Educational Aims
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To identify the similarities and differences in the guidelines for CRMS from Cystic Fibrosis Foundation and from European Cystic Fibrosis Society.
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To understand the diagnostic challenges for CRMS in patients with prenatally identified CFTR variants.
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To identify the various sources of information for classifying CFTR variants as disease causing and how these assignments may change over time.
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To recognize and monitor for the possibility of progression over time from a diagnosis of CRMS to CF in a subset of patients with CRMS.
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To identify gaps in the guidelines that may not cover every clinical scenario that is encountered during the long-term follow up of patients with CRMS.
Abstract
Newborn screening (NBS) for cystic fibrosis (CF) has enabled earlier diagnosis and has improved nutritional and growth-related outcomes in children with CF. For those with a positive NBS for CF that do not meet the diagnostic criteria for CF, the clinical entity called CFTR-Related Metabolic Syndrome (CRMS) or CF Screen- Positive, Inconclusive Diagnosis (CFSPID) is used. Although most children with CRMS remain relatively asymptomatic, studies have shown that between 11% and 48% of these patients may eventually progress to a diagnosis of CF over time. Although the CF Foundation guidelines for CRMS management and European CF Society guidelines for CFSPID have some similarities, there are also some differences. Here, we review challenging case scenarios that highlight remaining gaps in CRMS guidelines, thus supporting the need to update and unify existing guidelines.
Introduction
Cystic fibrosis (CF) is the most common life-limiting autosomal recessive genetic disorder caused by pathogenic variants in the CF transmembrane conductance regulator ( CFTR ) gene, resulting in reduced quantity or function of the CFTR protein . Since the gene’s discovery in 1989, over 2000 disease-causing CFTR variants have been reported . Depending on the type of CFTR variant, the CFTR protein function may be affected to varying degrees, resulting in a wide spectrum of clinical phenotypes ranging from mild to severe disease .
The inclusion of CF as part of state newborn screening (NBS) programs in the United States has enabled significantly earlier diagnosis and has helped to improve nutritional and growth-related outcomes for children with CF . However, some patients with a positive NBS for CF do not meet criteria for a CF diagnosis, yet CFTR dysfunction cannot be fully excluded. These patients are diagnosed with CFTR-Related Metabolic Syndrome (CRMS) — a terminology used in the United States for healthcare delivery purposes . In other countries, the term CF Screen- Positive, Inconclusive Diagnosis (CFSPID) is used; both terminologies describe a unified definition of an inconclusive diagnosis for CF following a positive NBS . The CRMS diagnostic criteria are summarized in Table 1 . Although most children with CRMS remain relatively asymptomatic, studies have shown that between 11% and 48% of these patients may eventually progress to a diagnosis of CF over time . There is currently insufficient data to predict which patients with CRMS/CFSPID are at risk of progression to CF. This uncertainty makes it challenging to provide accurate prognostic information to families and may negatively impact caregiver mental health and adherence to follow up .
| CRMS/CFSPID | Infants with a positive NBS for CF |
| AND either | |
| |
| OR | |
|
In 2008, the CF Foundation (CFF) published guidelines for the management of CRMS. ( Table 2 ) . The diagnostic guidelines for CF were updated in 2015 and included a harmonized definition of CRMS and CFSPID . The CFF CRMS/CFSPID guidelines are currently undergoing an update, while the European CF Society (ECFS) recently published CRMS/CFSPID guidelines in 2020 ( Table 2 ) . Both guidelines emphasize the importance of early detection of children with CRMS who may progress to a diagnosis of CF, and otherwise may not be diagnosed until later in childhood or in adulthood once CFTR-related disease is established. Despite these guidelines, a review of several patients receiving care at our institution has led to the identification of clinical scenarios where knowledge gaps remain. In this review, we describe 4 scenarios that highlight diagnostic and management challenges along with a review of the literature related to these cases.
| By 2 months of age | 6 months of age | 12 months of age | 2 years of age | Annually 3–5 years of age | 6 years of age | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| CFF | ECFS | CFF | ECFS | CFF | ECFS | CFF | ECFS | CFF | ECFS | CFF | ECFS | |
| Diagnostic testing | ||||||||||||
| Sweat chloride concentration | X | X | X | X | C | X | C | X | ||||
| Extended CFTR analysis | X | C | ||||||||||
| Check for CFTR variant classification updates in CFTR2 | X | X | X | X | X | X | X | X | X | X | X | X |
| Fecal elastase measurement | X | C | C | C | X | C | C | C | C | C | C | |
| Care Management | ||||||||||||
| Discuss diagnosis of CRMS/CFSPID with PCP | X | X | C | X | C | X | C | C | C | C | C | X |
| Genetic counseling | X | X | C | C | C | C | ||||||
| H&P and growth assessment | X | X | X | X | X | X | X | X | X | X | ||
| Respiratory cultures | X | C | X | X | X | X | X | C | X | C | X | C |
| Chest imaging | C | C | C | C | C | C | C | C | C | C | C | X |
| MBW/LCI measurement | C | C | X | |||||||||
| Spirometry | X | X | X | |||||||||
| Tobacco smoke exposure avoidance | X | X | X | C | X | C | X | C | X | C | X | C |
| CFF | ECFS | |||||||||||
| Initial intermediate sweat chloride value (30–59 mmol/L) should be repeated by 2 months of age | X | |||||||||||
| Extended CFTR analysis at the initial visit | X | |||||||||||
| Infants with persistently elevated sweat chloride values in the intermediate range should have extended CFTR analysis | X | |||||||||||
| In the case of a sweat chloride value becoming positive (>59 mmol/L) in an asymptomatic child, ideally 2 consecutive positive sweat tests are required to confirm the diagnosis of CF | X | |||||||||||
| Evaluation and sweat testing in older siblings should be discussed and obtained if felt appropriate | X | |||||||||||
| An extensive evaluation should be performed at 6 years of age including sweat testing, lung function testing, chest imaging, and should consider fecal elastase measurement | X | |||||||||||
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