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Endocrine Care: C. Moran, R. Azziz, N. Weintrob, S. F. Witchel, V. Rohmer, D. Dewailly, J. A. M. Marcondes, M. Pugeat, P. W. Speiser, D. Pignatelli, B. B. Mendonca, T. A. S. Bachega, H. F. Escobar-Morreale, E. Carmina, F. Fruzzetti, and F. Kelestimur Reproductive Outcome of Women with 21-Hydroxylase-Deficient Nonclassic Adrenal Hyperplasia J Clin Endocrinol Metab 2006; 91: 3451-3456 [Abstract] [Full text] [PDF]

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Ricardo Azziz, C. Moran, N. Weintrob, S. F. Witchel, V. Rohmer, D. Dewailly, J. A. M. Marcondes, M. Pugeat, P. W. Speiser, D. Pignatelli, B. B. Mendonca, T. A. S. Bachega, H. F. Escobar-Morreale, E. Carmina, F. Fruzzetti, and F. Kelestimur   (1 February 2007)

Prevalence of Congenital Adrenal Hyperplasia

Heinrich Vierhapper, Sabina Baumgartner-Parzer   (30 October 2006)

Authors' Response to Letter 1 February 2007
Ricardo Azziz, MD Cedars-Sinai Medical Center, Los Angeles, CA, C. Moran, N. Weintrob, S. F. Witchel, V. Rohmer, D. Dewailly, J. A. M. Marcondes, M. Pugeat, P. W. Speiser, D. Pignatelli, B. B. Mendonca, T. A. S. Bachega, H. F. Escobar-Morreale, E. Carmina, F. Fruzzetti, and F. Kelestimur Send letter to journal: Re: Authors' Response to Letter azzizr{at}cshs.org Ricardo Azziz, et al.	We thank Vierhapper and Baumgartner-Parzer for their comments about our paper (1). The primary goal of this study was to determine the prevalence of children with classic congenital adrenal hyperplasia (CAH) born to women known to have nonclassic CAH. In this context, the important statistic is the heterozygote frequency for classic CAH in the general population. Vierhapper and Baumgartner-Parzer misquote the heterozygote frequency described by Fitness et al. (2) determined by genotyping more than 600 infants evaluated through the New Zealand newborn screening program. Those investigators found a 2.8% classic heterozygote rate (or about 1 in 36 persons). Baumgartner-Parzer et al. (3) studied 200 European patients and found 5-6% to be heterozygotes for classic CAH. The heterozygote prevalence may be skewed by the ethnicity of the population. Moreover, extrapolation of population frequencies from such small samples may not be entirely valid. This is why our study provided 95% confidence limits to our estimated frequencies. Our rate of finding classic CAH children born to women known to have nonclassic CAH was 2.5%, slightly higher than the calculated estimate of <1%. It should be noted, however, that the 95% confidence limits extend to 0.7% in this small study of 162 live births. It is extremely unlikely that classic CAH would have been missed in infants or children who have had serum 17-hydroxyprogesterone measured, even if only in the basal state. Genotyping is not required to make the diagnosis of CAH, except in equivocal cases, which are rare. This is the position of the international endocrine community (4, 5). We agree with the concept of a continuum of CAH phenotypes. However, there is also the practical matter of reassuring patients and family members with mild forms of CAH that they do not have a life- threatening disease. References 1. Moran C, Azziz R, Weintrob N, Witchel SF, Rohmer V, Dewailly D, Marcondes JA, Pugeat M, Speiser PW, Pignatelli D, Mendonca BB, Bachega TA, Escobar-Morreale HF, Carmina E, Fruzzetti F, Kelestimur F. 2006. Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia. J Clin Endocrinol Metab 91:3451-3456 2. Fitness J, Dixit N, Webster D, Torresani T, Pergolizzi R, Speiser PW, Day DJ. 1999. Genotyping of CYP21, linked chromosome 6p markers, and a sex- specific gene in neonatal screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 84:960-966 3. Baumgartner-Parzer SM, Nowotny P, Heinze G, Waldhausl W, Vierhapper H. 2005. Carrier frequency of congenital adrenal hyperplasia (21-hydroxylase deficiency) in a middle European population J Clin Endocrinol Metab 90:775-778 4. Joint LWPES/ESPE CAH Working Group. 2002. Consensus statement on 21-hydroxylase deficiency from the Lawson Wilkins Pediatric Endocrine Society and the European Society for Paediatric Endocrinology. J Clin Endocrinol Metab 87:4048-4053 5. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser PW; ESPE/ LWPES CAH Working Group. 2002. Consensus statement on 21-hydroxylase deficiency from the European Society for Paediatric Endocrinology and the Lawson Wilkins Pediatric Endocrine Society. Horm Res 58:188-195
Prevalence of Congenital Adrenal Hyperplasia 30 October 2006
Heinrich Vierhapper, M.D. Dept.Clin.Endocrinol.&Metab., Clinic Int.Med.III, Medical University of Vienna, Vienna, Austria, Sabina Baumgartner-Parzer Send letter to journal: Re: Prevalence of Congenital Adrenal Hyperplasia h.vierhapper{at}meduniwien.ac.at Heinrich Vierhapper, et al.	Moran et al. (1) report the frequency of children affected by congenital adrenal hyperplasia (CAH) born to mothers with “non-classic” CAH to be higher than they expected. Their quoted general prevalence of heterozygosity for severe and mild CYP21A2 gene mutations (1:60 and of 1:16, respectively) are based on findings (2,3) antedating molecular genetic techniques. More recently, heterozygosity for CAH in a general population has been found to be 4.8 % [= 1:21 (4)] or 9.5 % [= 1:11 (5)]. Therefore the “higher than expected” rate of CAH births among mothers with NCAH may simply be due to the fact that carriers of CAH mutations are more common than assumed by the authors. In addition, Moran et al. state that they have not investigated all children born to CAH mothers. Even in those actually studied it is unclear whether this was done by molecular genetics. Clearly, if genotyping was not obtained in all children (regardless of a seemingly normal clinical appearance and apparently normal ACTH-stimulated concentrations of 17-OH-progesterone), the diagnosis will probably have been missed in some individuals. Furthermore, we do not agree with the authors’ recommendation to screen the offspring of NCAH mothers by biochemical methods alone. Rather this should be done by genotyping in each case. As indicated by the data of Moran et al. themselves, biochemical tests are not sufficiently accurate to achieve that goal. Finally, the spectrum of patients affected by CAH represents a broad spectrum of various point mutations, deletions and conversions. Patients have been diagnosed with “classic” CAH at the age of 39 (6). While the separation of so-called "classic" and "non-classic" forms of CAH may be clinically helpful it is of little scientific relevance and should be abandoned. References 1. Moran C, Azziz R, Weintrob N, Witchel SF, Rohmer V, Dewailly D, Marcondes JA, Pugeat M, Speiser PW, Pignatelli D, Mendonca BB, Bachega TA, Escobar-Morreale HF, Carmina E, Fruzzetti F, Kelestimur F. 2006. Reproductive outcome of women with 21-hydroxylase-deficient nonclassic adrenal hyperplasia. J Clin Endocrinol Metab 91:3451-3456. 2. Speiser PW, Dupont B, Rubinstein P, Piazza A, Kastelan A, New MI. 1985. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am-J-Hum- Genet 37:650-667. 3. Sherman SL, Aston CE, Morton NE, Speiser PW, New MI. 1988. A segregation and linkage study of classical and nonclassical 21-hydroxylase deficiency. Am- J-Hum-Genet 42:830-838. 4. Fitness J, Dixit N, Webster D, Torresani T, Pergolizzi R, Speiser PW, Day DJ. 1999. Genotyping of CYP21, linked chromosome 6p markers, and a sex- specific gene in neonatal screening for congenital adrenal hyperplasia. J Clin Endocrinol Metab 84:960-966. 5. Baumgartner-Parzer SM, Nowotny P, Heinze G, Waldhausl W, Vierhapper H. 2005. Carrier frequency of congenital adrenal hyperplasia (21-hydroxylase deficiency) in a middle European population. J Clin Endocrinol Metab 90:775-778. 6. Müssig K, Kaltenbach S, Maser-Gluth C, Hartmann MF, Wudy SA, Horger M, Gallwitz B, Raue F, Häring H-U, Schulze E. 2006. Late Diagnosis of Congenital Adrenal Hyperplasia Due to 21-Hydroxlyse Deficiency. Clin Exp Endocrinol Diab 114:208-214.