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A couple prepares for the birth of their first child. The mother's pregnancy is uneventful, and prenatal sonograms reveal that they are having a boy. His delivery is normal, and the parents immediately call family and friends with the joyous news. Within 24 hours, however, their world is turned upside down. "Because his testicles hadn't descended, our pediatrician said they were going to do a sonogram and if there was a problem, it could easily be corrected with surgery," recalls the mother. "So they took my baby away and did an ultrasound and that's when they determined that there was a uterus and ovaries. Based on the tests that the endocrinologist did, and after monitoring her for a couple of days, we had no doubt. We knew then that it was congenital adrenal hyperplasia. That's when it was very clear to us that we had a baby girl."

"For most parents, learning that their child has congenital adrenal hyperplasia is at first shocking news and difficult to absorb," says Dix P. Poppas, MD, Chief of Pediatric Urology, Department of Urology, Komansky Center for Children's Health at NewYork-Presbyterian Hospital/ Weill Cornell Medical Center. "Whether they've been told their boy is really a girl, or the diagnosis is made by newborn screening—it can be very frightening. The good news, however, is that the majority of children can go on to lead normal lives with proper diagnosis and treatment."

What is Congenital Adrenal Hyperplasia?

Congenital adrenal hyperplasia (CAH) is a family of genetic disorders affecting the adrenal glands and can interfere with growth and development in children, including the normal development of the genitals. CAH is an inherited disorder which causes an enzyme deficiency (most commonly 21-hydroxylase) that results in the inability of the adrenal glands to make hormones necessary to maintain life (cortisol, and in the salt-wasting form also the salt-retaining hormone). Cortisol is responsible for maintaining the body's energy supply, blood sugar, and controls the body's reaction to stress. The salt-retaining hormone (aldosterone) is necessary for maintaining a normal balance of salt and water in the body.

The production of adrenal enzymes is controlled by genes, with the chromosomal composition of an individual coming from each of the parents. "CAH results when two defective genes for adrenal enzyme production, one from each parent, are inherited by a child," says Maria Vogiatzi, MD, Chief of Pediatric Endocrinology. "Parents usually do not have this disorder because they are only carriers of it. Scientists have pinpointed the location of the group of genes that causes the most common forms of CAH to chromosome 6. DNA testing is now available to diagnose CAH and to detect carriers of the gene mutations."

Types of Congenital Adrenal Hyperplasia

There are two major types of congenital adrenal hyperplasia:

• Classic congenital adrenal hyperplasia. This more severe form of the disease affects very young children and newborns.
• Nonclassic congenital adrenal hyperplasia. This milder form usually develops in late childhood or early adulthood.

Classic congenital adrenal hyperplasia is usually detected in infancy or early childhood. Female newborns with the salt-wasting form of CAH may make the infant appear partially or very much like a male. In girls, the most obvious sign is often abnormal-appearing genitals that look more male than female, a condition called ambiguous external genitalia. The clitoris is enlarged and sometimes looks like a penis, and the labial folds may look something like a scrotum. Girls will usually have normal internal female reproductive organs (ovaries, uterus, and fallopian tubes). As they get older, they can develop a deep voice, the early appearance of pubic and armpit hair, facial hair, and fail to menstruate. The condition is not typically as evident in boys, although some affected male infants have an enlarged penis.

A child with congenital adrenal hyperplasia may also experience a decline in the adrenal glands' production of aldosterone, leading to low blood pressure, lower sodium level and higher potassium level. Sodium and potassium help maintain the right balance of fluids in the body, transmit nerve impulses, and contract and relax muscles.

Children with CAH may also experience an excess production of the male sex hormones (androgens such as testosterone), which can result in shortened stature, early puberty in boys, abnormal genital development in girls and severe acne. Signs and symptoms may vary, depending on which specific gene is defective.

Some forms of congenital adrenal hyperplasia are more severe and cause adrenal crisis in the newborn due to loss of salt. In this form of congenital adrenal hyperplasia, newborns develop severe symptoms shortly after birth, including:

• Cardiac arrhythmias
• Dehydration
• Electrolyte changes
• Vomiting

Treatment for CAH

Medication Dosing and Monitoring

"In most cases, treatment includes replacement hormone medication to boost the levels of deficient hormones to normal levels," says Dr. Vogiatzi. "These may include hydrocortisone or dexamethasone to replace cortisol, and fludrocortisone to replace aldosterone. At times, children with congenital adrenal hyperplasia need multiple drugs, with even higher doses prescribed during periods of illness or severe stress."

During infancy, the initial reduction of markedly elevated adrenal sex hormones may require up to 25 mg hydrocortisone (HC)/m 2.d, but typical dosing is 10-15 mg/m 2.d divided three times daily. While HC is preferred during infancy and childhood, long-acting glucocorticoids may be an option at or near completion of linear growth.

Proper monitoring of a child with CAH is essential for optimizing treatment and ensuring normal development. Following height and weight is extremely important in the monitoring process, and frequent follow-up is recommended. Bone ages are also useful, as they reflect long-term androgen secretion.

Surgery

In some infant girls who have ambiguous genitalia, reconstructive surgery may be required to correct the appearance and function of the genitals, a procedure that may involve reducing the size of the clitoris and reconstructing the vaginal opening.

The Komansky Center for Children's Health at NewYork-Presbyterian Hospital/Weill Cornell Medical Center is one of the world's major referral centers for genital reconstructive surgery. Dr. Poppas has performed over 100 of these complex surgeries. Earlier this year, he was honored by the CARES (Congenital Adrenal Hyperplasia Research Education and Support) Foundation as the first recipient of its Visionary Award for his contributions and commitment to CARES and the congenital adrenal hyperplasia community. CARES Foundation is a national nonprofit organization committed to improving the lives of families and individuals affected by congenital adrenal hyperplasia. A member of CARES' Scientific and Advisory Board, Dr. Poppas has performed genital reconstructive surgery on children from all over the world. Most recently, he was appointed to chair the guidelines committee for establishing surgical centers of excellence across the United States.

"The quality of our team at Cornell is excellent. We work together with our pediatric and endocrine colleagues as well as our outstanding pediatric anesthesia and ICU doctors. ," says Dr. Poppas. "We are also developing a large data base and following these children to determine their sexual function, pregnancy rates, and psychological outcomes as they get older."

Dr. Poppas and his team are also currently reaching out to urogynecologists for help in developing a program to provide treatment and counseling for adult women with CAH. "We're hoping to have a center where these women can feel comfortable knowing that they're getting expert care and a thorough evaluation and opinion of their particular situation," says Dr. Poppas. "We've found that a lot of these women have never been told what CAH is or even why they were operated on as children. Just having that conversation with them and explaining things changes them—in a good way." We are also looking to expand the care of these women with assistance in both male and female infertility and sex therapy. This combined approach to caring for women with CAH will set the standard of care for this underserved population.

Faculty contributing to this article:

Dix P. Poppas, MD, is Chief of the Institute for Pediatric Urology at the Komansky Center for Children's Health in the Department of Urology of NewYork-Presbyterian Hospital/Weill Cornell Medical Center. He is also Director of the Laboratory for Minimally Invasive Urologic Surgery at NewYork-Presbyterian/Weill Cornell. Dr. Poppas is the Richard Rodgers Professor of Pediatric Urology in the James Buchanan Brady Department of Urology at Weill Cornell Medical College. He also holds joint appointments as Professor of Pediatrics, Professor of Obstetrics and Gynecology, and Professor of Plastic and Reconstructive Surgery at Weill Cornell Medical College.

Maria Vogiatzi, MD, is Chief of Pediatric Endocrinology at the Komansky Center for Children's Health of NewYork-Presbyterian Hospital/Weill Cornell Medical Center. She is also Associate Professor of Clinical Pediatrics at Weill Cornell Medical College.