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Types

Cystic fibrosis (CF) is an autosomal-recessive disease that results from a mutation in the CFTR gene, which codes for the cystic fibrosis transmembrane regulator (CFTR) chloride channel. CF affects more than one organ system and is associated with measurable CFTR dysfunction. Patients with evidence of CFTR dysfunction and involvement of a single organ system who do not meet the criteria for a diagnosis of CF are classified as having CFTR-related disorder (CFTR-RD). Newborns with positive results on serum immunoreactive trypsinogen screening who are apparently healthy and do not meet the criteria for a diagnosis of CF are considered to have CFTR-related metabolic syndrome (CFMS).

Cystic Fibrosis Classes

CF is caused by pathogenic mutations in the CFTR gene. Abnormalities of CFTR protein result in dehydration of the surface of mucus-secreting epithelia with the production of thick, mucopurulent secretions and impaired mucociliary clearance. The most common mutation is Phe508del. CFTR mutations are classified into classes I through VI according to their effect on CFTR protein expression and function¹:

Class I: No full-length proteins are produced. CFTR genes may have premature truncation codons, resulting in the formation of short, unstable mRNA and the absence of full-length CFTR protein.
Class II: Misfolded CFTR protein is produced, resulting in failure of maturation and intracellular trafficking to the cell surface.
Class III: CFTR protein is properly located at the cell surface; however, the ion pore fails to open in response to chemical signaling (abnormal gaiting).
Class IV: CFTR protein is properly located at the cell surface; however, conductance through the ion pore is decreased.
Class V: CFTR is properly located at the cell surface; however, a reduced amount of CFTR protein is produced.
Class VI: These mutations result in the production of unstable CFTR with a short half-life.

Class IV, V, and VI mutations are considered residual function mutations because the proteins retain a residual capacity for ionic transport.¹ Diagnostic criteria for CF are the presence of clinical symptoms consistent with CF in at least one organ system and evidence of CFTR protein dysfunction as demonstrated by an elevated level of sweat chloride, the presence of 2 disease-causing mutations in the CFTR gene, or an abnormal nasal potential difference test result. If a newborn has positive screening results, clinical symptoms are not required for a diagnosis of CF.²

CFTR-Related Disorder

CFTR-related disorder (CFTR-RD) is a clinical entity associated with CFTR protein dysfunction in which a single organ system is affected and the diagnostic criteria for CF are not met.^1,3 The 3 main clinical entities that have been described include CBAVD (congenital bilateral absence of the vas deferens), acute recurrent or chronic pancreatitis, and disseminated bronchiectasis. For each of these CFTR-RD phenotypes, CFTR dysfunction is demonstrated by an elevated level of sweat chloride, the presence of 2 disease-causing mutations in the CFTR gene, or an abnormal nasal potential difference test result; however, disease is limited to a single organ system.³ Additional symptoms of CFTR-RD include primary sclerosing cholangitis, chronic sinusitis with nasal polyps, and aquagenic palmoplantar keratoderma.¹

CFTR-Related Metabolic Syndrome

A child with hypertrypsinemia detected through newborn screening who does not fulfill the criteria for a diagnosis of CF and who is apparently healthy is considered to have CFTR-related metabolic syndrome (CFMS). The term used in Europe is cystic fibrosis screen positive, inconclusive diagnosis. Patients with CFMS either have a sweat chloride concentration of less than 30 mmol/L and 2 CFTR variants (1 or both variants being of varying clinical consequence) or have a sweat chloride concentration of 30 to 59 mmol/L with 0 or 1 CFTR mutation and 0 or 1 of varying clinical consequence. In most patients with CFMS, a biochemical or clinical picture of CF will not develop in childhood, but clinical disease may appear during adolescence or adulthood.¹

References

1. Shteinberg M, Haq IJ, Polineni D, Davies JC. Cystic fibrosis. Lancet. 2021;397(10290):2195-2211. doi:10.1016/S0140-6736(20)32542-3

2. Farrell PM, White TB, Ren CL, et al. Diagnosis of cystic fibrosis: consensus guidelines from the Cystic Fibrosis Foundation. J Pediatr. 2017;181(Suppl):S4-S15.e1. doi:10.1016/j.jpeds.2016.09.064

3. Bombieri C, Claustres M, De Boeck K, et al. Recommendations for the classification of diseases as CFTR-related disorders. J Cyst Fibros. 2011;10(Suppl 2):S86-S102. doi:10.1016/S1569-1993(11)60014-3

Reviewed by Harshi Dhingra, MD, on 1/31/2022.

Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.

Cystic Fibrosis (CF)