Summary of the Consensus Statement from the Pediatric Endocrine Societies

Fall 2002 CARES Foundation, Inc.

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Summary of The CAH Consensus Statement of the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology

From the Journal of Clinical Endocrinology and Metabolism 87(9):4048-4053 September 2002

This past March 2002, 40 physicians, psychologists, scientists, and surgeons from countries in North America, Europe, Japan and Australia met in Gloucester, Massachusetts to discuss the management of congenital adrenal hyperplasia (21-OHD) and to develop a set of universal guidelines. The group recognized the difficulty in managing CAH, despite over 50 years of experience with steroid replacement therapy as well as the substantial variation in clinical practice. The highlights of the guidelines are as follows:

Neonatal Diagnosis, Treatment and Clinical Evaluation

The Group recommended that all babies suspected of having congenital adrenal hyperplasia (CAH), whether through adrenal crisis or symptoms, virilized genitalia or an abnormal newborn screening result, the infants should receive immediate expert medical attention and evaluation by a pediatric endocrinologist. Further, "[a] well-organized multidisciplinary team (including specialists in pediatric endocrinology, psychosocial services, pediatric surgery/urology, and genetics) is essential for the diagnosis and management of the infant with ambiguous genitalia. It is important that the coordinator of the team has experience in the long-term care of the patient with CAH and provides a consistent message to the parents." A comprehensive evaluation of the infant suspected of having CAH should be made, including "a complete history, a physical examination, a reliable ultrasound investigation of the internal genitalia and adrenals, karyotype or fluorescence in situ hybridization for sex chromosome material, and a rapid, reliable plasma or serum measurement of 17OHP. Premature newborns may need serial measurements of 17OHP to differentiate false positive results from affected infants with CAH."

Newborn Screening For CAH

The group found newborn screening for CAH to be "beneficial and recommended". The report states that CAH newborn screening is sensitive enough to detect almost all classical and some non-classical CAH affected infants. The report goes on to set forth the parameters and methodology recommended for laboratories conducting CAH newborn screening. With respect to DNA analysis, it states that such testing is not essential, but may be helpful to the diagnosis and in genetic counseling. The genetic defects may not always correspond to the clinical manifestations of the disorder. The DNA of the parents is required for best results when conducting DNA testing of children.

Prenatal Treatment and Diagnosis

The report states "[p]renatal treatment has been advocated for fetuses at risk for classic CAH but is not appropriate for nonclassic CAH." While still considered some-what controversial, current medical research has shown that "very early institution of treatment ameliorates the genital virilization in all affected females and completely eliminates it in more than 85%." Therapy must begin earlier than 9 weeks after the last period. The group also sets forth specific inclusion criteria for prenatal treatment and gives the dosage formula. The group states, "[n]o consistent untoward effects have been reported, and birth weight is not reduced. However, few treated fetuses have reached adulthood, and long-term prospective studies have not been done. Thus, all agree that the results to date are very good, but long-term safety has not yet been proven in patients treated to term or in the 7 of 8 fetuses in whom treatment is stopped because they are male or unaffected." The side effects for treated mothers include edema, weight gain and stretch marks, but no increased risk for gestational diabetes or hypertension has been shown. The group clearly states, however, that prenatal treatment should not be undertaken by general obstetricians in the community. Such treatment requires a level of expertise and should be monitored by a team including, "a pediatric endocrinologist, an expert in high-risk obstetrics, a genetic counselor, and a reliable molecular genetics laboratory." Specialized teams should be designated using approved protocols and subject to reviews boards in recognized centers only. Parents must give written informed consent to prenatal treatment after reviewing the benefits and risks. The group states that further long-term follow-up studies are recommended.

Surgical Management and Psychological Issues

Decisions about genital surgery should only be made "after complete disclosure of all relevant clinical information and all available options have been discussed and after informed consent has been obtained." The report sets forth the goals of surgery and describes the degree of virilization of the female infant that warrants a recommendation of surgical intervention. It notes that lesser degrees of virilization may not warrant surgery. "Surgery to reduce clitoral size requires careful consideration." The group recommends that any such surgery be done when the infant is between the ages of 2-6 months because surgery is technically easier than when the child is older. "The early operation should be a one-stage complete repair using the newest techniques of vaginoplasty, clitoral, and labial surgery [….] and should be carried out at a center with experience of at least 3–4 cases/yr. Revision vaginoplasty is often required at adolescence, and the timing should be decided with the patient and family." The group does not recommend surgery between the ages of 12 months and adolescence absent complications with specific medical problems. Vaginal dilatations should not be done in childhood and genital examinations should be minimized. Genital photography is discouraged. These designated centers for genital reconstruction should have one surgical team responsible for all CAH reconstruction. Outcomes should be audited. The group acknowledged concerns about early surgery, but stated that surgical techniques have improved and cautioned against judging outcomes from outdated procedures.

The report notes that females with CAH often show behavioral masculinization, "most pronounced in gender role behavior, less so in sexual orientation, and rarely in gender identity". The group concludes that, with respect to Prader 5 (extremely virilized) CAH female infants, there is insufficient evidence to support a sex assignment of male. The group indicates that optimism is warranted for the outcome of CAH females who undergo surgery using current techniques and skilled surgeons. The group pointed to the importance of professional psychological services and support groups for affected individuals and their families. The group concluded that, "[a]s the pace of societal change, including the flexibility of gender role, increases, more frequent review of management policies and long-term outcomes is important."

Treatment Considerations

Classical CAH

The report sets forth a dosing schedule for physicians to follow and recommends hydrocortisone in tablets (divided or crushed) for infants and children. The group cautions against use of hydrocortisone oral suspensions and against excessive doses. "Excessive doses, especially during infancy, may cause persistent growth suppression, obesity, and other Cushingoid features. Therefore, complete adrenal suppression should be avoided."Long-acting glucocorticoids may be an option after a child has finished growing. The group recommends prednisolone over prednisone and gives dosing amounts for physicians and recommended tests for monitoring patients. The group states that all classical CAH infants at diagnosis be treated with fludrocortisone. The report gives dosing requirements for this medication as well as for sodium chloride supplements. The report also recommends the frequent monitoring for children and sets forth the tests that should be conducted during the office visits. It also notes, "Patients receiving adequate replacement therapy may have hormone levels above the normal range."

Nonclassical CAH

"The standard method of diagnosis involves a 60-min stimulation test with (1–24)ACTH. However, a single early-morning (before 0800 h) level of 17OHP may also serve as a fairly reliable screening tool." The group recommends treatment only for those patients with nonclassical CAH who experience symptoms of the disorder.

Stress Dosing

"Patients with CAH should carry medical identification and information concerning therapy for stress. Caregivers should have an emergency supply of IM [intramuscular] HC or glucocorticoid suppositories." Patients should be given stress doses of hydrocortisone during illness with fever over 101F, when vomiting or when unable to take food by mouth, after serious injury and before any surgery. While engaging in endurance sports may require extra medication, mental and emotional stress does not. The stress dose is 2-3 times the regular glucocorticoids dose. The report also gives dosages for intravenous infusions of hydrocortisone for surgery, trauma or adrenal crisis.

Management of CAH and NCCAH

Genital examinations should be avoided absent specific clinical necessity. Psychological support and evaluations of the teenage patient and her family "should be a routine component of the comprehensive care and management of these patients…. Counseling regarding sexual function, future surgeries, gender role, and issues related to living with a chronic disorder should be addressed."

The Adolescent Patient

When care is transferred from the pediatric endocrinologists to an adult endocrinologist, the group recommends that, "a transition team should also include, as needed, a gynecologist, a urologist, and a psychologist with specific expertise and interest in the treatment of such patients." Adult and adolescent males need to be informed of the necessity of compliance with treatment to enhance fertility and reduce the risk of nodules in the testes, and of the importance of for frequent self-examination of the testes for nodules. Surgical removal of these masses may be necessary to preserve or improve fertility. Adult and adolescent females need to be assessed for the effectiveness of genital repair and vaginal stenosis should be addressed. Psychological counseling should be a part of management of these patients. Fertility issues should be addressed with nonclassical patients. "The risk of women with CAH or NCCAH having an affected fetus is low."

The Pregnant CAH Woman

The pregnant CAH/NCCAH woman should be cared for in a tertiary center with experience and equipment to handle such pregnancies. The patient should be treated with glucocorticoids that do not cross the placenta, such as hydrocortisone and prednisolone, and dexamethasone (which crosses the placenta) should be avoided. Dexamethasone in the pregnant CAH/NCCAH patient is only appropriate when used in prenatal therapy. In classical CAH women who have undergone reconstructive surgery, elective cesarean section is recommended to avoid damaging the genital area. Hydrocortisone will need to be increased during cesarean section surgery and a pediatrician should be present to care for the newborn and to begin diagnosis and treatment if an affected infant is expected.

Experimental Therapies and Future Developments

Adenalectomy should only be considered when conventional therapy is failing and long-term follow-up can be secured. This therapy requires life-long monitoring and vigilance in administering medication.

CRH antagonists for adrenal suppression holds promise but needs further study.

Antiandrogens and aromatase inhibitors used with hydrocortisone and fludrocortisone have shown some benefit in short-term studies. However, no long-term safety data is available and liver function must be monitored carefully.

Epinephrine ("adrenaline" the flight/fright hormone) deficiency in CAH may play a role in responsiveness to stress. This is being studied now for possible therapeutic implications.

Preimplantation genetic diagnosis has been done in a single published case, and gene therapy is being investigated in a mouse model of the disease, but neither is available for common use in humans.

DHEA replacement is being studied in Addison's patients, but it is unclear whether this holds any relevance to CAH.

11 beta-HSD inhibitors are not recommended, but may have potential to decrease the dose of glucocorticoids (i.e., hydrocortisone) needed for treatment.

Growth hormone combined with depot leuprolide acetate (Lupron) treatment has been studied in a small group of short CAH patients. Growth rate and final predicted height (which is not the same as actual final height) significantly improved, but the adult heights are not yet available.

CARES Foundation wishes to thank the participants at this conference for tackling these important issues in the management and care of CAH/NCCAH patients. We encourage this group to convene regularly to continue the discussion of these important issues and to attempt to provide further guidance to their colleagues in the field. The benefits to the CAH community will be far reaching and hopefully will lead to a higher and more consistent standard of care for those affected. Moreover, we wish to thank Lawson Wilkins Pediatric Endocrine Society and the European Society for Pediatric Endocrinology for sponsoring this conference.

* * * *

The participants were: Sheri Berenbaum (PA), George Chrousos (MD), Peter Clayton (UK), Gordon Cutler (IN), Sabine De Muinck Keizer-Schrama (The Netherlands), Patricia K. Donahoe (MA), Patricia A. Donahoue (IA), Malcolm Donaldson (UK), Maguelone Forest (France), Kenji Fujieda (Japan), Lucia Ghionizz (Italy), Maria Ginalska-Malinowska (Poland), Melvin M. Grumbach (CA), Annette Grüters (Germany), Kerstin Hagenfeldt (Sweden), Raymond L. Hintz (CA), John W. Honour (UK), Ieuan A. Hughes (UK), Ursula Kuhnle-Krahl (Germany), Peter A. Lee (PA), Heino Meyer-Bahlburg (NY), Claude Migeon (MD), Walter L. Miller (CA), Jorn Müller (Denmark), Maria I. New (NY), Sharon E. Oberfield (NY), Michael Peter (Germany), E. Martin Ritzén (Sweden), Paul Saenger (NY), Martin O. Savage (UK), Justine M. Schober (PA), Wolfgang G. Sippell (Germany), Janos Solyom (Hungary), Phyllis W. Speiser (NY), Bradford L. Therrell (TX), Judson J. Van Wyk ( NC), Garry L. Warne (Australia), Perrin C. White (TX), Ludwig Wildt (Germany), and Selma Witchell (PA). The following also contributed to the material for the article: Peter C. Hindmarsh (UK), Lewis B. Holmes (MA), Lourdes Ibañez (Spain), Lenore S. Levine (NY), Songya Pang (IL), and Anna Wedell (Sweden).

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