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  1. 1. 0013-7227/02/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 87(9):4048 – 4053 Printed in U.S.A. Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2002-020611 CONSENSUS Consensus Statement on 21-Hydroxylase Deficiency from The Lawson Wilkins Pediatric Endocrine Society and The European Society for Paediatric Endocrinology JOINT LWPES/ESPE CAH WORKING GROUP Writing Committee: Peter E. Clayton, Royal Manchester Children’s Hospital, Manchester, United Kingdom; Walter L. Miller*, University of California, San Francisco, California; Sharon E. Oberfield, Columbia University, New York, New York; E. Martin Ritzen, Karolinska Institute, Stockholm, Sweden; Wolfgang G. Sippell*, University Children’s Hospital, ´ Kiel, Germany; Phyllis W. Speiser, New York University, New York, New York (*co-chairs) Despite over 50 yr of experience with steroid replacement ambiguous genitalia includes a complete history, a physical therapy, the management of congenital adrenal hyperplasia examination, a reliable ultrasound investigation of the in- (CAH) remains difficult, and clinical practice varies substan- ternal genitalia and adrenals, karyotype or fluorescence in tially throughout the world. To consider the evidence for best situ hybridization for sex chromosome material, and a rapid, practice, to formulate management guidelines, and to con- reliable plasma or serum measurement of 17OHP. Pre- sider innovative therapies, The Lawson Wilkins Pediatric mature newborns may need serial measurements of 17OHP Endocrine Society (LWPES) and The European Society for to differentiate false positive results from affected infants Pediatric Endocrinology (ESPE) convened a meeting in with CAH. Gloucester, MA, March 14 –17, 2002. The 40 participating physicians, psychologists, scientists, and surgeons from 12 Newborn screening for CAH. Neonatal mass screening for 21- countries on 4 continents agreed with the following consen- hydroxylase deficiency identifies both male and female af- sus statement; this statement is concerned exclusively with fected infants, prevents incorrect sex assignment, and de- CAH caused by 21-hydroxylase deficiency and does not ad- creases mortality and morbidity (1– 4). Therefore, newborn dress the other, rarer forms of CAH. screening for CAH is beneficial and is recommended. New- born screening is sufficiently specific and sensitive to detect Neonatal diagnosis and treatment almost all infants with classical CAH and some infants with The newborn female with CAH and ambiguous external nonclassical CAH (NCCAH). Sampling of blood spots genitalia requires urgent expert medical attention. The am- should be performed, ideally between 48 and 72 h of age, and biguity is highly distressing to the family; therefore, imme- sent to the screening laboratory without delay. At present, diate comprehensive evaluation is needed by referral to, or direct binding assays for blood-spot 17OHP are the only a visit by, a pediatric endocrinologist. An important goal is practical method for screening. to ensure that the parents develop a positive relationship Each screening laboratory needs to establish validated cut- with their child. A well-organized multidisciplinary team off levels related to gestational age and birth-weight, because (including specialists in pediatric endocrinology, psychoso- 17OHP levels decline with increasing gestational age. Only cial services, pediatric surgery/urology, and genetics) is es- laboratories with excellent internal and external quality con- sential for the diagnosis and management of the infant with trol, demonstrated accuracy, and a rapid turn-around time ambiguous genitalia. It is important that the coordinator of on a large number of samples should be used. The laboratory the team has experience in the long-term care of the patient should report immediately any abnormal result to the phy- with CAH and provides a consistent message to the parents. sician responsible for the patient. A reliable CAH screening program requires both clinical Clinical evaluation in term and premature neonates. Every new- evaluation and laboratory investigation for diagnostic con- born with ambiguous genitalia, a suspected diagnosis of firmation. A positive screening result needs to be confirmed CAH, or an abnormal result in a newborn screen for 17- either by a validated 17OHP measurement of a second hydroxyprogesterone (17OHP) should be evaluated by a pe- serum/plasma sample, a urine sample for a steroid profile, diatric endocrinologist. The evaluation of an infant with or analysis of the CYP21 gene. Newborn screening, using 17OHP, may detect other forms of CAH. In uncertain cases, Abbreviations: BP, Blood pressure; CAH, congenital adrenal hyper- additional specific tests are required. Measurements of an- plasia; ESPE, European Society for Pediatric Endocrinology; HC, hy- drocortisone; 11 -HSD, 11 -hydroxysteroid dehydrogenase; LWPES, drostenedione, aldosterone, cortisol, and testosterone by di- Lawson Wilkins Pediatric Endocrine Society; NCCAH, nonclassical rect immunoassays are of limited value for diagnosis in the CAH; 17OHP, 17-hydroxyprogesterone; PRA, plasma renin activity. newborn. 4048 Downloaded from at University of Oklahoma Bird Hlth Sci Lib on April 23, 2009
  2. 2. Joint LWPES/ESPE CAH Working Group • Consensus J Clin Endocrinol Metab, September 2002, 87(9):4048 – 4053 4049 CYP21 analysis. Molecular genetic analysis is not essential for prepregnancy genetic counseling and genotyping of the pro- the diagnosis but may be helpful to confirm the basis of the band and parents, followed by diagnosis on fetal DNA defect, to aid in genetic counseling, and to establish the obtained by chorionic villous biopsy. Fetal sex should be diagnosis in uncertain cases. Ten mutations account for 90 – determined by Y chromosome PCR or karyotype. Allele- 95% of the affected alleles, but molecular genetic analysis is specific PCR should identify at least 90% of affected alleles. complicated by multiple copies of the genes and the possi- This number can be increased to nearly 100% with micro- bility of multiple mutations on one allele (5, 6). The clinical satellite analysis; Southern blotting; and, occasionally, DNA features may not correlate with the genetic mutation in a sequencing (5, 6). Competent core laboratories should study small percentage of cases. Parental DNA samples are essen- large numbers of samples. tial to segregate alleles. Inclusion criteria for prenatal treatment include: 1) a pre- viously affected sibling or first-degree relative with known Diagnosis of salt-wasting CAH. Salt wasters may not be ap- mutations causing classic CAH, proven by DNA analysis; parent in the first days, or even weeks, after birth by elec- 2) reasonable expectation that the father is the same as the trolyte measurements. Salt wasters may be differentiated proband’s; 3) availability of rapid, high-quality genetic anal- from simple virilizers by serial serum/plasma and/or urine ysis; 4) therapy started less than 9 wk after the last menstrual electrolytes, plasma renin activity (PRA) or direct renin, and period; 5) no plans for therapeutic abortion; and 6) reason- the results of CYP21 molecular analysis. able expectation of patient compliance. The optimal dosage and timing is 20 g/kg maternal body weight d, in three Prenatal diagnosis and treatment divided doses, starting as soon as pregnancy is confirmed, Prenatal treatment has been advocated for fetuses at risk and no later than 9 wk after the last menstrual period. for classic CAH but is not appropriate for nonclassic CAH. Treatment is continued to term in the affected female fetus The appropriateness, ethics, and outcomes of the prenatal and discontinued in all other fetuses. Maternal blood pres- treatment of CAH with dexamethasone remain controversial sure (BP), weight, glycosuria, HbA1C plasma cortisol, dehy- (7, 8). However, based on more than 200 fetuses treated to droepiandrosterone sulfate, and androstenedione should be term and more than 1000 partially treated fetuses, it is clear measured initially and then every 2 months, adding plasma that very early institution of treatment ameliorates the gen- or urinary estriol after 15–20 wk of gestation. ital virilization in all affected females and completely elim- There is substantial difference of opinion concerning inates it in more than 85% (7, 9). Variations in outcome may whether prenatal treatment of CAH is a research endeavor. be attributable to starting treatment late, interruption of However, all are agreed that this requires a team consisting treatment, and individual differences in dexamethasone me- of a pediatric endocrinologist, an expert in high-risk obstet- tabolism and androgen sensitivity. No consistent untoward rics, a genetic counselor, and a reliable molecular genetics effects have been reported, and birth weight is not reduced. laboratory. It is not the “standard of care” for obstetricians However, few treated fetuses have reached adulthood, and in the community. long-term prospective studies have not been done. Thus, all The treatment of 7 out of 8 fetuses who cannot be helped agree that the results to date are very good, but long-term by prenatal treatment creates an ethical dilemma for which safety has not yet been proven in patients treated to term or there is no clear answer, and parents should be aware of this. in the 7 of 8 fetuses in whom treatment is stopped because We believe that this specialized and demanding therapy they are male or unaffected. should be undertaken by designated teams using nationally Treated mothers experience greater weight gain, edema, and or multinationally approved protocols, subject to institu- striae than untreated mothers, but present data do not show tional review boards or ethics committees in recognized cen- increased risk of hypertension or gestational diabetes (9). ters. Written informed consent must be obtained after the Feto/maternal glucocorticoid physiology and pharmacol- balanced review of the risks and benefits of treatment. Fam- ogy are poorly understood. Available data indicate that hu- ilies and clinicians should be obliged to undertake prospec- man fetal cortisol levels are low, approximately 20 nm or 0.7 tive follow-up of prenatally treated children whether they g/dl (10); the administered dose of dexamethasone may have CAH or not. The data should be entered into a central result in fetal concentrations of glucocorticoid that greatly database audited by an independent safety committee. exceed normal levels. However, the data on serum cortisol Study protocols should consider all psychological/behav- values in the fetus are scanty, and fetal serum dexametha- ioral and somatic effects of excess prenatal glucocorticoids sone values have not been reported. and androgens that have been observed in animal experi- Several recent reports have raised concerns about the use ments or in human studies. Long-term follow-up into late of short-term, very-high-dose glucocorticoids in late preg- adolescence is mandatory. Relevant control populations nancy or in premature infants (11). Animal studies have should be identified. These studies should also include the reported numerous complications from long-term, high- partially treated fetuses. Funding agencies, such as the Na- dose treatment of pregnant rodents and primates. Treatment tional Institutes of Health or the European Commission, of pregnant rats with 20 g/kg d dexamethasone was asso- should be encouraged to support such long-term studies. ciated with decreased birth weight and adult hypertension, whereas similar treatment of pregnant sheep caused no ap- Surgical management and psychological issues parent complications. However, the relevance of any of these studies to human physiology is not known. Genital surgery. The decision about surgery should be made Components of a prenatal treatment program include by the parents, together with the clinical team, after complete Downloaded from at University of Oklahoma Bird Hlth Sci Lib on April 23, 2009
  3. 3. 4050 J Clin Endocrinol Metab, September 2002, 87(9):4048 – 4053 Joint LWPES/ESPE CAH Working Group • Consensus disclosure of all relevant clinical information and all avail- Psychological issues. Females with CAH show behavioral mas- able options have been discussed and after informed consent culinization, most pronounced in gender role behavior, less has been obtained. The goals of surgery are: 1) genital ap- so in sexual orientation, and rarely in gender identity (17–19). pearance compatible with gender; 2) unobstructed urinary Even in females with psychosexual problems, general psy- emptying without incontinence or infections; and 3) good chological adjustment seems to be similar to that of females adult sexual and reproductive function. without CAH. Currently, there is insufficient evidence to Once a decision has been made to raise a newborn as support rearing a 46,XX infant at Prader stage 5 as male. female, surgery for those with virilized genitalia caused by Whereas studies of women whose surgery was performed CAH is recommended when the patient has a high proximal 20 –30 yr ago indicate a range of psychosexual difficulties, junction between the vagina and urethra (12, 13). Surgery on there is reason for optimism that outcome will be better with infants with ambiguous genitalia requires a high degree of current surgical and medical treatment. We recognize a need expertise and should only be performed in centers with sig- for greater availability of professional psychological services nificant experience. Based on recent clinical experience, the and support groups for patients and families. Decisions con- cerning sex assignment and associated genital surgery must recommended time for surgery is at age 2– 6 months; al- consider the culture in which a child and her/his family are though, at present, this is not universal practice. It is impor- embedded. As the pace of societal change, including the tant to note that surgery at this stage is technically easier than flexibility of gender role, increases, more frequent review of at later stages. management policies and long-term outcomes is important. When the degree of virilization is less (minimal clitoro- megaly and the junction between the vagina and urethra near the perineum), surgery may not be necessary. In such cases, Treatment considerations in patients with CAH the decision to operate should be based on appropriate con- Optimal glucocorticoid dosing. Recognizing that treatment trast studies of the urinary tract and examination under does not mimic physiologic secretion, the goal is to replace anesthesia, with cystoscopy. Surgery to reduce clitoral size deficient steroids while minimizing adrenal sex hormone requires careful consideration. Total removal of the clitoris and glucocorticoid excess, preventing virilization, optimiz- should never be performed. If clitoral reduction is elected, it ing growth, and protecting potential fertility. Outcome is not is crucial to preserve the neurovascular bundle, the glans, always ideal. Consensus is based on clinical experience. Dur- and the preputial skin related to the glans (14, 15). The early ing infancy, initial reduction of markedly elevated adrenal operation should be a one-stage complete repair using the sex hormones may require up to 25 mg hydrocortisone newest techniques of vaginoplasty, clitoral, and labial sur- (HC)/m2 d, but typical dosing is 10 –15 mg/m2 d divided gery (12–14, 16) and should be carried out at a center with three times daily. HC oral suspension is not recommended experience of at least 3– 4 cases/yr. Revision vaginoplasty is (20); divided or crushed tablets of HC should be used in often required at adolescence, and the timing should be de- growing children. Cortisone acetate requires conversion to cided with the patient and family. Patients who wish to cortisol for bioactivity (21); HC is considered the drug of first consider further procedures should be treated by a surgeon choice. Excessive doses, especially during infancy, may cause experienced in the current techniques. persistent growth suppression, obesity, and other Cushin- Surgery between the age of 12 months and adolescence is goid features. Therefore, complete adrenal suppression not recommended in the absence of complications causing should be avoided. Insufficient data exist to recommend medical problems. Vaginal dilatations are contraindicated at higher morning or evening dosages. this stage, although this procedure is often useful in adoles- Whereas HC is preferred during infancy and childhood, cence and in adulthood. Repeated genital examinations long-acting glucocorticoids may be an option at or near the should be minimized. Genital photography should be dis- completion of linear growth. Prednisone and prednisolone couraged and only be done with parental consent and, except need to be given twice daily. Prednisolone may be preferable, because this is the active drug. The dose (2– 4 mg/m2 d) in infancy, performed only under anesthesia. should be approximately one fifth the dose of HC. The dos- At each designated center, one surgical team should be age of dexamethasone is 0.25– 0.375 mg/m2 d, given once responsible for all surgery involving ambiguous genitalia. daily. Monitoring of these more potent glucocorticoids There should be close cooperation between centers to should include BP, in addition to weight, and other clinical broaden experience, to audit results, and to allow adequate and laboratory variables. These steroids have minimal min- evaluation of outcomes. We acknowledge that there are con- eralocorticoid effect, compared with HC. In children with cerns about early surgery. However, surgical techniques advanced bone age, such as in boys with nonsalt-losing have improved. We urge caution in judging outcome from CAH, initiation of therapy may precipitate central preco- outdated procedures. Systematic studies are needed to eval- cious puberty, requiring treatment with a GnRH agonist. uate ultimate function for all girls undergoing surgery. It is recognized that 46,XX children with significant viril- Mineralocorticoid use. All classic CAH patients should be ization may present at a later age. Consideration for sex treated with fludrocortisone at diagnosis in the newborn reassignment must be undertaken only after thorough psy- period. Dosage requirements in early infancy range from chological evaluation of patient and family. Surgery appro- 0.05– 0.30 mg/d, whereas typical maintenance doses are priate to gender assignment should be undertaken after a 0.05– 0.2 mg/d, depending on the sodium intake. Such ther- period of endocrine treatment. apy will reduce vasopressin and ACTH levels and lower the Downloaded from at University of Oklahoma Bird Hlth Sci Lib on April 23, 2009
  4. 4. Joint LWPES/ESPE CAH Working Group • Consensus J Clin Endocrinol Metab, September 2002, 87(9):4048 – 4053 4051 dosage of glucocorticoid required. The need for continuing LWPES and ESPE and made available to other pediatric mineralocorticoids should be assessed based on PRA and BP endocrine societies. Examples of websites potentially useful (22). Sodium chloride supplements are often needed in in- as family resources include: fancy, at 1–3 gm/d (17–51 mEq/d), distributed in several pediatricendocrinology/patient.html and www.rch. feedings (23). . Criteria for the diagnosis and treatment of NCCAH. The standard method of diagnosis involves a 60-min stimulation test with Management of classical CAH and NCCAH in adolescence (1–24)ACTH. However, a single early-morning (before Physical and genital examinations over the life span. The prior 0800 h) level of 17OHP may also serve as a fairly reliable practice of frequent genital examinations in females should screening tool. Treatment is only recommended for symp- be abandoned. Therefore, unless there is clinical or labora- tomatic patients [e.g. those with an advanced bone age cou- tory evidence of poor control or one seeks to assess the pled with a poor height prediction (compared with the pubertal progress and size of the clitoris, genital examina- family target height), hirsutism, severe acne, menstrual tions should not be performed. In adolescent females or if irregularities, testicular masses, and (in the young adult) questions arise regarding the progress of puberty, the use of infertility]. tampons, or initiation of sexual intercourse, genital exami- nation with attention to the adequacy of the vaginal introitus Monitoring treatment for classic CAH. Monitoring may be ac- may need to be performed. Most importantly, the patient complished based on physical and hormonal findings sug- and/or her family should be appraised of the reasons for the gestive of excessive or inadequate steroid therapy. Labora- examinations (25). tory measurements may include serum/plasma electrolytes, serum 17OHP, androstenedione, and/or testosterone, and Safeguarding psychological well-being. Psychological assess- PRA or direct renin, every 3 months during infancy and ment and support of the patient (with both classic and every 4 –12 months thereafter. The time from the last glu- NCCAH) and his/her family should be a routine component cocorticoid dose should be noted; the diurnal rhythm of the of the comprehensive care and management of these pa- adrenal axis should be taken into account. Patients receiving tients. Parents and/or patients should be offered the option adequate replacement therapy may have hormone levels of age- and sex-appropriate psychologic counseling at the above the normal range. Alternative measurements include time of the initial diagnosis. Counseling regarding sexual urinary metabolites (pregnanetriol) or filter paper blood and function, future surgeries, gender role, and issues related to salivary hormones. Ideally, laboratory data will indicate a living with a chronic disorder should be addressed. need for dose adjustments before physical changes, growth, and skeletal maturation indicate inadequate or excessive Management issues during transition of care of the young adult dosing. patient. Traditionally, the pediatric endocrinologist directly Stress dosing. Patients with CAH should carry medical iden- or indirectly cares for infants, children, and adolescents with tification and information concerning therapy for stress. CAH. In late adolescence or even early adulthood, care is Caregivers should have an emergency supply of im HC or usually transferred to an internal medicine (adult) endocri- glucocorticoid suppositories. Because circulating levels of nologist in the same institution or clinical setting. We rec- cortisol normally increase during stress, patients should be ommend that a transition team should also include, as given increased doses of glucocorticoids during febrile ill- needed, a gynecologist, a urologist, and a psychologist with ness ( 38.5 C/101 F), when vomiting or when unable to take specific expertise and interest in the treatment of such oral feedings, after trauma, and before surgery. Participation patients. in endurance sports may also require extra steroid dosing. Adult males should be counseled that compliance with Mental and emotional stress, such as school examinations, treatment is important to enhance normal fertility and reduce does not require increased dosing. the risk of a palpable testicular mass (26). Although fre- Stress dosing should be 2–3 times the maintenance glu- quently found by sonography, testicular masses may not be cocorticoid dose for patients able to take oral medications. of clinical importance. Nonetheless, we recommend periodic Surgical and trauma patients and those unable to take oral physical examinations and, as indicated, hormonal measure- steroids require rectal or parenteral HC. Glucose concentra- ments, sonography, and magnetic resonance imaging of both tions should be monitored, and iv sodium and glucose re- testes to assist in delineating the extent of such lesions. Sur- placement may be required. Surgical or trauma patients may gical removal of a glucocorticoid unresponsive nodule may receive rectal, im, or iv HC. When practical, an iv bolus may be effective in preserving or improving fertility (27). be followed by continuous iv infusion of HC. Guidelines for The effectiveness of the genital repair in adolescent and iv bolus and subsequent dosage are as follows: for children adult women needs to be assessed, and vaginal stenosis younger than 3 yr of age, 25 mg followed by 25–30 mg/d; for should be repaired. Counseling about anxiety, depression, children 3–12 yr of age, 50 mg followed by 50 – 60 mg/d; dyspareunia, and other sexual matters, as well as contracep- and for adolescents and adults, 100 mg followed by tion, is useful (28). 100 mg/d (24). Women with NCCAH should be counseled regarding an increased risk of infertility. However, the actual numerical Resources for patients and families with CAH. Official CAH risk is not available and may vary depending on the ethnic websites, videos, and pamphlets should be developed by background and degree of overlap with polycystic ovarian Downloaded from at University of Oklahoma Bird Hlth Sci Lib on April 23, 2009
  5. 5. 4052 J Clin Endocrinol Metab, September 2002, 87(9):4048 – 4053 Joint LWPES/ESPE CAH Working Group • Consensus syndrome. The risk of women with CAH or NCCAH having DHEA replacement in CAH. CAH patients on glucocorticoid an affected fetus is low. treatment have low DHEA levels. Studies in adult patients with Addison s disease have shown beneficial effects of Management of a CAH woman in pregnancy. Pregnant women DHEA replacement (36), but the relevance in CAH is with CAH should be monitored and delivered in a tertiary unknown. center equipped and experienced to handle such pregnan- cies. Glucocorticoids that do not cross the placenta, such as 11 -Hydroxysteroid dehydrogenase (11 -HSD) inhibitors in HC and prednisolone, should be used. Dexamethasone CAH. 11 -HSD inhibitors have the potential for modulating should be avoided (except when used in prenatal therapy). tissue-specific activity of glucocorticoids (37). At present, Glucocorticoid doses should be adjusted to maintain mater- there are no specific compounds that are selective inhibitors nal serum testosterone concentrations near the upper range of 11 -HSD type I or type II, and clinical experience with of normal for pregnancy (29). When reconstructive surgery nonspecific 11 -HSD inhibitors is limited. Therefore, the use has been performed, we recommend elective cesarean sec- of these inhibitors cannot be recommended, at present. tion to avoid damage to the genital tract. When cesarean GH treatment with or without administration of GnRH agonists. section is performed, doses of HC have to be increased before A meta-analysis of 561 patients with CAH (the majority with and tapered after delivery. A pediatrician should be present 21OH deficiency) revealed an overall mean final height sd during delivery to take care of the newborn and to initiate score of –1.4 (38). Thus, an acceptable height is achieved by diagnostic procedures when an affected child is expected many patients with CAH, and the mean adult height deficit according to the results of prenatal testing (30, 31). is substantially less than frequently thought. However, some CAH patients fail to reach normal adult height. A small Experimental therapies and future developments group of short CAH patients have been treated with GH for The place of adrenalectomy in CAH. Bilateral adrenalectomy by 2 yr, either alone or in combination with a GnRH agonist. laparoscopy is effective in decreasing adrenal androgens and This significantly improved growth rate and predicted final the likelihood of iatrogenic hypercortisolism (32, 33). It height (39), but adult height data are not yet available. should be considered only in cases where conventional ther- apy is failing. Vigilance in maintaining regular substitution Conclusions of HC and fludrocortisone is mandatory, with prompt in- These guidelines are designed to cover all aspects of the stitution of stress dosages at the onset of illness. The patient management of this complex disease in children, from di- must be monitored, throughout life, for activation of ectopic agnosis through adulthood. The multidisciplinary nature of adrenal rest tissue. The procedure should only be carried out management is emphasized, with the recognition that such where long-term follow-up is secured, and in the form of expert teams need appropriate reimbursement and govern- ethically approved clinical studies. mental support. There remain important deficits in our CRH antagonists for adrenal suppression in CAH. The use of knowledge about this disorder; and again, these have been CRH antagonists in CAH is promising on theoretical highlighted. New therapeutic strategies are emerging but, as grounds but awaits future developments of drugs with im- yet, require longer evaluation before being introduced into proved pharmacological properties. routine practice. In the meantime, we should focus on early diagnosis, optimal medical and surgical treatment, and at- Treatment with antiandrogens and aromatase inhibitors in addi- tention to compliance. tion to HC and fludrocortisone. Based on the success of an earlier approach in familial male sexual precocity, it was Acknowledgments hypothesized that the deleterious effects of elevated andro- The LWPES gratefully acknowledges Aventis Pharmaceuticals for gens on adult height could be prevented by using an anti- partial support of the consensus meeting in Gloucester. androgen to block androgen action and/or an aromatase The following participants convened in Gloucester, Massachusetts, inhibitor to block conversion of androgen to estrogen. Lim- March 14 –17, 2002, and contributed to this manuscript: Sheri Berenbaum (College Station, PA), George Chrousos (Bethesda, MD), Peter Clayton ited short-term (2 yr) studies in CAH show improved control (Manchester, UK), Gordon Cutler (Indianapolis, IN), Sabine De Muinck of height velocity and bone maturation at reduced glucocor- Keizer-Schrama (Rotterdam, The Netherlands), Patricia K. Donahoe ticoid dosage (34). Long-term safety data are not available, (Boston, MA), Patricia A. Donahoue (Iowa City, IA), Malcolm Donald- and reproductive effects are not known. Liver function has son (Glasgow, UK), Maguelone Forest (Lyon, France), Kenji Fujieda to be carefully monitored. (Asahikawa, Japan), Lucia Ghionizz (Parma, Italy), Maria Ginalska- Malinowska (Warsaw, Poland), Melvin M. Grumbach (San Francisco, Epinephrine deficiency in CAH. Patients with CAH suffer from CA), Annette Gruters (Berlin, Germany), Kerstin Hagenfeldt (Stock- ¨ holm, Sweden), Raymond L. Hintz (Stanford, CA), John W. Honour varying degrees of dysplasia and dysfunction of the adrenal (London, UK), Ieuan A. Hughes (Cambridge, UK), Ursula Kuhnle-Krahl medulla, expressed primarily as epinephrine deficiency (35). (Munchen, Germany), Peter A. Lee (Hershey, PA), Heino Meyer- ¨ This may play a role in response to stress. Possible thera- Bahlburg (New York, NY), Claude Migeon (Baltimore, MD), Walter L. peutic implications are under study. Miller (San Francisco, CA), Jorn Muller (Copenhagen, Denmark), Maria ¨ I. New (New York, NY), Sharon E. Oberfield (New York, NY), Michael Innovative genetic approaches. Preimplantation genetic diag- Peter (Kiel, Germany), E. Martin Ritzen (Stockholm, Sweden), Paul ´ Saenger (Bronx, NY), Martin O. Savage (London, UK), Justine M. nosis for CAH is possible, but further research is required to Schober (Erie, PA), Wolfgang G. Sippell (Kiel, Germany), Janos Solyom determine its utility. Gene therapy is currently not possible (Budapest, Hungary), Phyllis W. Speiser (Manhasset, NY), Bradford L. in humans with this disorder. Therrell (Austin, TX), Judson J. Van Wyk (Chapel Hill, NC), Garry L. Downloaded from at University of Oklahoma Bird Hlth Sci Lib on April 23, 2009
  6. 6. Joint LWPES/ESPE CAH Working Group • Consensus J Clin Endocrinol Metab, September 2002, 87(9):4048 – 4053 4053 Warne (Melbourne, Australia), Perrin C. White (Dallas, TX), Ludwig ior. In: Eugster E, Pescovitz OH, eds. Developmental endocrinology: from Wildt (Erlangen, Germany), and Selma Witchell (Pittsburgh, PA). research to clinical practice. Totowa, NJ: Humana Press; 293–311 The working group also acknowledges the contributions of Peter C. 20. Merke DP, Cho D, Anton Calis K, Keil MF, Chrousos GP 2001 Hydrocor- tisone suspension and hydrocortisone tablets are not bioequivalent in the Hindmarsh (London, UK), Lewis B. Holmes (Boston, MA), Lourdes treatment of children with congenital adrenal hyperplasia. J Clin Endocrinol Ibanez (Barcelona, Spain), Lenore S. Levine (New York, NY), Songya ˜ Metab 86:441– 445 Pang (Chicago, IL), and Anna Wedell (Stockholm, Sweden). 21. Nordenstrom A, Marcus C, Axelson M, Wedell A, Ritzen EM 1999 Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of de- Received April 19, 2002. Accepted May 19, 2002. fective 11 -hydroxysteroid dehydrogenase reductase activity. J Clin Endocri- Address requests for reprints to: Dr. Raymond L. Hintz, Secretary, nol Metab 84:1210 –1213 22. Jansen M, Wit JM, van den Brande JL 1981 Reinstitution of mineralocorticoid Lawson Wilkins Pediatric Endocrine Society, 867 Allardice Way, Stan- therapy in congenital adrenal hyperplasia. Effects on control and growth. Acta ford, California 94305, E-mail:; or Dr. Martin O. Paediatr Scand 70:229 –233 Savage, Secretary, European Society for Pediatric Endocrinology, St. 23. Mullis PE, Hindmarsh PC, Brook CG 1990 Sodium chloride supplement at Bartholomew’s Hospital, London EC1A 7BE, United Kingdom, E-mail: diagnosis and during infancy in children with salt-losing 21-hydroxylase de- ficiency. Eur J Pediatr 150:22 24. 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