REVISED PDF
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MLO
Cystic fibrosis:
newborn
screening in
America
PG.COVER
I
CIRCLE/RS#
LIT#
By Daniel T. Kleven, MD;
SHOWLINE
Christopher R. McCudden, PhD;
I/O CHECK
and Monte S. Willis, MD, PhD
PROD MGR
C
To earn CEUs, see current test at www.mlo-online.com under the
CE Tests tab.
ystic fibrosis (CF) is the most common lethal genetic
disease in Caucasians, occurring in 1/2,500 births.1,2 In
its most common form, CF manifests as progressive lung
dysfunction, pancreatic insufficiency, and intestinal disease
(see Figure 1). The gene which harbors mutations responsible
Nelson Publishing
for disease was identified in 1989, after which the protein
it
encodes was determined to function as a chioride channel
2500 that
Tamiami Tr N
indirectly controls sodium transport. Since then, geneticNokomis,
testingFL 34275
has expanded our appreciation of the spectrum of disease
that
1-800-226-6113
CF represents. Our continued desire to improve outcomes in the
quality and quantity of life of CF patients has led to the recent
implementation of newborn screening for CF in the United
States. In this review, we will discuss exciting new developments in newborn screening for CF in the context of our current
standards for diagnosis, therapy, and improved outcomes.
LEARNING OBJECTIVES
The CFTR gene
CONTINUING
e D U C AT I O N
Upon completion of this article, the reader will be able to:
1.describe the specific classes of mutations related to CF
phenotype variations.
2.identify diagnostic criteria and specific tests for CF.
3.describe the basis for serious complications related to
CF.
4.describe newborn-screening tests used by most states.
16
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The pathophysiology of CF results from mutations in the cystic-fibrosis transmembrane regulator (CFTR) gene. The CFTR
gene encodes a protein that regulates chloride transport. As a
consequence of chloride transport, the CFTR protein regulates
multiple ion channels and cellular processes, most notably the
epithelial sodium (Na+) channel (also known as ENaC). In
general, when mutations in CFTR result in a non-functional
protein, ENaC activity increases, and sodium transport across
the membrane is augmented. In the lungs and intestine, this
results in the accelerated uptake of water from the lumen, leaving dehydrated mucous layers (see Figure 2). Conversely, in
the sweat gland, defective chloride transport impairs sodium
uptake in the sweat duct, resulting in elevated NaCl levels in
sweat (see Figure 2). Accordingly, sweat chloride has allowed
effective non-invasive diagnosis for decades.
The CFTR gene spans 250,000 bases encoding 1,480 amino
acids (see Figure 3). The CFTR protein has multiple membranespanning regions, two nucleotide-binding domains (NBD), and
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c y s t ic f i b r o s i s
tions of CF occur in the lungs, due to
fying the underlying cause (discussed in
an “R domain” which contains sites to
abnormal epithelial-cell transport of
diagnostic genotyping of CF section).
which phosphate groups can be attached.
Cl-, resulting in altered surface fluid6
The severity of disease in cystic fibrosis
Cystic-fibrosis pathophysiology
(see Figure 2). The airway surface fluid
varies greatly, generally based on the
is decreased due to an
specific types of CFTR
Classification of CFTR mutations
increased uptake of som u t at io n s th a t a r e
Class I:
Defective protein synthesis
No CFTR
dium (and water), represent.3 Greater than
sulting in a dehydrated
1,250 mutations have
Class II:
Defective processing
CFTR degraded
mucous. These changes
been identified to date
Class III:
Defective regulation
Impaired response to ATP
impede the necessary
(www.genet.sickkids.
Class IV:
Transmembrane mutations
Diminished ion flow
ciliary clearance of mion.ca/cftr). These mucroorganisms and debris
tations have been diClass V:
Intronic splice sites/CFTR pro mutations
Decreased abundance
in the lungs, promoting
vided into five different
obstruction of the airclasses, based on the Table 1.
ways
and
infections.
These recurrent
fundamental defects that they cause in
Cystic fibrosis affects epithelial cells in
infections
lead
to
airway
impairment
the CFTR protein (see Figure 4). Class
organs where the CFTR protein is found,
and can cause permanent damage to the
I and II mutations (see Table 1) result in
including lungs, pancreas, intestine, vas
lungs.6 CF patients become infected with
no CFTR protein at the cell surface and
deferens, liver, and sweat glands. It is
specific
bacteria, such as Staphylococcus
are present in patients with more severe
the distribution of the CFTR in these
aureus
or
Haemophilus influenza, early
disease.3 In contrast, Class III, IV, and V
organs that explains much of the mulin life. As disease progresses, Pseudomomutations (see Table 1) have diminished
tiorgan nature of CF. Defects in CFTR
nas aeruginosa and Burkholderia spp.
activity and can result in milder disease
function within these organs results in
may infiltrate the lung.7,8 Despite current
(see Figure 4).
lung disease,BASE
pancreatic
insufficiency,
CLE
2008
POST-A-NOTE
AD
therapies, lung disease in CF patients still
The most common CF mutation is a
multifocal biliary cirrhosis, male inferworsens over time; milder forms of CF
deletion of a phenylalanine at position
tility, and increased sweat ion loss.
are associated with a later onset of lung
508 (DF508), which resides in the first
Lungs. The most serious complicaContinues on page 18
nucleotide-binding domain (see Figure
3). Patients with two of these mutations suffer from classic CF symptoms:
bronchiectasis, pancreatic insufficiency,
male infertility, and hepatic cirrhosis
(see Figure 3). Since CF is an autosomal
recessive disorder, disease phenotypes
are only observed in individuals with two
inherited mutations in the CFTR gene.
It is the effect of these two CFTR mutations on the function of the CFTR protein
that, ultimately, determines the clinical
phenotype seen in patients. CF, however,
is a complex disorder and other factors
such as modifying genes, environment,
and treatment affect disease progression
and severity.
Despite the large number of CFTR
mutations that have been identified, a
small number of patients have clinical
evidence of CF, including a positive
sweat-chloride test, but no identifiable
CFTR gene defect. For example, in one
study of non-classical (mild) CF, 40%
of patients did not have any detectable
mutations, despite exhaustive analysis.4,5
It is not exactly clear what the underlying
defect is in these cases; however, factors other than CFTR mutations appear
to lead to phenotypes indistinguishable
from CF in some patients. It is clear,
however, that even with exhaustive
searches CF mutations may miss identiVisit www.rsleads.com/807ml-005
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MLO  ■  July 2008
17
cover story
disease, which progresses as a slower place.9 Lung involvement is responsible for greater than 90% of the mortality in
CF patients.
Pancreas. The exocrine function of the pancreas is responsible for the secretion of enzymes essential for the breakdown
of food. In the pancreas, defective CFTR protein causes reduced
HCO3- secretion (see Figure 2), leading to congestion of acini
and inappropriate activation of pancreatic proteases. This process effectively impairs secretion of the pancreatic enzymes
necessary for digestion. Approximately 85% of patients with
CF have exocrine pancreas insufficiency, which manifests as
poor nutrition and increased fat in stool. This results in weight
loss, abdominal pain, and flatulence.10 Replacement of pancreatic enzymes and careful diet planning can overcome many of
these problems.
Figure 1. Clinical effects of cystic fibrosis. Cystic fibrosis can affect numerous
organs; the most severely affected of these are the lung and pancreas. In
mild cases, affected males may be infertile. Abnormal sweat secretion is a
hallmark of cystic fibrosis, and is the gold standard for detecting disease.
Liver disease. While pulmonary and pancreatic disease
occurs in 90% of CF patients, liver manifestations occur in no
more than one-third of patients.11 In the hepatic biliary system,
CFTR is expressed in cholangiocytes and gall-bladder epithelial cells but not hepatocytes.12 The main role of CFTR within
these cells is to regulate the fluid and electrolyte content of
bile; its absence or dysfunction results in impaired secretory
function, secondary to increased bile viscosity and bile-duct
occlusion.11 This stasis results in damage to the hepatocytes
and increases pro-inflammatory cytokines, growth factors, and
lipid peroxidation. These derangements prompt liver stellate
cells to synthesize collagen, leading to fibrosis.11 Liver disease
is the most common non-pulmonary cause of death resulting
in approximately 2.5% of all CF mortality.13
Figure 2. Cystic-fibrosis disease mechanisms. In the sweat glands, a defective CFTR channel results in excess sodium and chloride concentration
in secretions. This abnormality is the biochemical basis for sweat testing.
In the lung, impaired chloride transport causes increased sodium transport into the cell. Water follows sodium and the mucus layer to become
dehydrated and more viscous, trapping pathogenic bacteria and leading
to chronic respiratory illness. In the pancreas, it is proposed that CFTR
impairment causes clogging of the acini and inappropriate activation of
enzymes leading to pancreatic insufficiency and malabsorption. CFTR
protein is red, other channels and transporters are grey. Adapted from
References 11, 58, and 59.
Infertility. Most males with CF are infertile as a result of azoospermia (complete lack of sperm) secondary to the congenital
bilateral absence of the vas deferens (CBAVD).14 In patients with
mild disease, infertility may be the first indication that they may
have CF. Due to advances in reproductive medicine, spermatozoa
can be retrieved in order to overcome the infertility.14 While 1%
to 2% of CBAVD occurs in infertile males without CF, as many
as 80% of men with CBAVD have CFTR gene mutations.15
Other organ systems. There are a number of associated morbidities in patients with CF (see Figure 1). These
Continues on page 22
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manifestations affect the
Sweat-chloride testing.
Diagnostic criteria of CF
intestine and upper airway,
The gold standard for CF
and include sinusitis, nasal 1. Presence of risk factors or clinical presentation:
diagnosis is sweat-chloride
a. one or more phenotypic features
polyps, distal ileum obstructesting. Sweat-chloride testtion, and meconium ileus. Up
ing will detect ~99% of pab. or history of sibling with CF
to one-fifth of newborns with
tients, is relatively inexpenc. or positive newborn screening
CF present with meconium
sive, and has a high degree
ileus, the retention of the 2. Laboratory evidence of CFTR dysfunction:
of accuracy. Sweat testing
meconium after birth. The
a. two abnormal sweat-chloride concentrations
is performed by stimulatidentification of meconium
ing sweat production by
b. or the presence of two disease-causing mutations in CFTR
ileus is nearly pathognopilocarpine iontophoresis;
c. or demonstration of abnormal nasal potential difference measurement
monic of CF, since it occurs
sweat is collected on preso infrequently in patients Table 2.
weighed gauze pads, and
without CF. Small-bowel
coulometric titration is used
obstruction can also occur in older
to measure the chloride concentraMedical conditions associated with elevated
children and adults in patients with
tion. A sweat-chloride value >60
sweat-chloride levels other than cystic fibrosis64-69
severe disease, sometimes requiring
mEq/L distinguishes most patients
surgical intervention to alleviate the
1. Addison’s
with cystic fibrosis; however, norobstruction.16 Most CF patients demal sweat-chloride concentrations
2 Pulmonary edema/sepsis
velop sinus disease (90% to 100%),
are observed in approximately
3. Pseudo-aldosteronism
while 10% to 32% develop abnormal
1% of patients, generally with
lesions of the nasal mucosa (nasal
4. Hypoparathyroidism
specific uncommon genotypes.23
polyps).17,18 In undiagnosed patients
Sweat-chloride testing should be
5. Hypothyroidism
with mild CF, recurring sinus inflamperformed by laboratories that permation and/or nasal polyps may Table 3.
form this test on an ongoing basis.
prompt the screening for CF.
The Cystic Fibrosis Foundation has
published guidelines for diagnostic sweat testing, which are
Clinical diagnosis of cystic fibrosis
mandated for accreditation in CF centers.24 It is important to
recognize that there are clinical conditions that falsely elevate
The diagnosis of cystic fibrosis is made on the basis of two
sweat-chloride levels (see Table 3), in order not to misdiagnose
criteria: 1) one or more phenotypic features and 2) laboratory
cystic fibrosis. This includes transient elevations that occur
evidence of CFTR dysfunction (see Table 2).19 In the absence
during the first 24 hours after birth (in up to 25% of normal
of typical phenotypic features, positive newborn screen or
newborns). Since this transient elevation rapidly declines the
history of a sibling can fulfill the first criteria. The second
second day after birth, sweat testing should not be performed
criteria can be met by either two positive sweat-chloride tests
on children less than 48 hours old. Sweat-test collection can be
or the presence of two disease-causing alleles. These place
performed by The Gibson-Cooke sweat-test apparatus (C&S
the focus of laboratory testing on the genotypic analysis of
Electronics, Columbus, NE) or commercial Wescor systems
mutations and sweat-chloride testing, the latter being the gold
(Macroduct/Nanoduct, Wescor Inc., Logan, UT).
standard for diagnosis.
Nasal potential difference (NPD). Impaired ion transport
in respiratory epithelia can be determined by measuring the
Despite the large number of CFTR mutations that have
potential difference in nasal mucosa. NPD testing is considerbeen identified, a small number of patients have clinical
ably more complex than detecting sweat-chloride concentraevidence of CF, including a positive sweat-chloride test
tions and is performed only in specialized centers.25 CF patients
but no identifiable CFTR gene defect.
have reduced chloride transport and increased absorption of
sodium, which results in a more negative potential difference
Diagnostic genotype analysis of CF. Direct analysis of
at baseline.26 When the sodium channel-blocker amiloride is
CFTR gene mutations is performed by a variety of techniques,
perfused with isoproterenol to stimulate CFTR function, no
including allele-specific oligonucleotide hybridization, allelechange in NPD occurs in patients with mutated or deficient
specific amplification, ligase amplification, direct sequencing,
CFTR channels. NPD may complement sweat testing, although
and restriction enzyme analysis. Most laboratories in the United
it is technically difficult and is used mainly on adults. It cannot
States screen for 20 to 30 of the most common mutations, idenbe used when nasal inflammation is present, including allergic
tifying 80% to 90% of CF patients.20-22 Over 1,000 mutations
rhinitis or infection, which can alter ion transport.26
then account for the remaining 10% to 20% of patients, making
Ancillary tests. Additional tests can be performed to assess
comprehensive testing impractical for everyone. Expanded
organ involvement of CF patients. CT scanning or X-rays can
testing can be performed to cover mutations more common
be used to evaluate the paranasal sinuses; pancreatic-exocrine
in particular ethnic groups, but the size of the gene makes
function can be assessed using fecal-fat analysis; sputum or
extensive genetic screening a time-consuming and expensive
broncho-alveolar lavage can be tested for the presence of
endeavor. Fortunately, sweat-chloride testing can identify up
bacteria: and semen analysis can be performed to determine if
to 99% of patients with phenotypic CF.
vas-deferens impairment is present.
Continues on page 24
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parents’ risks should be considered. Currently, the American
College of Obstetricians and Gynecologists (ACOG) recommends offering CF screening to 1) individuals with a family
history of CF; 2) reproductive partners of individuals with
CF; and 3) couples in which one or both are Caucasian and/
or European or Ashkenazi Jewish descent who are planning a
pregnancy or seeking prenatal care.27 Either couple-based or
sequential testing may be done, whereby the woman is tested
first, and her partner is tested only if she is a carrier. Screening for a specific panel of the 25 most common CF mutations
should be performed, and reflex tests performed as indicated.27
Consultation is recommended if either partner has 1) CF or a
positive screening test for CF; 2) a family history of CF; 3)
Figure 3. CFTR gene, protein, and mutations. The CFTR gene spans 250
an affected fetus (female); or 4) infertility due to vas-deferens
kilobases and is encoded by 24 exons that transcribe a 1,480-amino-acid
absence or atresia (male).27
protein. The CFTR protein has 12 membrane-spanning regions bisected
Maternal screening. Currently, ACOG recommends that
by a regulatory region (R) and a nucleotide-binding domain (NBD-1). This
DNA testing for CFTR mutations be offered to all couples seekbinding catalyzes hydrolysis of ATP in order to open the chloride channel; it is counter-regulated by another nucleotide-binding region (NBD-2)
ing prenatal or preconception care.28,29 This recommendation is
at the C-terminus that closes the channel. The location and frequency of
extended beyond couples that belong to high-risk ethnic groups
the five most common mutations are indicated; the frequency is based on
or individuals with a family history of CF. This recommendation
the screening of 43,849 CF chromosomes (www.genet.sickkids.on.ca/cftr/
is in conjunction with an American College of Medical Genetics
resource/Table1.html). Adapted from References 59 and 60.
(ACMG) recommendation for a standard
panel of mutations to be detected by any
specific screening modality. The ACMG
set a standard that all screening panels
include mutations that have a frequency of
at least 0.1% in the CF-patient population.
Testing for these more frequent mutations
detects 80% to 90% of CF carriers. The
testing of more frequent mutations is
necessary due to the large complex CFTR
gene and the number of diverse mutations
present. Testing is typically performed
on a whole-blood sample where DNA is
extracted from nucleated cells. The DNA
sample is then subjected to multiplex PCR
to amplify fragments of the CFTR gene;
individual mutations are then identified
by various molecular techniques indicated
above. Additional reflex testing is required
for some mutations due to interfering
polymorphisms and so on. If one parent
Figure 4. Severity of cystic fibrosis as related to mutation, CFTR activity, and sweat-test positivity. The is discovered to be a carrier of CF, a more
most severe clinical phenotypes are associated with the absence of expression (<1% CFTR activity) and extensive screening of the other parent is
defective processing and regulation. In these cases, sweat-chloride tests are almost always abnormal. initiated. This is typically accomplished
In less severe cases, there may only be mild disease and infertility associated with reduced activity (5% using an extended-panel-mutation screen
to 10% CFTR activity) or reduced expression. Sweat testing may not be abnormal in these mild clinical
or whole-gene screening. Most of the
phenotypes. CBAVD-congenital bilateral absence of vas deferens. Based on References 61 and 62.
whole-gene-screening assays available
utilize high-performance liquid chromatography to targeting
Screening for CF
specific regions of the gene followed by sequencing. These
Pre-natal genetic screening. The goal of screening for CF
methodologies promise to have increased detection rates but
mutations either before pregnancy or prenatally is to identify
may be hampered by large deletions or interpretation of poorly
couples who are at risk for having a child with CF.27 Prenatal
characterized nucleotide changes.30,31
diagnosis is performed in order for prospective parents to
have the best medical data for making medical and personal
Newborn screening
decisions. CF screening should be available to all couples
Why screen newborns? In brief, CF patients live longer and
planning a pregnancy who are at increased risk, particularly
healthier lives if the disease is diagnosed earlier, as this enables
if of Caucasian, European, or Ashkenazi Jewish ancestry27;
therapies to be initiated sooner. An analysis of randomized
ideally, testing should be completed pre-pregnancy. Since the
trials evaluating newborn screening in Europe and Australia
fetus must inherit an affected CF gene from each parent, both
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c y s t ic f i b r o s i s
identified a 5% to 10% reduction in deaths by 10 years of age
in CF patients.32 It has been reported in observational trials that
CF patients identified by newborn screening have better lung
function and growth with less intensive treatment compared
to CF patients diagnosed clinically.33-39 CF patients identified
earlier who have nutritional intervention also have improved
brain function.38,40-43 From a healthcare perspective, screening
programs may be less costly because the patients have improved outcomes. A study of the United Kingdom CF database
compared annual costs of therapy in CF patients identified by
newborn screening to patients identified after two months of
age by clinical symptoms.37 The cost of therapy in patients identified by newborn screening was significantly lower, indicating
unintended benefits from CF screening programs.
National programs to identify CF patients using circulating
immunoreactive trypsinogen (IRT) exist in England, Scotland,
France, Wales, Northern Ireland, New Zealand, and Australia.44-47
In Canada, as of April 2008, Alberta and Ontario were the only
provinces to perform universal newborn screening. In the United
States, the Centers for Disease Control and Prevention identified
that CF-screening programs were justified but made the decision to implement these programs dependent on the resources
and priorities of individual states.48,49 Currently, 37 states have
adopted CF newborn screening, and the list is growing (www.
KRgen.halfh_MLO807
6/6/08 1:24 PM Page 1
cff.org/AboutCF/Testing/NewbornScreening/#What_states_do_
newborn_screening_for_CF).
Newborn screening of CF by immunoreactive trypsinogen
(IRT) and mutational analysis. Newborns with cystic fibrosis
have increased levels of circulating IRT, an enzyme produced
in the exocrine pancreas. Using an immunoassay, dried-blood
samples routinely taken for newborn screening allows the
detection of at least 95% CF newborns.44,50,51 Since IRT levels
drop precipitously during infancy, a negative result becomes
less useful after eight weeks of age.44,51 It is reported, however,
that both false-positive and false-negative test results can occur
frequently.44,52 Therefore, this test is not diagnostic and requires
confirmation by established diagnostic methods such as sweatchloride testing or CFTR mutational analysis.
Therapy. Due to complexity and diversity of CF, a multidisciplinary approach to comprehensive therapy has been
established to improve prognosis. While our understanding
of the pathophysiology of disease improves, treatment still
focuses on resolving symptoms and organ dysfunction in both
children and the growing number of adult patients.22 Since
pulmonary impairment is the principal cause of morbidity
and death, treatment of the lung component of disease can
help slow the progression. A standard pulmonary regimen
includes antibiotics, bronchial hygiene, mucolytic agents,
bronchodilators, anti-inflammatory agents, nutritional support,
and oxygen.53 Lung transplant is related to greater survival and
quality of life in patients with advanced lung involvement.54
Recent studies have suggested, however, that older patients
Continues on page 26
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cover story
benefit more than younger patients with transplantation.55,56
Exocrine-pancreas insufficiency is treated by supplementing
pancreatic enzymes with meals and snacks. Since patients
with pancreatic insufficiency have poor absorption of lipid
soluble vitamins (A,D,E,K), supplementation is routinely
recommended.57 Patients with liver disease have been treated
with a secondary bile acid (ursodeoxycholic acid) to promote
bile flow and reduce cholesterol update; although there is currently limited data regarding patient survival and drug safety,
secondary bile-acid therapy is widely used. In the 6% to 8%
of patients that evolve to liver failure, transplant has been the
major therapeutic strategy.57
and growth with less intensive therapy, and reduced cost of
therapy. To date, 37 states in the United States have adopted
similar programs, in the hopes of improving CF outcomes.
This welcome trend should help improve the lives of CF
patients living in America.
Daniel T. Kleven, MD; Christopher McCudden, PhD; and Monte S. Willis, MD, PhD,
are affiliated respectively with the University of North Carolina Hospitals, McLendon
Clinical Laboratories, and Department of Pathology and Laboratory Medicine, and the
University of North Carolina at Chapel Hill.
References
1. Wilcken B, Wiley V, Sherry G, Bayliss U. Neonatal screening for cystic fibrosis: a
comparison of two strategies for case detection in 1.2 million babies. J Pediatr.
1995;127(6):965-970.
2. Massie RJ, Delatycki MB, Bankier A. Screening couples for cystic fibrosis carrier
status: why are we waiting? Med J Aust. 2005;183(10):501-502.
3. Tsui LC, Durie P. Genotype and phenotype in cystic fibrosis. Hosp Pract (Minneap). 1997;32(6):115-118, 123-119, 134, passim.
4. Groman JD, Karczeski B, Sheridan M, Robinson TE, Fallin MD, Cutting GR. Phenotypic and genetic characterization of patients with features of “nonclassic”
forms of cystic fibrosis. J Pediatr. 2005;146(5):675-680.
5. Groman JD, Meyer ME, Wilmott RW, Zeitlin PL, Cutting GR. Variant cystic fibrosis
phenotypes in the absence of CFTR mutations. N Engl J Med. 2002;347(6):401407.
6. Chmiel JF, Davis PB. State of the art: why do the lungs of patients with cystic
fibrosis become infected and why can’t they clear the infection? Respir Res.
2003;4:8.
7. Parameswaran GI, Murphy TF. Infections in chronic lung diseases. Infect Dis
Clin North Am. 2007;21(3):673-695, viii.
Figure 5. Median predicted survival of CF patients. Data from cystic
fibrosis foundation, 2008.63
New treatment strategies. Most current treatments focus on
resolving symptoms and organ dysfunction, however, a wide
spectrum of approaches are being explored to improve the underlying pathology (www.cff.org/treatments/Pipeline/). These
include therapies to replace defective genes (gene therapy);
correction of abnormally folded proteins (i.e., DF508); induction of alternative ion channels; suppression of inflammatory
responses; and the development of antibiotics to continue to
improve survival.
Summary
Cystic fibrosis is the most common lethal genetic disease in
Caucasians, manifesting as progressive lung dysfunction,
pancreatic insufficiency, and intestinal disease. CF was
traditionally diagnosed clinically, either because of a family history or occurrence of meconium ileus, or as a result
of intestinal malabsorption and chronic pulmonary disease.
In 1979, it was discovered that immunoreactive trypsinogen
was increased in neonatal dried-blood specimens on Guthrie
cards,50 making it possible to screen neonates. During the past
decades, survival rates of patients with CF have improved significantly (see Figure 5). To continue this progress, universal
newborn screening has been implemented in many states as an
addition to the arsenal of therapies and strategies to improve
survival. National newborn-screening programs to identify
CF patients after birth have been adopted for a number of
years in Europe, Australia, and Canada. As expected, many
benefits have been seen due to the early identification of CF
patients, including improved survival, better lung function
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8. Mahenthiralingam E, Baldwin A, Dowson CG. Burkholderia cepacia complex
bacteria: opportunistic pathogens with important natural biology. J Appl Microbiol. 2008;104(6):1539-1551.
9. Yiallouros PK, Neocleous V, Zeniou M, et al. Cystic fibrosis mutational spectrum
and genotypic/phenotypic features in Greek-Cypriots, with emphasis on dehydration as presenting symptom. Clin Genet. 2007;71(3):290-292.
10. Baker SS, Borowitz D, Baker RD. Pancreatic exocrine function in patients with
cystic fibrosis. Curr Gastroenterol Rep. 2005;7(3):227-233.
11. Colombo C. Liver disease in cystic fibrosis. Curr Opin Pulm Med. 2007;13(6):529536.
12. Cohn JA, Strong TV, Picciotto MR, Nairn AC, Collins FS, Fitz JG. Localization of
the cystic fibrosis transmembrane conductance regulator in human bile duct
epithelial cells. Gastroenterology. 1993;105(6):1857-1864.
13. Cystic Fibrosis Foundation. Patient Registry 2003: Annual Report to the Center
Directors. Bethesda, MD: Cystic Fibrosis Foundation; 2003.
14. Popli K, Stewart J. Infertility and its management in men with cystic fibrosis: review of literature and clinical practices in the UK. Hum Fertil (Camb).
2007;10(4):217-221.
15. Khaitov S, Nissan A, Beglaibter N, Freund HR. Failure of medical treatment in an
adult cystic fibrosis patient with meconium ileus equivalent. Tech Coloproctol.
2005;9(1):42-44.
16. Chaun H. Colonic disorders in adult cystic fibrosis. Can J Gastroenterol.
2001;15(9):586-590.
17. Ramsey B, Richardson MA. Impact of sinusitis in cystic fibrosis. J Allergy Clin
Immunol. 1992;90(3, pt 2):547-552.
18. Yung MW, Gould J, Upton GJ. Nasal polyposis in children with cystic fibrosis:
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MLO  ■  July 2008
27
Cystic-fibrosis products
New Products
New Technology
New Services
Simplifies sweat test
External quality control
Nanoduct is a complete, integrated
system for inducing and analyzing
sweat for cystic-fibrosis diagnosis that
produces a result while attached to the
patient. Nanoduct simplifies the CF
sweat test and, for the first time, makes
possible reliable CF diagnosis in the
first days of life.
The INTROL Cystic Fibrosis Panel I
Control is intended for use as a control
product to monitor the analytical performance of the extraction, amplification,
and detection of test systems used in the
qualitative measurement of the cysticfibrosis transmembrane conductance
regulator (CFTR) gene.
The xTAG Cystic Fibrosis Kit is for
cystic-fibrosis genotyping. With validated performance criteria, this highly
accurate and reproducible (>99.9%)
assay gives wide mutation coverage
for carrier screening in adults and aid
in the diagnosis in newborns.
Carrier detection
Comprehensive test
Detect and identify
The eSensor CF Carrier Detection
System offers highly accurate and reproducible
cystic-fibrosis-carrier results
delivered
in an easyt o - i n t e rpret report. Each
kit includes all reagents necessary for
PCR amplification and mutation detection in a single box. Reports include a
summary “carrier” or “non-carrier.”
CF AMPLIFIED is a comprehensive
CF test, detecting approximately 99%
of mutations, including gross deletions and duplications, in patients
of all ethnicities. The test begins
with full gene sequence analysis
detecting 97% to
98% of mutations. Testing is done in
steps to control costs and the average
turnaround time is reduced from 15 to
35 days to 14 to 28 days
The InPlex CF Molecular Test has an
easy multiplex format with few steps
and few repeats, no necessary reflex
testing, and very little hands-on time.
After extraction, results are achieved in
four hours or less. Low start-up costs,
low hands-on time, fast time to results.
Runs with common lab equipment and
common extraction methods.
Direct sequence analysis
Expanded panel
The full
CF Gene
Sequencing
Test is direct
sequence
analysis of
the CFTR
gene, identifying every nucleotide of
all 27 exons, their associated splice site
regions, and clinically relevant regions
of introns that contain disease-causing
mutations. Also offered is partial CFgene sequencing for families with
known mutations not detectable in a
general screening assay.
The CF70 Genotype is a 70-mutation
screening panel for cystic-fibrosis carrier, pre-natal, and diagnostic testing.
The broad mutation coverage of the CF70
Genotype exceeds the minimum recommendations of the American College of
Medical Genetics and the American College of Obstetricians and Gynecologists
for general population screening
Wescor
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Osmetech
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Genzyme
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28
July 2008
■
Maine Molecular Quality Controls
Visit www.rsleads.com/807ml-169
Ambry Genetics
Visit www.rsleads.com/8071ml-172
Specialty Labs
Visit www.rsleads.com/807ml-175
 MLO
Mutation coverage
Luminex
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Third Wave Technologies
Visit www.rsleads.com/807ml-173
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