Cystic Fibrosis: Overview

Question 1

What is CF? (2)

Answer 1

1. Chronic, progressive and life limiting autosomal recessive genetic disease characterized by chronic respiratory disease, pancreatic insufficiency, elevation of sweat electrolytes and male infertility
2. Diagnosed when an individual has both a clinical presentation of the disease and evidence of CFTR dysfunction

Question 2

Cystic fibrosis related metabolic syndrome (CRMS)/Cystic fibrosis screen positive, inconclusive diagnosis (CFSPID)

Answer 2

CRMS/CFSPID applies to infants who have a positive NBS test for CF and either:

1. A sweat chloride value <30mmol/L and 2 CFTR mutations, at least 1 of which has unclear phenotypic consequences

OR

2. An intermediate sweat chloride value (30-59 mmol/L) and 1 or 0 CF causing mutations

Question 3

CFTR-Related disorder

Answer 3

A monosymptomatic clinical entity associated with CFTR dysfunction that does not fulfill the diagnostic criteria for CF

Question 4

CF Recessive Disorder 94)

Answer 4

1. Located on chromosome 7, the CF transmembrane conductance regulator gene (CFTR) is the most common genetic mutation.
   a. Vital in sweat, digestive tissue, and mucus
   b. Over 2000 mutations
2. Cause ineffective transport of chloride across the cell membrane, which changes the chloride concentration gradient and the direction of sodium transport.
3. Results in physiological dysfunction in the body and affects many organ systems
   a. Lung
   b. Pancreas
   c. Liver
   d. Sinuses
   e. Male reproductive Tract; Females can carry children but males will usually be infertile
4. Can get polyps (don’t assume it’s allergies → must sweat test them)

Question 5

CF Epidemiology (5)

Answer 5

1. Most common autosomal recessive profoundly life- shortening disease
2. 1 in 4000 live births (CF Guidelines, 2017)
3. 30,000 affected in the US Carriage rate is 1 out of 2500
4. Prevalence rate
   a. 1 in 15,000 to 20,000 African-American (Sanders & Fink, 2016)
   b. 1 in 4,000 to 10,000 Hispanic
   c. 1 in 35,000 Asian descent (much lower)
5. Median age of survival: just under 40

Question 6

History of CF (5)

Answer 6

1. Scarring and cyst formation was first recognized in the 1930’s
2. First described by Dr. Andersen 1938 as “Cystic Fibrosis of the Pancreas”
3. Due to scarring of pancreatic tissue due to presumed auto digestions
4. Not really fibrosis but rather severe and chronic Bronchiectasis
5. Restrictive fat diet to avoid bulky, large, foul smelling stool was done prior to 1970 leading to vitamin deficiency

Question 7

Genetics of CF simplified (2)

Answer 7

1. If you have a carrier and someone that marries a carrier → 25% risk of having child with CF, 50% risk of having child be a carrier
2. Several mutations associated with CF 508 mutation
   - I, II, III is highest risk for severe disease
   - IV and V is lower risk for severe disease
   - There is also VI

Question 8

Class I Mutation (CFTR defect and risk category)

Answer 8

CFTR Defect: Defect in biosynthesis with little to no protein made

Risk Category: high risk with pancreatic insufficiency likely

Question 9

Class II Mutation (CFTR defect and risk category)

Answer 9

CFTR Defect: Defective protein processing and trafficking to the cell surface

Risk Category: high risk with pancreatic insufficiency likely

Question 10

Class III Mutation (CFTR defect and risk category)

Answer 10

CFTR Defect: abnormal gating

Risk Category: high risk with pancreatic insufficiency likely

Question 11

Class IV Mutation (CFTR defect and risk category)

Answer 11

CFTR Defect: defective chloride conductance

Risk Category: low risk with association of pancreatic insufficiency

Question 12

Class V Mutation (CFTR defect and risk category)

Answer 12

CFTR Defect: reduce protein quantity

Risk Category: low risk with association of pancreatic insufficiency

Question 13

Class VI Mutation (CFTR defect and risk category)

Answer 13

CFTR Defect: reduced stability at cell surface

Risk Category: risk not classified

Question 14

Genotype-Phenotype Relationships (5)

Answer 14

1. Pancreatic status may vary according to genotype III to the cell surface
2. Abnormal Gating
3. Pulmonary status cannot be predicted on the basis of genotype
4. Genetic aspects beyond the mutation may influence phenotype
5. All mutations must disrupt the CFTR protein quantity or function to cause CF

Question 15

Diagnosis of CF (6) – must know about gold standard information

Answer 15

1. The diagnosis of CF is made on the basis of clinical features and laboratory findings
2. Gold standard for diagnosis is the pilocarpine iontophoresis sweat test
   a. Patients must have one of more of the clinical features of CF
   b. Chronic sinopulmonary disease
   c. Gastrointestinal and nutritional abnormalities
   d. Salt loss syndrome
   e. Chronic metabolic alkalosis
   f. Male urogenital abnormalities resulting in obstructive azoospermia
3. In addition, one or more laboratory findings that indicate a CFTR abnormality must be present.
4. Results of the sweat test are determined differently depending on age
5. Can have a negative mutation but a positive sweat test
6. Child must be seen at a CF center when diagnosed

Question 16

Diagnostic Criteria for CF (6)

Answer 16

1. Positive newborn screen
2. Or signs/symptoms of CF
3. Or positive family history in parent or sibling

AND

4. Either a sweat chloride level greater than or equal to 60mmol/L
5. Or identification of 2 CF causing mutation in trans
6. Or nasal potential difference measurement consistent with CF

Question 17

Diagnosis of CF: Sweat Test (4)

Answer 17

1. The diagnosis of CF can be made in patients with clinical features of the disease under the following guidelines:
2. The concentration of sweat chloride is greater than 60 mmol/L.
   a. Suggests CF
   b. 30 to 59 mmol/L for infants less than 6 months or in the range of 40 to 59 mmol/L for older individuals.
   c. Need further genetic testing
3. Less then 30 mmol/L makes CF unlikely
4. Rare to have someone with two mutations have a negative sweat test

Question 18

Newborn Screen (4)

Answer 18

1. State labs may measure Immunoreactive trypsinogen (IRT) in the newborn’s blood
2. The state will either perform 2 IRT measurement (IRT/ IRT), a DNA CFTR mutation panel if the IRT is elevated (IRT/CFTR), or two IRT concentrations with a follow-up DNA CFTR mutation panel
3. If the IRT is elevated or the child has one CFTR mutation, the infant’s primary provider is notified and the child is referred for sweat testing.
4. There are false negative screens and so if an infant has symptoms and signs of CF, a sweat test should be performed

Screening test is IRT!

Question 19

Indications for sweat testing: respiratory (4)

Answer 19

1. Chronic cough
2. Recurrent pneumonia
3. Nasal polyps
4. Digital clubbing

Question 20

Indications for sweat testing: non-respiratory (6)

Answer 20

1. Meconium ileus
2. Prolonged neonatal jaundice
3. Rectal prolapse
4. Pancreatitis
5. Intussusception
6. Metabolic alkalosis

Question 21

Signs and Symptoms Consistent with CFTR dysfunction in Children and Adolescents: Nutritional (5)

Answer 21

1. failure to thrive
2. hypoproteinemia
3. hypochloremic
4. dehydration
5. Chronic metabolic alkalosis

Question 22

Signs and Symptoms Consistent with CFTR dysfunction in Children and Adolescents: GI (4)

Answer 22

1. Intestinal: meconium ileus, rectal prolapse, distal intestinal obstructive syndrome,
2. Steatorrhea
   - Fatty stools float and are yellow/pale
3. Pancreatic: exocrine pancreatic insufficiency, recurrent pancreatitis
   - Recurrent pancreatitis presents with abdominal pain
4. Hepatic: protracted neonatal jaundice, biliary cirrhosis

Question 23

Signs and Symptoms Consistent with CFTR dysfunction in Children and Adolescents: Respiratory (6)

Answer 23

1. Sinopulmonary: Chronic wet or productive cough
2. Bronchiectasis on chest imaging
3. Respiratory infection with Pseudomonas Aeruginosa or other atypical gram-negative organisms
4. Nasal polyposis in children
5. Digital clubbing
6. Allergic bronchopulmonary aspergillosis

Question 24

Signs and Symptoms Consistent with CFTR dysfunction in Children and Adolescents: Male Reproductive

Answer 24

Obstructive azoospermia in boys

Question 25

New Info about CF (5)

Answer 25

1. Mucus is adhesive and stringy leading to tenacious secretions that have poor cough clearance.
   a. Airway has fluid depletion → depleted sodium ions
2. Myth: sputum is very thick and viscous
3. The airway in CF have osmolar fluid depletion leading to a loss of water and increased concentration of ions.
4. Myth: Secretions are dehydrated
5. The secretions need to have increased volume of pericilliary fluid to help with expectoration

Question 26

CF Pneumonic: CF PANCREAS

Answer 26

Chronic respiratory disease
Failure to thrive

Polyps
Alkalosis, metabolic
Neonatal intestinal obstruction
Clubbing of fingers
Rectal prolapse
Electrolyte increase in sweat
Aspermia/absent vas deferens
Ssputum - S. aureus/P. aeruginosa

Question 27

Pulmonary Defects and Cystic Fibrosis Transmembrane regulator (CFTR) (4)

Answer 27

1. Airway surface liquid depletion
2. Abnormal pH
3. Inflammation
4. Chronic infection

Question 28

Airway Inflammation in CF (3)

Answer 28

1. Inflammation → Obstruction → Infection (pulmonary exacerbations)
2. Upper airway → lower airway
3. Bronchiolitis → Bronchiectasis (will see on chest X-ray)

Question 29

Signs and Symptoms of Pulmonary Exacerbation (12)

Answer 29

1. Increased cough
2. Increased/change in sputum
3. Weight loss of at least 1 kg
4. New chest findings
5. Rales, wheezes
6. Decreased exercise tolerance
7. Decreased FEV1; Down 10%
8. New radiographic findings
9. School/work absenteeism
10. Increased dyspnea
11. Fever
12. Neutrophils >15,000/mm