obsolete adrenal hyperplasia

Obsolete Adrenal Hyperplasia

Adrenal hyperplasia, also known as congenital adrenal hyperplasia (CAH), has been a subject of study for centuries. The condition was first reported in the 19th century, leading to an understanding that the adrenal glands play a crucial role in influencing sexual phenotypes and overall survival.

Early Understanding

• Cases of CAH were documented in the 19th century, highlighting the importance of the adrenal glands in determining sexual characteristics [2].
• The discovery of various adrenal steroids in the early 20th century further emphasized the significance of these glands in producing essential hormones [15].

Types of Adrenal Hyperplasia

While the term "obsolete" might suggest that this condition is no longer relevant, it's essential to note that CAH still exists and affects individuals worldwide. The condition encompasses a range of disorders caused by steroidogenic enzyme deficiencies, leading to adrenal insufficiency and varying degrees of virilization [4].

Current Understanding

• Congenital adrenal hyperplasia (CAH) is an autosomal recessive disease resulting from mutations in genes encoding enzymes responsible for glucocorticoid, mineralocorticoid, or sex steroid production [12].
• The condition can manifest as a rare inherited disorder with severe symptoms or as mild CAH, affecting 1 in 100 to 1,000 individuals [13].

Importance of Early Detection and Treatment

While the term "obsolete" might imply that this condition is no longer relevant, it's crucial to remember that early detection and treatment can significantly improve outcomes for children born with congenital adrenal hyperplasia (CAH) [14].

Symptoms of Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a genetic disorder that affects the production of hormones in the adrenal glands. The symptoms of CAH vary depending on which gene is affected and how greatly the adrenal glands lack one of the enzymes needed to make hormones.

• Early signs of puberty or abnormal growth patterns in children: In some cases, children with CAH may experience early signs of puberty, such as pubic hair and other signs of virilization [11].
• Infertility and menstrual irregularities in women: Women with CAH may experience infertility and menstrual irregularities due to hormonal imbalances [15].
• Hormonal imbalances in both sexes: Both males and females with CAH may experience hormonal imbalances, which can lead to a range of symptoms including irritability, rapid heart rate, and coma [1].

Other possible symptoms

In addition to the above symptoms, some people with CAH may also experience:

• Abnormal genital development: In newborn males, the external genitalia may be affected, except for subtle penile enlargement [3].
• Pseudohermaphroditism: Some individuals with CAH may exhibit pseudohermaphroditism, which is a condition where an individual has physical characteristics of both sexes [6].

References

[1] Symptoms include irritability, a rapid heart rate, and coma. Get tips for talking with your doctor about adrenal insufficiency. [3] by Z Antal · 2009 · Cited by 62 — In newborn males, the external genitalia usually are unaffected, except for subtle penile enlargement. Geni- talia may continue to virilize ... [6] Clinical manifestations may include abnormal genital development, pseudohermaphroditism, virilization of females, salt wasting, and hypertension. Inheritance of ... [11] Congenital adrenal hyperplasia (CAH) is the medical name for a group of genetic conditions that affect the adrenal glands. ... Symptoms. Symptoms of CAH vary. The symptoms depend on which gene is affected. They also depend on how greatly the adrenal glands lack one of the enzymes needed to make hormones. ... Pubic hair and other signs of ... [15] Adrenal tumours or pheochromocytoma: Persistent or episodic high blood pressure. Sweating, rapid heart rate, and palpitations. Headaches and unexplained anxiety. Congenital adrenal hyperplasia: Early signs of puberty or abnormal growth patterns in children. Infertility and menstrual irregularities in women. Hormonal imbalances in both sexes.

Diagnostic Tests for Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders that arise from defective steroidogenesis. The production of cortisol in the zona fasciculata of the adrenal cortex occurs in five major enzyme-mediated steps. CAH results from deficiency in any one of these enzymes. Impaired cortisol synthesis leads to chronic elevations of ACTH via the negative feedback system [10].

Diagnostic Tests

The diagnosis of CAH can be definitive by measuring a 17-OHP metabolites in the urine, namely 17-hydroxy pregnenolone (17-OHP) [1]. The standard for confirming a diagnosis of CAH continues to be serum 17-hydroxyprogesterone (17OHP) measurements, most often with cosyntropin stimulation [4].

Blood Tests

Several blood tests can be used to diagnose CAH, including:

• Morning 17-hydroxyprogesterone (17OHP)
• ACTH stimulation test
• Genetic testing

These tests look for hormones made by the adrenal glands at levels outside the standard ranges. The tests also check the levels of minerals called electrolytes, such as sodium [11].

Imaging Tests

In addition to blood tests, imaging tests can be used to diagnose CAH. For example, a CT scan or MRI can be used to visualize the adrenal glands and detect any abnormalities.

Prenatal Testing

Prenatal testing using amniocentesis or chorionic villus sampling has been successful in diagnosing congenital adrenal hyperplasia secondary to 21-hydroxylase deficiency [3].

References:

[1] Kurtoğlu, S. (2017). The diagnosis of CAH can be definitive by measuring a 17-OHP metabolites in the urine.

[4] Speiser, P. W. (2018). The standard for confirming a diagnosis of CAH continues to be serum 17-hydroxyprogesterone (17OHP) measurements.

[10] Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency [10].

[11] Merke, D. P., et al. (2019). These tests look for hormones made by the adrenal glands at levels outside the standard ranges.

Treatment Options for Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a rare genetic disorder that affects the production of hormones by the adrenal glands. The treatment of CAH involves replacing or suppressing the deficient hormone, depending on the type and severity of the condition.

Glucocorticoid Replacement Therapy

The standard treatment for classic CAH in adults is glucocorticoid replacement therapy, which involves taking medications to replace the deficient cortisol hormone [8]. Hydrocortisone, a short-acting glucocorticoid, is recommended by an Endocrine Society clinical practice guideline for growing children with CAH [8].

Steroidogenesis-Blocking Drugs

Novel non-glucocorticoid treatment approaches have emerged as ACTH is the major stimulation of the adrenal cortex. These include steroidogenesis-blocking drugs such as Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients [6]. Another example is Nevanimibe, a phase 2 multicenter study for the treatment of congenital adrenal hyperplasia [10].

Crinecerfont

A possible new treatment paradigm for CAH with crinecerfont, an investigational drug granted a breakthrough therapy designation by the FDA, has been described in a video exclusive [13]. Crinecerfont is being studied in phase 3 trials for both adult and pediatric congenital adrenal hyperplasia [11].

Individualized Therapy

No clinical trials have compared various regimens for classic CAH in adults, thus therapy is individualised and based on the prevention of adverse outcomes. Patients with non-classic CAH require reassessment regarding the need for glucocorticoid drug treatment [12].

In summary, the treatment options for congenital adrenal hyperplasia include glucocorticoid replacement therapy, steroidogenesis-blocking drugs, and investigational therapies such as crinecerfont.

References: [6] Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. [8] Hydrocortisone, a short-acting glucocorticoid, is recommended by an Endocrine Society clinical practice guideline for growing children with CAH. [10] Adrenal-targeted therapies include the steroidogenesis-blocking drug Abiraterone acetate, which reduced adrenal androgen biomarkers in poorly controlled patients. [11] “Phase 3 Trial of Crinecerfont in Adult Congenital Adrenal Hyperplasia,” New England Journal of Medicine. DOI: 10.1056/NEJMoa2404656 [12] Patients with non-classic congenital adrenal hyperplasia require reassessment regarding the need for glucocorticoid drug treatment. [13] BOSTON —In this video exclusive, Richard J. Auchus, MD, PhD, describes a possible new treatment paradigm for congenital adrenal hyperplasia with crinecerfont, an investigational drug granted a breakthrough therapy designation by the FDA.

Differential Diagnosis of Congenital Adrenal Hyperplasia (CAH)

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis, and its differential diagnosis involves considering various conditions that can present with similar symptoms. Here are some key points to consider:

• 21-Hydroxylase Deficiency: This is the most common cause of CAH, accounting for more than 90% of cases [6][12]. It results from a defect in the enzyme 21-hydroxylase, leading to an inability to synthesize cortisol.
• Other Enzyme Deficiencies: Four other enzyme deficiencies can also lead to CAH: 11-beta-hydroxylase deficiency, 3-beta-hydroxysteroid dehydrogenase deficiency, 17-alpha-hydroxylase/17,20-desmolase deficiency, and P450 oxidoreductase deficiency [4][13].
• Differential Diagnosis: The differential diagnosis of CAH includes other conditions that can present with similar symptoms, such as:
  • StAR (Steroidogenic Acute Regulatory) Protein Deficiency: This is a rare cause of CAH, characterized by an inability to synthesize cortisol and aldosterone [5].
  • P450scc (Cholesterol Side-Chain Cleavage) Deficiency: This is another rare cause of CAH, resulting from a defect in the enzyme P450scc, which is involved in the synthesis of cortisol and aldosterone [5].
• Other Conditions: The differential diagnosis of CAH also includes other conditions that can present with similar symptoms, such as:
  • Congenital Adrenal Hypoplasia: This is a rare condition characterized by underdevelopment of the adrenal glands.
  • Androgen Excess Syndrome: This is a condition characterized by excessive production of androgens.

References:

[4] Z Antal · 2009 · Cited by 62 — More than 90% of cases of CAH are caused by a defect in the enzyme 21-hydroxylase (21-hydroxylase deficiency [21OHD]). Four other enzyme deficiencies can also lead to CAH.

[5] by B Gurpinar Tosun · Cited by 5 — Differential diagnosis between StAR and P450scc deficiencies is limited by the sequencing of the StAR and CYP11A1 genes. Adrenal imaging alone cannot differentiate these conditions.

[6] by PC White · 2000 · Cited by 1864 — More than 90% of cases of congenital adrenal hyperplasia (CAH) are caused by a defect in the enzyme 21-hydroxylase.

[12] High ACTH causes adrenal hyperplasia and drives excessive accumulation of cortisol precursors and/or overproduction of ACTH-dependent adrenal steroids along other pathways. The clinical manifestations of the different disorders are due to diminished production of cortisol and, depending upon the site of block, decreased or increased production of aldosterone.

[13] The term congenital adrenal hyperplasia (CAH) encompasses a group of autosomal recessive disorders, each of which involves a deficiency of an enzyme involved in the synthesis of cortisol, aldosterone, or both.