Cystic
Fibrosis (CF) (Mucoviscidosis)
Epidemiology:
- Caucasions
- 1 in 3600 births
- 1 in 28 is a
carrier
- Manifestations may
appear at any point from before birth to adolescence
- Autosomal recessive
- Carriers do not
have and will never develop CF
- 25% chance of
carrier parents having an affected child
Common sites:
Gross features:
- lungs:
- bronchioles
distended with thick mucus
- bronchiectasis
- lung abscesses
- pancreas:
- accumulations of
mucus in small ducts
- dilation of
exocrine glands
- atrophy of
exocrine glands and progressive fibrosis
- GI tract:
- Meconium ileus in
infants sometimes
- Liver:
- Congenital
bilateral absence of the vas deferens (CBAVD)
- Recurrent sinonasal polyps
Histologic features:
- Lungs:
- bronchioles distended
with thick mucus
- marked hyperplasia
and hypertrophy of mucus-secreting cells
- severe chronic
bronchitis and bronchiectasis
- pancreas:
- accumulations of
mucus in small ducts
- dilation of
exocrine glands
- atrophy of
exocrine glands and progressive fibrosis
- may
show total atrophy of exocrine pancreas, leaving islets within a fibrofatty stroma
- squamous metaplasia
of pancreatic ducts (due to avitaminosis A)
- Liver:
- Bile canaliculi are plugged with mucinous
material
- Ductular proliferation
- Portal
inflammation
- Steatosis not uncommon
- Cirrhosis (late)
(5%)
- Salivary glands:
- Progressive
dilation of ducts
- Squamous metaplasia
of ductal epithelium
- Glandular atrophy
- fibrosis
Immunophenotype:
Marker:
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Sensitivity:
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Specificity:
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Molecular features:
- cystic fibrosis transmembrane conductance regulator (CFTR) gene is
mutated on 7q31.2
- CFTR gene function
- encodes
a chloride channel which also regulates other ion channels
- Epithelial
Na channel is most important in pathogenesis
- Tissue-specific
effects, but in respiratory and intestinal epithelium, results in
decreased Cl secretion into lumen, and
increased Na absorption into cells
- results
in passive water resorption from lumen
- varying types of
mutations modify the severity of the disease
- over 1300
mutations have been identified
- DF508 is most common (70-72% of Northern European
alleles)
- 5T
variant of intron 8 T-tract (splice acceptor
site) (5% of alleles in the general population)
- Mild
mutation by itself (it is the most inefficient splice variant)
- Causes
inefficient transcription of the gene
- R117H
mutation in cis with 7T or 9T variant, coupled
with a severe CFTR mutation in trans, may result in mild symptoms of
CF, or male infertility (CBAVD)
- R117H
mutation in cis with 5T variant, coupled
with a severe CFTR mutation in trans, will have CF (pancreas
sufficient)
- Who should be
tested?
- Clinically
suspected
- Family history and
spouses
- Parents of a fetus
with echogenic bowel
- Gamete donors
- Testing
methodology:
- Direct mutation
analysis
- Multiplex
PCR for common recurrent mutations (90% in North American Caucasians,
95% Ashkenazi Jewish)
- Direct
sequence analysis
- Dosage
analysis to detect deletions/duplications
- Linkage analysis
- ACMG testing
recommendations:
- Any mutation
occurring in > 0.1% of CF chromosomes is recommended for screening
- 23
mutations
- 88% of
non-Ashkenazi Jewish (AJ) carriers
- 95% of
AJ carriers
- Reflex testing for
5T variant of intron 8 T-tract for R117H
mutation
Other features:
- testing:
- sweat chloride
test
- sensitive,
specific, but difficult for newborns
- newborn screening:
- elevated levels of
immunoreactive trypsinogen
(IRT)
- nasal potential
difference:
- requires special
equipment
- CFTR sequencing
- Specific but not
entirely sensitive
- simple AR heredity
- abnormally viscid
mucous secretions obstruct organ passages, resulting in most of the
clinical features of CF:
- chronic lung
disease
- pancreatic
insufficiency
- steatorrhea
- malnutrition
- hepatic cirrhosis
- significant liver
disease occurs late
- 3rd
most common cause of death after cardiopulmonary and
transplantation-related complications
- intestinal obstruction
- male infertility
- Pseudomonas
aeruginosa
often colonize the lower respiratory tract
- Staphylococcus aureus, Hemophilus influenza also cause lung
infections
References:
- Kumar V, Fausto N, Abbas A. Robbins
& Cotran Pathologic Basis of Disease, Seventh
Edition. 7th ed. Saunders; 2004.
- Emedicine.medscape.com