Criteria for Diagnosis of Cystic Fibrosis

One or more characteristic phenotypic features,

••OR a history of cystic fibrosis in a sibling,

••OR a positive newborn screening test result

AND

An increased sweat chloride concentration on two or more occasions

••OR identification of two cystic fibrosis mutations,

••OR demonstration of abnormal epithelial nasal ion transport

Adapted with permission from Rosenstein BJ, Cutting GR: The diagnosis of cystic fibrosis: a consensus statement. J Pediatrics 132:589;1998.

from onset at birth to onset years later, and from involvement of one organ system to involvement of many. Approximately 5% to 10% of the cases come to clinical attention at birth or

soon after because of an attack of meconium ileus. Distal intestinal obstruction can also occur in older individuals, manifesting as recurrent episodes of right lower quadrant pain sometimes

associated with a palpable mass in the right iliac fossa.

Exocrine pancreatic insufficiency occurs in the majority (85–90%) of patients with cystic fibrosis and is associated with "severe" CFTR mutations on both alleles (e.g., DF508/DF508),

whereas 10% to 15% of patients with one "severe" and one "mild" CFTR mutation (DF508/R117H) or two "mild" CFTR mutations retain enough pancreatic exocrine function so as not to

require enzyme supplementation (pancreas sufficient phenotype). [80] Pancreatic insufficiency is associated with protein and fat malabsorption and increased fecal loss. Manifestations of

malabsorption (e.g., large, foul stools, abdominal distention, and poor weight gain) appear during the first year of life. The faulty fat absorption may induce deficiency of the fat-soluble

vitamins, resulting in manifestations of avitaminosis A, D, or K. Hypoproteinemia may be severe enough to cause generalized edema. Persistent diarrhea may result in rectal prolapse in up

to 10% of children with cystic fibrosis. The pancreas sufficient phenotype is usually not associated with other gastrointestinal complications, and in general, these individuals demonstrate

excellent growth and development. The diagnosis of an underlying CFTR mutation in individuals with pancreas sufficient cystic fibrosis is suspected because of abnormal or borderline

sweat chloride levels, a positive family history, or because of concomitant infertility in a male patient. "Idiopathic" chronic pancreatitis occurs in a subset of patients with pancreas

sufficient cystic fibrosis and is associated with recurrent abdominal pain with

life-threatening complications.[85] These patients have other features of cystic fibrosis, such as pulmonary disease. By contrast, "idiopathic" chronic pancreatitis can also occur as an

isolated late-onset finding in the absence of other stigmata of cystic fibrosis ( Chapter 19 ); bi-allelic CFTR mutations (usually one "mild", one "severe") are demonstrable in the majority of

these individuals, qualifying their inclusion as nonclassic or atypical cystic fibrosis. Endocrine pancreatic insufficiency (i.e., diabetes) is uncommon in cystic fibrosis, and usually

accompanied by substantial destruction of pancreatic parenchyma.

Cardiorespiratory complications, such as persistent lung infections, obstructive pulmonary disease, and cor pulmonale, are the single most common cause of death (~80%) in patients in the

United States. By age 18, 80% of patients with classic cystic fibrosis harbor P. aeruginosa, and 3.5% harbor Burkholderia cepacia. [86] With the indiscriminate use of antibiotic

prophylaxis against Staphylococcus, there has been an unfortunate resurgence of resistant strains of Pseudomonas in many patients. Individuals who carry a "severe" CFTR mutation on

one allele and a "mild" CFTR mutation on the other allele may exhibit late-onset mild pulmonary disease, another example of nonclassic or atypical cystic fibrosis.[81] Patients with mild

pulmonary disease usually have mild or no pancreatic disease. Idiopathic bronchiectasis, a poorly defined entity in adults where no discernible cause for the bronchiectasis can be found,

has been linked to CFTR mutations in a subset of cases. Recurrent sinonasal polyps can occur in up to 25% of patients with cystic fibrosis; hence, children who present with this finding

should be tested for abnormalities of sweat chloride.

Significant liver disease occurs late in the natural history of cystic fibrosis and used to be foreshadowed by pulmonary and pancreatic involvement; however, with increasing life

expectancies, liver disease has also received increasing attention. In fact, after cardiopulmonary and transplantation-related complications, liver disease is the most common cause of death

in cystic fibrosis. Most studies suggest that symptomatic or biochemical liver disease in cystic fibrosis has its onset at or around puberty, with a prevalence of approximately 13% to 17%.

[87] However, asymptomatic hepatomegaly may be present in up to a third of the individuals. Obstruction of the common bile duct may occur due to stones or sludge; it presents with

abdominal pain and the acute onset of jaundice. As previously noted, diffuse biliary cirrhosis may develop in up to 5% of individuals with cystic fibrosis.

Approximately 95% of males with cystic fibrosis are infertile, as a result of obstructive azoospermia. As mentioned earlier, this is most commonly due to bilateral absence of vas deferens

(also called CBAVD). CBAVD can occur as a consequence of several conditions, but bi-allelic CFTR mutations are the most common cause (present in 50% to 75% of cases).[88] [89]

In most cases, the diagnosis of cystic fibrosis is based on persistently elevated sweat electrolyte concentrations (often the mother makes the diagnosis because her infant tastes salty),

characteristic clinical findings (sinopulmonary disease and gastrointestinal manifestations), or a family history. A minority of patients with cystic fibrosis, especially those with at least one

"mild" CFTR mutation, may have a normal or near-normal sweat test (<60 mM/L). Measurement of nasal transepithelial potential difference in vivo can be a useful adjunct under these

circumstances; individuals with cystic fibrosis demonstrate a significantly more negative baseline nasal potential difference than controls. Sequencing the CFTR gene is, of course, the

"gold standard" for diagnosis of cystic fibrosis. Therefore, in patients with suggestive clinical findings or family history (or both), genetic analysis may be warranted. It is important to

inform the molecular laboratory whether the individual has classic cystic fibrosis or conforms to one of the nonclassic or atypical variants (CBAVD, late-onset pulmonary disease, or

idiopathic chronic pancreatitis), so the appropriate "mild" CFTR mutations are also analyzed. A recent study has demonstrated that a subset of patients with nonclassic or atypical cystic

fibrosis may not reveal CFTR mutations in one or both alleles.[90] This indicates that other genetic loci (perhaps those that encode proteins interacting with CFTR) may also produce a

partial phenotype resembling cystic fibrosis.

Advances in management of cystic fibrosis include both improved control of infections and bilateral lung (or lobar), heart-lung, liver, pancreas, or liver-pancreas transplantation. Children

and adolescents undergoing bilateral lung transplantation have overall survival rates around 70%. These improvements in management mean that more patients are now surviving to

adulthood; the median life expectancy is close to 30 years and continues to increase. In principle, cystic fibrosis, like other single gene disorders, should be amenable to gene therapy. In

vitro, it has been possible to correct the chloride defect in epithelial cells of cystic fibrosis patients by both viral and nonviral vector-based transfer of the CFTR gene; even a single copy of

the wild-type CFTR gene is able to revert the cystic fibrosis phenotype. Clinical trials with gene therapy in humans are still in their early stages but provide a source of hope for millions of

cystic fibrosis patients worldwide.

Date: 2016-04-22; view: 730