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

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

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

Fast facts (cont.) *Genzyme Genetics, 2006 Frequency of CFTR mutations in ethnic groups* Caucasians ^ ^ CF is the most common autosomal recessive condition in Caucasians 1 in 25 carries at least one CFTR mutation Hispanics 1 in 46 carries at least one CFTR mutation African-Americans 1 in 65 carries at least one CFTR mutation

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

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

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

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)

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

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

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

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

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

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

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)

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

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

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

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

Autosomal recessive inheritance

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

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

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

CFF-accredited clinics in Indiana* Clinic name & addressHours of operationContact information Riley Hospital for Children Wednesdays 10 am – 5 pm 702 Barnhill Drive, ROC 4270 Indianapolis, IN Deaconess Hospital Outreach Clinic During 4 th week of month: Monday, 8:40 am – 4:30 pm Tuesday, 7 am – 4:30 pm Wednesday, 7 – 11 am 4011 Gateway Boulevard Newburgh, Indiana Lutheran Hospital Tuesdays and 3 rd Wednesday of each month (times variable) 7950 W. Jefferson Boulevard Fort Wayne, IN St. Joseph Regional Medical Center CF & Pulmonary Disease Clinic 2 nd and 4 th Friday of each month 720 E. Cedar Street South Bend, IN * For a list of CFF-accredited centers in neighboring states, please contact ISDH

CFF-accredited sweat chloride testing laboratories in Indiana Laboratory name & addressContact information Riley Hospital for Children 702 Barnhill Drive Indianapolis, IN Deaconess Hospital 600 Mary Street Evansville, IN Lutheran Hospital 7950 W. Jefferson Boulevard Fort Wayne, IN South Bend Medical Foundation (provides testing for St. Joseph Hospital) 530 N. Lafayette Boulevard South Bend, IN

For more information If you would like to receive an electronic copy of this review, please contact: Constance Burrus, BS Cystic Fibrosis Coordinator Indiana State Department of Health

For more information (cont.) Constance Burrus, BS Cystic Fibrosis Program Director Indiana State Department of Health Courtney Eddy, MT(ASCP), MS Genomics Program Director Indiana State Department of Health