Cystic Fibrosis Newborn Screening Lori Vanscoy M D
Cystic Fibrosis Newborn Screening Lori Vanscoy, M. D. LCDR, MC, USN National Naval Medical Center December 2007
Courtesy of P. Farrell
Overview • Pathophysiology of Cystic Fibrosis • Newborn Screening – Benefits – Methods of Screening • Evaluation of infant with positive newborn screen
Cystic Fibrosis • Autosomal recessive disorder • CFTR gene on long arm of chromosome 7 • 1: 3200 live births (Caucasians) • Carrier rate for a CFTR mutation 1: 25 • Most patients have no family history
www. hopkinscf. org
Ackerman, NEJM (1997) 336: 1575
www. hopkinscf. org
Median Predicted Survival Age, 1985 -2005 36. 5 years old Median Survival Age (Years) 40 38 36 34 32 30 28 26 24 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 Year
Diagnosis • • Meconium ileus Direct hyperbilirubinemia Failure to thrive Recurrent respiratory problems Chronic sinus disease Rectal prolapse Newborn screening Prenatal screening
Potential Benefits of CF NBS • Disease-oriented outcomes – Growth and Nutrition – Lung Function • Patient-oriented outcomes – Survival • Benefits to families – Quality of life – Resource utilization (e. g. hospitalization)
Percent 3 rd of patients less than the percentile for weight * * * p <0. 05 SYMP vs NBS each age range * * * CFF Patient Registry, 2002
Nutrition and Pulmonary Function Are Intertwined 100 FEV 1 Percent Predicted 95 90 85 80 75 70 65 60 55 50 <5 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 BMI Percentile Males Patients 6 to 20 Years Old Females CFF Patient Registry, 2006
Percent predicted FEV 1 2002 CFF Registry * * * p <0. 05 SYMP vs NBS each age range CFF Patient Registry, 2002
Survival from CFF Registry Lai et al. J. Pediatr (2005) 147(3): S 57 -S 63
Risks and Harms of CF NBS • False positives – Increased anxiety – Misunderstanding of information • False sense of security with negative NBS • Possibility of overwhelming available resources – Sweat testing – Genetic counseling • Person-to-person transmission is a potentially dangerous harm – Can be managed by rigorous infection control
Approaches to CF NBS • IRT/IRT – Initial screen: elevated immunoreactive trypsinogen (IRT) – Secondary screen: Repeat IRT ~2 weeks later – Avoids dealing with genetic data • IRT/DNA – Initial screen: elevated IRT – Secondary screen: limited genotyping – Avoids need to obtain follow-up blood
Approaches Vary • IRT/IRT – Maryland • IRT/IRT (conditional) – Virginia • IRT/∆F 508 – DC – (Maryland too)
IRT/IRT Negative Measure IRT Elevated Positive 2 elevated IRT
IRT/IRT (Conditional) Negative Measure IRT Elevated Negative Measure IRT Positive 2 elevated IRT
IRT/DNA Negative Measure IRT Elevated Negative Analyze for CFTR Mutations Positive 1 or 2 mutations Very elevated IRT
National Capital Area Military Newborn Screen • Contract with Pediatrix • Uses INNOGENETICS CFTR Assay • Hybrid of the two approaches (to ensure that they meet Maryland criteria) – 1 st IRT/∆F 508 – if one ∆F 508 mutation is identified, then extended panel is performed – 2 nd IRT – if second IRT is elevated, then extended mutation panel is performed
Pediatrix – 1 st Sample Negative Measure IRT Elevated Analyze for ΔF 508 0 1 Positive 2 Perform extended mutation panel
Pediatrix – 2 nd Sample Negative Measure IRT Elevated – 2 nd sample Analyze for extended mutation panel Positive
Now What? Remember Newborn Screening is a Screening Test !!
“Positive” CF Newborn Screen • False positive rate 70% • False negative rate 5. 4% • Children with Meconium Ileus have LOW IRT values – False negative rate 8. 2% • IRT values are elevated in premature infants Colorado 1, 153, 339 births (2 elevated IRT)
Diagnosis • Sweat Chloride • CFTR mutation analysis
Sweat testing • Pilocarpine Iontophoresis • Two Collection Methods – Gauze (Gibson-Cooke) – Microbore tubing (Macroduct®) • Should not be performed in the first 48 hours of life • Must measure chloride content (not conductivity)
Sweat Testing 1338 infants in Massachusetts Parad et al. J. Pediatr (2005) 147: S 69 -S 72
Sweat Chloride Results Normal <40 meq/L Borderline 40 -60 meq/L Abnormal (CF) >60 meq/L
Sweat Chloride in Infants Parad et al. J. Pediatr (2005) 147: S 69 -S 72
Diagnosis in Infants Normal <30 meq/L Borderline 30 -60 meq/L Abnormal (CF) >60 meq/L
1526 CFTR Mutations www. genet. sickkids. on. ca/cftr as of 9/1/2006
Detection of Cystic Fibrosis by Mutation Analysis Ethnic Group Detection Rate Mutations tested 25 97 Caucasian African American Hispanic Ashkenazi Jewish 90% 69% 57% 93% 81% 72% 97% unknown Other
CF Diagnosis is Confirmed • Refer to a CF Specialist • Multidisciplinary team approach – – – Pulmonologist Nutritionist Physical Therapist Social Worker Other specialists – GI, Endocrinology
Summary • Early intervention has the potential to decrease morbidity and improve survival • Newborn screening can identify MOST children with cystic fibrosis • Children with a negative newborn screen can still have cystic fibrosis – Meconium Ileus
Summary • Positive newborn screens must be followed up with a sweat test • Children with elevated (or borderline) sweat tests should be referred to a CF specialist
- Slides: 40