Recognizing genetic disease: A key aspect of pediatric pulmonary care

Abstract

Advancement in technology has improved recognition of genetic etiologies of disease, which has impacted diagnosis and management of rare disease patients in the pediatric pulmonary clinic. This review provides an overview of genetic conditions that are likely to present with pulmonary features and require extensive care by the pediatric pulmonologist. Increased familiarity with these conditions allows for improved care of these patients by reducing time to diagnosis, tailoring management, and prompting further investigation into these disorders.

Keywords: bronchiectasis and primary ciliary dyskinesia; cystic fibrosis (CF); genetics/Genome-Wide Association Studies (GWAS); immunology and immunodeficiency; surfactant biology and pathophysiology.

FIGURE 1

Cartoon overview of disorders of surfactant dysfunction. The lower airway and alveolus are represented. Type I and type II alveolar cells line the airway. Type II cells contain lamellar bodies that are responsible for generating surfactant. Normal type II alveolar cells have a circumferential organized appearance. SFTPC mutations cause milder surfactant dysfunction and may have normal or disorganized lamellar bodies. ABCA3 and NKX2–1 mutations can also have a range of severity of surfactant dysfunction and both have small disorganized lamellar bodies. Of note, neuroendocrine hyperplasia of infancy has also been reported in association with NKX2–1 mutations, which affects the lower airways rather than the alveolus. Mutations in SFTPB cause the most severe surfactant dysfunction, often lethal in the newborn period, and lamellar bodies are often decreased or absent. Mutations causing pulmonary alveolar proteinosis have normal lamellar bodies and normal surfactant secretions, rather, antibodies are generated to disrupt mechanisms of surfactant homeostasis. GM-CSF, granulocyte-macrophage colony-stimulating factor; PAS, periodic acid-Schiff

FIGURE 2

This cartoon represents the four main genetic categories of bronchiectasis, or dilation of the airway: (1) ciliary abnormalities, such as primary ciliary dyskinesia, which is caused by mutations in over 40 genes affecting cilia function or structure (2) abnormal epithelial Chloride (Cl⁻) transport, characteristic of cystic fibrosis, and mutations in CFTR, resulting build-up of thick tenacious airway secretions. (3) Abnormal sodium (Na⁺) transport as seen in pseudohypoaldosteronism due to mutations in SCNN1A, SCNN1B, and SCNN1G, which also cause thickened dehydrated airway secretions. (4) Primary immunodeficiencies, which comprise over 200 genetic conditions that cause impaired immune responses to infection, triggering increased mucus production and impaired airway clearance. CFTR, cystic fibrosis transmembrane conductance regulator; PCD, primary ciliary dyskinesia

FIGURE 3

This Venn diagram illustrates the phenotypic overlap of connective tissue disorders associated with pneumothorax, Marfan syndrome (FBN1), Loeys-Dietz (TGFBR1 and TGFBR2), vascular Ehlers-Danlos syndrome (COL3A1), cutis laxa (FBLN5, EFEMP2, LTBP4, and ELN), and Williams syndrome (7q11.23 deletion, which includes ELN). Central features of these diseases, however, include pneumothorax, joint hypermobility, and vascular disease, including aortopathies