation, acne, and excess body hair (hirsutism).

Treatment for 21-hydroxylase deficiency depends on the severity of symptoms and the form of the condition. The goals of treatment are to manage to symptoms. Infants identified at birth with 21-hydroxylase deficiency are treated with hormones and steroids to prevent a salt-wasting crisis. In childhood and adulthood, other medications may be used to improve growth and fertility. Males should be monitored for the growth of testicular adrenal rest tumors, a benign tumor that can cause infertility. In some cases, females with ambiguous genitalia may be offered surgical correction. Some people with this condition have psychological issues and may benefit from therapy.

Prognosis

The long-term outlook (prognosis) for people with non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is generally good. NCAH is usually not life-threatening and is relatively mild compared to classic congenital adrenal hyperplasia. Some women may have no signs or symptoms of the condition while others may require treatment for hirsutism, infertility or other health problems. Little has been published about males with NCAH. They may have early beard growth and relatively small testes. Typically, they have normal sperm counts.

The long-term outlook for people with 21-hydroxylase deficiency is dependent on the severity of the symptoms, the response to medications and the presence of any other medical conditions. In general, with early diagnosis and continuous lifetime treatment, the long-term outlook for people with this disorder is good. Long term complications of this condition may include fertility and mental health issues.

Primary Prevention

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is inherited and can’t be prevented.

Risk factors

Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is inherited in an autosomal recessive manner. This means that to be affected, a person must have a mutation in both copies of the responsible gene in each cell. The parents of an affected person usually each carry one mutated copy of the gene and are referred to as carriers. Carriers typically do not show signs or symptoms of the condition. When two carriers of an autosomal recessive condition have children, each child has a 25% (1 in 4) risk to have the condition, a 50% (1 in 2) risk to be a carrier like each of the parents, and a 25% chance to not have the condition and not be a carrier.

21-hydroxylase deficiency is inherited in an autosomal recessive pattern. All individuals inherit two copies of each gene. To have 21-hydroxylase deficiency, a person must have a mutation in both copies of the responsible gene in each cell. There is nothing either parent can do, before or during a pregnancy, to cause a child to have this.

People with autosomal recessive conditions inherit one mutation from each of their parents. The parents, who each have one mutation, are known as carriers. Carriers of an autosomal recessive disorder typically do not have any signs or symptoms (they are unaffected). When two carriers of an autosomal recessive condition have children, each child has a:

  • 25% (1 in 4) chance to have the disorder
  • 50% (1 in 2) chance to be an unaffected carrier like each parent
  • 25% (1 in 4) chance to be unaffected and not be a carrier

Signs or Symptoms

The signs and symptoms of non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) may develop any time after birth. Affected people generally experience symptoms of androgen (male hormone) excess such as acne, premature development of pubic hair, accelerated growth, advanced bone age, and reduced adult height.

Women with NCAH are generally born with normal female genitalia. Later in life, signs and symptoms of the condition can vary but may include hirsutism, frontal baldness, delayed menarche (first period), menstrual irregularities, and infertility.

Little has been published about males with NCAH. They may have early beard growth and relatively small testes. Typically, they have normal sperm counts.

Some men and women affected by NCAH have no signs or symptoms of the condition.

The symptoms of 21-hydroxylase deficiency may be different from person to person. Some people may be more severely affected than others, even people who have the same form. Not everyone with 21-hydroxylase deficiency will have the same symptoms, and some may have few or no symptoms.

Studies

Active Not Recruiting

Number of studies: 6

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Completed

Number of studies: 42

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Enrolling by Invitation

Number of studies: 2

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Not Yet Recruiting

Number of studies: 6

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Recruiting

Number of studies: 29

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Results Available

Number of studies: 10

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Results Not available

Number of studies: 97

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Suspended

Number of studies: 2

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Terminated

Number of studies: 1

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Withdrawn

Number of studies: 4

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Types

There are three forms of 21-hydroxylase deficiency: the classic salt wasting form, the simple virilizing form, and the non-classic form. Most patients with 21-hydroxylase deficiency will have the classic salt-wasting form or the simple virilizing form.

Typical Test

A diagnosis of non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (NCAH) is often suspected based on the presence of characteristic signs and symptoms. Additional testing can then be ordered to confirm the diagnosis. This may include a blood test to measure the concentration of 17-hydroxyprogesterone (17-OHP) and/or an adrenocorticotropic hormone (ACTH) stimulation test. An ACTH stimulation test involves measuring the concentration of 17-OHP in the blood before ACTH is administered and 60 min after ACTH is given.

Babies born are screened at birth through newborn screening for the classic salt wasting and simple virilizing forms of 21-hydroxylase deficiency.  For babies that test positive on the newborn screen for this disorder, additional biochemical and genetic testing is done to confirm the diagnosis. The less severe, non-classical form of 21-hydroxylase def is diagnosed based on the clinical symptoms, biochemical testing to look for excess hormone production. Genetic testing may also be helpful to determine the type and severity of 21-hydroxylase deficiency.

Testing Resources

The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

References:

https://rarediseases.info.nih.gov/diseases/9592/non-classic-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910408/
https://emedicine.medscape.com/article/919218-overview
https://www.wikidoc.org/index.php/Congenital_adrenal_hyperplasia

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