Cystic Fibrosis (CF)
Primary dysphagia
with chronic descending tracheal aspiration and primary gastroesophageal reflux (GER) with or without ascending tracheal aspiration. Both conditions can cause chronic cough in infancy and may be associated with failure to thrive. However, in infants without CF, the cough is often temporally associated with feedings; and steatorrhea is not associated with primary dysphagia or primary GER.
Severe combined immunodeficiency
and other immunodeficiency disorders. Individuals with immunodeficiency may present with recurrent respiratory infections and chronic diarrhea in infancy. These individuals are also prone to non-respiratory infections (e.g., otitis media, cellulitis) not specifically associated with CF.
Asthma. CF and asthma both present with chronic cough and persistent wheeze following respiratory viral infections, allergen exposure, or exertion. However, individuals with asthma typically improve on asthma therapy, do not experience recurrent pneumonia, are not colonized with CF-related bacteria, have normal growth and weight gain, and do not have steatorrhea.
Congenital airway anomalies can cause chronic cough and wheezing during infancy similar to CF. Gastrointestinal or nutritional manifestations that are typically present in infants with CF are not seen in children with congenital airway anomalies. Stridor is not common in CF.
Primary ciliary dyskinesia
(PCD) is associated with situs abnormalities, abnormal sperm motility, and abnormal ciliary structure and function that result in retention of mucus and bacteria in the respiratory tract leading to chronic oto-sino-pulmonary disease. Individuals with PCD present with respiratory distress in infancy, cough and sputum production with recurrent pneumonias that may progress to chronic bronchiectasis, Pseudomonas aeruginosa or other opportunistic bacterial pathogens that may be cultured from airway secretions, and chronic sinus disease. Situs inversus is present in 50% of individuals with PCD; steatorrhea and failure to thrive are not associated with PCD. PCD is associated with pathogenic variants in multiple genes encoding different structural components of cilia and is inherited in an autosomal recessive manner.
Shwachman-Diamond syndrome
(SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure. SDS can be distinguished from CF by the presence of hematologic abnormalities with single- or multilineage cytopenias, susceptibility to myelodysplasia syndrome (MDS) and acute myelogenous leukemia (AML), and skeletal abnormalities (most commonly chondrodysplasia or asphyxiating thoracic dystrophy). SDS is caused by biallelic pathogenic variants in SBDS and is inherited in an autosomal recessive manner.
Primary biliary atresia. Rarely, individuals with CF may present in infancy with symptoms of biliary obstruction without other clinically apparent GI or respiratory manifestations. Serum levels of immunoreactive trypsinogen and stool levels of elastase should be normal in primary biliary atresia, whereas CF liver disease is invariably associated with evidence of pancreatic duct obstruction.
Bronchiectasis with or without elevated sweat chloride. Pathogenic variants in SCNN1A, SCNN1B, and SCNN1G encoding the beta subunit of the epithelial sodium channel cause a non-classic CF phenotype [Sheridan et al 2005]. Individuals with SCNN1A, SCNN1B, or SCNN1G pathogenic variants may also have mild lung disease and elevated sweat chloride concentration.
Isolated hyperchlorhidrosis, characterized by elevated sweat chloride levels and failure to thrive, is caused by pathogenic variants in CA12, which encodes carbonic anhydrase XII [Feldshtein et al 2010].