Congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Encyclopedia
Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21-OH CAH), in all its forms, accounts for over 95% of diagnosed cases of congenital adrenal hyperplasia
, and "CAH" in most contexts refers to 21-hydroxylase
deficiency. An overview of the other types of CAH are presented in the main article
.
The salt-wasting and simple virilizing types are sometimes grouped together as "classical".
The CYP21A2
gene for the P450c21 enzyme (also known as 21-hydroxylase
) is at 6p21.3, amid genes HLA B and HLA DR coding for the major human histocompatibility loci (HLA
). CYP21A2 is paired with a nonfunctional pseudogene
CYP21A1P. Scores of abnormal allele
s of CYP21A2 have been documented, most arising from recombination
s of homologous regions of CYP21A2 and CYP21A1P. Differences in residual enzyme activity of the various alleles account for the various degrees of severity of the disease. Inheritance of all forms of 21-hydroxylase CAH is autosomal recessive.
Persons affected by any forms of the disease have two abnormal alleles, and both parents are usually heterozygotes (or carriers
). When both parents carry an abnormal allele, each child has a 25% chance of having the disease, a 50% chance of being a carrier like the parents, and a 25% chance of having two normal genes.
It is now possible to test for heterozygosity by measuring 17-hydroxyprogesterone elevation after ACTH stimulation, or more recently by direct gene sequencing.
The incidence of 21-hydroxylase deficient CAH detectable in childhood is about 1 in 15,000 births. The severe salt-wasting form accounts for the majority of these cases, which is high enough that many states and countries routinely include it in mandated newborn screening
tests. The incidence of simple virilizing CAH is about 1 in 60,000 children.
The defective enzyme P450c21, commonly referred to as 21-hydroxylase (21-OH), is embedded in the smooth endoplasmic reticulum
of the cells of the adrenal cortex
. It catalyzes hydroxylation
of 17-hydroxyprogesterone
to 11-deoxycortisol in the glucocorticoid
pathway from pregnenolone
to cortisol
. It also catalyzes hydroxylation of progesterone
to 11-deoxycorticosterone (DOC) in the mineralocorticoid
pathway on its way from pregnenolone to aldosterone
.
Deficient activity of this enzyme reduces the efficiency of cortisol synthesis, with consequent hyperplasia of the adrenal cortex and elevation of ACTH levels. ACTH stimulates uptake of cholesterol
and synthesis of pregnenolone. Steroid precursors up to and including progesterone, 17-hydroxypregnenolone, and especially 17-hydroxyprogesterone (17OHP) accumulate in the adrenal cortex and in circulating blood. Blood levels of 17OHP can reach 10-1000 times the normal concentration.
Since 21-hydroxylase activity is not involved in synthesis of androgen
s, a substantial fraction of the large amounts of 17-hydroxypregnenolone is diverted to synthesis of DHEA, androstenedione
, and testosterone
beginning in the third month of fetal life in both sexes.
Synthesis of aldosterone
is also dependent on 21-hydroxylase activity. Although fetal production is impaired, it causes no prenatal effects, as the placenta
l connection allows maternal blood to "dialyze
" the fetus and maintain both electrolyte
balance and blood volume.
, he will appear healthy and normal and be quickly discharged home to his family.
However, the lack of aldosterone results in a high rate of sodium
loss in the urine. Urinary sodium concentrations may exceed 50 mEq/L. With this rate of salt loss, the infant cannot maintain blood volume, and hyponatremic
dehydration
begins to develop by the end of the first week of life. Potassium
and acid
excretion are also impaired when mineralocorticoid
activity is deficient, and hyperkalemia
and metabolic acidosis
gradually develop. Ability to maintain circulation is further limited by the effect of cortisol deficiency. The early symptoms are spitting and poor weight gain, but most infants with severe CAH develop vomiting, severe dehydration, and circulatory collapse (shock) by the second or third week of life.
When brought to a hospital, the 1-3 week old infant will be both underweight and dehydrated by appearance. Blood pressure may be low. Basic chemistries will reveal hyponatremia
, with a serum Na+ typically between 105 and 125 mEq/L. Hyperkalemia
in these infants can be extreme—levels of K+ above 10 mEq/L are not unusual—as can the degree of metabolic acidosis
. Hypoglycemia
may be present. This is termed a salt-wasting crisis and rapidly causes death if not treated.
As ill as these infants can be, they respond rapidly to treatment with hydrocortisone and intravenous saline and dextrose quickly restores blood volume, blood pressure, and body sodium content, and reverses the hyperkalemia. With appropriate treatment, most infants are out of danger within 24 hours.
are normal and since they have not been exposed to testicular antimullerian hormone (MIF), the uterus
, fallopian tube
s, upper vagina
, and other mullerian structures are normally formed as well. However, the high levels of testosterone in the blood can enlarge the phallus
, partially or completely close the vaginal opening, enclose the urethra
l groove so that it opens at the base of the phallus, on the shaft or even at the tip like a boy. Testosterone can cause the labial skin to become as thin and rugated as a scrotum
, but cannot produce palpable gonads (i.e., testes) in the folds.
Thus, depending on the severity of hyperandrogenism, a female infant can be mildly affected, obviously ambiguous, or so severely virilized as to appear to be a male. Andrea Prader devised the following Prader scale as a way of describing the degree of virilization.
When the genitalia are determined to be ambiguous at birth, CAH is one of the leading diagnostic possibilities. Evaluation reveals the presence of a uterus, extreme elevation of 17OHP, levels of testosterone approaching or exceeding the male range but low AMH levels. The karyotype is that of an ordinary female: 46,XX. With this information, the diagnosis of CAH is readily made and female sex confirmed.
Evaluation of ambiguous genitalia is described in detail elsewhere. In most cases it is possible to confirm and assign
female sex within 12–36 hours of birth. The exception are the rare, completely virilized genetic females (Prader stage 5), who present the most challenging assignment and surgery dilemmas, discussed below.
When the degree of ambiguity is obvious, corrective surgery is usually offered and performed. As reconstructive surgery on infant genitalia has become a focus of controversy, the issues are described in more detail below.
appropriate sex for most infants with CAH. Genetic males have normal male genitalia and gonads and simply need hormone replacement. Most virilized females are assigned and raised as girls even if their genitalia are ambiguous or look more male than female. They have normal ovaries and uterus and potential fertility with hormone replacement and surgery
. However, the dilemmas surrounding sex assignment
of the most severely virilized XX infants have helped shape our understanding of gender identity
and sexual orientation
, and continue to be a subject of debate.
Until the 1950s, some virilized XX infants were assigned and raised as girls, and some as boys. Most developed gender identities congruent with their sex of rearing. In a few cases of male rearing, a sex reassignment
was attempted in mid-childhood when newly discovered karyotyping revealed "female" chromosomes. These reassignments were rarely successful, leading John Money
and other influential psychologists and physicians to conclude that gender identity was (1) unrelated to chromosomes, (2) primarily a result of social learning, and (3) could not be easily changed after infancy.
By the 1960s, CAH was well understood, karyotyping
was routine, and standard management was to assign and raise all children with CAH according to their gonad
s and karyotypes, no matter how virilized. Markedly virilized girls were usually referred to a pediatric surgeon
, often a pediatric urologist
for a reconstructive vaginoplasty and clitoral reduction
or recession—surgery to create or enlarge a vaginal opening and reduce the size or protrusion of the clitoris. This approach was designed to preserve fertility for both sexes and remains the standard management, but two aspects of this management have been challenged: assignment of completely virilized genetic females and the value and age of corrective surgery.
The first questions about assignment were raised in the early 1980s when Money and others reported an unexpectedly high rate of failure to achieve normal adult sexual relationships (i.e., heterosexual orientation, marriage, and children) in grown women with CAH (though all had female gender identities). However, the sample was small, and results seemed interpretable in many ways: selection bias, early hormone effects on orientation, sexual dysfunction created by residual body abnormalities, or by the genital surgery itself. From a perspective two decades later, the report was one of the first pieces of evidence that the standard management paradigm was not always producing hoped-for outcomes.
Despite these concerns, no significant opposition to standard management arose until the mid-1990s, when a confluence of evidence and opinion from several sources led to a re-examination of outcomes. Several intersex support and advocacy groups (e.g., Intersex Society of North America
) began to publicly criticize infant genital surgery based on unsatisfactory outcomes of some adults who had been operated on as infants. Their complaints were that they had reduced ability to enjoy sexual relations or that they resented not having had the choice of gender assignment or surgical reconstruction left until they were old enough to participate. (See History of intersex surgery
.)
In 1997, influential articles by Reiner, Diamond
, and Sigmundson advocated consideration of (1) male sex assignment in the unambiguously male XX infants (most of whom are considered male until the CAH is recognized at 1–2 weeks of age), and (2) delaying reconstructive surgery until the patient is old enough to participate in the decision. (See Ambiguous genitalia and Intersex
for more on this debate, as well as complete citations.)
Although the standard management approach remains "standard", more time and consideration are being given in many cases to explaining alternatives to parents and a small number of XX children with unambiguously male external genitalia are again being raised as boys.
. After the diagnosis is confirmed, and any salt-wasting crisis averted or reversed, major management issues include
and to suppress the excessive adrenal androgen
production.
Glucocorticoid
s are provided to all children and adults with all but the mildest and latest-onset forms of CAH. The glucocorticoids provide a reliable substitute for cortisol
, thereby reducing ACTH levels. Reducing ACTH also reduces the stimulus for continued hyperplasia and overproduction of androgens. In other words, glucocorticoid replacement is the primary method of reducing the excessive adrenal androgen production in both sexes. A number of glucocorticoids are available for therapeutic use. Hydrocortisone or liquid prednisolone
is preferred in infancy and childhood, and prednisone
or dexamethasone
are often more convenient for adults.
The glucocorticoid dose is typically started at the low end of physiologic replacement (6–12 mg/m² but is adjusted throughout childhood to prevent both growth suppression from too much glucocorticoid and androgen escape from too little. Serum levels of 17OHP
, testosterone
, androstenedione
, and other adrenal steroids are followed for additional information, but may not be entirely normalized even with optimal treatment. (See Glucocorticoid
for more on this topic.)
Mineralocorticoid
s are replaced in all infants with salt-wasting and in most patients with elevated renin
levels. Fludrocortisone
is the only pharmaceutically available mineralocorticoid and is usually used in doses of 0.05 to 2 mg daily. Electrolyte
s, renin, and blood pressure
levels are followed to optimize the dose.
To prevent this, all persons taking replacement glucocorticoids are taught to increase their doses in the event of illness, surgery, severe injury, or severe exhaustion. More importantly, they are taught that vomiting warrants an injection within hours of hydrocortisone (e.g., SoluCortef) or other glucocorticoid. This recommendation applies to both children and adults. Because young children are more susceptible to vomiting illnesses than adults, pediatric endocrinologists usually teach parents how to give hydrocortisone injections.
As an additional precaution, persons with adrenal insufficiency
are advised to wear a medical identification tag
or carry a wallet card to alert those who may be providing emergency medical care of the urgent need for glucocorticoids.
for severely virilized XX infants is often performed and has become a subject of debate
in the last decade.
Surgical reconstruction of abnormal genitalia has been offered to parents of severely virilized girls with CAH since the first half of the 20th century. The purposes of surgery have generally been a combination of:
In the 1950s and 1960s, surgery often involved clitorectomy (removal of most of clitoris), an operation that also reduced genital sensation. In the 1970s, new operative methods were developed to preserve innervation and clitoral function. However, a number of retrospective surveys in the last decade suggest that (1) sexual enjoyment is reduced in many women even after nerve-sparing procedures, and (2) women with CAH who have not had surgery also have a substantial rate of sexual dysfunction. (See Intersex surgery
for an overview of procedures and potential complications, and History of intersex surgery
for a fuller discussion of the controversies.) Many patient advocates and surgeons argue for deferring surgery until adolescence or later, while some surgeons continue to argue that infant surgery has advantages.
, which accelerates bone maturation
and can lead to early epiphyseal
closure. This narrow target of optimal dose is made more difficult to obtain by the imperfect replication of normal diurnal plasma cortisol levels produced by 2 or 3 oral doses of hydrocortisone. As a consequence, average height losses of about 4 inches (10 cm) have been reported with traditional management.
Traditionally, pediatric endocrinologists have tried to optimize growth by measuring a child every few months to assess current rate of growth, by checking the bone age
every year or two, by periodically measuring 17OHP and testosterone
levels as indicators of adrenal suppression, and by using hydrocortisone for glucocorticoid replacement rather than longer-acting prednisone
or dexamethasone
.
The growth problem is even worse in the simple virilizing forms of CAH which are detected when premature pubic hair
appears in childhood, because the bone age
is often several years advanced at the age of diagnosis. While a boy (or girl) with simple virilizing CAH is taller than peers at that point, he will have far fewer years remaining to grow, and may go from being a very tall 7-year-old to a 62-inch 13-year-old who has completed growth. Even with adrenal suppression, many of these children will have already had central precocious puberty
triggered by the prolonged exposure of the hypothalamus
to the adrenal androgens and estrogens. If this has begun, it may be advantageous to suppress puberty with a gonadotropin-releasing hormone
agonist such as leuprolide
to slow continuing bone maturation.
In recent years some newer approaches to optimizing growth have been researched and are beginning to be used. It is possible to reduce the effects of androgens on the body by blocking the receptors with an antiandrogen such as flutamide
and by reducing the conversion of testosterone to estradiol. This conversion is mediated by aromatase
and can be inhibited by aromatase blockers such as testolactone
. Blocking the effects and conversions of estrogens will allow use of lower doses of glucocorticoids with less risk of acceleration of bone maturation. Other proposed interventions have included bilateral adrenalectomy to remove the androgen sources, or growth hormone treatment
to enhance growth.
For a more extensive review of the difficulties of optimizing growth, see Migeon CJ, Wisneiewski AB. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency: growth, development, and therapeutic considerations. Endocrinol Metab Clin N Am 30:193-206, 2001.
, resulting in irregularity of menses
or amenorrhea, as well as infertility
. Continued monitoring of hormone balance and careful readjustment of glucocorticoid dose can usually restore fertility, but as a group, women with CAH have a lower fertility rate than a comparable population.
CAH has little effect on male fertility unless an adult stops taking his glucocorticoid medication entirely for an extended period of time, in which case excessive adrenal testosterone may reduce testicular production as well as spermatogenesis.
s display sex-dimorphic
reproductive and sexual behavior (e.g., lordosis
and mounting in rodent
s). Much research has made it clear that prenatal and early postnatal androgens play a role in the differentiation of most mammalian brains. Experimental manipulation of androgen levels in utero or shortly after birth can alter adult reproductive behavior.
Girls and women with CAH constitute the majority of genetic females with normal internal reproductive hormones who have been exposed to male levels of testosterone throughout their prenatal lives. Milder degrees of continuing androgen exposure continue throughout childhood and adolescence as a consequence of the imperfections of current glucocorticoid treatment for CAH. The psychosexual development of these girls and women has been analyzed as evidence of the role of androgens in human sex-dimorphic behaviors.
Girls with CAH have repeatedly been reported to spend more time with "sex-atypical" toys and "rough-and-tumble" play than unaffected sisters. These differences continue into adolescent, as expressed in social behaviors, leisure activities, and career interests. Interest in babies and becoming mothers is significantly lower by most measures.
Cognitive effects are less clear and reports have been contradictory. Two studies reported spatial abilities above the average for sisters and for girls in general. Other evidence in males with and without androgen deficiencies suggest that androgens may play a role in these aptitudes.
However, gender identity of girls and women with CAH is nearly always unequivocally female. Sexual orientation is more mixed, though the majority are heterosexual. In one study, 27% of women with CAH were rated as bisexual in their orientations. Abnormalities of body image due to the effects of the disease likely play a role in the sexual development of these women, and one cannot conclude that the androgens are the major determinant of their sexuality.
for any disorder include (1) a simple test with an acceptable sensitivity and specificity, (2) a dire consequence if not diagnosed early, (3) an effective treatment if diagnosed, and (4) a frequency in the population high enough to justify the expense. In the last decade more states and countries are adopting newborn screening for salt-wasting CAH due to 21-hydroxylase deficiency, which leads to death in the first month of life if not recognized.
The salt-wasting form of CAH has an incidence of 1 in 15,000 births, is potentially fatal within a month if untreated, and steroid replacement is a simple, effective treatment. However, the screening test itself is less than perfect. While the 17OHP
level is easy to measure and sensitive (rarely missing real cases), the test has a poorer specificity. Screening programs in the United States have reported that 99% of positive screens turn out to be false positives upon investigation of the infant. This is a higher rate of false positives than the screening tests for many other congenital metabolic diseases.
When a positive result is detected, the infant must be referred to a pediatric endocrinologist to confirm or disprove the diagnosis. Since most infants with salt-wasting CAH become critically ill by 2 weeks of age, the evaluation must be done rapidly despite the high false positive rate.
Levels of 17-hydroxyprogesterone
, androstenedione
, and cortisol
may play a role in screening.
of a girl. There is no known prenatal harm to a male fetus from CAH, so treatment can begin at birth.
Adrenal glands of female fetuses with CAH begin producing excess testosterone
by the 9th week of gestation. The most important aspects of virilization (urogenital closure and phallic urethra) occur between 8 and 12 weeks. Theoretically, if enough glucocorticoid
could be supplied to the fetus to reduce adrenal testosterone production by the 9th week, virilization could be prevented and the difficult decision about timing of surgery
avoided.
The challenge of preventing severe virilization of girls is twofold: detection of CAH at the beginning of the pregnancy, and delivery of an effective amount of glucocorticoid to the fetus without causing harm to the mother.
The first problem has not yet been entirely solved, but it has been shown that if dexamethasone
is taken by a pregnant woman enough can cross the placenta to suppress fetal adrenal function.
At present no program screens for risk in families who have not yet had a child with CAH. For families desiring to avoid virilization of a second child, the current strategy is to start dexamethasone as soon as a pregnancy has been confirmed even though at that point the chance that the pregnancy is a girl with CAH is only 12.5%. Dexamethasone is taken by the mother each day until it can be safely determined whether she is carrying an affected girl.
Whether the fetus is an affected girl can be determined by chorionic villus sampling
at 9–11 weeks of gestation, or by amniocentesis
at 15–18 weeks gestation. In each case the fetal sex can be determined quickly, and if the fetus is a male the dexamethasone can be discontinued. If female, fetal DNA
is analyzed to see if she carries one of the known abnormal alleles of the CYP21 gene. If so, dexamethasone is continued for the remainder of the pregnancy at a dose of about 1 mg daily.
Most mothers who have followed this treatment plan have experienced at least mild cushingoid
effects from the glucocorticoid, but have borne daughters whose genitalia are much less virilized.
deficiency is less significant and salt-wasting does not occur. However, genital ambiguities are possible.
excess is mild enough that virilization
is not apparent or goes unrecognized at birth and in early childhood. However, androgen levels are above normal and slowly rise during childhood, producing noticeable effects between 2 and 9 years of age.
Appearance of pubic hair
in mid-childhood is the most common feature that leads to evaluation and diagnosis. Other accompanying features are likely to be tall stature and accelerated bone age
(often 3–5 years ahead). Often present are increased muscle mass, acne
, and adult body odor
. In boys the penis
will be enlarged. Mild clitoral
enlargement may occur in girls, and sometimes a degree of prenatal virilization is recognized that may have gone unnoticed in infancy.
The principal goals of treatment of non-classical CAH are to preserve as much growth as possible and to prevent central precocious puberty
if it has not already been triggered. These are more difficult challenges than in CAH detected in infancy because moderate levels of androgen
s will have had several years to advance bone maturation and to trigger central puberty
before the disease is detected.
A diagnosis of non-classical CAH is usually confirmed by discovering extreme elevations of 17-hydroxyprogesterone
along with moderately high testosterone levels. A cosyntropin stimulation test may be needed in mild cases, but usually the random levels of 17OHP are high enough to confirm the diagnosis.
The mainstay of treatment is suppression of adrenal testosterone production by a glucocorticoid
such as hydrocortisone. Mineralocorticoid is only added in cases where the plasma renin
activity is high.
A third key aspect of management is suppression of central precocious puberty if it has begun. The usual clues to central puberty in boys are that the testes are pubertal in size, or that testosterone remains elevated even when the 17OHP has been reduced toward normal. In girls central puberty is less often a problem, but breast development would be the main clue. Central precocious puberty is suppressed when appropriate by leuprolide
.
As outlined above, recent additions to treatment to preserve growth include aromatase
inhibition to slow bone maturation by reducing the amount of testosterone converted to estradiol
, and use of blockers of estrogen for the same purpose.
Once adrenal suppression has been achieved, the patient needs stress steroid coverage as described above for significant illness of injury.
Other alleles result in even milder degrees of hyperandrogenism that may not even cause problems in males and may not be recognized until adolescence or later in females. Mild androgen effects in young women may include hirsutism
, acne, or anovulation
(which in turn can cause infertility
). Testosterone levels in these women may be mildly elevated, or simply above average. These clinical features, of course, are those of polycystic ovary syndrome
, and a small percentage of women with PCOS are found to have late-onset CAH when investigated.
Diagnosis of late-onset CAH may be suspected from a high 17-hydroxyprogesterone level, but some cases are so mild that the elevation is only demonstrable after cosyntropin
stimulation. Treatment may involve a combination of very low dose glucocorticoid to reduce adrenal androgen production and any of various agents to block the androgen effects and/or induce ovulation.
It was characterized in 1979. Prevalence has been described as 1 in 100 in certain populations.
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
, and "CAH" in most contexts refers to 21-hydroxylase
21-Hydroxylase
Steroid 21-hydroxylase is a cytochrome P450 enzyme that is involved with the biosynthesis of the steroid hormones aldosterone and cortisol.In humans, 21-Hydroxylase is encoded by the gene CYP21A2.-Names and classification:...
deficiency. An overview of the other types of CAH are presented in the main article
Congenital adrenal hyperplasia
Congenital adrenal hyperplasia refers to any of several autosomal recessive diseases resulting from mutations of genes for enzymes mediating the biochemical steps of production of cortisol from cholesterol by the adrenal glands ....
.
Degree of severity
The condition can be classified into "salt-wasting", "simple virilizing", and "non-classical" forms.| Type | Sex steroid Sex steroid Sex steroids, also known as gonadal steroids, are steroid hormones that interact with vertebrate androgen or estrogen receptors. Their effects are mediated by slow genomic mechanisms through nuclear receptors as well as by fast nongenomic mechanisms through membrane-associated receptors and... effects |
Other effects |
|---|---|---|
| Severe 21-hydroxylase deficiency causes salt-wasting CAH | The most common cause of ambiguous genitalia due to prenatal virilization Virilization In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens... of genetically female (XX) infants. |
Life-threatening vomiting and dehydration Dehydration In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism... occurring within the first few weeks of life. Aldosterone and cortisol levels are both reduced. |
| Moderate 21-hydroxylase deficiency is referred to as simple virilizing CAH | Typically is recognized as causing virilization of prepubertal children. | Cortisol is reduced, but aldosterone is not. |
| Still milder forms of 21-hydroxylase deficiency are referred to as non-classical CAH | Can cause androgen Androgen Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors... effects and infertility Infertility Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term... in adolescent and adult women. |
Neither aldosterone nor cortisol are reduced. |
The salt-wasting and simple virilizing types are sometimes grouped together as "classical".
Genetic prevalence
21-Hydroxylase
Steroid 21-hydroxylase is a cytochrome P450 enzyme that is involved with the biosynthesis of the steroid hormones aldosterone and cortisol.In humans, 21-Hydroxylase is encoded by the gene CYP21A2.-Names and classification:...
gene for the P450c21 enzyme (also known as 21-hydroxylase
21-Hydroxylase
Steroid 21-hydroxylase is a cytochrome P450 enzyme that is involved with the biosynthesis of the steroid hormones aldosterone and cortisol.In humans, 21-Hydroxylase is encoded by the gene CYP21A2.-Names and classification:...
) is at 6p21.3, amid genes HLA B and HLA DR coding for the major human histocompatibility loci (HLA
Human leukocyte antigen
The human leukocyte antigen system is the name of the major histocompatibility complex in humans. The super locus contains a large number of genes related to immune system function in humans. This group of genes resides on chromosome 6, and encodes cell-surface antigen-presenting proteins and...
). CYP21A2 is paired with a nonfunctional pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
CYP21A1P. Scores of abnormal allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
s of CYP21A2 have been documented, most arising from recombination
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
s of homologous regions of CYP21A2 and CYP21A1P. Differences in residual enzyme activity of the various alleles account for the various degrees of severity of the disease. Inheritance of all forms of 21-hydroxylase CAH is autosomal recessive.
Persons affected by any forms of the disease have two abnormal alleles, and both parents are usually heterozygotes (or carriers
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
). When both parents carry an abnormal allele, each child has a 25% chance of having the disease, a 50% chance of being a carrier like the parents, and a 25% chance of having two normal genes.
It is now possible to test for heterozygosity by measuring 17-hydroxyprogesterone elevation after ACTH stimulation, or more recently by direct gene sequencing.
The incidence of 21-hydroxylase deficient CAH detectable in childhood is about 1 in 15,000 births. The severe salt-wasting form accounts for the majority of these cases, which is high enough that many states and countries routinely include it in mandated newborn screening
Newborn screening
Newborn screening is the process by which infants are screened shortly after birth for a list of disorders that are treatable, but difficult or impossible to detect clinically. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the...
tests. The incidence of simple virilizing CAH is about 1 in 60,000 children.
Pathophysiology
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
of the cells of the adrenal cortex
Adrenal gland
In mammals, the adrenal glands are endocrine glands that sit atop the kidneys; in humans, the right suprarenal gland is triangular shaped, while the left suprarenal gland is semilunar shaped...
. It catalyzes hydroxylation
Hydroxylation
Hydroxylation is a chemical process that introduces a hydroxyl group into an organic compound. In biochemistry, hydroxylation reactions are often facilitated by enzymes called hydroxylases. Hydroxylation is the first step in the oxidative degradation of organic compounds in air...
of 17-hydroxyprogesterone
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
to 11-deoxycortisol in the glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
pathway from pregnenolone
Pregnenolone
Pregnenolone is a steroid hormone involved in the steroidogenesis of progesterone, mineralocorticoids, glucocorticoids, androgens, and estrogens. As such it is a prohormone. Pregnenolone sulfate is a GABAA antagonist and increases neurogenesis in the hippocampus.-Chemistry:Like other steroids,...
to cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
. It also catalyzes hydroxylation of progesterone
Progesterone
Progesterone also known as P4 is a C-21 steroid hormone involved in the female menstrual cycle, pregnancy and embryogenesis of humans and other species...
to 11-deoxycorticosterone (DOC) in the mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
pathway on its way from pregnenolone to aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
.
Deficient activity of this enzyme reduces the efficiency of cortisol synthesis, with consequent hyperplasia of the adrenal cortex and elevation of ACTH levels. ACTH stimulates uptake of cholesterol
Cholesterol
Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...
and synthesis of pregnenolone. Steroid precursors up to and including progesterone, 17-hydroxypregnenolone, and especially 17-hydroxyprogesterone (17OHP) accumulate in the adrenal cortex and in circulating blood. Blood levels of 17OHP can reach 10-1000 times the normal concentration.
Since 21-hydroxylase activity is not involved in synthesis of androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s, a substantial fraction of the large amounts of 17-hydroxypregnenolone is diverted to synthesis of DHEA, androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
, and testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
beginning in the third month of fetal life in both sexes.
Synthesis of aldosterone
Aldosterone
Aldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
is also dependent on 21-hydroxylase activity. Although fetal production is impaired, it causes no prenatal effects, as the placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
l connection allows maternal blood to "dialyze
Dialysis
In medicine, dialysis is a process for removing waste and excess water from the blood, and is primarily used to provide an artificial replacement for lost kidney function in people with renal failure...
" the fetus and maintain both electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
balance and blood volume.
Severe, early onset 21-hydroxylase deficient CAH
The two most serious neonatal consequences of 21-hydroxylase deficiency occur when there is minimal measurable hydroxylase activity from prenatal life: life-threatening salt-wasting crises in the first month of life for XX and XY infants alike and severe virilization of female infants.Salt-wasting crises in infancy
The excessive amounts of adrenal testosterone produce little effect on the genitalia of male infants with severe CAH. If a male infant with CAH is not detected by newborn screeningNewborn screening
Newborn screening is the process by which infants are screened shortly after birth for a list of disorders that are treatable, but difficult or impossible to detect clinically. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the...
, he will appear healthy and normal and be quickly discharged home to his family.
However, the lack of aldosterone results in a high rate of sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
loss in the urine. Urinary sodium concentrations may exceed 50 mEq/L. With this rate of salt loss, the infant cannot maintain blood volume, and hyponatremic
Hyponatremia
Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. In the vast majority of cases, hyponatremia occurs as a result of excess body water diluting the serum sodium and is not due to sodium deficiency. Sodium is the dominant extracellular...
dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
begins to develop by the end of the first week of life. Potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...
and acid
Acid
An acid is a substance which reacts with a base. Commonly, acids can be identified as tasting sour, reacting with metals such as calcium, and bases like sodium carbonate. Aqueous acids have a pH of less than 7, where an acid of lower pH is typically stronger, and turn blue litmus paper red...
excretion are also impaired when mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
activity is deficient, and hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
and metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
gradually develop. Ability to maintain circulation is further limited by the effect of cortisol deficiency. The early symptoms are spitting and poor weight gain, but most infants with severe CAH develop vomiting, severe dehydration, and circulatory collapse (shock) by the second or third week of life.
When brought to a hospital, the 1-3 week old infant will be both underweight and dehydrated by appearance. Blood pressure may be low. Basic chemistries will reveal hyponatremia
Hyponatremia
Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. In the vast majority of cases, hyponatremia occurs as a result of excess body water diluting the serum sodium and is not due to sodium deficiency. Sodium is the dominant extracellular...
, with a serum Na+ typically between 105 and 125 mEq/L. Hyperkalemia
Hyperkalemia
Hyperkalemia refers to the condition in which the concentration of the electrolyte potassium in the blood is elevated...
in these infants can be extreme—levels of K+ above 10 mEq/L are not unusual—as can the degree of metabolic acidosis
Metabolic acidosis
In medicine, metabolic acidosis is a condition that occurs when the body produces too much acid or when the kidneys are not removing enough acid from the body. If unchecked, metabolic acidosis leads to acidemia, i.e., blood pH is low due to increased production of hydrogen by the body or the...
. Hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
may be present. This is termed a salt-wasting crisis and rapidly causes death if not treated.
As ill as these infants can be, they respond rapidly to treatment with hydrocortisone and intravenous saline and dextrose quickly restores blood volume, blood pressure, and body sodium content, and reverses the hyperkalemia. With appropriate treatment, most infants are out of danger within 24 hours.
Virilization of female infants
Virilization of genetically female (XX) infants usually produces obvious genital ambiguity. Inside the pelvis, the ovariesOvary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
are normal and since they have not been exposed to testicular antimullerian hormone (MIF), the uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
, fallopian tube
Fallopian tube
The Fallopian tubes, also known as oviducts, uterine tubes, and salpinges are two very fine tubes lined with ciliated epithelia, leading from the ovaries of female mammals into the uterus, via the utero-tubal junction...
s, upper vagina
Vagina
The vagina is a fibromuscular tubular tract leading from the uterus to the exterior of the body in female placental mammals and marsupials, or to the cloaca in female birds, monotremes, and some reptiles. Female insects and other invertebrates also have a vagina, which is the terminal part of the...
, and other mullerian structures are normally formed as well. However, the high levels of testosterone in the blood can enlarge the phallus
Phallus
A phallus is an erect penis, a penis-shaped object such as a dildo, or a mimetic image of an erect penis. Any object that symbolically resembles a penis may also be referred to as a phallus; however, such objects are more often referred to as being phallic...
, partially or completely close the vaginal opening, enclose the urethra
Urethra
In anatomy, the urethra is a tube that connects the urinary bladder to the genitals for the removal of fluids out of the body. In males, the urethra travels through the penis, and carries semen as well as urine...
l groove so that it opens at the base of the phallus, on the shaft or even at the tip like a boy. Testosterone can cause the labial skin to become as thin and rugated as a scrotum
Scrotum
In some male mammals the scrotum is a dual-chambered protuberance of skin and muscle containing the testicles and divided by a septum. It is an extension of the perineum, and is located between the penis and anus. In humans and some other mammals, the base of the scrotum becomes covered with curly...
, but cannot produce palpable gonads (i.e., testes) in the folds.
Thus, depending on the severity of hyperandrogenism, a female infant can be mildly affected, obviously ambiguous, or so severely virilized as to appear to be a male. Andrea Prader devised the following Prader scale as a way of describing the degree of virilization.
- An infant at stage 1 has a mildly large clitorisClitorisThe clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not...
and slightly reduced vaginal opening size. This degree may go unnoticed or may be simply assumed to be within normal variation. - Stages 2 and 3 represent progressively more severe degrees of virlization. The genitalia are obviously abnormal to the eye, with a phallus intermediate in size and a small vaginal opening.
- Stage 4 looks more male than female, with an empty scrotum and a phallus the size of a normal penis, but not quite free enough of the perineum to be pulled onto the abdomen toward the umbilicus (i.e., what is termed a chordeeChordeeChordee is a condition in which the head of the penis curves downward or upward, at the junction of the head and shaft of the penis. The curvature is usually most obvious during erection, but resistance to straightening is often apparent in the flaccid state as well. In many cases but not all,...
in a male). The single small urethral/vaginal opening at the base or on the shaft of the phallus would be considered a hypospadiasHypospadiasHypospadias is a birth defect of the urethra in the male that involves an abnormally placed urinary meatus...
in a male. X-rays taken after dye injection into this opening reveal the internal connection with the upper vagina and uterus. This common opening can predispose to urinary obstruction and infectionUrinary tract infectionA urinary tract infection is a bacterial infection that affects any part of the urinary tract. Symptoms include frequent feeling and/or need to urinate, pain during urination, and cloudy urine. The main causal agent is Escherichia coli...
. - Stage 5 denotes complete male virilization, with a normally formed penis with the urethral opening at or near the tip. The scrotum is normally formed but empty. The internal pelvic organs include normal ovaries and uterus, and the vagina connects internally with the urethra as in Stage 4. These infants are not visibly ambiguous are usually assumed to be ordinary boys with undescended testesCryptorchidismCryptorchidism is the absence of one or both testes from the scrotum. It is the most common birth defect regarding male genitalia. In unique cases, cryptorchidism can develop later in life, often as late as young adulthood. About 3% of full-term and 30% of premature infant boys are born with at...
. In most cases, the diagnosis of CAH is not suspected until signs of salt-wasting develop a week later.
When the genitalia are determined to be ambiguous at birth, CAH is one of the leading diagnostic possibilities. Evaluation reveals the presence of a uterus, extreme elevation of 17OHP, levels of testosterone approaching or exceeding the male range but low AMH levels. The karyotype is that of an ordinary female: 46,XX. With this information, the diagnosis of CAH is readily made and female sex confirmed.
Evaluation of ambiguous genitalia is described in detail elsewhere. In most cases it is possible to confirm and assign
Sex assignment
Sex assignment refers to the assigning of the biological sex at the birth of a baby. In the majority of births, a relative, midwife, or physician inspects the genitalia when the baby is delivered, sees ordinary male or female genitalia, and declares, "it's a girl" or "it's a boy" without the...
female sex within 12–36 hours of birth. The exception are the rare, completely virilized genetic females (Prader stage 5), who present the most challenging assignment and surgery dilemmas, discussed below.
When the degree of ambiguity is obvious, corrective surgery is usually offered and performed. As reconstructive surgery on infant genitalia has become a focus of controversy, the issues are described in more detail below.
Sex assignment issues and controversies
There are no difficulties assigningSex assignment
Sex assignment refers to the assigning of the biological sex at the birth of a baby. In the majority of births, a relative, midwife, or physician inspects the genitalia when the baby is delivered, sees ordinary male or female genitalia, and declares, "it's a girl" or "it's a boy" without the...
appropriate sex for most infants with CAH. Genetic males have normal male genitalia and gonads and simply need hormone replacement. Most virilized females are assigned and raised as girls even if their genitalia are ambiguous or look more male than female. They have normal ovaries and uterus and potential fertility with hormone replacement and surgery
Intersex surgery
Intersex surgery is one of several terms referring to surgery performed to correct birth defects or early injuries of the genitalia, primarily for the purposes of making the appearance more normal and to reduce the likelihood of future problems...
. However, the dilemmas surrounding sex assignment
Sex assignment
Sex assignment refers to the assigning of the biological sex at the birth of a baby. In the majority of births, a relative, midwife, or physician inspects the genitalia when the baby is delivered, sees ordinary male or female genitalia, and declares, "it's a girl" or "it's a boy" without the...
of the most severely virilized XX infants have helped shape our understanding of gender identity
Gender identity
A gender identity is the way in which an individual self-identifies with a gender category, for example, as being either a man or a woman, or in some cases being neither, which can be distinct from biological sex. Basic gender identity is usually formed by age three and is extremely difficult to...
and sexual orientation
Sexual orientation
Sexual orientation describes a pattern of emotional, romantic, or sexual attractions to the opposite sex, the same sex, both, or neither, and the genders that accompany them. By the convention of organized researchers, these attractions are subsumed under heterosexuality, homosexuality,...
, and continue to be a subject of debate.
Until the 1950s, some virilized XX infants were assigned and raised as girls, and some as boys. Most developed gender identities congruent with their sex of rearing. In a few cases of male rearing, a sex reassignment
Sex reassignment
Sex reassignment may refer to:* Sex reassignment, changing the sex assignment of an infant or child by parents and doctors, usually because of fuller understanding of an intersex condition....
was attempted in mid-childhood when newly discovered karyotyping revealed "female" chromosomes. These reassignments were rarely successful, leading John Money
John Money
John William Money was a psychologist, sexologist and author, specializing in research into sexual identity and biology of gender...
and other influential psychologists and physicians to conclude that gender identity was (1) unrelated to chromosomes, (2) primarily a result of social learning, and (3) could not be easily changed after infancy.
By the 1960s, CAH was well understood, karyotyping
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
was routine, and standard management was to assign and raise all children with CAH according to their gonad
Gonad
The gonad is the organ that makes gametes. The gonads in males are the testes and the gonads in females are the ovaries. The product, gametes, are haploid germ cells. For example, spermatozoon and egg cells are gametes...
s and karyotypes, no matter how virilized. Markedly virilized girls were usually referred to a pediatric surgeon
Pediatric surgery
Pediatric surgery or paediatric surgery is a subspecialty of surgery involving the surgery of fetuses, infants, children, adolescents, and young adults...
, often a pediatric urologist
Pediatric urology
Pediatric urology is a surgical subspecialty of medicine dealing with the disorders of children's genitourinary systems. Pediatric urologists provide care for both boys and girls ranging from birth to early adult age...
for a reconstructive vaginoplasty and clitoral reduction
Intersex surgery
Intersex surgery is one of several terms referring to surgery performed to correct birth defects or early injuries of the genitalia, primarily for the purposes of making the appearance more normal and to reduce the likelihood of future problems...
or recession—surgery to create or enlarge a vaginal opening and reduce the size or protrusion of the clitoris. This approach was designed to preserve fertility for both sexes and remains the standard management, but two aspects of this management have been challenged: assignment of completely virilized genetic females and the value and age of corrective surgery.
The first questions about assignment were raised in the early 1980s when Money and others reported an unexpectedly high rate of failure to achieve normal adult sexual relationships (i.e., heterosexual orientation, marriage, and children) in grown women with CAH (though all had female gender identities). However, the sample was small, and results seemed interpretable in many ways: selection bias, early hormone effects on orientation, sexual dysfunction created by residual body abnormalities, or by the genital surgery itself. From a perspective two decades later, the report was one of the first pieces of evidence that the standard management paradigm was not always producing hoped-for outcomes.
Despite these concerns, no significant opposition to standard management arose until the mid-1990s, when a confluence of evidence and opinion from several sources led to a re-examination of outcomes. Several intersex support and advocacy groups (e.g., Intersex Society of North America
Intersex Society of North America
The Intersex Society of North America was a non-profit advocacy group founded in 1993 by Cheryl Chase to represent the interest of intersex people. Their objective was to end shame, secrecy, and unwanted genital surgeries...
) began to publicly criticize infant genital surgery based on unsatisfactory outcomes of some adults who had been operated on as infants. Their complaints were that they had reduced ability to enjoy sexual relations or that they resented not having had the choice of gender assignment or surgical reconstruction left until they were old enough to participate. (See History of intersex surgery
History of intersex surgery
The history of intersex surgery is intertwined with the development of the specialities of pediatric surgery, pediatric urology, and pediatric endocrinology, with our increasingly refined understanding of sexual differentiation, with the development of political advocacy groups united by a sexual...
.)
In 1997, influential articles by Reiner, Diamond
Milton Diamond
Milton Diamond is a retired professor of anatomy and reproductive biology at the University of Hawai'i at Mānoa. He has had a very long and productive career in the study of human sexuality...
, and Sigmundson advocated consideration of (1) male sex assignment in the unambiguously male XX infants (most of whom are considered male until the CAH is recognized at 1–2 weeks of age), and (2) delaying reconstructive surgery until the patient is old enough to participate in the decision. (See Ambiguous genitalia and Intersex
Intersex
Intersex, in humans and other animals, is the presence of intermediate or atypical combinations of physical features that usually distinguish female from male...
for more on this debate, as well as complete citations.)
Although the standard management approach remains "standard", more time and consideration are being given in many cases to explaining alternatives to parents and a small number of XX children with unambiguously male external genitalia are again being raised as boys.
Long-term management of CAH
Management of infants and children with CAH is complex and warrants long term care in a pediatric endocrine clinicPediatric endocrinology
Pediatric endocrinology is a medical subspecialty dealing with variations of physical growth and sexual development in childhood, as well as diabetes and other disorders of the endocrine glands....
. After the diagnosis is confirmed, and any salt-wasting crisis averted or reversed, major management issues include
- Initiating and monitoring hormone replacement
- Stress coverage, crisis prevention, parental education
- Reconstructive surgery
- Optimizing growth
- Optimizing androgen suppression and fertility in women with CAH
Testicular Adrenal Rest Tumors
Infertility observed in adult males with congenital adrenal hyperplasia (CAH) has been associated with testicular adrenal rest tumors (TART) that may originate during childhood. TART in prepubertal males with classic CAH could be found during childhood (20%). Martinez-Aguayo et al. reported differences in markers of gonadal function in a subgroup of patients, especially in those with inadequate control.Hormone replacement
The primary goals of hormone replacement are to protect from adrenal insufficiencyAdrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
and to suppress the excessive adrenal androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
production.
Glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s are provided to all children and adults with all but the mildest and latest-onset forms of CAH. The glucocorticoids provide a reliable substitute for cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
, thereby reducing ACTH levels. Reducing ACTH also reduces the stimulus for continued hyperplasia and overproduction of androgens. In other words, glucocorticoid replacement is the primary method of reducing the excessive adrenal androgen production in both sexes. A number of glucocorticoids are available for therapeutic use. Hydrocortisone or liquid prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...
is preferred in infancy and childhood, and prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
or dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
are often more convenient for adults.
The glucocorticoid dose is typically started at the low end of physiologic replacement (6–12 mg/m² but is adjusted throughout childhood to prevent both growth suppression from too much glucocorticoid and androgen escape from too little. Serum levels of 17OHP
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
, testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
, androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
, and other adrenal steroids are followed for additional information, but may not be entirely normalized even with optimal treatment. (See Glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
for more on this topic.)
Mineralocorticoid
Mineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
s are replaced in all infants with salt-wasting and in most patients with elevated renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
levels. Fludrocortisone
Fludrocortisone
Fludrocortisone is a synthetic corticosteroid with moderate glucocorticoid potency and much greater mineralocorticoid potency. The brand name in the U.S. and Canada is Florinef.-Uses:...
is the only pharmaceutically available mineralocorticoid and is usually used in doses of 0.05 to 2 mg daily. Electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....
s, renin, and blood pressure
Blood pressure
Blood pressure is the pressure exerted by circulating blood upon the walls of blood vessels, and is one of the principal vital signs. When used without further specification, "blood pressure" usually refers to the arterial pressure of the systemic circulation. During each heartbeat, BP varies...
levels are followed to optimize the dose.
Stress coverage, crisis prevention, parental education
Even after diagnosis and initiation of treatment, a small percentage of children and adults with infancy or childhood onset CAH die of adrenal crisis. Deaths from this are entirely avoidable if the child and his family understand that the daily glucocorticoids cannot be allowed to be interrupted by an illness. When a person is well, missing a dose, or even several doses, may produce little in the way of immediate symptoms. However, our glucocorticoid needs are increased during illness and stress, and missed doses during an illness such as the "flu" (or viral gastroenteritis) can lead within hours to reduced blood pressure, shock, and death.To prevent this, all persons taking replacement glucocorticoids are taught to increase their doses in the event of illness, surgery, severe injury, or severe exhaustion. More importantly, they are taught that vomiting warrants an injection within hours of hydrocortisone (e.g., SoluCortef) or other glucocorticoid. This recommendation applies to both children and adults. Because young children are more susceptible to vomiting illnesses than adults, pediatric endocrinologists usually teach parents how to give hydrocortisone injections.
As an additional precaution, persons with adrenal insufficiency
Adrenal insufficiency
Adrenal insufficiency is a condition in which the adrenal glands, located above the kidneys, do not produce adequate amounts of steroid hormones , primarily cortisol, but may also include impaired aldosterone production which regulates sodium, potassium and water retention...
are advised to wear a medical identification tag
Medical identification tag
A medical identification tag is a small emblem or tag worn on a bracelet, neck chain, or on the clothing bearing a message that the wearer has an important medical condition that might require immediate attention...
or carry a wallet card to alert those who may be providing emergency medical care of the urgent need for glucocorticoids.
Reconstructive surgery
Surgery need never be considered for genetically male (XY) infants because the excess androgens do not produce anatomic abnormality. However, surgeryIntersex surgery
Intersex surgery is one of several terms referring to surgery performed to correct birth defects or early injuries of the genitalia, primarily for the purposes of making the appearance more normal and to reduce the likelihood of future problems...
for severely virilized XX infants is often performed and has become a subject of debate
History of intersex surgery
The history of intersex surgery is intertwined with the development of the specialities of pediatric surgery, pediatric urology, and pediatric endocrinology, with our increasingly refined understanding of sexual differentiation, with the development of political advocacy groups united by a sexual...
in the last decade.
Surgical reconstruction of abnormal genitalia has been offered to parents of severely virilized girls with CAH since the first half of the 20th century. The purposes of surgery have generally been a combination of:
- to make the external genitalia look more female than male
- to make it possible for these girls to participate in normal sexual intercourseSexual intercourseSexual intercourse, also known as copulation or coitus, commonly refers to the act in which a male's penis enters a female's vagina for the purposes of sexual pleasure or reproduction. The entities may be of opposite sexes, or they may be hermaphroditic, as is the case with snails...
when they grow up - to improve their chances of fertility
- to reduce the frequency of urinary infections
In the 1950s and 1960s, surgery often involved clitorectomy (removal of most of clitoris), an operation that also reduced genital sensation. In the 1970s, new operative methods were developed to preserve innervation and clitoral function. However, a number of retrospective surveys in the last decade suggest that (1) sexual enjoyment is reduced in many women even after nerve-sparing procedures, and (2) women with CAH who have not had surgery also have a substantial rate of sexual dysfunction. (See Intersex surgery
Intersex surgery
Intersex surgery is one of several terms referring to surgery performed to correct birth defects or early injuries of the genitalia, primarily for the purposes of making the appearance more normal and to reduce the likelihood of future problems...
for an overview of procedures and potential complications, and History of intersex surgery
History of intersex surgery
The history of intersex surgery is intertwined with the development of the specialities of pediatric surgery, pediatric urology, and pediatric endocrinology, with our increasingly refined understanding of sexual differentiation, with the development of political advocacy groups united by a sexual...
for a fuller discussion of the controversies.) Many patient advocates and surgeons argue for deferring surgery until adolescence or later, while some surgeons continue to argue that infant surgery has advantages.
Optimizing growth in CAH
One of the challenging aspects of long-term management is optimizing growth so that a child with CAH achieves his or her height potential because both undertreatment and overtreatment can reduce growth or the remaining time for growth. While glucocorticoids are essential for health, dosing is always a matter of approximation. In even mildly excessive amounts, glucocorticoids slow growth. On the other hand, adrenal androgens are readily converted to estradiolEstradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
, which accelerates bone maturation
Bone age
Bone age is a way of describing the degree of maturation of child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray. The "bone age" of a child is the...
and can lead to early epiphyseal
Epiphysis
The epiphysis is the rounded end of a long bone, at its joint with adjacent bone. Between the epiphysis and diaphysis lies the metaphysis, including the epiphyseal plate...
closure. This narrow target of optimal dose is made more difficult to obtain by the imperfect replication of normal diurnal plasma cortisol levels produced by 2 or 3 oral doses of hydrocortisone. As a consequence, average height losses of about 4 inches (10 cm) have been reported with traditional management.
Traditionally, pediatric endocrinologists have tried to optimize growth by measuring a child every few months to assess current rate of growth, by checking the bone age
Bone age
Bone age is a way of describing the degree of maturation of child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray. The "bone age" of a child is the...
every year or two, by periodically measuring 17OHP and testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
levels as indicators of adrenal suppression, and by using hydrocortisone for glucocorticoid replacement rather than longer-acting prednisone
Prednisone
Prednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
or dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
.
The growth problem is even worse in the simple virilizing forms of CAH which are detected when premature pubic hair
Pubic hair
Pubic hair is hair in the frontal genital area, the crotch, and sometimes at the top of the inside of the legs; these areas form the pubic region....
appears in childhood, because the bone age
Bone age
Bone age is a way of describing the degree of maturation of child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray. The "bone age" of a child is the...
is often several years advanced at the age of diagnosis. While a boy (or girl) with simple virilizing CAH is taller than peers at that point, he will have far fewer years remaining to grow, and may go from being a very tall 7-year-old to a 62-inch 13-year-old who has completed growth. Even with adrenal suppression, many of these children will have already had central precocious puberty
Precocious puberty
As a medical term, precocious puberty describes puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is...
triggered by the prolonged exposure of the hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
to the adrenal androgens and estrogens. If this has begun, it may be advantageous to suppress puberty with a gonadotropin-releasing hormone
Gonadotropin-releasing hormone
Gonadotropin-releasing hormone , also known as Luteinizing-hormone-releasing hormone and luliberin, is a tropic peptide hormone responsible for the release of follicle-stimulating hormone and luteinizing hormone from the anterior pituitary. GnRH is synthesized and released from neurons within...
agonist such as leuprolide
Leuprolide
Leuprorelin or leuprolide acetate is a GnRH analog. Proper Sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt - Mode of action:Leuprolide acts as an agonist at pituitary GnRH receptors...
to slow continuing bone maturation.
In recent years some newer approaches to optimizing growth have been researched and are beginning to be used. It is possible to reduce the effects of androgens on the body by blocking the receptors with an antiandrogen such as flutamide
Flutamide
Flutamide is an oral nonsteroidal antiandrogen drug primarily used to treat prostate cancer. It competes with testosterone and its powerful metabolite, dihydrotestosterone for binding to androgen receptors in the prostate gland. By doing so, it prevents them from stimulating the prostate cancer...
and by reducing the conversion of testosterone to estradiol. This conversion is mediated by aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
and can be inhibited by aromatase blockers such as testolactone
Testolactone
Testolactone, or Teslac is an antineoplastic agent that is a derivative of progesterone and is used to treat advanced stage breast cancer.It is nonselective.-Pharmacology:...
. Blocking the effects and conversions of estrogens will allow use of lower doses of glucocorticoids with less risk of acceleration of bone maturation. Other proposed interventions have included bilateral adrenalectomy to remove the androgen sources, or growth hormone treatment
Growth hormone treatment
Growth hormone treatment refers to the use of growth hormone in medical treatment. Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. In the past, growth hormone was extracted from human pituitary glands. GH is now produced by...
to enhance growth.
For a more extensive review of the difficulties of optimizing growth, see Migeon CJ, Wisneiewski AB. Congenital adrenal hyperplasia owing to 21-hydroxylase deficiency: growth, development, and therapeutic considerations. Endocrinol Metab Clin N Am 30:193-206, 2001.
Preventing hyperandrogenism and optimizing fertility
As growth ends, management in girls with CAH changes focus to optimizing reproductive function. Both excessive testosterone from the adrenals and excessive glucocorticoid treatment can disrupt ovulationOvulation
Ovulation is the process in a female's menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum . Ovulation also occurs in the estrous cycle of other female mammals, which differs in many fundamental ways from the menstrual cycle...
, resulting in irregularity of menses
Menstrual cycle
The menstrual cycle is the scientific term for the physiological changes that can occur in fertile women for the purpose of sexual reproduction. This article focuses on the human menstrual cycle....
or amenorrhea, as well as infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
. Continued monitoring of hormone balance and careful readjustment of glucocorticoid dose can usually restore fertility, but as a group, women with CAH have a lower fertility rate than a comparable population.
CAH has little effect on male fertility unless an adult stops taking his glucocorticoid medication entirely for an extended period of time, in which case excessive adrenal testosterone may reduce testicular production as well as spermatogenesis.
Psychosexual development and issues
Nearly all mammalMammal
Mammals are members of a class of air-breathing vertebrate animals characterised by the possession of endothermy, hair, three middle ear bones, and mammary glands functional in mothers with young...
s display sex-dimorphic
Sexual dimorphism
Sexual dimorphism is a phenotypic difference between males and females of the same species. Examples of such differences include differences in morphology, ornamentation, and behavior.-Examples:-Ornamentation / coloration:...
reproductive and sexual behavior (e.g., lordosis
Lordosis behavior
Lordosis behavior, or mammalian lordosis, is a sexual response in mammals, such as mice and cats, that consists of a ventral arching of the spine. During lordosis, the spine curves so that the apex points in the ventral direction. That is, the spine arches inward toward the abdomen.Lordosis aids in...
and mounting in rodent
Rodent
Rodentia is an order of mammals also known as rodents, characterised by two continuously growing incisors in the upper and lower jaws which must be kept short by gnawing....
s). Much research has made it clear that prenatal and early postnatal androgens play a role in the differentiation of most mammalian brains. Experimental manipulation of androgen levels in utero or shortly after birth can alter adult reproductive behavior.
Girls and women with CAH constitute the majority of genetic females with normal internal reproductive hormones who have been exposed to male levels of testosterone throughout their prenatal lives. Milder degrees of continuing androgen exposure continue throughout childhood and adolescence as a consequence of the imperfections of current glucocorticoid treatment for CAH. The psychosexual development of these girls and women has been analyzed as evidence of the role of androgens in human sex-dimorphic behaviors.
Girls with CAH have repeatedly been reported to spend more time with "sex-atypical" toys and "rough-and-tumble" play than unaffected sisters. These differences continue into adolescent, as expressed in social behaviors, leisure activities, and career interests. Interest in babies and becoming mothers is significantly lower by most measures.
Cognitive effects are less clear and reports have been contradictory. Two studies reported spatial abilities above the average for sisters and for girls in general. Other evidence in males with and without androgen deficiencies suggest that androgens may play a role in these aptitudes.
However, gender identity of girls and women with CAH is nearly always unequivocally female. Sexual orientation is more mixed, though the majority are heterosexual. In one study, 27% of women with CAH were rated as bisexual in their orientations. Abnormalities of body image due to the effects of the disease likely play a role in the sexual development of these women, and one cannot conclude that the androgens are the major determinant of their sexuality.
Newborn screening
Conditions justifying newborn screeningNewborn screening
Newborn screening is the process by which infants are screened shortly after birth for a list of disorders that are treatable, but difficult or impossible to detect clinically. Screening programs are often run by state or national governing bodies with the goal of screening all infants born in the...
for any disorder include (1) a simple test with an acceptable sensitivity and specificity, (2) a dire consequence if not diagnosed early, (3) an effective treatment if diagnosed, and (4) a frequency in the population high enough to justify the expense. In the last decade more states and countries are adopting newborn screening for salt-wasting CAH due to 21-hydroxylase deficiency, which leads to death in the first month of life if not recognized.
The salt-wasting form of CAH has an incidence of 1 in 15,000 births, is potentially fatal within a month if untreated, and steroid replacement is a simple, effective treatment. However, the screening test itself is less than perfect. While the 17OHP
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
level is easy to measure and sensitive (rarely missing real cases), the test has a poorer specificity. Screening programs in the United States have reported that 99% of positive screens turn out to be false positives upon investigation of the infant. This is a higher rate of false positives than the screening tests for many other congenital metabolic diseases.
When a positive result is detected, the infant must be referred to a pediatric endocrinologist to confirm or disprove the diagnosis. Since most infants with salt-wasting CAH become critically ill by 2 weeks of age, the evaluation must be done rapidly despite the high false positive rate.
Levels of 17-hydroxyprogesterone
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
, androstenedione
Androstenedione
Androstenedione is a 19-carbon steroid hormone produced in the adrenal glands and the gonads as an intermediate step in the biochemical pathway that produces the androgen testosterone and the estrogens estrone and estradiol.-Synthesis:Androstenedione is the common precursor of male and female sex...
, and cortisol
Cortisol
Cortisol is a steroid hormone, more specifically a glucocorticoid, produced by the adrenal gland. It is released in response to stress and a low level of blood glucocorticoids. Its primary functions are to increase blood sugar through gluconeogenesis; suppress the immune system; and aid in fat,...
may play a role in screening.
Prenatal diagnosis and treatment
Since CAH is an autosomal recessive disease, most children with CAH are born to parents unaware of the risk and with no family history. Each child will have a 25% chance of being born with the disease. Families would wish to minimize the degree of virilizationVirilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
of a girl. There is no known prenatal harm to a male fetus from CAH, so treatment can begin at birth.
Adrenal glands of female fetuses with CAH begin producing excess testosterone
Testosterone
Testosterone is a steroid hormone from the androgen group and is found in mammals, reptiles, birds, and other vertebrates. In mammals, testosterone is primarily secreted in the testes of males and the ovaries of females, although small amounts are also secreted by the adrenal glands...
by the 9th week of gestation. The most important aspects of virilization (urogenital closure and phallic urethra) occur between 8 and 12 weeks. Theoretically, if enough glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
could be supplied to the fetus to reduce adrenal testosterone production by the 9th week, virilization could be prevented and the difficult decision about timing of surgery
History of intersex surgery
The history of intersex surgery is intertwined with the development of the specialities of pediatric surgery, pediatric urology, and pediatric endocrinology, with our increasingly refined understanding of sexual differentiation, with the development of political advocacy groups united by a sexual...
avoided.
The challenge of preventing severe virilization of girls is twofold: detection of CAH at the beginning of the pregnancy, and delivery of an effective amount of glucocorticoid to the fetus without causing harm to the mother.
The first problem has not yet been entirely solved, but it has been shown that if dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
is taken by a pregnant woman enough can cross the placenta to suppress fetal adrenal function.
At present no program screens for risk in families who have not yet had a child with CAH. For families desiring to avoid virilization of a second child, the current strategy is to start dexamethasone as soon as a pregnancy has been confirmed even though at that point the chance that the pregnancy is a girl with CAH is only 12.5%. Dexamethasone is taken by the mother each day until it can be safely determined whether she is carrying an affected girl.
Whether the fetus is an affected girl can be determined by chorionic villus sampling
Chorionic villus sampling
Chorionic villus sampling , sometimes misspelled "chorionic villous sampling", is a form of prenatal diagnosis to determine chromosomal or genetic disorders in the fetus. It entails sampling of the chorionic villus and testing it...
at 9–11 weeks of gestation, or by amniocentesis
Amniocentesis
Amniocentesis is a medical procedure used in prenatal diagnosis of chromosomal abnormalities and fetal infections, in which a small amount of amniotic fluid, which contains fetal tissues, is sampled from the amnion or amniotic sac surrounding a developing fetus, and the fetal DNA is examined for...
at 15–18 weeks gestation. In each case the fetal sex can be determined quickly, and if the fetus is a male the dexamethasone can be discontinued. If female, fetal DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
is analyzed to see if she carries one of the known abnormal alleles of the CYP21 gene. If so, dexamethasone is continued for the remainder of the pregnancy at a dose of about 1 mg daily.
Most mothers who have followed this treatment plan have experienced at least mild cushingoid
Cushing's syndrome
Cushing's syndrome is a hormone disorder caused by high levels of cortisol in the blood. This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone or CRH...
effects from the glucocorticoid, but have borne daughters whose genitalia are much less virilized.
Childhood onset (simple virilizing) CAH
Mutations that result in some residual 21-hydroxylase activity cause milder disease, traditionally termed simple virilizing CAH (SVCAH). In these children the mineralocorticoidMineralocorticoid
Mineralocorticoids are a class of steroid hormones characterised by their similarity to aldosterone and their influence on salt and water balances.-Physiology:...
deficiency is less significant and salt-wasting does not occur. However, genital ambiguities are possible.
Late onset (nonclassical) CAH
The androgenAndrogen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
excess is mild enough that virilization
Virilization
In biology and medicine, virilization refers to the biological development of sex differences, changes that make a male body different from a female body. Most of the changes of virilization are produced by androgens...
is not apparent or goes unrecognized at birth and in early childhood. However, androgen levels are above normal and slowly rise during childhood, producing noticeable effects between 2 and 9 years of age.
Appearance of pubic hair
Pubic hair
Pubic hair is hair in the frontal genital area, the crotch, and sometimes at the top of the inside of the legs; these areas form the pubic region....
in mid-childhood is the most common feature that leads to evaluation and diagnosis. Other accompanying features are likely to be tall stature and accelerated bone age
Bone age
Bone age is a way of describing the degree of maturation of child's bones. As a person grows from fetal life through childhood, puberty, and finishes growth as a young adult, the bones of the skeleton change in size and shape. These changes can be seen by x-ray. The "bone age" of a child is the...
(often 3–5 years ahead). Often present are increased muscle mass, acne
Acne vulgaris
Acne vulgaris is a common human skin disease, characterized by areas of skin with seborrhea , comedones , papules , pustules , Nodules and possibly scarring...
, and adult body odor
Body odor
Body odor or body odour, sometimes colloquially abbreviated as B.O., is the smell of bacteria growing on the body. The bacteria multiply rapidly in the presence of sweat, but sweat itself is almost completely odorless to humans....
. In boys the penis
Penis
The penis is a biological feature of male animals including both vertebrates and invertebrates...
will be enlarged. Mild clitoral
Clitoris
The clitoris is a sexual organ that is present only in female mammals. In humans, the visible button-like portion is located near the anterior junction of the labia minora, above the opening of the urethra and vagina. Unlike the penis, which is homologous to the clitoris, the clitoris does not...
enlargement may occur in girls, and sometimes a degree of prenatal virilization is recognized that may have gone unnoticed in infancy.
The principal goals of treatment of non-classical CAH are to preserve as much growth as possible and to prevent central precocious puberty
Precocious puberty
As a medical term, precocious puberty describes puberty occurring at an unusually early age. In most of these children, the process is normal in every respect except the unusually early age, and simply represents a variation of normal development. In a minority of children, the early development is...
if it has not already been triggered. These are more difficult challenges than in CAH detected in infancy because moderate levels of androgen
Androgen
Androgen, also called androgenic hormone or testoid, is the generic term for any natural or synthetic compound, usually a steroid hormone, that stimulates or controls the development and maintenance of male characteristics in vertebrates by binding to androgen receptors...
s will have had several years to advance bone maturation and to trigger central puberty
Puberty
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
before the disease is detected.
A diagnosis of non-classical CAH is usually confirmed by discovering extreme elevations of 17-hydroxyprogesterone
17-Hydroxyprogesterone
17-Hydroxyprogesterone is a C-21 steroid hormone produced during the synthesis of glucocorticoids and sex steroids.As a hormone, 17OHP also interacts with the progesterone receptor.-Production:...
along with moderately high testosterone levels. A cosyntropin stimulation test may be needed in mild cases, but usually the random levels of 17OHP are high enough to confirm the diagnosis.
The mainstay of treatment is suppression of adrenal testosterone production by a glucocorticoid
Glucocorticoid
Glucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
such as hydrocortisone. Mineralocorticoid is only added in cases where the plasma renin
Renin
Renin , also known as an angiotensinogenase, is an enzyme that participates in the body's renin-angiotensin system -- also known as the Renin-Angiotensin-Aldosterone Axis -- that mediates extracellular volume , and arterial vasoconstriction...
activity is high.
A third key aspect of management is suppression of central precocious puberty if it has begun. The usual clues to central puberty in boys are that the testes are pubertal in size, or that testosterone remains elevated even when the 17OHP has been reduced toward normal. In girls central puberty is less often a problem, but breast development would be the main clue. Central precocious puberty is suppressed when appropriate by leuprolide
Leuprolide
Leuprorelin or leuprolide acetate is a GnRH analog. Proper Sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt - Mode of action:Leuprolide acts as an agonist at pituitary GnRH receptors...
.
As outlined above, recent additions to treatment to preserve growth include aromatase
Aromatase
Aromatase is an enzyme responsible for a key step in the biosynthesis of estrogens. It is a member of the cytochrome P450 superfamily , which are monooxygenases that catalyze many reactions involved in steroidogenesis. In particular, aromatase is responsible for the aromatization of androgens into...
inhibition to slow bone maturation by reducing the amount of testosterone converted to estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...
, and use of blockers of estrogen for the same purpose.
Once adrenal suppression has been achieved, the patient needs stress steroid coverage as described above for significant illness of injury.
Other alleles result in even milder degrees of hyperandrogenism that may not even cause problems in males and may not be recognized until adolescence or later in females. Mild androgen effects in young women may include hirsutism
Hirsutism
Hirsutism or frazonism is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal - for example, a beard or chest hair. It refers to a male pattern of body hair and it is therefore primarily of cosmetic and psychological concern...
, acne, or anovulation
Anovulation
An anovulatory cycle is a menstrual cycle during which the ovaries do not release an oocyte. Therefore, ovulation does not take place. However, a woman who does not ovulate at each menstrual cycle is not necessarily going through menopause...
(which in turn can cause infertility
Infertility
Infertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
). Testosterone levels in these women may be mildly elevated, or simply above average. These clinical features, of course, are those of polycystic ovary syndrome
Polycystic ovary syndrome
Polycystic ovary syndrome is one of the most common female endocrine disorders. PCOS is a complex, heterogeneous disorder of uncertain aetiology, but there is strong evidence that it can to a large degree be classified as a genetic disease....
, and a small percentage of women with PCOS are found to have late-onset CAH when investigated.
Diagnosis of late-onset CAH may be suspected from a high 17-hydroxyprogesterone level, but some cases are so mild that the elevation is only demonstrable after cosyntropin
Cosyntropin
Cosyntropin is a synthetic derivative of adrenocorticotropic hormone that is used in the ACTH stimulation test to evaluate and diagnose cortisol disorders...
stimulation. Treatment may involve a combination of very low dose glucocorticoid to reduce adrenal androgen production and any of various agents to block the androgen effects and/or induce ovulation.
It was characterized in 1979. Prevalence has been described as 1 in 100 in certain populations.
External links
- GeneReviews/NCBI/NIH/UW entry on 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
- OMIM entry on 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia
- CARES Foundation: Congenital Adrenal Research, Education, and Support
- CongenitalAdrenalHyperplasia.org
- Texas Department of Health, Congenital Adrenal Hyperplasia
- Guide to Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency for parents or patients from Johns Hopkins
- A more advanced discussion of 21-hydroxylase deficiency by an eminent researcher of the disease.
- Interactive animation of the Prader scale