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Pulmonary fibrosis

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Respiratory Presentations/Interstitial lung disease

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An adult with interstitial lung disease, usually a usual interstitial pneumonia (UIP) pattern on high-resolution CT, or an infant or child with diffuse lung disease, where the question is whether there is an inherited cause. About 20% of people with what looks like idiopathic pulmonary fibrosis have an affected relative, and a monogenic cause is identifiable in a meaningful fraction of those families. The pediatric and adult ends of this presentation have almost no overlap in gene list, so age of onset is the first branch point.

Three questions sort this presentation faster than any imaging detail.

  1. Is there disease outside the lung in the patient or the family? Short telomere syndromes announce themselves through the marrow and the liver, not the lung. Ask directly about low blood counts, unexplained cirrhosis, and premature grey hair.
  2. How old is the patient? Neonatal and infantile diffuse lung disease is a surfactant problem until proven otherwise. Adult fibrosis is a telomere problem until proven otherwise.
  3. Is this actually secondary? Connective tissue disease, hypersensitivity pneumonitis, and drug exposure account for a large share of what gets referred as idiopathic, and they are treatable in ways the genetic causes are not.

Telomere biology disorders (short telomere syndromes)

The largest identifiable genetic contributor to adult familial pulmonary fibrosis. Autosomal dominant with markedly incomplete penetrance: TERT (most common), TERC, RTEL1, PARN, NAF1, ZCCHC8, TINF2.

  • The extrapulmonary triad is the tell: pulmonary fibrosis + bone marrow failure + liver disease. Macrocytosis, mild cytopenias, cryptogenic cirrhosis, and nodular regenerative hyperplasia of the liver all belong to the same gene
  • Premature greying, often before age 30, is a real clue rather than folklore
  • Genetic anticipation: telomeres shorten with each generation, so children present younger and more severely than the parent. A family where the grandparent had fibrosis at 70 and the parent at 50 is showing the mechanism
  • The severe childhood end of this same spectrum is dyskeratosis congenita, with nail dystrophy, lacy pigmentation, and oral leukoplakia
  • Management consequences are large. These patients tolerate immunosuppression poorly, and lung transplant is complicated by marrow and liver disease, so marrow and hepatic assessment belongs in the pre-transplant workup

Surfactant-related genes in adults

  • SFTPC (autosomal dominant): childhood or adult fibrosis, frequently de novo
  • SFTPA1 and SFTPA2 (autosomal dominant): fibrosis with an added lung adenocarcinoma risk, which changes surveillance

Common variant risk, not a clinical test

The MUC5B promoter variant rs35705950 is the strongest common genetic risk factor known for idiopathic pulmonary fibrosis, carried by roughly 10 to 20% of people of European ancestry. It illustrates multifactorial inheritance well, but it has no clinical testing role: it is neither necessary nor sufficient, and a result would not change management.

Syndromic and secondary causes to exclude

  • Hermansky-Pudlak syndrome (HPS-1 and HPS-4 subtypes): oculocutaneous albinism + bleeding + fibrosis, and fibrosis is the leading cause of death in those subtypes
  • Alpha-1 antitrypsin deficiency: emphysema-predominant rather than fibrotic, but it belongs in the differential of familial lung disease
  • Connective tissue disease: rheumatoid arthritis, systemic sclerosis, and the antisynthetase syndromes. Serologies are mandatory before calling anything idiopathic
  • Exposures: hypersensitivity pneumonitis (birds, mold, hot tubs), amiodarone, methotrexate, nitrofurantoin, bleomycin, chest radiation
  • SFTPB (autosomal recessive): fatal neonatal respiratory distress with congenital alveolar proteinosis in a term infant. Historically the definition of an unexplained term-infant respiratory failure
  • ABCA3 (autosomal recessive): the widest range, from lethal neonatal respiratory distress to childhood interstitial lung disease
  • SFTPC (autosomal dominant, often de novo): infantile or childhood interstitial lung disease
  • NKX2-1 (brain-lung-thyroid syndrome): the triad of benign hereditary chorea + congenital hypothyroidism + neonatal respiratory distress or childhood interstitial lung disease. The neurologic and endocrine features are what bring it to genetics
  • CSF2RA and CSF2RB: hereditary pulmonary alveolar proteinosis
  • FLNA: infantile lung disease with emphysematous change, alongside periventricular nodular heterotopia
  • Fibrosis + macrocytosis or cytopenias + cirrhosis anywhere in the family → telomere biology disorder. These three often present to three different specialists who never speak to each other
  • Grey hair before 30 in a fibrosis family → send telomere length
  • Successive generations presenting younger → anticipation, which here means telomere shortening rather than repeat expansion
  • Albinism + easy bruising + fibrosis → Hermansky-Pudlak
  • Chorea + hypothyroidism + lung disease → NKX2-1
  • Term newborn with unexplained refractory respiratory failure and no infection or meconium → surfactant gene panel, starting with SFTPB and ABCA3
  • Fibrosis plus adenocarcinoma clustering in one family → consider SFTPA1 and SFTPA2
  1. High-resolution CT to establish the pattern (UIP, nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis)
  2. Three-generation pedigree asked the right way: lung fibrosis, liver disease or cirrhosis, low blood counts, myelodysplastic syndrome or leukemia, early grey hair, unexplained early deaths
  3. CBC with MCV and liver function tests in every patient, since these catch the extrapulmonary triad cheaply
  4. Telomere length by flow-FISH on lymphocyte subsets, the screening test for short telomere syndromes
  5. Autoimmune serologies (antinuclear antibody, rheumatoid factor, cyclic citrullinated peptide, myositis panel) to exclude connective tissue disease
  6. Alpha-1 antitrypsin level and phenotype where emphysema is part of the picture
  7. Gene panel covering telomere and surfactant genes, or exome, depending on age and phenotype
  8. Pediatric cases: surfactant gene panel first, and consider lung biopsy only when genetic testing is uninformative
  • Blood counts and liver tests are the highest-yield genetics screen in an adult with pulmonary fibrosis, and they are almost always already in the chart.
  • Telomere length testing is a screen, not a diagnosis. A short result directs sequencing; a normal result in a strongly suggestive family does not close the question.
  • Do not order MUC5B clinically. It is a population risk marker and reporting it to a patient creates anxiety without action.
  • Testing changes transplant management, which is the main reason to pursue a diagnosis in an adult who already has established fibrosis. Conditioning, immunosuppression, and donor selection all shift.
  • Screen relatives with the pedigree, not just the proband. An asymptomatic relative found to have short telomeres should avoid smoking and lung-toxic drugs, and that counseling has value even without disease.
  • A negative family history does not exclude an inherited cause, because penetrance in telomere biology disorders is low and earlier generations were often labeled with something else.