 Newborn Screening Baylor College of Medicine Anoop Agrawal, M.D.

History of Newborn Screening  Began in the early 1960s  In 1961, Dr. Robert Guthrie developed an assay that could detect elevated levels of phenylalanine from a single drop of an infant’s blood.  By 1965, over half of U.S. states had mandated PKU testing.  In 1995, most states screened for five disorders on average.

Expansion of Screening  In the 1990s, a new technology was developed known as tandem mass spectromety or MS/MS. This tool was able to screen for multiple biochemical markers (and hence disorders) using the same drop of blood.  In March 2005, the American College of Medical Genetics (ACMG) issued a report advocating for a mandated uniform panel of 29 disorders.  Prior to 2005, there was significant variablity amongst states in mandated screening – ranging from zero to eight  By 2005, average number of conditions tested for by states increased to 24

Newborn Screening  Currently, how many genetic diseases are available for newborn screening?  The ACMG recommends states screen for 48 genetic diseases.  How many genetic diseases are currently screened for in the state of Texas?  As of Dec ‘09, Texas now screens for 28.

Extent of Mandatory Expanded Screening Fourteen states do not mandate the expanded testing. Parents are offered the testing through a voluntary pilot program.

Screening in Texas  In 2005, HB790 was passed requiring expansion of the newborn screening program using the ACMG (American College of Medical Genetics) recommended panel as funds allowed.  As of Dec ’09, the number of diseases screened increased to from 27 to 28.  Prior to that, only five diseases were screened: PKU, hypothyroidism, galactosemia, sickle cell disease, congenital adrenal hyperplasia  In Texas, the Department of State Health Services (DSHS) operates the newborn screening case management program.

What conditions are screened for in Texas? Amino Acid Disorders (6) Fatty Acid Oxidation Disorders (5) Organic Acid Disorders (9) Hemoglobin- opathies (3) Endocrine disorders (3) Other (2)

Newborn Screens for Texas Amino Acid Disorders PKU MSUD CIT ASA HCY TYR-I Fatty Acid Oxidation MCAD CUD LCHAD TFP VLCAD Organic Acidemias 3-MCC BKT GA-I HMG IVA Cbl A, B form MUT MCD PROP Endocrine CAH Congenital Hypothyroidism Cystic Fibrosis Hemoglobin Disorders Hb S/S Hb S/A Hb S/C Other Biotinidase Deficiency Galactosemia

Incidence of inborn errors Which of the following inborn errors of metabolism has the highest incidence? A. congenital adrenal hyperplasia B. congenital hypothyroidism C. cystic fibrosis D. galactosemia E. phenylketonuria 1 in 12,000 1 in 3,500 1 in 4,000 1 in 60,000-80,000 1 in 10,000-25,000 *Cystic fibrosis is now tested for in the state of Texas.

Most common congenital defect  What is the most common congenital defect screened for?  The overall number one most common disease screened for is hearing loss.  It has an incidence of 2-3 in 1,000. Almost 20x more common than PKU  Currently screened for via OAE, ABER  DNA testing for hearing loss is already possible, but not yet employed.  50% of newborns with hearing loss is due to genetic factors  90% of newborns with hearing loss are born to hearing parents

Estimated Expansion Statistics In Texas: Approximately 400,000 births a year Approximately 800,000 specimens a year collected and tested Follow-up on approximately 15,000 abnormal screens a year Approximately 600 diagnosed cases per year

More is better, right?  Expanded newborn screen has raised concerns amongst some.  The identification of an abnormality that does not become clinically apparent is termed ‘pseudodisease.’  Several of the newly added biochemical disorders maybe pseudodiseases.  Currently research suggests 3-MCC (is done in Texas) and SCAD (not in Texas) may not lead to significant ‘disease.’  Histidenemia is one that has been removed from screening due to lack of clinical disease in long-term studies

More is better, right?  This raises the question of ‘How many more of the conditions added to the expanded list will become pseudodiseases?’  Expanded screen for multiple rare disorders inevitably leads to more false positive results even when specificity is high  Indirect costs of expanded newborn screening:  Parental anxiety  Cost of more diagnostic testing  Potential lack of meaningful intervention

Scenario One  You receive a phone call from the Texas Department of State Health Services. A six day old patient you saw yesterday has a positive newborn screening test for increased methionine and may have Homocystinuria. A review of the chart shows the child had a normal exam and seemed to be doing well.  What should you do next?  Where do you go for more information?

What do you do next?  Know what resources are available to assist you.  FACT sheets – created by the AAP to provide pediatricians and parents with general information on the condition  Can be found on AAP website or Texas State Department of Health website:  These are also available in spanish on the Texas site.  ACT sheets – created by the American College of Medical Genetics. Provides physicians with the ‘action’ plan – diagnostic workup and clinical manifestations to watch for.  Also found on Texas’ website or on ACMG’s website –

FACT Sheets Example of FACT sheet from Texas Department of State Health Services FACT sheets on AAP website are geared more towards physicians. This covers causes, symptoms, overview of treatment and outcomes. This sheet by DSHS is designed for parents and physicians.

ACT Sheets Example from ACMG for increased methionine - Texas Dept of State Health Services has adapted the same information on their website. In this case, obtain quantitative amino acids, plasma homocysteine level and urine homocysteine level. Consult with metabolic specialist. Counsel and educate family about homocystinuria. Report findings to newborn screening program.

Scenario Two  You are seeing a newborn infant in the Level I nursery. The parents tell you they do not want their child to have newborn screening testing. They feel that such testing is not part of ‘God’s plan.’ What should you do?  In the state of Texas, a parent has the right to object to screening if it conflicts with their religious tenets or practices.

Scenario Three  You are examining a two week old female in your office. The family has recently moved to Houston from Miami. After your exam, you inform the parents the infant will need a newborn screen. The parents ask you why she needs a second screen? In Florida, their older child only had newborn screening performed once.  Texas mandates ALL infants have two newborn screens. The first must be collected between hours of life. The second may be performed between 7-14 days of life.  What if the baby is 6 months old and has only one newborn screen on file?  In Texas, every child must have 2 newborn screens documented by age of 12 months.

Hot off the presses!

The Future  Current screening relies on detecting biochemical markers via tandem mass spectrometry (MS/MS).  This methodology enabled expansion of newborn screening in an inexpensive, rapid and easy manner.  The future lies in DNA-based screening.  This will undoubtedly raise the specter of diseases screened for along with requiring more of the pediatrician.  DNA testing also raises a host of privacy, societal and medical issues which will need to be addressed.

Bibiliography  Tarini, BA, Freed GL. Keeping up with the newborn screening revolution. Contemporary Pediatrics 2007;24:4,  Texas State Department of Health Services,  National Newborn Screening and Genetics Resource Center,