It did help having access to Mom’s computer and all of my articles....
Kelly

Alyssa Leight
Biology - Section G
I did this work in accordance with the Newark Academy honor code.________________

Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia is an autosomal recessive disorder caused by a deficiency of the enzyme 21-hydroxylase. The adrenal glands which sit on top of the kidneys are divided into two different parts: the adrenal cortex and the adrenal medulla. The adrenal cortex is where cortisol is synthesized. Cortisol is used in the body to combat all physical and emotional stress and is essential for life. 21-Hydroxylase is the enzyme, which converts cholesterol into cortisol. People with congenital adrenal hyperplasia (CAH) are deficient in this enzyme making them unable to produce sufficient cortisol. There are two main forms of CAH classical (severe form) and nonclassical (mild form).
Adrenal Gland Figure

The first documented case of what is now known to be classical congenital adrenal hyperplasia was discovered by a man named Luigi De Crecchio. Luigi De Crecchio was a professor of forensic medicine at the University of Naples who studied the corpses of interesting cases in the morgues of hospitals. This case was documented in a paper called “ Sopra un caso di apparenze virili in una donna” (“On a case of male appearances in a woman”). This paper describes his findings from the autopsy he performed. The patient is described as being male, short, bulky and virile. The inside of the patient’s body is described as having no male structures, but instead having a vagina, uterus, and ovaries. The abdomen is described as normal, but the adrenal glands on top of the kidneys are described as “huge, bigger than the kidneys themselves”. De Crecchio describes the patient’s life as being one of a normal male, but being frequently ill. Although he did not identify the patient as having classical congenital adrenal hyperplasia, he described the symptoms of the pseudohermaphroditism that lead to the belief that the patient was the first documented person with classical CAH (Virdis). Then in 1950 Dr. Lawson Wilkins along with Drs. John Crigler, Robert Klein, Lytt Gardener, Claude Migeon, and Eugenia Rosemberg successfully used cortisone to treat classical congenital adrenal hyperplasia. (Blizzard)
It was not until the 1980’s when the nonclassical form of CAH was discovered. They studied the families of patients with classical CAH and determined that some family members had biochemical signs of 21-hydoxylase deficiency but no symptoms. They named this form cryptic. They studied the HLA (closely linked genetic markers) and found that all of the members of the families with the cryptic form had identical HLA (OMIM). In 1983 Dr. Maria New published a nomogram (graphic below) that plotted the ACTH-stimulation test results of different types of CAH. This allowed doctors to distinguish between the severe classical form of CAH and the milder nonclassical form.

Nomogram by Dr. Maria New


Classical congenital adrenal hyperplasia usually presents within a few weeks of birth. Infants present with signs of adrenal crisis, which may include; poor feeding, listlessness, and seizures. If immediate diagnosis and treatment do not occur it may result in death. Infant females also present with genital anomalies from excessive androgen secreted by the fetus’s adrenals while in the womb. These anomalies can include an enlarged clitoris, a fused labia, and some may appear physically identical to males although their internal reproductive organs remain normal. Infant males show no external symptoms at birth and are often diagnosed after suffering from a life threatening adrenal crisis or upon autopsy (caresfoundation.org). The most common form of classical CAH is called salt wasting CAH. Salt wasters are also unable to produce aldosterone. Aldosterone is a hormone that maintains the normal fluid volume of the body, potassium in the body, and stabilizes heart function. Salt wasters lose too much salt in the urine, resulting in dehydration. If the potassium levels in the body become too high it can result in cardiac arrest and other heart rhythm problems. 75% of people with classical congenital adrenal hyperplasia are salt wasting. The other 25% have a form called simple virilizing classical CAH.
Nonclassical CAH can present from early childhood through adulthood and many are cryptic going their whole lives with no symptoms leading them to seek medical help. The symptoms of nonlassical CAH in children are varied and include things like premature puberty, quick growth spurt, but advanced bone age, oily hair and skin, acne, depression, mood swings, and migraines. The symptoms for women after puberty include infertility, amenorrhea, or irregular periods, androgenic alopecia; male pattern balding, hirsutism, and previous diagnosis of polycystic ovarian syndrome (caresfoundation.org).
Classical congenital adrenal hyperplasia is treated in a few ways. The body needs cortisol so a cortisol mediation is needed along with other replacement medications. They use steroids called glucocorticiods to replace the cortisol, suppress ACTH (Adrenocorticotropic Hormone that secreted by the pituitary gland and tells the adrenal gland to produce more cortisol), and excess androgens. For those who have salt wasting classical CAH a salt retaining steroid is also necessary; this mineralocortociod is called fludrocortisone. Salt wasting babies also require sodium chloride for the first two years of life. Some adult women also need an anti-androgen medicine to suppress the excessive androgens in the body, like an oral contraceptive. These medications must be taken for the rest of the patients life. Some of the babies who have classical CAH are severely virilized and have severe genital anomalies. These babies may require a surgery to reconstruct the genital area, to allow for menstruation, intercourse, and normal psychosocial development. Careful monitoring during childhood is necessary to attain the appropriate management of the disease (Warne). To ensure that a classical CAH baby is detected and treated before life threatening adrenal crisis occurs 48 states screen newborns for the disease. Newborn screening is a test done by the states’ department of health, in which a drop of blood from a baby’s heel is tested for CAH and many other life threatening genetic diseases. This allows the baby with classical CAH to be diagnosed early and treated before adrenal crisis can occur (caresfoundation.org).
Nonclassical congenital adrenal hyperplasia is treated similarly to classical CAH. The patients need cortisol medications to suppress ACTH and excess androgens. This is done with a glucocorticoid. Men with nonclassical CAH may stop treatment after final height is achieved, but women often stay on the medication throughout life to prevent infertility and unwanted symptoms of androgen excess. Some women with very mild symptoms of nonclassical CAH find that an oral contraceptive is sufficient and do not take glucocorticoids.

Diagram of Chromosome 6

The gene for 21-hydroxylase is called CYP21A2 and is located on the short arm of the sixth chromosome. 21-hydroxylace is an autosomal recessive gene, where each parent must be a carrier or affected with the disease. There are many mutations that cause CAH. The most common genetic mutations and deletions for CAH can be tested using molecular genetic testing of the CYP21A2 gene. The majority of people with CAH have are compound heterozygotes. Compound heterozygotes are a mix of more than one mutation. In people with compound heterozygotes the dominant allele is that which has more 21-hydoxylase activity. There are 12 most frequently found mutations and gene deletions for CAH that strongly correlate to disease severity (New, Nimkarn).

Common Gene Mutations for CAH

This is the case study of Anna Canenberg. Anna has nonclassical
congenital adrenal hyperplasia. Anna began showing symptoms at the age of five. Her symptoms included oily hair and body odor which continued to advance with under arm and pubic hair (precocious adrenarche). At the age of seven a blood test revealed that she had very high levels of 17-OHP (17 hydroxyprogesterone). A pediatric endocrinologist ordered a ACTH stimulation test and DNA testing. On the basis of those tests the diagnosis was made with a clear case of nonclassical CAH. A bone age x-ray was also done which showed a two-year advancement in bone age. The doctor proscribed 10mg of a glucocorticoid called Cortef to stop the progression of the symptoms. She would stay on this medication for many more years, the dose being changed by growth and 17-OHP levels. She went into puberty at a normal age, but ended up being much shorter than she should have been due to her bone age advancement. Anna inherited from her mother the 8 base pair deletion in exon 3 mutation, and the V281L in exon 7 mutation from her father. Anna is known as a compound heterozygote because she has the mutations for both the classical and nonclassical forms of CAH, but the nonclassical is dominant because it has more 21-hydroxylase activity. Anna will continue on medication through her reproductive years to preserve fertility and minimize hirsutism.
Common CYP21A2 Mutations

Research is ongoing to improve treatment of CAH and hopefully one-day find a cure. Sex steroid blockades (anti-androgen and aromatase inhibitors which blocks estrogen) which have been used in the past as a cancer treatment, are now showing promising results in patients with congenital adrenal hyperplasia. In addition a new drug has been developed in London and will go into clinical trials in the US in the fall of 2007. This drug is called Chronocort which studies have shown mimics the body’s natural secretion of ACTH allowing the patient to be accurately medicated at the correct time the body needs it (Phoqus). The bilateral adrenalectomy has shown good results in patients with salt wasting classical CAH. Although this is highly experimental, it has shown to drastically improve the quality of life for salt wasters. Gene therapy and stem cells (adult and embryonic) are concepts that hold promise for curing CAH. Stem cells would allow for the transplant of new functioning adrenal glands. Gene therapy would allow the adrenal glands to function on their own by injecting a virus containing the gene for 21-hydroxylase into the adrenal glands (Merke, Bornstein). All of these are exciting areas of research and hold a lot of hope for those with CAH.
Congenital Adrenal Hyperplasia is a genetic disease that affects the adrenal glands. It is a common disorder that varies from severe to unnoticeable. CAH has varied symptoms, but for those with the disease offers many treatments. There is much hope for people with CAH and as long as it is caught early enough one can have a mostly normal life. Scientists and doctors are working everyday to find better treatments and give those suffering from CAH promising hopes for a cure.
References

New, Maria; Nimkarn, Saroj. "21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia" Gene Reviews (2002):

New, Maria; Wilson, Robert. "Steroid disorders in children: Congenital adrenal hyperplasia and apparent mineralocorticiod excess" PNAS 96 (1999):

Warne, G.L.. “Your Child with Congenital Adrenal Hyperplasia”, Melbourne, Australia; Royal Children’s Hospital, 1989.

Speiser, Phyllis; White, Perrin. "Congenital Adrenal Hyperplasia", The New England Journal of Medicine 349(2003): 776-88.

Online Mendelian Inheritance in Man, OMIM ™. John Hopkins University, MD. MIM Number. February 13, 2007. http://www.ncbi.nlm.nih.gov/omim

"Cares Foundation", CARESFoundation.org. 2006. 13 Feb 2007, http://caresfoundation.org

Virdis, R.. "Historical milestones in endocrinology", J.Endocrinol.Invest. 28(2005): 944-928.

Merke, Deborah; Bornstein, Stefan. "Congenital adrenal hyperplasia", Lancet 36518 June 2005 2125-36. 12 February 2007 http://www.thelancet.com

"Phoqus group plc-For Immediate release", Phoqus. 12 Feb 2007 http://www.phoqus.com/fPREndChron.html

Leight Kelly, personal interview, February 12, 2007

Blizzard, Robert (2003, June). LAWSON WILKINS - PIONEER IN PEDIATRIC ENDOCRINOLOGY AND GROWTH DISORDERS: REVISITED 2003. GGH Journal, 19, Retrieved February 9, 2007, from http://www.gghjournal.com/volume19/19_2/articles/lw.htm