Interstitial lung disease (ILD)

The term chILD encompasses a large, heterogeneous group of rare disorders that impair gas exchange, affecting lung parenchyma, interstitium, and pulmonary vasculature. Affected children present with chronic or recurrent respiratory symptoms and diffuse abnormalities on chest imaging. Neonates and infants show tachypnoea, chest retractions, failure to thrive, and hypoxaemia. Older children may also experience dry cough, coughing up blood, and intolerance to physical exertion. The forms presenting in infancy are grouped into defined categories in the .

Clinical presentation ranges from severe, often lethal diffuse developmental disorders of the lung in newborns (e.g., FOXF1-related alveolar capillary dysplasia) to surfactant-metabolism disorders, which can present anywhere from lethal neonatal respiratory distress to variable-onset interstitial lung disease in older children and adults. Both non-syndromic and syndromic forms occur. In NKX2-1-related brain-lung-thyroid syndrome, pulmonary disease occurs together with congenital hypothyroidism and childhood-onset chorea. X-linked FLNA-related lung disease typically presents with infantile emphysema, congenital lung hyperinflation, or subpleural cysts, and may be accompanied by extrapulmonary features such as periventricular nodular heterotopia, valvular heart disease, or vascular anomalies. Age of onset spans the neonatal period to adulthood, although most genetic forms present in the neonatal period, infancy or early childhood.

Epidemiological studies from France and Spain estimate the prevalence at 44 to 46.4 per million children and the incidence at 4.4 to 8.2 per million children per year. These figures cover childhood interstitial lung disease of any cause and are not specific to the genetic forms.

This panel targets eight genes associated with childhood interstitial lung disease, categorised by biological pathway:

• Disorders of surfactant metabolism: Surfactant protein B deficiency (SFTPB), ABCA3 deficiency, surfactant protein C deficiency (SFTPC), and brain-lung-thyroid syndrome (NKX2-1).
• Disorders of lung development & structure: Alveolar capillary dysplasia with misalignment of pulmonary veins (FOXF1) and structural/extracellular matrix abnormalities (FLNA).
• Disorders of macrophage function: Hereditary pulmonary alveolar proteinosis resulting from impaired GM-CSF receptor signalling due to biallelic CSF2RA or CSF2RB variants.

Inheritance across these conditions is heterogeneous. Autosomal recessive inheritance applies to surfactant protein B (SFTPB) and ABCA3 deficiency. Hereditary (CSF2RA, CSF2RB) is recessive; CSF2RA is located in pseudoautosomal region 1 (PAR1) of the X and Y chromosomes and exhibits pseudoautosomal recessive inheritance. Surfactant protein C dysfunction (SFTPC) and brain-lung-thyroid syndrome (NKX2-1) are autosomal dominant, while FLNA-related lung disease is X-linked. Alveolar capillary dysplasia with misalignment of pulmonary veins (FOXF1) is autosomal dominant and frequently displays a parent-of-origin effect. De novo variants are frequent across the dominant conditions.

• Where childhood interstitial lung disease is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity supports condition-specific monitoring and management decisions; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

• Marczak H, Krenke K, Griese M, Carlens J, Seidl E, Gilbert C, et al. An update on diagnosis and treatments of childhood interstitial lung diseases. Breathe (Sheff). 2025;21(2):250004. PMID: .
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• Chen MH, Walsh CA. FLNA deficiency. 2002 Oct 8 [updated 2021 Sep 30]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: .