A Presentation by: Jayatheeswaran. Vijayakumar
“Woe to the child which when
kissed on the forehead tastes salty.
He is bewitched and soon will die” –
Cystic fibrosis is a disease of exocrine gland function that
involves multiple organ systems but chiefly results in
chronic respiratory infections, pancreatic enzyme
insufficiency, and associated complications in untreated
Is a lethal autosomal recessive disease
Has an incidence: 1 in 2000-3000; predominantly in
Caucasian populations (carrier frequency 1 in 22-28)
Median age at diagnosis of cystic fibrosis is 6-8 months;
two thirds of patients are diagnosed by 1 year of age.
The disease gene CFTR (cystic fibrosis transmembrane
conductance regulator) is a regulated epithelial Cl-
channel; influences other ion channels
The age at diagnosis, the clinical presentation, the
severity of the symptoms, and the rate of disease
progression in the organs involved varies widely.
Clinical manifestations vary with the patient's age at
presentation. e.g. : patients diagnosed later in childhood
or in adulthood are more likely to have pancreatic
sufficiency and often present with chronic cough and
GENOTYPE & PHENOTYPE RELATIONSHIP
Cystic fibrosis (CF) is caused by mutations in the CF
transmembrane conductance regulator (CFTR) gene
which encodes a protein expressed in the apical
membrane of exocrine epithelial cells.
This genotypic variation provides a rationale for
phenotypic effects of the specific mutations. The
extent to which various CFTR alleles contribute to
clinical variation in CF is evaluated by genotype-
The poor correlation between CFTR genotype and
severity of lung disease strongly suggests an
influence of environmental and secondary genetic
factors (CF modifiers).
GENOTYPE & PHENOTYPE RELATIONSHIP
Several candidate genes related to innate and
adaptive immune response have been
implicated as pulmonary CF modifiers. In
addition, the presence of a genetic CF modifier
for meconium ileus has been demonstrated on
human chromosome 19q13.2.
The phenotypic spectrum associated with
mutations in the CFTR gene extends beyond
the classically defined CF. Besides patients with
atypical CF, there are large numbers of so-
called monosymptomatic diseases such as
various forms of obstructive azoospermia,
idiopathic pancreatitis or disseminated
bronchiectasis associated with CFTR mutations
uncharacteristic for CF.
2 membrane spanning
2 nucleotide binding
domains (NBD, for ATP
1 regulatory domain (R).
Functions in lungs, liver,
reproductive tract & skin.
In normal airway cells, there
are two Cl- channels. One
channel is regulated by cyclic
AMP and ATP (CFTR), and the
other is activated by Ca2+.
ATP binding and hydrolysis open
CFTR, so that Cl- can move down
its electrochemical gradient, into
the mucus of the lungs.
Presence of Cl- in the mucus
ensures its sufficient water
content, required for mucus
removal by the cilia of the airway
In individuals with CF, the defect in
CFTR protein causes decreased
secretion of Cl- ions which cause a
compensatory influx of Na+ ions to
maintain the electro-neutrality of the
Increase in the osmolarity inside the
cell causes a water influx from
outside the cell. This leads to the
dehydration of the mucus membrane.
The now sticky mucus traps
bacteria, is not remove by cilia of the
lung epithelium. As the lungs have
the perfect environment for bacterial
propagation patients with CF typically
get lung infections.
Class I: normal level of
mRNA ; defective protein
production (premature stop
No or little CFTR protein is
Class II: Defective trafficking:
the protein does not reach
Class III: defective regulation
(opening/closing) of the
Class IV: defective conduction
(Cl- doesn’t pass through the
Class V: reduced synthesis
of functional CFTR
The most common CFTR mutant ΔF508, is a
class II defect.
The defective protein retains substantial
chloride-channel function in cell-free lipid
When synthesized by the normal cellular
machinery, however, the protein is rapidly
recognized as misfolded and is degraded shortly
after synthesis , via proteasome degradation
pathway at endoplasmic reticulum (ER).
THE MOST COMMON CFTR MUTATION
Around 75% of mutations
observed in CF patients
result from a deletion of
three base pairs in CFTR's
nucleotide sequence. This
deletion causes loss of the
amino acid phenylalanine
located at position 508 in
the protein; therefore, this
mutation is referred to as
delta F508 or ΔF508.
Nose examination may reveal
Findings related to the pulmonary
system may include the following:
Respiratory distress with
Wheeze or crackles
Cough (dry or productive of mucoid
or purulent sputum)
diameter of chest
Hyperresonant sound heard upon
chest percussion (crackles are
heard acutely in associated
pneumonitis or bronchitis and
chronically with bronchiectasis)
Findings related to the
GI tract include the
(fatty liver and portal
(vitamin A deficiency)
Cheilosis (vitamin B
Findings related to the
Urogenital tract include
In males: due to the
absence of the vas
In females: fertility is
maintained although it is
Examination of other systems may reveal the
Swelling of submandibular gland or parotid gland
Aquagenic wrinkling of the palms (AWP)
One study reported an association between AWP and
cystic fibrosis.Among patients with cystic fibrosis, a greater
degree of AWP is observed in patients who are
homozygous for the ΔF508 mutation.
Clinical variants have been described, such as adult males with bilateral
absence of the vas deferens who have little other clinical involvement.
Absence of the vas deferens is considered an atypical presentation of
cystic fibrosis, and 80% of men with this presentation have at least
one CFTR gene mutation. Zielenski et al reported that the most common
of these mutations is the IVS8/5T mutation.
Another atypical manifestation of cystic fibrosis is polyuria and
polyphagia in an infant. Despite not having any initial intestinal
symptoms, such as diarrhea, an infant in Belgium with failure to thrive
was initially treated for diabetes insipidus before being diagnosed with
cystic fibrosis. Although a sweat test result may be abnormal in diabetes
insipidus, cystic fibrosis must be excluded upon any positive sweat test
THE RELATIONSHIP BETWEEN CLINICAL
PRESENTATIONS & RESIDUAL CFTR FUNCTION
% of Normal CFTR Function Clinical Presentations
< 1 Pancreatic insufficiency and below
< 4.5 Pulmonary infection and below
< 5 Positive sweat test and symptoms below
< 10 Congenital absence of vas deferens
34% of patients reach adulthood
10% live past age of 30
Average Life Expectancy
•Male : 31
• The major goal in treating CF is to clear the
abnormal and excess secretions, control
infections in the lungs and to prevent
obstruction in the intestines.
• For patients with advanced stages of the
disease, a lung transplant operation may be
• Although treating the symptoms does not cure
the disease, it can greatly improve the quality of
life for most patients.
Due to pancreatic disorders, children with CF require
a modified diet, including vitamin supplements
(vitamins A, D, E, and K) and pancreatic enzymes.
Maintaining adequate nutrition is essential. The diet
calls for a high-caloric content (twice what is
considered normal for the child's age), which is
typically low in fat and high in protein. Patients or
their caregivers should consult with their health care
providers to determine the most appropriate diet.