Clinical Guidance

The Clinical and Functional Translation of CFTR website provides genotype-phenotype information for CFTR pathogenic variants including sweat chloride, lung function, pancreatic status, and pseudomonas infection rates. The strongest genotype-phenotype correlations have been identified in the context of pancreatic function. The most common CFTR pathogenic variants have been classified as pancreatic sufficient (PS) or pancreatic insufficient (PI). Individuals who are PS usually have one or two PS alleles, indicating that PS alleles are dominant with respect to pancreatic phenotype . Beyond pancreatic function, genotype does not consistently predict phenotype. Pulmonary disease severity varies widely among individuals with identical genotypes (see Molecular Genetics, ).

Source: GeneReviews — "Cystic Fibrosis"

Diagnostic Criteria

Consensus clinical diagnostic criteria for cystic fibrosis (CF) have been established .

Suggestive Findings

Scenario 1: Abnormal newborn screening (NBS) result

• NBS for CF is based on quantification of immunoreactive trypsinogen (IRT) and subsequent molecular testing including either CFTR targeted analysis or sequence analysis on dried blood spots.

• Elevated IRT values with or without the presence of CFTR pathogenic variants are considered out of range and require diagnostic sweat chloride testing.

Source: GeneReviews — "Cystic Fibrosis"

Differential Diagnosis

Genetic disorders of interest in the differential diagnosis of cystic fibrosis (CF) are summarized in . Table 3. Genetic Disorders in the Differential Diagnosis of Cystic Fibrosis

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in a newborn diagnosed with cystic fibrosis (CF), the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. For those individuals diagnosed after the newborn period, the evaluations summarized in are recommended .

Table 4a.

Recommended Evaluations Following Initial Diagnosis of Cystic Fibrosis in Newborn Period

System/Concern | Evaluation | Comment

General

| • Assess growth (weight, length, head circumference).

• Refer to CF specialist.

|

Pancreatic

| Fecal elastase measurement | Can be obtained while on pancreatic enzyme replacement therapy

Genetic counseling

| Genetic counseling by genetics professionals1 | To inform affected persons families re nature, MOI, implications of CF to facilitate medical personal decision making2

CF = cystic fibrosis; MOI = mode of inheritance

1. Medical geneticist, certified genetic counselor, certified advanced genetic nurse

2.

Table 4b.

Recommended Evaluations Following Initial Diagnosis of Cystic Fibrosis After the Newborn Period

System/Concern | Evaluation | Comment

General

| • Assess growth (weight, length, head circumference).

• Refer to CF specialist.

|

Pulmonary

| • Pulmonary function testing

• Respiratory culture for CF-specific pathogens by expectorated sputum or deep oropharyngeal swab

|

Pancreatic

| Assess fat-soluble vitamin levels (vitamins A, E, D, PT as a marker of vitamin K). |

Source: GeneReviews — "Cystic Fibrosis"

Clinical Guidance

Avoid the following:

• Environmental smoke

• Exposure to respiratory infections

• Dehydration

Source: GeneReviews — "Cystic Fibrosis"

Therapies Under Investigation

Therapeutic interventions for CF are continually evolving (see cff.org). Restoration of CFTR function continues to advance with improved modulators and gene therapy. Modulator therapy studies include using approved medications in individuals of younger ages and testing new modulators, once-daily dosing, and new combination therapies. Therapies under study that focus specifically on the approximately 10% of individuals who are not eligible for current therapy due to nonsense or rare variants that do not produce any CFTR protein include read-through agents and gene therapy. Read-through agents are particularly interesting as a treatment for those with nonsense variants.

Source: GeneReviews — "Cystic Fibrosis"

Surveillance Guidelines

To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, partnership with a CF specialist is critical in addition to the following recommended surveillance. Table 7. Cystic Fibrosis: Recommended Surveillance

Source: GeneReviews — "Cystic Fibrosis"