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. CAH is marked by acute hirsutism or virilization, sometimes infertility, other signs of masculinity, and possibly stunted height compared to parents.

Mineralocorticoid (primarily ALDOSTERONE) synthesis can also be affected, resulting in electrolyte disturbances, hypotension and syncope (full or partial loss of consciousness).

More than 90% of CAH cases involves an enzyme deficiency of:

-   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 hypertension 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, with an allele frequency of 1 in 70 to 1 in 84 and a carrier frequency of 1 in 35 to 1 in 42.

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 or the native Berber tribes who lived in the region of the Atlas Mountains in the southern region of Morocco before the destruction of the Second Temple by the Romans, in the year 70 C.E.

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 phenotype forms (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 (hypotension / volume depletion), hyponatremia (low serum sodium), and hyperkalemia (high serum potassium). 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; identified by early pubic hair and possibly clitoromegaly, often accompanied by accelerated growth and skeletal maturation 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 adolescence /early adulthood; with signs of 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-hydroxylasedeficiency, 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 hypertension.

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 theprimary precursor of natural

• DHEA and DHEA-Shave 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
• DHEAand DHEA-Sare 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, Slavs^2,3,6 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 may include:

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;
• Hypotension (21α-hydroxylase deficiency);
• Hypertension (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. Wait one hour. Draw post-stimulation serum to determine 17-OHP and 21-deoxycortisol levels;

▪ 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) and11-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 releases hormones, such as 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 sugar 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, which production is impaired by deficient enzyme activity related to CAH

• 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 - with symptoms, such as those seen in Addison's disease, where, because of some underlying problem (such as an adrenal enzyme deficiency in CAH), the adrenal glands do not produce glucocorticoids (E.g. 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

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 illness, surgery) can require short-term dosages 3-10 times that used for maintenance therapy
• 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 -symptoms include rapid weight gain, high blood pressure, pigmented skin, stretch marks, and fragile bones.
• Lower dosages may leave the effects of excess androgen production unchecked

Treatment may also require anti-hypertensive therapy