JOURNAL OF THE LOUISIANA STATE MEDICAL SOCIETY
REFERENCES
Consistent with prior studies, 5,6,7 we have identified five female patients missed by our newborn screening program. Diagnosis was established from birth to age four. Three of the patients presented with ambiguous genitalia at birth while the other two presented with premature adrenarche. The true incidence of false negatives could be obscured due to underreporting of patients missed by the screening evaluation. A possible explanation for the unidentified cases is that the newborn screen identifies the severe form of the disease rather than the milder simple virilizing form. Female infants seem to be missed more frequently than males due to higher 17-OHP levels in males at birth. 8 Colorado examined their experience with second tier screening over a period of 10 years. 9 Chan et al. found that about 30% of classic CAH patients were missed using the first newborn screen. There was only one false negative female with normal first and second screens later recognized due to ambiguous genitalia. Contrary to other studies, they found 17- OHP levels to be higher in females than in males. Similarly, a study done in Eastern Europe found the false negative rate to approximate ~30%. 10 Some investigators 11 have found cutoff levels that are based on gestational age will lead to a higher sensitivity than cutoff levels that are based on birth weight at the same specificity. This could be due to the fact that the development of the adrenal glands is most closely related to gestational age than birth weight. Based on these findings, we could consider using gestational age for the 17-OHP cutoffs or perhaps a second-tier screen might be necessary. As the levels of 17-OHP decrease a few days after birth, this will increase the PPV of the screening test. Another possibility could be to change the FIA to a more specific liquid chromatography mass spectrometry or, in the future, use routine genetic testing for mutations in the CYP21A2. In conclusion, the current cutoff and assay used for screening of CAH satisfies the goal of “catching” the majority of the salt wasters. On the other hand, we still have to recall a significant number of families labeled false positives and this can cause significant psychological and financial burden to the parents. A second-tier newborn screen, although less cost effective, would identify those patients with the simple virilizing or nonclassic form. The use of tandemmass spectrometry to measure 17-OHP should always be considered to confirm the diagnosis if clinically suspected.
1. Nascimento ML, Baptista Cristiano AN, de Campos T, et al. Ten-year evaluation of a Neonatal Screening Program for Congenital Adrenal Hyperplasia. Arq Bras Endocrinol Metab . 2014;58: 765-771. 2. Therrell BL Jr, Berenbaum SA, Manter-Kapanke V, et al. Results of screening 1.9millionTexas newborns for 21-hydroxylase-deficient congenital adrenal hyperplasia. Pediatrics . 1998; 101:583-90. 3. Dhondt JL. Neonatal screening: from the ‘Guthrie age’ to the ‘genetic age’. J Inherit Metab Dis . 2007; 30:418–22. 4. Pass KA, Neto EC. Update: Newborn Screening for Endocrinopathies. Endocrinol Metab Clin N Am. 2009; 38:827–837. 5. Held PK, Shapira SK, Hinton CF, et al. Congenital adrenal hyperplasia cases identified by newborn screening in one- and two-screen states. Molecular Genetics and Metabolism. 2015; 116:133–138. 6. Thil’en A, NordenstromA, Hagenfeldt L, et al. Benefits of neonatal screening for congenital adrenal hyperplasia (21-hydroxylase deficiency) in Sweden. Pediatrics . 1998;101:E11. 7. Brosnan PG, Brosnan CA, Kemp SF, et al. Effect of newborn screening for congenital adrenal hyperplasia. Arch Pediatr Adolesc Med . 1999 Dec;153(12):1272-8. 8. Varness TS, Allen DB, Hoffman GL. Newborn screening for congenital adrenal hyperplasia has reduced sensitivity in girls. J Pediatr. 2005; 147(4):493. 9. Chan CL, McFann K, Taylor L, et al. Congenital Adrenal Hyperplasia and the Second Newborn Screen. J Pediatr. 2013;163:109-13. 10. Votava F, Torok D, Kovacs J, et al. Estimation of the false-negative rate in newborn screening for congenital adrenal hyperplasia. Eur J Endocrinol. 2005;152:869-74. 11. van der Kamp HJ, Oudshoorn CGM, Elvers BH, et al. Cutoff Levels of 17-OH- hydroxyprogesterone in Neonatal Screening for Congenital Adrenal Hyperplasia Should Be Based on Gestational Age Rather Than on Birth Weight. J Clin Endocrinol Metab , July 2005; 90(7):3904–3907. Dania Felipe, MD and Ricardo Gomez, MD, are affiliated with the Department of Pediatrics, Endocrinology and Diabetes, LSUHealth Sciences Center, Children's Hospital, in New Orleans, LA. Joseph Ortenberg, MD and Aaron Martin, MD, MPH, are affiliated with the Department of Urology, Division of Pediatric Urology, LSU Health Sciences Center, Children's Hospital, in New Orleans, LA. Robin Ortenberg, MD, is affiliated with the LSU School of Medicine, in New Orleans, LA. Michael Marble, MD, is affiliated with the LSU Health Sciences Center, Children's Hospital, in New Orleans, LA.
ACKNOWLEGEMENTS
We would like to thank Stephen Martin PhD, Colleen Clarke CLS, Cheryl Harris MPH, and Terry Crockett from the Louisiana Department of Health, Newborn Screening Program for providing data and participating in discussions.
J La State Med Soc VOL 170 JANUARY/FEBRUARY 2018 17
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