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$Unique_ID{BRK03429}
$Pretitle{}
$Title{Adrenal Hyperplasia, Congenital}
$Subject{Adrenal Hyperplasia, Congenital Adrenogenital Syndrome Adrenal
Virilism Hydroylase Deficiency CAH 21-Hydroxylation Deficiency
11-Hydroxylation Deficiency Pregnenolone Deficiency 3-Beta Hydroxysteroid
Dehydrogenase Deficiency, also known as 3-Beta-HSD 17-Hydroxylation
Deficiency, also known as 17 alpha hydroxylase Deficiency 17,20-Lyase
Deficiency 17-Beta Hydroxysteroid Deficiency, also known as 17-Ketosteroid
Reductase Deficiency or 17-Beta-HSD Deficiency Corticosterone Methyloxidase
Deficiency, Types I and II}
$Volume{}
$Log{}

Copyright (C) 1986, 1987, 1990 National Organization for Rare Disorders,
Inc.

97:
Adrenal Hyperplasia, Congenital

** IMPORTANT **
It is possible that the main title of the article (Congenital Adrenal
Hyperplasia) is not the name you expected.  Please check the SYNONYM listing
to find the alternate names and disorder subdivisions covered by this
article.

Synonyms

     Adrenogenital Syndrome
     Adrenal Virilism
     Hydroylase Deficiency
     CAH

DISORDER SUBDIVISIONS

     21-Hydroxylation Deficiency
     11-Hydroxylation Deficiency
     Pregnenolone Deficiency
     3-Beta Hydroxysteroid Dehydrogenase Deficiency, also known as 3-Beta-HSD
     17-Hydroxylation Deficiency, also known as 17 alpha hydroxylase
     Deficiency
     17,20-Lyase Deficiency
     17-Beta Hydroxysteroid Deficiency, also known as 17-Ketosteroid Reductase
     Deficiency or 17-Beta-HSD Deficiency
     Corticosterone Methyloxidase Deficiency, Types I and II

General Discussion

** REMINDER **
The information contained in the Rare Disease Database is provided for
educational purposes only.  It should not be used for diagnostic or treatment
purposes.  If you wish to obtain more information about this disorder, please
contact your personal physician and/or the agencies listed in the "Resources"
section of this report.


Congenital Adrenal Hyperplasia (CAH) is a group of disorders resulting
from defective synthesis of the corticosteroid hormones of the adrenal gland.
The adrenal gland becomes enlarged because it tries to produce more and more
of the hormones to compensate for their lack of effectiveness.  The adrenal
gland produces "male" sex hormones (androgens) in both males and females;
because these are overproduced in certain forms of CAH, the external
genitalia of some females with this disorder are masculinized to various
degrees.  Lack of glucocorticoids, especially cortisol, causes various kinds
of metabolic problems.  Lack of mineralocorticoids, primarily aldosterone,
causes salt and water imbalances.  In some cases, this can be fatal.

Symptoms

As mentioned previously, congenital adrenal hyperplasia is characterized by
defective synthesis of cortisol and related hormones, and enlargement of the
adrenal gland in compensation.  In several kinds of CAH, enlarged adrenal
glands then produce abnormally large amounts of androgens.  Abnormalities of
sexual development may be the most conspicuous consequences of this,
particularly in females.  Deficiencies of glucocorticoids, however, occur in
some cases despite the hypertrophy of the adrenal gland, causing symptoms of
Addison's disease.  These include weakness, nausea, vomiting, lack of
appetite, irritability, depression, darkening or pigmentation of the skin,
low blood pressure, lack of resistance to cold, and inability to respond
physiologically to physical stress.  Even patients who produce adequate
corticosteroids under normal conditions cannot usually meet the increased
requirement under stressful conditions.  Addisonian crisis, which is life
threatening, can then occur.  A deficiency of aldosterone can lead to salt
depletion, dehydration, and circulatory collapse.  (For more information on
this disorder, choose Addison's disease as your search term in the Rare
Disease Database.)

The different forms of CAH will be discussed in the following paragraphs.
They represent defects in different steps of the synthesis of
corticosteroids, usually hydroxylation reactions at certain positions on the
original cholesterol molecule.  (The numbers denote the various positions.)
All CAH patients excrete elevated quantities of intermediate molecules in the
production of cortisol, although the particular molecules vary according to
the step at which the synthesis is blocked.

21-HYDROXYLATION DEFICIENCY
     A defect in 21-Hydroxylation occurs in 95% of persons with congenital
adrenal hyperplasia.  Two forms occur, one in which salt metabolism is
normal, and another in which the body excretes large quantities of salt.

Female infants are born with abnormalities of the external genitalia.
These can range from mild enlargement of the clitoris to fusion of the labia
so that the child seems to have a male phallus with undescended testes.
Internally, all the female reproductive organs are present:  uterus, ovaries,
and a vagina that may or may not be sealed off from the exterior by fusion of
the labial folds.  Often, such children are raised as boys until about age 4,
when the smaller relative size of the phallus becomes apparent.  In some
extreme cases, genetic females have lived their entire lives as males.  Such
individuals are known as pseudohermaphrodites.  Untreated females with CAH do
not menstruate, and they are infertile.  They tend to grow rapidly at first,
but stop growing relatively early, thus remaining rather short.  The disorder
can cause serious psychological difficulties.

Male infants appear normal; they are usually not identified until age 3
or 4, when unusually rapid growth and sexual development, the appearance of
pubic and axillary hair, enlargement of the penis, deepening of the voice,
and acne occurs.  The disorder nevertheless prevents normal puberty,
testicular development, and sperm production because the high levels of
androgen suppress hormones required for these processes to take place.  The
fact that the disorder is not immediately apparent in boys places them at
some risk, since a crisis of potentially fatal gluco- or mineralocorticoid
deficiency can occur without any warning.

About a third of CAH patients with defective 21-hydroxylation have a
deficiency of aldosterone, the hormone responsible for maintaining proper
levels of salt in the body.  These patients loose salt in their urine; water
follows the salt out of the body, and the patient may become dehydrated.  The
blood volume decreases and blood pressure falls.  Patients with this form of
CAH develop symptoms 5 to 10 days after birth.  They include lethargy,
vomiting, diarrhea, and circulatory collapse.  Untreated, this form of the
disorder is rapidly fatal.

11-HYDROXYLATION DEFICIENCY
     A defect in 11-hydroxylation is less common than the 21-hydroxylation
defect.  Females are virilized as in defective 21-hydroxylation.  Both males
and females additionally have hypertension.  They usually have normal
corticosteroid levels, although these may fail to respond adequately to
physiologic stress.

PREGNENOLONE DEFICIENCY
     Pregnenolone is an early precursor of all the corticosteroids, including
the androgens.  Defective synthesis of this substance therefore causes
adrenal insufficiency and a lack of virilization in both boys and girls.
Because even the testes seem to be unable to produce testosterone, and male
fetuses require androgens to develop male external genitalia, afflicted male
infants resemble females at birth.  The lack of gluco- and mineralocorticoid
hormones has led to death during infancy in undiagnosed cases.  This form of
congenital adrenal hyperplasia is extremely rare and occurs primarily in
individuals of Japanese extraction.

3-BETA-HSD DEFICIENCY
     A deficiency of 3-Beta-Hydroxysteroid Dehydrogenase (3-Beta-HSD) also
occurs early in the chain of reactions required to produce adrenal steroid
hormones.  Androgens, glucocorticoids, and mineralocorticoids all fail to be
synthesized, and affected infants usually survive no more than a few hours.
Boys are born with female or ambiguous external genitalia.  Females may have
slight virilization because of the presence of a weak androgen.  A few
patients with incomplete forms of this defect have been described.  These
fail to show symptoms until later in childhood (first menstruation between
the ages of 4 and 6, enlarged clitoris, acne, and advanced maturation of the
skeleton), or until adulthood.  This late onset form is characterized by
menstrual irregularity and hirsutism (unusual hairiness).  The variability of
expression of this defect suggests that several different genes are involved
in this step of steroid synthesis.

17-HYDROXYLATION DEFICIENCY
     The defect of 17-Hydroxylation (17-alpha hydroxylase deficiency) usually
goes undetected until adolescence.  Adrenal gland and testes fail to produce
androgens, while the ovaries produce no estrogens.  Because genetic males are
not exposed to androgens during fetal development, they are born with female
external genitalia, although testes are buried within the abdominal cavity.
Failure to menstruate or to develop secondary sexual traits such as breasts
or body hair, as well as hypertension and low blood levels of potassium,
indicative of elevated levels of aldosterone, are characteristic.
Undescended testes in males may become malignant later in life.  This defect,
too, may be expressed atypically.

17,20-LYASE DEFICIENCY
     In 17,20-Lyase Deficiency, only the sex steroids fail to be produced
normally.  Genetic males have female or ambiguous external genitalia.  The
adrenal glands remain normal in size, and gluco- and mineralocorticoids are
produced adequately.  Only 11 patients with this disorder, which appears to
be inherited by an autosomal recessive mechanism, are known.

     17-BETA HSD
     17-Beta Hydroxysteroid Dehydrogenase Deficiency (which is also known as
     17- Ketosteroid Reductase Deficiency and 17-Beta HSD) has similar
manifestations to those of 17,20-Lyase Deficiency.  Only the production of
sex steroids is impaired, with male pseudohermaphroditis and no enlargement
of the adrenal gland.  This defect is either autosomal recessive or X-linked
recessive.

CORTICOSTERONE METHYLOXIDASE DEFICIENCY
     Corticosterone Methyloxidase Deficiency prevents the conversion of
corticosterone to aldosterone, a reaction which normally occurs in two steps.
This deficiency is classified as Type I and Type II, according to which of
the two steps is impaired.  SEverely affected infants are subject to
significant and potentially fatal loss of salt and dehydration because of the
absence of mineralocorticoids.  The physiological response to sodium
depletion is inadequate.  Sex hormone production, however, is normal.  This
disorder exists during early infancy.  Individuals with a moderate form tend
to have short stature and drastic blood pressure reduction with changes in
posture such as standing up (postural hypotension.  Mild forms may be
asymptomatic during adulthood.

Causes

Twenty-one-hydroxylase deficiency is transmitted from one generation to the
next by an autosomal recessive mechanism.  (Hereditary traits are usually
determined by two analogous genes.  In a recessive disorder, both genes are
defective.  If one is normal and one is defective, the individual is usually
healthy.  If both parents have one defective gene, each child has a 25%
chance of inheriting the disorder.  If an affected individual marries a
carrier, each child has a 50% chance of inheriting the disorder.)  The
location on the chromosome of the defective gene is known.  The other
congenital adrenal hyperplasias are also autosomal recessive disorders.
However, 17-Beta HSD can also be inherited as an x-linked recessive trait.
(X-linked recessive traits are expressed predominantly in males.  Females
carry the gene on one of their two X chromosomes.  The second X chromosome
will "mask" the trait, however, if the trait is x-linked recessive.  The trait
is expressed in males because instead of a second X chromosome, they have a Y
chromosome which does not "mask" the harmful gene.  Affected males cannot
transmit the trait to their sons.)

Affected Population

The incidence of 21-hydroxylase deficiency, one of the commoner CAHs, is
estimated between 1 in 5000 and 1 in 15,000 in the United States and Europe.
The other CAHs are much rarer.  The disorder is far more common among the
Eskimos.

Related Disorders

Addison's disease, or adrenal insufficiency, usually develops later in life,
and is due to other causes.  Virilization of female fetuses and/or children,
or accelerated sexual maturation of males may also result from androgen
producing tumors or ingestion by the mother of androgenic substances.  The
congenital absence of gonads, and cryptorchidism, or the failure of the
testes to descend into the scrotal sacs, can also result in abnormal sexual
development.

Female pseudohermaphroditism is a disorder inherited through recessive
genes, caused by an overproduction of adrenal "male" sex hormones
(androgens).  The disorder is characterized by obesity, a thick, short neck,
protruding abdomen, and thin arms and legs.  External sex organs vary in
degrees of masculinization, ranging from enlargement of the clitoris to
complete fusion of labia and scrotum and a common outlet for urethra and
vagina.  Severely masculinized females may be mistaken for males, while a
milder form of the disorder appears after puberty as an absence of
menstruation (amenorrhea), absence of breast development, excessive body hair
(hirsutism), and increased muscle development similar to males.

Noonan Syndrome is a genetic disorder that can affect both males and
females.  The condition is characterized by a lack of sexual development,
short stature, possible mental retardation, a webbed neck, skeletal and/or
heart defects, and various other inborn deformities.  Persons with Noonan
Syndrome have normal chromosomes, while their physical appearance is different
from their peers.  (For more information on this disorder, choose "Noonan" as
your search term in the Rare Disease Database.

Therapies:  Standard

In patients with Congenital Adrenal Hyperplasia, early diagnosis and
determination of the genetic sex of the child are extremely important, both
to prevent unexpected circulatory crises and to allow early modification of
the external genitalia if necessary.  Corticosteroid replacement therapy must
continue throughout life.  Glucocorticoids are replaced orally, with
hydrocortisone, cortisol, prednisone, etc.  This therapy supplies necessary
hormones and regulates the production of androgens.  Treated girls menstruate
and may have normal pregnancies.  In boys, androgen suppression permits
normal puberty, development of the testes, and the production of viable
sperm.

Hydrocortisone therapy corrects for the mineralocorticoid deficiency as
well in most cases, although sometimes intravenous preparations such as
desoxycorticosterone acetate or fluorocortisol are necessary to maintain
proper salt and water balances.

A decrease in the quantity of androgens may cause some regression of
enlarged genital structures, but in many cases, especially when therapy
begins late, surgical reconstruction of the external genitalia of girls must
be performed.

Researchers have recently identified a less severe form of Adrenal
Hyperplasia due to a more common genetic mutation which is called
Nonclassical Adrenal Hyperplasia.  Symptoms include infertility, premature
sexual development, severe acne, excessive facial hair in women and short
stature in men.  These symptoms are all caused by excess androgen production
starting at or before birth.  Once identified, individuals with the defective
genes in the nonclassical form of the disorder can be treated with cortisol
orally to reverse most of the symptoms, including infertility.  The
nonclassical form of the disorder afflicts approximately 1 in 30 Ashkenazi
Jews, 1 in 40 Hispanic persons, 1 in 50 Yugoslavians, and 1 in 300 Italians.
Thus far, 1 in 100 people in the non-Jewish ethnic groups which have been
studied have the nonclassical disorder.

Therapies:  Investigational

Treatment of female fetuses affected with 21-Hydroxylase Deficiency has been
started during early pregnancy with dexamethasone, and continued until birth.
This experimental treatment suppressed the adrenal glands and the external
sex organs were normal at birth.  More research is needed before this
treatment can be used more widely.
Scientists are trying to treat pregnant women who are at risk of
Hydroylase Deficiency in the fetus with deramethasone to achieve normal organ
development in the infant.

This disease entry is based upon medical information available through
January 1990.  Since NORD's resources are limited, it is not possible to keep
every entry in the Rare Disease Database completely current and accurate.
Please check with the agencies listed in the Resources section for the most
current information about this disorder.

Resources

For more information on Congenital Adrenal Hyperplasia, please contact:

     National Organization for Rare Disorders (NORD)
     P.O. Box 8923
     New Fairfield, CT  06812-1783
     [phone]

     Congenital Adrenal Hyperplasia (Division of The Magic Foundation)
     409 Avenida Salvador
     San Clemente, CA  92672
     [phone]

     Congenital Adrenal Hyperplasia Support Group
     10 County Highway, #4
     Wrenshall, MN  55797
     [phone]

     The National Adrenal Diseases Foundation
     505 Northern Blvd., Suite 200
     Great Neck, NY  11021
     [phone]

     NIH/National Institute of Child Health and Human Development
     9000 Rockville Pike
     Bethesda, MD  20892
     (301) 496-513

     Research Trust for Metabolic Diseases in Children
     Golden Gates Lodge, Weston Rd.
     Crewe CW1 1XN, England
     Telephone:  [phone]

For information on genetics and genetic counseling referrals, please
contact:

     March of Dimes Birth Defects Foundation
     1275 Mamaroneck Ave.
     White Plains, NY  10605
     [phone]

     Alliance of Genetic Support Groups
     35 Wisconsin Circle, Suite 440
     Chevy Chase, MD  20815
     (800) 336-GENE
     [phone]

References

Nelson, Don H.  The Adrenal Cortex:  Physiological Function and Disease.
Volume XVIII in series:  Major Problems in Internal Medicine.  Chapter 10:
Congenital adrenal hyperplasia and defects in biosynthesis of the
corticosteroids.  pp. 177-97.  W.B. Saunders and Co., Philadelphia, PA: 1980.

New, M.I. and L.S. Levine.  Congenital Adrenal Hyperplasia.  (In series:
Monographs on Endocrinology, vol. 26.)  Springer Verlag, New York:  1984.

DIURNAL VARIATION IN BLOOD 17-HYDROXYPROGESTERONE CONCENTRATIONS IN
UNTREATED CONGENITAL ADRENAL HYPERPLASIA:  J. Slonim; Archives Dis Child
(August 1984:  issue 59(8)).  Pp. 743-747.

RECENT ADVANCES IN 21-HYDROXYLASE DEFICIENCY:  M.I. New, et al.; Annual
Rev Med (1984:  issue 35).  Pp. 649-663.

PRENATAL TREATMENT OF CONGENITAL ADRENAL HYPERPLASIA RESULTING FROM 21-
HYDROXYLASE DEFICIENCY:  M. David, et al.; Journal Pediatr (November 1984:
issue 105(5)).  Pp 799, 803.