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Congenital adrenal hyperplasia main page
Overview
Classification 21-hydroxylase deficiency
11β-hydroxylase deficiency
17 alpha-hydroxylase deficiency
3 beta-hydroxysteroid dehydrogenase deficiency
Cytochrome P450-oxidoreductase (POR) deficiency (ORD)
Lipoid congenital adrenal hyperplasia
Differential Diagnosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mehrian Jafarizade, M.D [2]

Synonyms and keywords: Congenital adrenal hyperplasia, CAH, Adrenal hyperplasia

Overview

Congenital adrenal hyperplasia (CAH) refers to any of several autosomal recessive conditions resulting from biochemical paths of the steroidogenesis of cortisol from cholesterol by the adrenal glands. Most of these conditions involve greater or lesser production of sex steroids and can alter development of primary or secondary sex characteristics in affected infants, children, and adults. Only a small minority of people with CAH can be said to have an intersex condition, but this attracted American public attention in the late 1990s and many accounts of varying accuracy have appeared in the popular media. Approximately 95% of cases of CAH are due to 21-hydroxylase deficiency. Prenatal diagnosis can be made in both of these disorders by chorionic villous sampling, but this can only be done at 8-10 weeks. In order to prevent the deleterious effect of excess androgens on genital (and brain!) development, therapy must be started earlier. This is most often considered if there is an affected sibling. Treatment is dexamethasone, which is not degraded by the placenta, but is associated with significant maternal weight gain, hypertension, and edema.

Historical Perspective

• Congenital adrenal hyperplasia first time seen in 1865 by Luigi De Crecchio, an Italian pathologist, in a man at autopsy, who had large adrenal glands and female internal organs.

• Important aspects of discovering adrenal hormones:
  • In 1563, Eustachius described the adrenals and then published by Lancisi in 1714.
  • In 1849, Thomas Addison, found on a bronzed appearance associated with the adrenal glands called melasma suprarenale while searching for the cause of pernicious anemia.
  • In 1855, Thomas Addison defined the clinical features and autopsy findings in 11 cases of diseases of the suprarenal capsules, and half of them were tuberculous in origin.
  • In 1856, In adrenalectomy experiments, Brown-Séquard found that the adrenal glands are nessesary for life.
  • In 1896, William Osler prepared an oral glycerin extract derived from pig adrenals and showed that it had clinical benefit in patients with Addison disease.
  • In 1905, Bulloch and Sequeira described patients with congenital adrenal hyperplasia.
  • In 1936, Selye described the concept of stress and its effect on pituitary-adrenal function.
  • In 1937-1952, Kendall and Reichstein, defined the isolation and structural characterization of adrenocortical hormones.
  • In 1943, Li and colleagues isolated adrenocorticotropic hormone from sheep pituitary.
  • In 1950, Hench, Kendall, and Reichstein shared the Nobel Prize in Medicine for describing the anti-inflammatory effects of cortisone in patients with rheumatoid arthritis
  • In 1956, Conn described primary aldosteronism.
  • In 1981, Vale defined characterization and synthesis of corticotropin-releasing hormone.
  • From 1980-present called the molecular era; highlights in this section are:
    • Cloning and functional characterization of steroid hormone receptors discovered.
    • Steroidogenic enzymes described.
    • Adrenal transcription factors were reported.
    • Molecular basis for human adrenal diseases described.

Pathophisiology

Gross Pathology

Gross pathology findings in patients with congenital adrenal hyperplasia are:

• Enlarged adrenal glands
• Wrinkled surface adrenal glands
• Cerebriform pattern adrenal glands (pathognomonic sign)
• Normal ultrasound appearances may also be seen
• Testicular masses may be identified representing adrenal rest tissue

Microscopic Pathology

In congenital adrenal hyperplasia, hyperplastic cells are usually but not always smaller, with cytoplasm that can be vacuolated also often more basophilic. Rare mitotic figures may be present, but the hyperplastic cells typically lack features of cellular atypia.

Adrenal gland, Cortex - Hyperplasia in a female rat from a chronic study. There is a hyperplastic lesion (H) in which cortical cells are increased in number but are smaller in size than adjacent normal cortical cells (NC)

Adrenal gland, Cortex - Hyperplasia in a male rat from a chronic study. There are two adjacent foci of hyperplasia (H) in the zona fasciculata.

Classification

Congenital adrenal hyperplasia is classified into seven types based on the genetic causes that lead to hyperplasia and hormonal imbalance.

Disease		History and symptoms		Laboratory findings			Defective gene
		Blood pressure	Genitalia	Increased	Decreased	K levels
21-hydroxylase deficiency	Classic type	Low in salt-wasting Normal in non-salt-wasting	Female: ambiguous Male: normal or scrotal pigmentation and large phallus	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone, mild elevation	Cortisol Corticosterone Aldosterone	High in salt wasting type Normal in non salt wasting	CYP21A1 and CYP21A2 gene
	Non-classic type	Normal	Female: virilization after puberty Male: normal appearance	17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone response to ACTH		Normal	CYP21A1 and CYP21A2 gene
17-α hydroxylase deficiency		Hypertension	Female: normal Male: ambiguous	Deoxycorticosterone Corticosterone Progesterone	Cortisol Aldosterone	Low	CYP17A1
11-β hydroxylase deficiency		Hypertension	Female: ambiguous Male: normal or scrotal pigmentation and large phallus	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone, mild elevation	Cortisol Corticosterone Aldosterone	Low	CYP11B1
3β-Hydroxysteroid Dehydrogenase				Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	Cortisol Aldosterone	High
Cytochrome P450-oxidoreductase (POR) deficiency (ORD)
Congenital lipoid adrenal hyperplasia
Cholesterol side-chain cleavage enzyme deficiency

Screening

According to Endocrine Society Clinical Practice Guideline, screening for 21-hydroxylase deficiency by measuring 17a-hydroxyprogesterone is recommended for all newborns.

• Blood sample on filter paper should be obtained from heel puncture preferably between two and four days after birth.
• Screening programs should be done using a two-tier protocol (initial immunoassay with further evaluation of positive tests by liquid chromatography/tandem mass spectrometry.
• Most affected neonates have concentrations greater than 3500 ng/dL (105 nmol/L).

Genetic counseling

The Endocrine Society's Clinical Practice Guideline recommends that genetic counseling be provided for individuals who are planning to conceive, and there is a family history of 21-hydroxylase deficiency.

Differentiating congenital adrenal hyperplasia from other diseases

Congenital adrenal hyperplasia must be differentiated from diseases that cause ambiguous genitalia:

Disease name	Laboratory tests		Important clinical findings
	Increased	Decreased
Classic type of 21-hydroxylase deficiency	17-hydroxyprogesterone Progesterone Androstenedione DHEA	Aldosterone Corticosterone (salt-wasting) Cortisol (simple virilizing)	Ambiguous genitalia in female Virilization in female Salt-wasting Hypotension and hyperkalemia
11-β hydroxylase deficiency	Deoxycorticosterone 11-Deoxy-cortisol 17-hydroxyprogesterone, mild elevation	Cortisol Corticosterone Aldosterone	Ambiguous genitalia in female Hypertension and hypokalemia Virilization
17-α hydroxylase deficiency	Deoxycorticosterone Corticosterone Progesterone	Cortisol Aldosterone	Ambiguous genitalia in male Hypertension Primary amenorrhea Absence of secondary sexual characteristics Minimal body hair
3β-Hydroxysteroid Dehydrogenase	Dehydroepiandrosterone 17-hydroxypregnenolone Pregnenolone	Cortisol Aldosterone	Vomiting, volume depletion, hyponatremia, and hyperkalemia 46-XY infants often show undervirilization, due to a block in testosterone synthesis
Gestational hyperandrogenism	Maternal serum androgen concentrations (usually testosterone and androstenedione) are high If virilization is caused by exogenous hormone administration, the values may be low because the offending hormone is usually a synthetic steroid not measured in assays for testosterone or other androgens		Androgen excess sign and symptoms in mother History of androgen containing medication consumption during pregnancy in mother Virilization in a 46,XX individual with normal female internal anatomy Causes include maternal luteoma or theca-lutein cysts, and placental aromatase enzyme deficiency

congenital adrenal hyperplasia must be differentiated from diseases that cause virilization and hirsutism in female:

Disease name	Steroid status	Other laboratory	Important clinical findings
Non-classic type of 21-hydroxylase deficiency	Increased: 17-hydroxyprogesterone Exaggerated Androstenedione, DHEA, and 17-hydroxyprogesterone response to ACTH	Low testosterone levels	No symptoms in infancy and male Virilization in females
11-β hydroxylase deficiency	Increased: DOC 11-Deoxy-Cortisol Decreased: Cortisol Corticosterone Aldosterone	Low testosterone levels	Hypertension and hypokalemia Virilization
3β-Hydroxysteroid Dehydrogenase	Increased: DHEA 17-hydroxypregnenolone Pregnenolone Decreased: Cortisol Aldosterone	Low testosterone levels	Salt-wasting adrenal crisis in infancy Mild virilization of genetically female infants Undervirilization of genetically male infants, making it the only form of CAH which can cause ambiguous genitalia in both genetic sexes.
Polycystic ovary syndrome	High DHEAS and androstenedione levels	Low testosterone levels	Polycystic ovaries in sonography Obesity PCOS is the most common cause of hirsutism in women No evidence another diagnosis
Adrenal tumors	Variable levels depends on tumor type	Low testosterone level	Older age Rapidly progressive symptoms
Ovarian virilizing tumor	Variable levels depends on tumor type	Testosterone is high	Older age Rapidly progressive symptoms
Cushing's syndrome	Increase cortisol & metabolites Variable other steroids	Variable mineralocorticoid excess	Cushingoid appearance
Hyperprolactinemia	Normal levels of most of steroids	Increased prolactin	Infertility, galactorrhea