More clinicians are now familiar with cystic fibrosis (CF), a relatively common single gene disorder, because CF screening is recommended in prenatal and neonatal (newborn screening) settings. Identifying affected individuals outside these two clinical settings, however, especially adults who do not manifest classic CF symptoms, can be challenging. When should CF screening be considered outside the prenatal and neonatal settings? What other differentials should be excluded when ruling out CF in an adult? This case scenario will highlight some of the challenges in CF screening in an adult population. A.F. is a 20-year-old Caucasian man presenting for a routine examination.

Initial visit

* Chief complaint: annual physical.

* Past medical history: admits to congestion and cough he attributes to allergy season "this is not unusual for me." Hospitalized for Pseudomonas aeruginosa pneumonia 2 years ago. Annual sinus infection in spring "almost every year." Body mass index: 18.6, admits to having a good appetite but never gaining much weight "I've always been thin."

* Social history: excited about his wedding next month. Never smoked. One to two beers, five to six times per week. No recreational drug use. Cycles occasionally on weekends up to one hour, otherwise no other cardiovascular exercise routine.

* Family history: mother healthy. Father smoked (22 pack years), but otherwise healthy. Older sister also suffers frequent sinus infections and has struggled with infertility. Younger brother and sister healthy.

* Pulmonary function test:

[white circle] FEV1 = 82%

[white circle] FEV/FVC = 0.75

[white circle] Post-albuterol administration increased FEV1 by 8%.

* Chest x-ray, unremarkable

* Sweat chloride test: positive

Discussion

The persistent, nonproductive cough, history of frequent sinus infections, and pneumonia with hospitalization make you suspect he (and perhaps his sister) has CF. Given the relatively mild symptoms, and his (and his sister's) older age, you suspect he may be a compound heterozygote; having inherited one copy of a more severe CF variant, and one less severe variant in the two cystic fibrosis transmembrane conductance regulator (CFTR) genes he inherited from his parents. One in 25 Northern European Caucasians are carriers of a CFTR variant; although the carrier frequencies are lower in African, Asian, and Hispanic Americans, individuals from these ethnic groups may also be mutation carriers and may have affected offspring (Cystic Fibrosis Foundation, n.d.a.).

More than 1,000 CFTR mutations have been identified, some of which are common (23 are particularly common in people of Ashkenazi Jewish descent and among other Northern European Caucasians), whereas others have only been found in one or two individuals worldwide, so screening for all 1,000 mutations is not performed. The "standard panel" for CF mutations includes the 23 mutations most common in individuals of Northern European or Ashkenazi descent. If an individual is symptomatic, or from another ethnic group, ordering an "expanded panel" which screens for up to 215 CFTR variants should be considered (Quest Diagnostics, 2016).

Cystic fibrosis symptoms manifest because the defective CFTR gene cannot produce functional chloride channels (receptors), which are needed to allow chloride and other ions to cross the cell wall. In the lungs, as chloride ions cross, they pull water with them. In the absence of chloride ions, pulmonary mucous becomes very thick and sticky, which impedes ciliary function and ultimately causes lungs and sinuses to become congested with mucous, greatly increasing the risk for infection (Genetics Home Reference; Cystic Fibrosis Mutation Database, 2010; Genetics Home Reference). Chloride channels also play important roles in pancreatic and reproductive function, and if impaired, fat malabsorption and infertility are commonly seen (Genetics Home Reference).

In A.F.'s case, determining whether he inherited two copies of CFTR variants, and if so, which mutations he inherited is key. Assuming we found that he was a compound heterozygote for two different CF variants, perhaps Phe508del, a more severe variant, and G551D, a less severe variant, treatment with oral ivacaftor twice a day would be appropriate. This drug directly targets the genetic defect by altering the function of the CFTR channel (Center for Disease Control and Prevention, 2017; Condren & Bradshaw, 2013) Other CF therapies specifically designed to help individuals with different CFTR genotypes are becoming available (Vargas Guerra & Marshall-Walker, 2014), and the Cystic Fibrosis Foundation continues to gather data to accelerate research for a cure. One area of exciting research is exploring the genetic makeup of P. aeruginosa, one of the most common and dangerous bacteria infecting the lungs of patients with CF. The hope is that by understanding the bacterial genome, more targeted and effective therapies will become available (Cystic Fibrosis Foundation, n.d.c.). Tests are also ongoing to identify more effective nebulized drugs (Hyde et al., 1993; Zabner et al., 1993), and gene therapies to find ways to correct pancreatic and reproductive chloride channels are being explored (Cystic Fibrosis Foundation, n.d.b.).

References