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Cystic fibrosis (CF) is the most common life-shortening autosomal recessive disease

among Caucasian populations, with a frequency of 1 in 2000 to 3000 live births. The median

predicted survival for CF patients in the United States was 39.3 years (95% CI, 37.3-41.4)

according to the Cystic Fibrosis Foundation 2014 Registry Report. The usual presenting

symptoms and signs include persistent pulmonary infection, pancreatic insufficiency, and

elevated sweat chloride levels. However, many patients demonstrate mild or atypical symptoms,

and clinicians should remain alert to the possibility of CF even when only a few of the usual

features are present.

Cystic fibrosis is an inherited disorder that causes severe damage to the lungs and digestive

system. Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These

secreted fluids are normally thin and slippery. But in people with cystic fibrosis, a defective gene

causes the secretions to become thick and sticky. Instead of acting as a lubricant, the secretions

plug up tubes, ducts and passageways, especially in the lungs and pancreas. Children need to

inherit one copy of the gene from each parent in order to have the disease. If children inherit only

one copy, they won't develop cystic fibrosis, but will be carriers and possibly pass the gene to

their own children.

In the past, most patients were diagnosed with CF after presenting with symptoms. Because of

the expansion of newborn screening programs during the past decade, there has been a dramatic

increase in the number of CF cases identified before presenting with symptoms. In 2001, less

than 10 percent of CF cases were diagnosed on the basis of newborn screening programs by

2014, 63 percent were diagnosed by newborn screening. Prior to the implementation of

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widespread newborn screening in the United States, infants and children were typically

diagnosed with CF after presenting with one or more of the following symptoms Meconium

ileus, Respiratory symptoms, Failure to thrive. For infants presenting with meconium ileus, the

median age of diagnosis was two weeks. For those presenting with other symptoms, the median

age of diagnosis was 14.5 months. Some cases of CF present with abnormal findings on routine

prenatal ultrasonography, including hyperechogenic bowel. The risk of CF is highest if there is

evidence of meconium peritonitis (scattered calcifications are seen throughout the fetal

peritoneum), bowel dilatation, or absent gallbladder (see "Fetal echogenic bowel" and "Overview

of echogenic masses and calcification in the fetal abdomen"). If these findings are present on

fetal ultrasonography, we suggest offering the parents prenatal CF carrier screen.

Symptomatic presentation in adulthood patients presenting with CF later in life are more

likely to have atypical symptoms. One large retrospective cohort study of more than 1000

patients with CF found that 7 percent were diagnosed at age ≥18 years. Patients diagnosed in

adulthood were more likely than children to present with gastrointestinal symptoms, diabetes

mellitus, and infertility. In addition, adults presenting with CF were more likely than children to

have unusual genetic mutations, normal pancreatic function, and equivocal results on sweat

chloride tests. Typical respiratory manifestations of CF include a persistent, productive cough,

hyperinflation of the lung fields on chest radiograph, and pulmonary function tests that are

consistent with obstructive airway disease. The onset of clinical symptoms varies widely, due to

differences in CFTR genotype and other individual factors, but pulmonary function

abnormalities often are detectable even in the absence of symptoms. As an example, in a cohort

of infants largely identified by newborn screening, 35 percent had respiratory symptoms (cough,

wheezing, or any breathing difficulty); mean pulmonary function scores were abnormal by six

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weeks of age and declined during the subsequent two years As the disease progresses, chronic

bronchitis and in most cases progressive bronchiectasis develop and are accompanied by acute

exacerbations, characterized by increased cough, tachypnea, dyspnea, increased sputum

production, malaise, anorexia, and weight loss. Digital clubbing is often seen in patients with

moderate to advanced disease. The clinical manifestations of pulmonary disease in CF are

discussed in detail separately.

The majority of CF patients develop sinus disease. Radiographs reveal pan-

opacification of the paranasal sinuses in 90 to 100 percent of patients older than eight months

of age Nasal polyposis is seen in 10 to 32 percent of patients. Chronic rhinosinusitis may be

associated with mutations in the CFTR gene even among patients who do not meet the

diagnostic criteria for CF; these patients are said to have "CFTR-related disease," as described

above. One case-control study of patients with chronic rhinosinusitis found a significantly

higher proportion of patients with a single CFTR mutation among patients with chronic

rhinosinusitis than in the general population.

Insufficiency of the exocrine pancreas is present from birth in about two-thirds of patients with

CF, and up to 90 percent have laboratory evidence of fat malabsorption by one year of age

Pancreatic disease tends to be progressive; many of the patients with apparently normal or

marginal pancreatic function at birth will develop overt evidence of pancreatic insufficiency in

childhood or adulthood. Clinically significant pancreatic insufficiency eventually develops in

about 85 percent of individuals with CF .

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Common symptoms and signs of pancreatic insufficiency include steatorrhea, characterized by

frequent, bulky, foul-smelling stools that may be oily, and failure to thrive or poor weight gain

due to malabsorption of fat and protein. In a patient with a clear diagnosis of CF, the diagnosis of

pancreatic insufficiency usually can be established based upon these clinical symptoms, a

clinical response to pancreatic enzyme replacement therapy (PERT), and/or laboratory testing

(eg, fecal elastase). Infants with severe untreated pancreatic insufficiency occasionally present

with a syndrome of edema, with hypoproteinemia, electrolyte loss, and anemia, due to

malabsorption of macro- and micronutrients. Such patients also may present with symptoms

caused by deficiencies of the fat-soluble vitamins A, D, E, and K. Vitamin K deficiency can

present as a coagulopathy, and vitamin D deficiency with rickets.

More than 95 percent of men with CF are infertile because of defects in sperm transport,

although spermatogenesis is not affected Most of these men have incompletely developed

Wolffian structures, most commonly, absent vas deferens. These anomalies probably reflect a

critical role for CFTR in the organogenesis of these structures. Nearly half of all men with

congenital bilateral absence of the vas deferens and normal lung function have two CFTR

mutations.

Microsurgical epididymal sperm aspiration and intracytoplasmic sperm injection can permit

affected men to become biological fathers. Females with CF are found to be less fertile than

normal healthy women. The reduced fertility is induced primarily by malnutrition and the

production of abnormally tenacious cervical mucus. Nonetheless, the assumption should always

be that females with CF may become pregnant, and patients should be counseled accordingly

about contraception and childbearing decisions. When patients with CF become pregnant,

maternal and fetal outcomes are generally favorable if the prepregnancy FEV1 exceeds 50 to 60

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percent of the predicted value. Careful genetic counseling is essential for prospective parents

with CF since all offspring of such individuals will be carriers of CF mutations and the risk of

children affected with CF is high.

Patients with CF have reduced bone mineral content and increased rates of fractures and

kyphoscoliosis. Clinically significant reductions in bone density are present in up to 30 percent

of patients with CF across all age groups and up to 75 percent of adults with CF. Several

different mechanisms appear to contribute to the bone disease, including malabsorption of

vitamin D, poor nutritional status, physical activity, glucocorticoid therapy, and delayed pubertal

maturation or hypogonadism .Limited evidence suggests that patients homozygous for the delta

F508 mutation are at particularly high risk of decreased bone mineral density .

The pathogenesis, assessment, and prevention of bone disease in patients with CF are discussed

separately. Hypertrophic osteoarthropathy is a syndrome characterized by abnormal proliferation

of the skin and osseous tissue at the distal parts of the extremities, occurring in association with

radiographically confirmed periosteal new bone formation. Clubbing of the digits and

hypertrophic osteoarthropathy appear to be different manifestations of the same disease

process .Although clubbed fingers and toes are common in patients with long-standing CF,

hypertrophic osteoarthropathy is uncommon (5 percent of patients).

CF appears to be a risk factor for recurrent venous thrombosis. In a review of 120 children and

young adults with acute venous thromboembolism, recurrent thrombosis occurred in 19. Among

these, six had CF (compared with none of the patients without recurrence), and five of the six

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were colonized with Burkholderia cepacia. Most, but not all, of the recurrent thrombosis events

occurred in the presence of a central venous catheter.

Newborn screening typically employs two serial assays; infants with abnormal results for the

first assay are retested with a second assay. The two assays used for newborn screening are

serum immunoreactive trypsinogen (IRT) and DNA analysis for mutations in CFTR. IRT is used

as the initial screening test in many protocols and is followed by a second IRT test on a different

sample from the infant (IRT/IRT protocol) or a DNA test on the initial sample (IRT/DNA

protocol). An IRT/IRT screening protocol has somewhat lower costs but more delayed or missed

diagnoses as compared with an IRT/DNA screening protocol . Most infants with cystic fibrosis

(CF) have elevated blood levels of IRT, which can be quantified by radioimmunoassay or by an

enzyme–linked immunoassay. IRT levels fall rapidly during infancy. After eight weeks of age,

negative result is not informative, although a positive result still strongly supports a diagnosis of

CF .The initial IRT test is approximately 80 percent sensitive for detecting CF using typical

cutoff values, and additional patients are not diagnosed through the IRT/IRT protocol if a second

sample is not returned for testing. In addition, the rates of false-positive and false-negative

results are relatively high in many series . The test is primarily used for neonatal screening but

also may be useful for small or malnourished infants, in whom the sweat chloride test cannot be

successfully performed.

DNA analysis for mutations in the CF gene is used for newborn screening in most US states.

This may be used as a secondary screen to confirm the diagnosis in patients with abnormal initial

IRT assays (IRT/DNA protocol), or it may be used as a primary method of screening. Many

IRT/DNA protocols use a floating IRT cutoff that improves sensitivity to as high as 96 percent

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The DNA assay tests for the 23 most common CFTR mutations, and infants with one or more

mutations are referred for sweat testing.

Infants with positive CF newborn screening results should undergo sweat chloride testing to

determine whether they have CF. For optimal accuracy, sweat testing should be performed when

the infant is at least two weeks of age and weighs >2 kg, using laboratory techniques stipulated

by the Cystic Fibrosis Foundation. The rationale for newborn screening is that early detection of

CF may lead to earlier intervention and improved outcomes because affected individuals are

diagnosed, referred, and treated earlier in life as compared with individuals who are diagnosed

after presenting with symptomatic CF. This perspective is supported by the following evidence

of a meta-analysis of randomized trials examining newborn screening in Europe and Australia

demonstrated a 5 to 10 percent reduction in mortality by 10 years of age in children with CF

without meconium ileus .

Early nutritional intervention appears to improve neurocognitive outcome in infants and

young children diagnosed with CF through newborn screening programs also may be cost

effective because of improved clinical outcomes. A study using the UK Cystic Fibrosis database

compared the yearly costs of long-term therapies and intravenous antibiotics for children whose

CF was identified through a newborn screening program as compared with those identified by

clinical symptoms after two months of age Treatment costs were significantly lower in the group

identified by newborn screening. Similar trends were seen when the analysis was restricted to

children with the common mutation associated with severe classic CF, delta F508, suggesting

that the reduction in cost was not due to finding only milder cases of CF.

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In the United States, the Centers for Disease Control and Prevention (CDC) concluded in 2004

that CF screening programs were justified on the basis of moderate benefit and low risk of harm

but noted that the decision to implement these programs was dependent upon the resources and

priorities of individual states. Statewide testing programs are in place in all states in the United

States.

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https://www.cff.org/

http://www.uptodate.com/contents/cystic-fibrosis-clinical-manifestations-and-diagnosis?

source=search_result&search=cystic+fibrosis&selectedTitle=1%7E150#H59098960

http://www.mayoclinic.org/diseases-conditions/cystic-fibrosis/basics/causes/con-20013731