Mendelian Disorders: Diseases Caused by Single-Gene Defects 253

is not required—the pancreas-sufficient phenotype.

Pancreatic insufficiency is associated with malabsorption
of protein and fat and increased fecal loss. Manifestations
of malabsorption (e.g., large, foul-smelling stools; abdomi-
nal distention; poor weight gain) appear during the first
year of life. The faulty fat absorption may induce defi-
ciency states of the fat-soluble vitamins, resulting in mani-
festations of avitaminosis A, D, or K. Hypoproteinemia
may be severe enough to cause generalized edema. Persis-
tent diarrhea may result in rectal prolapse in as many as
10% of children with CF. The pancreas-sufficient pheno-
type usually is not associated with other gastrointestinal
complications, and in general, these patients demonstrate
excellent growth and development. In contrast to exocrine
insufficiency, endocrine insufficiency (i.e., diabetes) is
uncommon in CF and occurs late in the course of the
disease especially with improved survival of patients with
CF.
Cardiorespiratory complications, such as chronic cough,
persistent lung infections, obstructive pulmonary disease,
and cor pulmonale, constitute the most common cause of
death (accounting for approximately 80% of fatalities) in
Fig. 7.6 Lungs of a patient who died of cystic fibrosis. Extensive mucous
patients who receive follow-up care in most CF centers
plugging and dilation of the tracheobronchial tree are apparent. The pul- in the United States. By 18 years of age, 80% of patients
monary parenchyma is consolidated by a combination of both secretions with classic CF harbor P. aeruginosa, and 3.5% harbor B.
and pneumonia; the greenish discoloration is the product of Pseudomo- cepacia. With the indiscriminate use of antibiotic prophy-
nas infections. (Courtesy of Dr. Eduardo Yunis: Children’s Hospital of Pittsburgh, laxis, there has been an unfortunate resurgence of resis-
Pittsburgh, Pennsylvania.) tant strains of Pseudomonas in many patients. Significant
liver disease occurs late in the natural history of CF and
is foreshadowed by pulmonary and pancreatic involve-
bronchiectasis. Development of lung abscesses is common. Staph- ment; with increasing life expectancy, liver disease is
ylococcus aureus, Haemophilus influenzae, and Pseudomonas aeru- now the third most common cause of death in patients
ginosa are the three most common organisms responsible for with CF (after cardiopulmonary and transplant-related
lung infections. Even more sinister is the increasing frequency of complications). More extensive DNA sequencing has
infection with another pseudomonad, Burkholderia cepacia. This shown that the spectrum of diseases caused by germline
opportunistic bacterium is particularly hardy, and infection with CFTR mutations (either biallelic or in heterozygous car-
this organism has been associated with fulminant illness (“cepacia riers) is broader than the “classic” multisystem disease
syndrome”). The liver involvement follows the same basic described earlier. For example, some patients suffering
pattern. Bile canaliculi are plugged by mucinous material, accom- from recurrent bouts of abdominal pain and pancreatitis
panied by ductular proliferation and portal inflammation. Hepatic since childhood who were previously classified as having
steatosis (“fatty liver”) is a common finding in liver biopsies. “idiopathic” chronic pancreatitis are now known to harbor
With time, cirrhosis develops, resulting in diffuse hepatic nodu- biallelic CFTR variants that are distinct from those seen in
larity. Such severe hepatic involvement is encountered in less “classic” CF. Patients with isolated pancreatitis or bilateral
than 10% of patients. Azoospermia and infertility are found absence of vas deferens (see earlier) resulting from CFTR
in 95% of the affected males who survive to adulthood; bilateral mutations are included under the umbrella of “CFTR-
absence of the vas deferens is a frequent finding in these opathies.” Similarly, whereas CF carriers were initially
patients. In some males, this may be the only feature suggesting thought to be asymptomatic, studies suggest that they
an underlying CFTR mutation. have an increased lifetime risk for chronic lung disease
(especially bronchiectasis) and recurrent sinonasal polyps.
In most cases, the diagnosis of CF is based on persistently
elevated sweat electrolyte concentrations (often the mother
Clinical Course makes the diagnosis because her infant “tastes salty”),
In few childhood diseases are clinical manifestations as characteristic clinical findings (sinopulmonary disease
protean as those of CF (Fig. 7.4). Approximately 5% to 10% and gastrointestinal manifestations), or a family history.
of the cases come to clinical attention at birth or soon after Sequencing the CFTR gene is the gold standard for diagnosis
because of an attack of meconium ileus. Exocrine pancre- of CF.
atic insufficiency occurs in a majority (85% to 90%) of There have been major improvements in the manage-
patients and is associated with “severe” CFTR mutations ment of acute and chronic complications of CF, including
on both alleles (e.g., ΔF508/ΔF508). By contrast, 10% to 15% more potent anti-microbial therapies, pancreatic enzyme
of patients, who have one “severe” and one “mild” CFTR replacement, and bilateral lung transplantation. Impor-
mutation, or two “mild” CFTR mutations, retain sufficient tantly, two new forms of treatment aimed at increasing
pancreatic exocrine function that enzyme supplementation CFTR protein function in certain CFTR variants have been

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