Living in the Gray Area

Although she has two CF mutations, my daughter does not have cystic fibrosis. She has CFTR-related metabolic syndrome. She’s healthy now, but what about the future?

Jan. 19, 2023 | 6 min read
Álvaro La Parra-Pérez
Álvaro La Parra-Pérez
Black and white photo of a girl on a swing set in a butterfly costume.

As an economics professor, one of the main messages I give to my students is that there are no easy answers in the social sciences. Our society is a highly complex system, and our predictions and expectations are constantly surrounded by uncertainty and limited knowledge about the underlying mechanisms. But, teaching and embracing uncertainty in my job is one thing — accepting uncertainty and limited knowledge when it affects our loved ones is very different. My lessons in the classroom proved much more difficult to extrapolate to my personal life when dealing with CFTR-related metabolic syndrome (CRMS) in my family. 

Two weeks after our daughter was born, she had to spend a few days at the hospital due to a RSV infection. The virus left a cough that would not disappear for more than one month. The sweat test she took as part of the battery of tests prescribed to her revealed that she was in an intermediate (indeterminate) range for a cystic fibrosis diagnosis. This was when we had to face CRMS uncertainty for the first time. Even if the label of the result (uncertain) is quite explicit (neither negative nor positive), I remember the anxiety and the rushed internet searches about CF, almost as if our daughter had already been diagnosed with CF. I was not alone in that reaction: parents of kids with inconclusive newborn screening often think that their kid had a sure case of CF. Processing uncertainty is never easy. 

Our next step was meeting with a genetic counselor after searching for potential CF-related mutations in my daughter’s genotype. “Surely, this will end the uncertainty,” I remember thinking. “The genes will conclusively say whether she is healthy or sick.” So naïve … but, again, so typical … We are used to thinking in terms of what some researchers call a “traditional medical model” where only the “healthy” or “ill” outcomes are envisaged. 

At this point, you will not be surprised that the meeting with the genetic counselor, far from getting rid of uncertainty, exacerbated it. Our daughter has a severe CF-related mutation and another “mild” variant that the CFTR2 database describes as one with “varying consequences.” When putting together my daughter’s two CFTR-related mutations, the database delivered the following information: 

“This variant combination has varying consequences. Some patients with this variant combination have CF. Other patients with this variant combination do not have CF. (…) Because the clinical manifestations of CF can vary over the course of a person’s lifetime, people who have this variant plus a variant that is known to cause CF should have periodic check-ups with their doctor even if they have no clinical signs or symptoms of CF at the present time.” 

Talk about uncertainty! 

This vague outcome for the genetic screening is, more often than not, the unfortunate reality of a CRMS diagnosis.

Persons with CRMS often do not have a classic case of CF, but there is the possibility of developing some CF-related complications. How severe would those complications be? When are they more likely to happen? Can we be out of the woods at some point? The desperately sad and vague answer is that it depends on the type of mutations.

Even when we know the exact nature of the mutations, more research is still needed to form a reliable expectation about the correlation between persons’ genotypes (their genetic makeup) and their phenotypes (the clinical manifestations during their lifetime). Our current knowledge about those correlations in CRMS is insufficient because, to begin with, it is a recently discovered condition for which there is not a lot of research. Long-term follow-ups of people with CRMS are also lacking (despite some encouraging efforts).

Even when researchers get a significant amount of people with the condition for a study, there is always the risk of selection bias in the observed sample. Imagine, for example, that only people with the most severe clinical symptoms with a given genetic mutation keep attending medical follow-ups, while asymptomatic people with those same mutations stop attending clinical appointments. Under these assumptions, the observed cases would suggest a significant (but exaggerated at best and spurious at worst) relationship between that genotype and severe clinical outcomes. Our knowledge about CRMS is so preliminary that even whether some mutations should be considered pathogenic or not is still debated

Because of the limited knowledge, we must rely on clinical evidence to assess our daughter’s evolution. Our annual check-ups at Children’s Hospital are always a brutal reminder of the threat that looms. The sweat test — a particularly unpleasant lengthy procedure — keeps returning the same message: intermediate levels. Not positive, not negative: uncertain. And, yet, we know we are fortunate. Our daughter is growing up without any symptoms that would make us think that the CRMS potential threat is manifesting in any way. There is good evidence at this point to hope that CF-related complications (at least of the severe type) are an unlikely outcome. We also enjoy good health insurance and coverage (something that, for the non-US reader, cannot be taken for granted where we live), and the excellent personnel at Salt Lake City Children’s Hospital also do everything they can to make our visits as comfortable as possible.  

What’s next? Likely, the CRMS diagnosis for our daughter will always hang over our heads as a sword of Damocles. While experts keep working to increase our understanding of CRMS, we will keep attending those exhausting annual check-ups. We will attend even if our daughter remains a beautiful, energetic, cheerful person who grows and develops without worrying symptoms. Hopefully, she will provide one more example of systematic good health outcomes for someone in that inconclusive grey area called CRMS. We also hope that future people with the same CFTR-related genotype will be able to look at our daughter’s case and be reminded that uncertain situations can also have perfectly normal and happy results. Because, no matter the uncertainty, there is always hope. 

Interested in sharing your story? The CF Community Blog wants to hear from you. 

This site contains general information about cystic fibrosis, as well as personal insight from the CF community. Opinions and experiences shared by members of our community, including but not limited to people with CF and their families, belong solely to the blog post author and do not represent those of the Cystic Fibrosis Foundation, unless explicitly stated. In addition, the site is not intended as a substitute for treatment advice from a medical professional. Consult your doctor before making any changes to your treatment.

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Álvaro La Parra-Pérez

Álvaro La Parra-Pérez is an associate professor of Economics at the Goddard School of Business and Economics (Weber State University, Ogden, Utah). He earned a bachelor's degree in economics from the University of Valencia in Spain in 2007 and a PhD in economics from the University of Maryland in 2014. When he is not reading "boring books," according to his daughter, he enjoys playing and watching soccer and pushing his physical limits with the endless games his daughter invents daily. 

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