Congenital adrenal hyperplasia


Congenital adrenal hyperplasia is any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of mineralocorticoids, glucocorticoids or sex steroids from cholesterol by the adrenal glands. Most of these conditions involve excessive or deficient production of sex steroids and can alter development of primary or secondary sex characteristics in some affected infants, children or adults.

Signs and symptoms

The symptoms of CAH vary depending upon the form of CAH and the sex of the patient. Symptoms can include:
Due to inadequate mineralocorticoids:
Due to excess androgens:
Due to insufficient androgens and estrogens:
Each form of CAH is associated with a specific defective gene. The most common type involves the gene for 21-hydroxylase, which is found on 6p21.3 as part of the HLA complex. 21-hydroxylase deficiency results from a unique mutation with two highly homologous near-copies in series consisting of an active gene and an inactive pseudogene. Mutant alleles result from recombination between the active and pseudogenes. About 5% of cases of CAH are due to defects in the gene encoding 11β-hydroxylase and consequent 11β-hydroxylase deficiency. Other, more rare forms of CAH are caused by mutations in genes including HSD3B2, CYP17A1, CYP11A1, STAR, CYB5A, and CYPOR.

Expressivity

Further variability is introduced by the degree of enzyme inefficiency produced by the specific alleles each patient has. Some alleles result in more severe degrees of enzyme inefficiency. In general, severe degrees of inefficiency produce changes in the fetus and problems in prenatal or perinatal life. Milder degrees of inefficiency are usually associated with excessive or deficient sex hormone effects in childhood or adolescence, while the mildest forms of CAH interfere with ovulation and fertility in adults.

Diagnosis

Clinical evaluation

Female infants with classic CAH have ambiguous genitalia due to exposure to high concentrations of androgens in utero. CAH due to 21-hydroxylase deficiency is the most common cause of ambiguous genitalia in genotypically normal female infants. Less severely affected females may present with early pubarche. Young women may present with symptoms of polycystic ovarian syndrome.
Males with classic CAH generally have no signs of CAH at birth. Some may present with hyperpigmentation, due to co-secretion with melanocyte-stimulating hormone, and possible penile enlargement. Age of diagnosis of males with CAH varies and depends on the severity of aldosterone deficiency. Boys with salt-wasting disease present early with symptoms of hyponatremia and hypovolemia. Boys with non-salt-wasting disease present later with signs of virilization.
In rarer forms of CAH, males are undermasculinized and females generally have no signs or symptoms at birth.

Laboratory studies

Genetic analysis can be helpful to confirm a diagnosis of CAH but it is not necessary if classic clinical and laboratory findings are present.
In classic 21-hydroxylase deficiency, laboratory studies will show:
Classic 21-hydroxylase deficiency typically causes 17α-hydroxyprogesterone blood levels >242 nmol/L. Salt-wasting patients tend to have higher 17α-hydroxyprogesterone levels than non-salt-wasting patients. In mild cases, 17α-hydroxyprogesterone may not be elevated in a particular random blood sample, but it will rise during a corticotropin stimulation test.

Classification

Cortisol is an adrenal steroid hormone that is required for normal endocrine function. Production begins in the second month of fetal life. Poor cortisol production is a hallmark of most forms of CAH. Inefficient cortisol production results in rising levels of ACTH, because cortisol feeds back to inhibit ACTH production, so loss of cortisol results in increased ACTH. This increased ACTH stimulation induces overgrowth and overactivity of the steroid-producing cells of the adrenal cortex. The defects causing adrenal hyperplasia are congenital.
. The enzymes affected in CAH are represented by one red and four green bars on the top half of the diagram. Depending upon which enzyme is unavailable, there is a reduced production of androgens or mineralocorticoids. This in turn can lead to increased production of other molecules, due to a buildup of precursors.
Cortisol deficiency in CAH is usually partial, and not the most serious problem for an affected person. Synthesis of cortisol shares steps with synthesis of mineralocorticoids such as aldosterone, androgens such as testosterone, and estrogens such as estradiol. The resulting excessive or deficient production of these three classes of hormones produce the most important problems for people with CAH. Specific enzyme inefficiencies are associated with characteristic patterns of over- or underproduction of mineralocorticoids or sex steroids.
Since the 1960s most endocrinologists have referred to the forms of CAH by the traditional names in the left column, which generally correspond to the deficient enzyme activity. As exact structures and genes for the enzymes were identified in the 1980s, most of the enzymes were found to be cytochrome P450 oxidases and were renamed to reflect this. In some cases, more than one enzyme was found to participate in a reaction, and in other cases a single enzyme mediated in more than one reaction. There was also variation in different tissues and mammalian species.
In all its forms, congenital adrenal hyperplasia due to 21-hydroxylase deficiency accounts for about 95% of diagnosed cases of CAH. Unless another specific enzyme is mentioned, "CAH" in nearly all contexts refers to 21-hydroxylase deficiency. CAH due to deficiencies of enzymes other than 21-hydroxylase present many of the same management challenges as 21-hydroxylase deficiency, but some involve mineralocorticoid excess or sex steroid deficiency.
Common medical term%OMIMEnzymeLocusSubstrateProductMineralocorticoidsAndrogens
21-Hydroxylase CAH90–95%P450c216p21.317-OH-Progesterone→
Progesterone→		11-Deoxycortisol
DOC		↓↑
11β-Hydroxylase CAH5%P450c11β8q21-2211-Deoxycortisol→
DOC→		Cortisol
Corticosterone		↑↑
3β-HSD CAHVery rare3βHSD21p13Pregnenolone→
17-OH-Pregnenolone→
DHEA→		Progesterone
17-OH-Progesterone
Androstenedione		↓↓
17α-Hydroxylase CAHVery rareCYP17A110q24.3Pregnenolone→
Progesterone→
17-OH-Pregnenolone→		17-OH-Pregnenolone
17-OH-Progesterone
DHEA		↑↓
Lipoid CAH
Very rareStAR
P450scc		8p11.2
15q23-q24		Transport of cholesterol
Cholesterol→		Into mitochondria
Pregnenolone		↓↓

Screening

Currently, in the United States and over 40 other countries, every child born is screened for 21-hydroxylase CAH at birth. This test will detect elevated levels of 17α-hydroxyprogesterone. Detecting high levels of 17-OHP enables early detection of CAH. Newborns detected early enough can be placed on medication and live a relatively normal life.
The screening process, however, is characterized by a high false positive rate. In one study, CAH screening had the lowest positive predictive value. According to this estimate, 200 unaffected newborns required clinical and laboratory follow-up for every true case of CAH.

Treatment

Treatment of all forms of CAH may include any of:
  1. Supplying enough glucocorticoid to reduce hyperplasia and overproduction of androgens or mineralocorticoids
  2. Providing replacement mineralocorticoid and extra salt if the person is deficient
  3. Providing replacement testosterone or estrogens at puberty if the person is deficient
  4. Additional treatments to optimize growth by delaying puberty or delaying bone maturation
All of these management issues are discussed in more detail in congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Dexamethasone is used as an off-label early prenatal treatment for the symptoms of CAH in female fetuses, but it does not treat the underlying congenital disorder. A 2007 Swedish clinical trial found that treatment may cause cognitive and behavioural defects, but the small number of test subjects means the study cannot be considered definitive. A 2012 American study found no negative short term outcomes, but "lower cognitive processing in CAH girls and women with long-term DEX exposure." Administration of pre-natal dexamethasone has been the subject of controversy over issues of informed consent and because treatment must predate a clinical diagnosis of CAH in the female fetus, especially because in utero dexamethasone may cause metabolic problems that are not evident until later in life; Swedish clinics ceased recruitment for research in 2010.
The treatment has also raised concerns in LGBT and bioethics communities following publication of an essay posted to the forum of the Hastings Center, and research in the Journal of Bioethical Inquiry, which found that pre-natal treatment of female fetuses was suggested to prevent those fetuses from becoming lesbians after birth, may make them more likely to engage in "traditionally" female-identified behaviour and careers, and more interested in bearing and raising children. Citing a known attempt by a man using his knowledge of the fraternal birth order effect to avoid having a homosexual son by using a surrogate, the essayists suggest that pre-natal "dex" treatments constitute the first known attempt to use in utero protocols to reduce the incidence of homosexuality and bisexuality in humans. Research on the use of prenatal hormone treatments to prevent homosexuality stretches back to the early 1990s or earlier.
Since CAH is a recessive gene, both the mother and father must be recessive carriers of CAH for a child to have CAH. Due to advances in modern medicine, those couples with the recessive CAH genes have an option to prevent CAH in their offspring through preimplantation genetic diagnosis. In PGD, the egg is fertilized outside the women's body in a petri dish. On the 3rd day, when the embryo has developed from one cell to about 4 to 6 cells, one of those cells is removed from the embryo without harming the embryo. The embryo continues to grow until day 5 when it is either frozen or implanted into the mother. Meanwhile, the removed cell is analyzed to determine if the embryo has CAH. If the embryo is determined to have CAH, the parents may make a decision as to whether they wish to have it implanted in the mother or not.
Meta-analysis of the studies supporting the use of dexamethasone on CAH at-risk fetuses found "less than one half of one percent of published 'studies' of this intervention were regarded as being of high enough quality to provide meaningful data for a meta-analysis. Even these four studies were of low quality"... "in ways so slipshod as to breach professional standards of medical ethics" and "there were no data on long-term follow-up of physical and metabolic outcomes in children exposed to dexamethasone".

Epidemiology

The incidence varies geographically. In the United States, congenital adrenal hyperplasia is particularly common in Native Americans and Yupik Eskimos.
Continued treatment and wellness is enhanced by education and follow up.

History

Before 20th century

An Italian anatomist, Luigi De Crecchio provided the earliest known description of a case of probable CAH.
I propose in this narrative that it is sometimes extremely difficult and even impossible to determine sex during life. In one of the anatomical theaters of the hospital..., there arrived toward the end of January a cadaver which in life was the body of a certain Joseph Marzo... The general physiognomy was decidedly male in all respects. There were no feminine curves to the body. There was a heavy beard. There was some delicacy of structure with muscles that were not very well developed... The distribution of pubic hair was typical of the male. Perhaps the lower extremities were somewhat delicate, resembling the female, and were covered with hair... The penis was curved posteriorly and measured 6 cm, or with stretching, 10 cm. The corona was 3 cm long and 8 cm in circumference. There was an ample prepuce. There was a first grade hypospadias... There were two folds of skin coming from the top of the penis and encircling it on either side. These were somewhat loose and resembled labia majora.

De Crecchio then described the internal organs, which included a normal vagina, uterus, fallopian tube, and ovaries.
It was of the greatest importance to determine the habits, tendencies, passions, and general character of this individual... I was determined to get as complete a story as possible, determined to get at the base of the facts and to avoid undue exaggeration which was rampant in the conversation of many of the people present at the time of the dissection.

He interviewed many people and satisfied himself that Joseph Marzo "conducted himself within the sexual area exclusively as a male", even to the point of contracting the "French disease" on two occasions. The cause of death was another in a series of episodes of vomiting and diarrhea.
This account was translated by Alfred Bongiovanni from De Crecchio in 1963 for an article in The New England Journal of Medicine.

20th and 21st century

The association of excessive sex steroid effects with diseases of the adrenal cortex have been recognized for over a century. The term adrenogenital syndrome was applied to both sex-steroid producing tumors and severe forms of CAH for much of the 20th century, before some of the forms of CAH were understood. Congenital adrenal hyperplasia, which also dates to the first half of the century, has become the preferred term to reduce ambiguity and to emphasize the underlying pathophysiology of the disorders.
Much of our modern understanding and treatment of CAH comes from research conducted at Johns Hopkins Medical School in Baltimore in the middle of the 20th century. Lawson Wilkins, "founder" of pediatric endocrinology, worked out the apparently paradoxical pathophysiology: that hyperplasia and overproduction of adrenal androgens resulted from impaired capacity for making cortisol. He reported use of adrenal cortical extracts to treat children with CAH in 1950. Genital reconstructive surgery was also pioneered at Hopkins. After application of karyotyping to CAH and other intersex disorders in the 1950s, John Money, JL Hampson, and JG Hampson persuaded both the scientific community and the public that sex assignment should not be based on any single biological criterion, and gender identity was largely learned and has no simple relationship with chromosomes or hormones. See Intersex for a fuller history, including recent controversies over reconstructive surgery.
Hydrocortisone, fludrocortisone, and prednisone were available by the late 1950s. By 1980 all of the relevant steroids could be measured in blood by reference laboratories for patient care. By 1990 nearly all specific genes and enzymes had been identified.
However, the last decade has seen a number of new developments, discussed more extensively in congenital adrenal hyperplasia due to 21-hydroxylase deficiency:
  1. Debate over the value of genital reconstructive surgery and changing standards
  2. Debate over sex assignment of severely virilized XX infants
  3. New treatments to improve height outcomes
  4. Newborn screening programs to detect CAH at birth
  5. Increasing attempts to treat CAH before birth