Congenital Adrenal Hyperplasia (CAH)- Focusing on its “Late-onset” non-classic form
CAH - Focusing on its "Late-onset" non-classic form
CAH is a family of inherited disorders caused by
deficiencies in the adrenal enzymes used to synthesize glucocorticoids.
There is a lack of CORTISOL
hormones, and an increased adrenal production of glucocorticoid precursors
and androgens
Mineralocorticoid (primarily
ALDOSTERONE ) synthesis can also be affected,
resulting in electrolyte disturbances, hypo
More than 90% of CAH cases involves an enzyme deficiency
- 21α-hydroxylase
(CYP21A2 gene deficiency)
And more rarely a deficiency of:
-
3β-HSD (3β-hydroxysteroid dehydrogenase)
or
-
11β-HD (11β-hydroxylase) .
8-9 % of CAH cases; occurs one per 100,000 births, but is more common
in those of Moroccan- or Iranian-Jewish descent; Resulting mild CAH is much more
common, and possibly responsible for 1-2% of female cases of hirsutism and infrequent
menstruation. Since 11β-HD
deficiency impairs glucocorticoid
synthesis, DEOXYCORTISOL accumulates,
which may result in hyper
due to the greater-than-physiologic concentrations of
DEOXYCORTICOSTERONE causing sodium retention.
11β-hydroxylase
deficiency is relatively frequent in Israel among North African Jews
ABSTRACT. Over a 39-year period, 38 affected individuals
from 25 families were diagnosed. Nineteen families came from Morocco, and in another
2, one parent came from Morocco (80% of all parents). Demographic studies showed
that most of their grandparents were born in the region of the Atlas Mountains.
In Israel, the overall incidence of the disorder is estimated between 1 in 30,000
to 1 in 40,000 births, but in offspring of Moroccan Jews the ratio is 1 in
5,000 to 1 in 7,000
The clinical expression is characterized by a wide
range of variability in the signs of androgen and mineralocorticoid excess. Virilization
in the female ranged from enlarged clitoris in the mildest forms, to markedly hypertrophied
clitoris with penile urethra and fused labial-scrotal folds in the most severe forms.
Hypertension causing vascular accidents and death was observed in both severe and
mildly virilized patients, whereas masculinized females were sometimes normotensive.
Based on historical evidence, the origin of the ancestors,
and the onomastic analysis of the families surnames, we propose that the mutation
of 11β-hydroxylase dificiency in Jews from Morocco may have originated in either
the ancient Jewish settlers
Dr Ariel Rösler, Esther Leiberman. Tirza Cohen, High
frequency of congenital adrenal hyperplasia (classic 11β-hydroxylase deficiency)
among Jews from Morocco. (April 1992) Am. J. of Med. Ethics, Volume 42, Issue 6,
pages 827-834
The Igbo Jews of Nigeria.
Said to have migrated from Syrian, Portuguese and Libyan Israelites
into West Africa. Historical records shows that this migration started around 740
C.E. According to amateur Jewish Historian and Forensic Science investigator Chinedu
Nwabunwanne of Aguleri, who resides in Los Angeles and has researched this subject
for more than 15 years at the UCLA libraries in Los Angeles, "the migration started
when the forces of Caliph Mohammed -the last leader of the Umayyads- and his Qaysi-Arab
supportes defeated the Yamani-Arab Umayyads of Syria in 744 C.E; sacked the Yamanis
and their Jewish supporters from Syria. The Syrian-Jewish migrants tribes Dan, Naphtali,
Gad, and Asher resettled in Nigeria where they became known as Sambatyon Jews. In
1484 and 1667 Judeans and Zebulonians from Portugal and Libya respectively joined
Sambatyon Jews of Nigeria. Thus, Nigerian Jews originated from the following six
Israelite tribes: Judah, Dan, Naphtali, Gad, Asher and Zebulon."
Wikipedia
New MI. Genetic disorders of adrenal hormone synthesis.
Horm Res 1992;37(suppl 3):22-33.
Miller WL. Congenital adrenal hyperplasias. Endocrinol
Metab Clin North Am 1991;20:721-49.
New MI. Congenital adrenal hyperplasia. In: DeGroot
LJ, ed. Endocrinology. 3d ed. Philadelphia: Saunders, 1995:1813-35.
White PC, Speiser PW. Steroid 11 beta-hydroxylase deficiency
and related disorders. Endocrinol Metab Clin North Am 1994;23:325-39.
Migeon CJ, Donohoue PA. Congenital adrenal hyperplasia
caused by 21-hydroxylase deficiency. Endocrinol Metab Clin North Am 1991;20:277-96.
CAH is inherited as any of three main (with clinical presentation given here for
females)
(1) Severe form
- Classical CAH / "Classic virilizing adrenal hyperplasia"
(sometimes called "Salt wasting"CAH). Due to near
total deficiencies of 21α -hydroxylase,
or 11β-hydroxylase
or 3B-HSD , usually detected as adrenal
insufficiency in newborn/early childhood, with or without salt-wasting, or later
with virilization (masculinization, precocious (early) puberty, hirsutism, acne,
amenorrhea); females usually have ambiguous genitalia at birth due to excess adrenal
androgen production in utero;
If adrenal glands
are unable to make
ALDOSTERONE: the result is salt wasting
(hypo hypo hyper ALDOSTERONE
is produced in the cortex of the adrenal gland, with secretion mediated principally
by ANGIOTENSION II, but also by ADRENOCORTICOTROPIC HORMONE (ACTH) and local potassium
levels. Individuals
affected by Classical CAH require glucocorticoid
(hydrocortisone, prednisone, dexamethasone) replacement
therapy. Those with a salt-wasting component to their insufficiency
also require mineralocorticoids
(fludrocortisone) and sodium.
(2) Mild form
- "Simple virilizing CAH". Due to deficiencies
of 21α-hydroxylase, usually develops
iin late childhood due to excess
postnatal exposure to adrenal androgens .
(3) Mildest form -
Non-classical "Late-onset"CAH (NCAH) / "Non-classic hyperplasia"
Due to deficiencies of 21α-hydroxylase
and more rarely 11β-hydroxylase ,
usually develops in /early adulthood androgen excess (E.g. hirsutism,
infrequent menstruation, and/or infertility) and possibly shortened stature compared
to parents; Girls born with NCAH have normal genitals. This milder form of CAH affects
one out of every 100 - 1,000 persons, most commonly due to partial
21α-hydroxylase deficiency, which is one of the most frequent autosomal recessive diseases.
http://emedicine.medscape.com/article/919218-clinical
"Genetics and clinical presentation of nonclassic (late-onset)
congenital adrenal hyperplasia due to 21-hydroxylase deficiency"
A rare form of CAH involves 17-hydroxylase deficiency.
Girls appear phenotypically female at birth but do not develop
breasts or menstruate in adolescence because of inadequate
ESTRADIOL production.
They may present with hyper tension.
The adrenal glands are a prominent source of
androgen (particularly in women and children)
Adrenal androgen
synthesis
-
The primary adrenal androgens are: dehydroepiandrosterone
(DHEA) and dehydroepiandrosterone sulfate
(DHEA-S) ( < 10% of DHEA and
DHEA-S are produced by the
testes or
ovaries). DHEA is the precursor of
other androgens and is theprimar y
precursor of natural
DHEA and
DHEA-S have
little androgenic activity -
however, small amounts are converted to ANDROSTENEDIONE
and then to Testosterone (and to
estrogens) in both the adrenal
glands and peripheral tissues, including hair follicles, sebaceous glands, the prostate,
external genitalia, and adipose tissue. Thus, while excess secretion of
DHEA-S defines adrenal hyperandrogenism, the hirsutism
and virilization are in fact caused by the more potent
androgens ,
ANDROSTENEDIONE and
Testosterone DHEA and
DHEA-S are metabolized primarily
by reduction and conjugation to sulfates or glucuronides in the liver - the metabolites
of these steroids and ANDROSTENEDIONE
are excreted as 17-ketosteroids in the urine.
- Androgens
are byproducts of pituitary ACTH (corticotropin)-stimulated
CORTISOL synthesis in the adrenal glands.
Note that when low CORTISOL
levels stimulate ACTH, the higher levels of ACTH indirectly raises levels
of DHEA and other
androgens and
estrogens . However, if the pituitary is NOT
producing enough ACTH, then the subsequent low CORTISOL
will not be associated with higher androgen
and estrogen
levels
NCAH (The milder Non-classic "Late-onset" form
of CAH)
www.caresfoundation.org
Clinical presentation of NCAH
-
Certain ethnic groups are at high risk for NCAH.
Ashkenazi Jews, Italians, Yupik of Alaska, Slavs2,3,6 and Hispanics
have higher rates of NCAH than the general population.
-
Symptoms of NCAH. Vary from person to person
and by degree, may come and go throughout life, may worsen over time, often mistaken
for premature puberty, may overlap with other disorders making diagnosis difficult,
and ma
Both
Females
and males
Premature development of body hair
- pubic and underarm;
Body odor - young children's perspiration
normally has no odor;
Early, rapid growth spurt, but ultimately
short stature as adult- however, many cases with NCAH do attain normal height,
but are shorter than their parents;
Oily hair and skin
History of severe acne - acne
found in ~ 33% of female NCAH cases at diagnosis.
Mood swings
Infertility - a few months of treatment
with glucocorticoids (E.g. Prednisone,
hydrocortisone) can often restore fertility. Many cases of NCAH do not have fertility
problems, however, ~15% of their offspring inherit their NCAH;
Chronic/recurrent mild syncope -
episodes of faint-headedness/near unconsciousness;
Mild hyperpigmentation
Enlarged clitoris/poorly developed labia - a possibility;
Hypo tension
(21α-hydroxylase deficiency);Hyper tension
(11β-hydroxylase deficiency);
Females -
symptoms frequently become apparent shortly after onset of menstruation;
Early age of first menstrual period
Menstrual irregularities - infrequent menstrual periods found in ~54% of NCAH cases at diagnosis.
Thinning hair on head - especially at
the temples (male pattern baldness);
Hirsutism/Excessive hair growth - facial
hair on chin and upper lip may be thick, coarse, and dark; hirsutism found in ~60%
NCAH cases at diagnosis. Note that glucocorticoid
treatment alone may not be sufficient to solve this problem, which will likely also
require some hair-removal therapy. (E.g. laser hair removal)
Previous diagnosis/symptoms of Polycystic
Ovarian Syndrome (PCOS).
Males
Early beard growth;
Enlarged penis with comparatively small
testes;
Low sperm count
Diagnostic tests for NCAH
NCAH (mild CAH, Nonclassic CYP21A2 deficiency)
should be considered in a patient presenting with.
Near-syncope, severe acne, mild hyperpigmentation and a poor response to stress
or infections. It should also be considered in female patients with signs of virilism,
such as clitorimegaly and hirsutism.
Elevated levels of
17-OHP suggest
NCAH related to 21α-hydroxylase
deficiency
-
A single morning blood test for adrenal steroid levels usually elevated with
21α-hydroxylase
deficiency may be sufficient to make the diagnosis.
Steroids tested are17-HYDROXYProgesterone ,
ANDROSTENEDIONE and
Testosterone;
Study results for
CAH patients. Of 161 unrelated women, 20 had a plasma
Testosterone level greater than 1.4 ng/m,
while values were normal in 56 (38.3%). By contrast
ANDROSTENEDIONE was elevated in most, being
normal in only 11 patients (8%);
Bidet M, Bellanné-Chantelot
C, et al, Clinical and molecular characterization of a cohort of 161 unrelated women
with nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency
and 330 family members. (May 2009) J.Clin Endocrin. Metab., 94(5):1570-8. Epub 2009
Feb 10.
Elevated serum levels
of 17-OHP▲ suggest
21α-hydroxylase deficiency. A basal, morning serum 17-OHP value >
200 ng/dL (6 nmol/L) (drawn in the early follicular phase) strongly suggests the
diagnosis. (> 82 ng/dL in children); A basal, morning serum 17-OHP value >
200 ng/dL (6 nmol/L) (drawn in the early follicular phase) strongly suggests the
diagnosis. (> 82 ng/dL in children);
When NCAH is
suspected, an ACTH stimulation test is done to confirm the diagnosis.
Blood samples are taken before an intravenous
dose of ACTH (adrenocorticotropic hormone) and again an hour later. People without
CAH respond to ACTH stimulation by releasing CORTISOL
into the bloodstream. NCAH blood samples taken after the dose of ACTH show
large amounts of 17-OHP ,
the "raw material"from which CORTISOL
is normally made. The results of the ACTH stimulating test are plotted on a "Nomogram",
see below, to determine whether the values indicate a diagnosis of CAH
ACTH Stimulation Test
▪ To perform ACTH stimulation
test -serum is drawn to determine baseline 17-OHP
and deoxycortisol levels. Administer 250 µg of ACTH intravenously. 17-OHP and 21-deoxycortisol
▪ The diagnosis is confirmed
by an exaggerated serum 17-OHP response to
high dose (250mcg) ACTH - for most patients serum
17-OHP values 60 minutes after stimulation
are typically ≥1500 ng/dL (≥43 nmol/L), and range between 1000 and 10,000 ng/dl
(30 and 300 nmol/L)
http://www.uptodate.com/contents/diagnosis-and-treatment-of-nonclassic-late-onset-congenital-adrenal-hyperplasia-due-to-21-hydroxylase-deficiency#H2
Elevated levels of
DEOXYCORTICOSTERONE (DOC) and
11-DEOXYCORTISOL suggest NCAH related to
11β-hydroxylase deficiency
-
Diagnosis tests for DEOXYCORTICOSTERONE
(DOC) and 11-DEOXYCORTISOL
will show elevated levels of these hormones
- since 11β-hydroxylase
converts DOC →
CORTICOSTERONE (precursor to ALDOSTERONE )
and 11-DEOXYCORTISOL →CORTISOL .
- 11β-hydroxylase
deficiency is characterized by:
Hypertension. ~2/3 of individuals affected by
11β-hydroxylase deficiency experience
monogenic (mutation to a single gene), low renin (precursor to ANGIOTENSIN II) hypertension
with ensuing low ALDOSTERONE
levels caused by accumulation of 11-DEOXYCORTISOL
and DEOXYCORTICOSTERONE (DOC). Excess
androgen production .
Steroid Hormone Conversion Chart
Other abnormalities that may be present with NCAH include:
-
High serum concentrations of: 17-hydroxypregnenolone ,
dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), 3-alpha-androstanediol
glucuronide and
Progesterone;
-
Increased urinary excretion of metabolites of
CORTISOL precursors.
Particularly pregnanetriol,
pregnanetriol glucuronide, (major metabolites of
17-OHP) and 17-ketosteroids (metabolites
of androgens, especially
DHEA and
DHEA-S );
-
Elevated DEOXYCORTICOSTERONE/11-DEOXYCORTISOL
levels suggest 11β-hydroxylase
deficiency
Effects of NCAH on CORTISOL and ALDOSTERONE
Those with NCAH have insufficient
21α-hydroxylase or more rarely
11β-hydroxylase needed by the adrenal
glands to convert
17-HYDROXYProgesterone(17-OHP)
into CORTISOL
( and/or ALDOSTERONE production
in more severe cases)
-
The adrenal glands are controlled by the pituitary gland (a
small pea-sized gland at the base of the brain). Stimulated by the pituitary
hormone ACTH (adrenocorticotropic hormone), the adrenal cortex CORTISOL
and ALDOSTERONE .
CORTISOL
secretion is ultimately controlled by the central nervous system (CNS) in
response to stress, which induces the hypothalamus to release CRH, which stimulates
the anterior pituitary to release ACTH.
CORTISOL Release
- CORTISOL
("The Pump-Up"Hormone) is a steroid
hormone produced by the adrenal cortex to deal with physical and emotional stress.
By putting the body on
"Red Alert"
and diverting all available energy and raw materials to immediate
survival tasks, CORTISOL :
Suppresses inflammatory processes,
healing processes and the immune system.
Maintains adequate
energy supply
and blood sug ar
levels. By converting
glycogen stores
into glucose
to elevate blood sugar
levels.
-
When the pituitary gland senses insufficient
CORTISOL
in the bloodstream. It releases ACTH
to stimulate the adrenals to produce more CORTISOL ,
Chronic adrenal stimulation by ACTH
results in adrenal hyperplasia. Continuing to sense the need for
CORTISOL ,
the pituitary pumps out more ACTH, resulting in an overabundance of
17-OHP, which is then
converted by the adrenals into excess androgens
(masculinizing steroid hormones), since the enzymatic pathway for
CORTISOL and/or
ALDOSTERONE is impaired.
ACTH partially stimulates adrenal
DHEA production. The precursor to other
androgens and also
estrogens
Lack of adequate
CORTISOL prevents the body from properly
metabolizing
sugar
and responding to stress, which can lead to hypoadrenia CORTISOL )
and sometimes
mineralcorticoids
(E.g. ALDOSTERONE ). Hypothyroidism,
reactive hypoglycemia and depressed immunity are also associated with hypoadrenia.
Some GENERAL symptoms
of hypoadrenia/adrenal exhaustion include:
(If you experience 5 or more of these symptoms,
you should suspect hypoadrenia and investigate further)
Excessive Fatigue
Light headedness (or dizzyness, etc.)
upon standing
Cravings for sweets
Alcohol Intolerance
Hypoglycemia (low blood sugar)
Poor resistance to infections (in general)
Chronic Infections
Chronic Allergies
Skin, Dry &/or "thin"
Low Blood Pressure
Easily irritated
General Nervousness
Weakness
Anxiety/Depression/Fearfulness
Food "sensitivities", or inhalant allergies
Become emotional after eating sweets
or starches
Hard to gain weight or to build muscle
mass (caused by too little CORTISOL )
Poor Memory
Excessive hunger
Low tendency to perspire
Dark circles under eyes
Indigestion, "Pit" of stomach, distress/pain
Insomnia
Tenderness in adrenal area
Low Sex Drive
"At-home"
Postural Hypotension Test for Hypoadrenia (a.k.a. Raglans test )
(Requires blood pressure cuff)
Prostrate position. You
need to lie down long enough to be in a relaxed state. While lying on
your back in a relaxed state, take and record your blood pressure.
Normally, with the help of your sympathetic nervous
system of which the adrenal glands are a part, your blood pressure will
rise 4 - 10 points (mm/Hg) when going from the lying to the standing
position. If your blood pressure drops, it may be an indication of hypoadrenia.
If your blood pressure drops noticably, you may also feel a little faint
upon standing.
Treatments for NCAH
In patients who have few or no symptoms of mild congenital
hyperplasia, the risks of treatment may outweigh the benefits
Consultation with an endocrinologist is recommended for patients
who require complex hormone regimens.
The following treatment suggestions were found at several internet sites
(You should do your own research on this):
Treatment for all forms of CAH requires CAREFULLY
MONITORED, LIFETIME glucocorticoid
replacement therapy. You will need:
-
Glucocorticoids -
E.g. hydrocortisone, prednisone or dexamethasone;
Maintenance therapy is generally achieved
with hydrocortisone. In a dosage of 6 - 25 mg per m2
per day given in 2-3 divided doses. Hydrocortisone is preferred over other glucocorticoids
because it is short acting and can be given in pulses that mimic natural cortisol
secretion. Equivalent bedtime dosages of prednisone (5-7.5mg) or dexamethasone (0.25
- 0.75 mg) can be used to simplify dosing regimens in noncompliant patients; One
website suggested dexamethasone as the preferred treatment for older adolescents
and adults after epiphyseal closure is complete.
Periods of physiologic stress (E.g
severe
Many patients benefit from the addition of
an ALDOSTERONE boosting therapy.
Even normotensive patients with 21α-hydroxylase deficiency may have improved adrenal androgen
suppression with the addition of the fludrocortisone (Florinef, aldosterone analog)
at dosages of 0.05 to 0.2 mg per day.
The use of flutamide (Eulexin, an
androgen inhibitor) in
patients with all types of CAH may permit hydrocortisone to be given at lower dosages.
In a dosage of ~ 10 mg / kg per day in three divided doses.
Merke DP, Cutler GB Jr. New approaches to the treatment of
congenital adrenal hyperplasia. JAMA 1997;277:1073-6.
Laue L, Merke DP, Jones JV, Barnes KM, Hill S, Cutler GB
Jr. A preliminary study of flutamide, testolactone, and reduced hydrocortisone dose
in the treatment of congenital adrenal hyperplasia. J Clin Endocrinol Metab 1996;81:3535-9.
- Therapy
should be at the lowest dosage that achieves prevention of adrenal insufficiency
and suppression of excess androgens
HYDROCORTISONE dosages that return
17-OHP /11-DEOXYCORTISOL
levels to normal can cause medically-induced Cushing Syndrome if not appropriately
monitored
Lower dosages may leave the effects of excess
androgen production unchecked
Treatment may also require anti-hypertensive therapy
