Cystic Fibrosis: A Review for Healthcare Providers

1. Cystic Fibrosis:A Review for Healthcare Providers Provided by the Indiana State Department of Health

2. Outline • Fast facts about CF • Diagnosis • CFTR gene • Newborn screening • Symptoms • Medical management / prognosis • Inheritance / recurrence risks

3. Fast facts about CF • Currently, there are approximately 30,000 people in the US with CF* • ISDH estimates that each year in Indiana, approximately 300 children with at least one CFTR mutation will be identified through newborn screening^ *Cystic Fibrosis Foundation Patient Registry Annual Data Report, 2005 ^Based on annual live birth rate of 87,000 children

4. Fast facts (cont.) *Genzyme Genetics, 2006

5. Newborn screening for CF • All infants receive IRT screen as part of newborn screening (heelstick) • IRT = immunoreactive trypsin • Infants with IRT above cutoff identified by the IU Newborn Screening Laboratory will receive DNA testing • IU Newborn Screening Laboratory tests for a panel of 44 common CFTR mutations • Note: CF newborn screening does NOT test for all known CFTR mutations

6. Newborn screening (cont.) • If an infant is found to have an elevated IRT and 1+ CFTR mutations: • IU Newborn Screening Laboratory will notify primary care physician • Phone call & letter • IU Newborn Screening Laboratory will notify ISDH • ISDH will contact PCPs to assist with: • Referring patients for sweat chloride testing • Referring patients to CF centers • Counseling / educating families

7. Timeline for referrals • Primary care physicians should refer infants with 2 identified mutations to a Cystic Fibrosis Center within 2 weeks for evaluation and treatment • Primary care physicians should refer infants with 1 identified mutation for sweat chloride testing within 2 weeks of receiving newborn screening result • ISDH recommends referring patients to Cystic Fibrosis Foundation (CFF) accredited laboratories for sweat chloride testing

8. Why refer to CFF-accredited labs? • Indiana has chosen to follow the national precedent by referring patients to CFF-accredited centers for sweat chloride testing and management • CFF-accredited laboratories meet nationally-accepted standards selected by the CFF in conjunction with the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS)

9. Why refer to CFF-accredited labs? (cont.) • National standards are imperative to ensure that sweat chloride test results are consistently accurate and reliable • Several different sweat chloride test procedures exist • Procedures not approved by CFF & CLSI have demonstrated high false-positive and false-negative rates • Collection procedure is highly sensitive • Other procedures are erroneous

10. What about children with one CFTR mutation? • All children with at least one identified CFTR mutation should be referred for sweat chloride testing

11. What about children with one CFTR mutation? • Children with one identified mutation are typically asymptomatic carriers... • ...however, some children with a single mutation will have CF • Again, newborn screening does not test for all known CFTR mutations • Some children could have a common mutation (identified through newborn screening) and a rare mutation that is not included in newborn screening panel

12. CFTR gene • Over 1,400 disease-causing mutations currently known • Most are rare • Found in a single family • Almost all are small deletions or “point mutations” • Note: CF newborn screening does NOT test for all known mutations • Most common mutation: F508 • Represents approximately 30 – 80% of all identified mutations in patients with CF • Results in “classic” features of CF if two copies are present

13. Features of CF • Complex, multisystem disease • Most commonly affects: • Respiratory system • Gastrointestinal system • Male reproductive system

14. Pulmonary system • Chronic sinopulmonary disease • Chronic cough / sputum production • Wheezing • Persistent infections with: • P. aeruginosa • S. aureus • H. influenzae • B. cepacia complex • Abnormal chest X-rays • Digital clubbing www.medicine.ufl.edu www.nlm.nih.gov

15. Gastrointestinal system • Pancreatic insufficiency (> 90% of patients) • Malabsorption • Especially of fats / fat-soluble vitamins • May lead to failure to thrive, skin rashes, anemia • Meconium ileus (15 – 20% of patients) • Pancreatitis • Hepatobiliary disease • Hypoproteinemia • Distal intestinal obstructions • CF-related diabetes (usually develops in teens)

16. Male reproductive system • > 95% males with CF are infertile • Abnormal development of Wolffian ducts leads to azoospermia • Testicular development / function and spermatogenesis are usually normal

17. Male reproductive system (cont.) • Congenital bilateral absence of vas deferens (CBAVD) can occur in males with specific CFTR mutations • Regardless of whether these males have other symptoms of CF • For more information, or with questions about specific gene changes, please contact ISDH • Contact information is provided at the end of this review

18. Medical management • Recommend referral to Cystic Fibrosis Foundation (CFF) accredited center if two mutations present or with a positive sweat test • Centers offer a multidisciplinary approach that includes: • MDs • RNs • Respiratory therapists • Dieticians • Social workers • Genetic counselors • A list of CFF-accredited centers in Indiana is included in this review • For a list of CFF-accredited centers in other states, please contact Constance Burrus at ISDH

19. Prognosis • Average lifespan into the upper 30s • Progressive pulmonary disease is most common cause of death • Available therapies include nutritional, pulmonary, insulin, etc. • Gene therapy is not currently available clinically

20. Autosomal recessive inheritance www.search.com

21. Recurrence risk(parents of child with CF) • For each pregnancy (same partner): • 1 in 4 (25%) chance to have a child with CF • 1 in 2 (50%) chance to have a child who is an asymptomatic carrier • 1 in 4 (25%) chance to have a child who is neither affected with CF nor a carrier

22. Recurrence risk (cont.) • Each unaffected sibling of a child with CF has a 2/3 chance of being an asymptomatic carrier of a single CFTR mutation • Other family members are also at increased risk of being asymptomatic carriers • Carriers would have increased risk of having children with CF • Recommend genetic counseling / testing for at-risk family members

23. Future pregnancies (parents of a child with CF) • Prenatal genetic counseling* recommended for any couple concerned about the risk of having a child with CF • Prenatal screening for CF routinely offered to: • All Caucasian couples • Couples with family history of CF / CBAVD *Contact ISDH for a list of prenatal genetic counselors & clinics in your area

24. For more information • If you would like to receive an electronic copy of this review, please contact: Malorie Hensley, MS Cystic Fibrosis Program Director Indiana State Department of Health 317.233.7019 MHensley@isdh.IN.gov

25. For more information (cont.) • Malorie Hensley, MS Cystic Fibrosis & Genomics Programs Director Indiana State Department of Health 317.233.7019 Mhensley@isdh.IN.gov • Courtney Eddy, MS, CGC, LGC, MT(ASCP) INSTEP Director Indiana State Department of Health 317.233.9260 CEddy@isdh.IN.gov