Cystic fibrosis (CF) is an autosomal recessive disorder that affects the digestive, respiratory, and reproductive systems, often leading to early death from pulmonary complications. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, a 250-kb gene found on the long arm of chromosome 7 that encodes a chloride transport protein.^1,2 More than 2000 mutations of the CFTR gene have been reported and more are still being discovered; however, most occur infrequently; approximately 10% are common enough to be well characterized.³ Among these gene mutations, some are disease causing, some are sequence variations that do not cause disease, some are associated with single or milder organ system involvement than typically seen in CF (sometimes called "CFTR-associated disorders" or "CFTR-related metabolic syndrome"), and some have variable or unknown consequences.⁴ The most common is the first mutation discovered, F508del, which is a 3-base pair deletion at codon 508 that leads to loss of a phenylalanine residue causing a protein-folding defect and a failure in processing through the cytoplasm to the epithelial surface of affected cells.¹ Approximately half of patients with CF are homozygous for F508del, and nearly 40% more have at least 1 such mutation; however, in the latter circumstance, it is the second mutation that determines genotype-phenotype implications.^5,6,7

The strongest relation between the genotype and the phenotype is observed for the exocrine pancreas.^5,6,7 Most people with CF have pancreatic insufficiency at birth or develop pancreatic insufficiency by 1 year of age.⁸ Most patients with the pancreatic insufficiency phenotype present with signs and symptoms of malabsorption or failure to thrive at an early age, although some may appear normal. Approximately 10% to 15% of children with CF have evidence of pancreatic dysfunction but retain sufficient residual pancreatic function to permit adequate digestion without the need for exogenous pancreatic enzyme supplements with meals. The term pancreatic sufficiency is used to describe patients with this phenotype who tend to have a milder form of CF.⁹ Analyses of large patient cohorts have revealed that different mutations in the CFTR gene confer either the pancreatic insufficiency or the pancreatic sufficiency phenotypes.^2,5

The lungs of infants with CF are structurally and functionally normal at birth, but there is often evidence of airway obstruction and structural changes within the first few months after birth.^10,11 The lungs of patients with CF are highly susceptible to infection, especially with the gram-negative bacterium Pseudomonas aeruginosa.¹² Intermittent, then chronic, pulmonary infection occurs over the course of months to years, leading to bronchiectasis and, ultimately, respiratory failure. Infection increases caloric requirements because of the increased work of breathing and ultimately causes premature death in 90% of affected individuals.

In the United States, most cases of CF in children are diagnosed in early infancy through newborn screening. Early screening and identification have allowed early aggressive intervention to maintain growth and preserve lung function. Up to 20% of newborn infants with the pancreatic insufficiency phenotype of CF present with meconium ileus.¹³ The spectrum of meconium ileus ranges from neonatal bowel obstruction attributable to thick meconium to intrauterine intestinal perforation with intraabdominal calcifications. Treatment depends on the degree of obstruction and injury to the colon. Microcolon frequently results from the prolonged intrauterine intestinal obstruction. Studies suggest children with CF who have meconium ileus have reduced fat mass, bone mineral density, and lung function compared with those who do not have meconium ileus.^14,15 The need for surgical intervention to relieve obstruction (as opposed to relief of the obstruction by enemas) increases the risk of poor growth.¹⁶

The introduction of highly effective modulator therapy is a significant improvement in the management of CF. Ivacaftor, developed for people with CF and gating mutations (CFTR protein does not open or close normally), was effective at improving pulmonary function and weight gain but had limited application as a single drug as the proportion of individuals with gating mutations is low.^17,18 The combination of elezacaftor, tezacaftor, and ivacaftor (ETI) improves the processing, trafficking, and gating of the CFTR protein, thus increasing the protein function.¹⁹ ETI is effective for individuals with the F508del mutation, either homozygous or heterozygous, as well as those with other CFTR mutations similar to F508del. As such, 90% of people with CF may benefit from this therapy.

ETI is now approved for children as young as 6 years of age who have the target CFTR mutations. The combination therapy improves the percentage of predicted forced expiratory volume in 1 second (FEV₁) significantly in all age groups reported thus far and most patients demonstrate increased weight.^20,21,22 Studies of the effect of ETI on specific areas of nutritional metabolism and gastrointestinal function are ongoing. However, for those caring for children with CF, their long-term prognosis and daily function have improved dramatically.

Pediatricians treating children with CF will see these improvements. Good communication with the patient's CF center is critical to managing care during this time of changing therapy. Important things to know as ETI is prescribed to more and more children:

• About 10% of children will not be eligible for ETI; these individuals will continue to need conventional CF care, including dietary care, and may be saddened that they are not included in this advance in treatment.

• Although some children will be able to reduce or eliminate some conventional CF therapies, this should be managed through their CF centers. Studies of reduced or withdrawn therapy are underway.

• There are side effects to ETI, including allergic reactions, liver enzyme elevations greater than 3 times the upper limit of normal, and interactions with other medications.²³