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Pulmonary Fibrosis, Familial

Synonym: Familial Interstitial Pneumonia

, MS, CGC and , MD.

Author Information
, MS, CGC
University of Colorado Denver
Aurora, Colorado
National Jewish Health
Denver, Colorado
, MD
University of Colorado Denver
Aurora, Colorado
National Jewish Health
Denver, Colorado

Initial Posting: ; Last Update: March 19, 2015.

Summary

Clinical characteristics.

Familial pulmonary fibrosis (FPF in this GeneReview) is defined as idiopathic interstitial pneumonia (IIP) in two or more first-degree relatives (parent, sib, or offspring). Up to 20% of cases of IIP cluster in families. The clinical findings of IIP are bibasilar reticular abnormalities, ground glass opacities, or diffuse nodular lesions on high-resolution computed tomography and abnormal pulmonary function studies that include evidence of restriction (reduced VC with an increase in FEV1/FVC ratio) and/or impaired gas exchange (increased P(A-a)O2 with rest or exercise or decreased diffusion capacity of the lung for carbon monoxide [DLCO]). FPF usually presents between ages 50 and 70 years. FPF may be complicated by lung cancer; bronchoalveolar cell carcinoma, small-cell carcinoma, and adenocarcinoma have been described.

Diagnosis/testing.

The diagnosis of FPF is based on established clinical diagnostic criteria. Some, but not all of the loci/genes associated with FPF are known. Pathogenic variants in TERT, TERC, SFTPC, and SFTPA2 have been identified in about 8%-15% of individuals with FPF and 1%-3% of simplex cases (i.e., a single occurrence in a family) of IIP.

Management.

Treatment of manifestations: Management of FPF and IIP is similar and depends on the type of IIP diagnosed in an individual; oxygen therapy may improve exercise tolerance in those with hypoxemia; lung transplantation may be considered, particularly in those who are unresponsive to immunosuppressive therapy, have significant functional impairment, and have no other major illnesses that would preclude transplantation. Generally, pharmacologic interventions have not been shown to alter the course of IPF (idiopathic pulmonary fibrosis, the most common form of IIP) or FPF; however, antifibrotic treatments have been shown in clinical trials to slow the decline in lung function in IPF.

Surveillance: The frequency of follow-up evaluations depends on the patient-specific diagnosis and status; those who are stable may be reevaluated every three to six months, while others may need more frequent follow up.

Agents/circumstances to avoid: Cigarette smoking.

Evaluation of relatives at risk: Every five years, in asymptomatic first-degree relatives (of an individual with FPF) age >50 years: pulmonary function tests, high-resolution computed tomography scan of the chest to detect early abnormalities, and standardized questionnaire to assess the presence of respiratory symptoms. Family members who have a positive screen (i.e., at least class 2 dyspnea [breathlessness when hurrying on a level surface or walking up a slight hill], a DLCO below 80% of predicted, or presence of at least ILO category I findings on chest x-ray) require further evaluation.

Genetic counseling.

The inheritance of familial pulmonary fibrosis is not clear. Complex inheritance including autosomal dominant inheritance with reduced penetrance appears likely, though autosomal recessive inheritance remains a possibility. Prenatal diagnosis is possible for pregnancies at increased risk in families in which the TERT, TERC, SFTPC, or SFTPA2 pathogenic variant has been identified; however, the predictive value of such test results is as yet unclear.

Diagnosis

Familial pulmonary fibrosis (FPF) is defined as idiopathic interstitial pneumonia (IIP) in two or more first-degree relatives (parent, sib, or offspring). Confirmation of the diagnosis of IIP is the first step in making the diagnosis of FPF.

Findings Suggestive of Idiopathic Interstitial Pneumonia (IIP)

Diagnosis of idiopathic interstitial pneumonia (IIP) should be suspected in individuals with the presence of at least three of the following four criteria:

  • Age older than 50 years
  • Insidious onset of otherwise unexplained dyspnea on exertion
  • Duration of illness ≥3 months
  • Bibasilar, inspiratory crackles (dry or "velcro"-type in quality)

Establishing the Diagnosis of IIP

The diagnosis of IIP is established by the presence of all of the following findings, based on criteria published as a consensus statement [American Thoracic Society 2000, American Thoracic Society & European Respiratory Society 2002, Raghu et al 2011] and approved by the American Thoracic Society, the American College of Chest Physicians, and the European Respiratory Society:

  • No significant exposure to environmental agents (e.g., asbestos, silica, metal dust, wood dust); no findings suggestive of hypersensitivity pneumonitis; no history of chronic infection or left ventricular failure; no evidence of collagen vascular disease (e.g., scleroderma or systemic lupus erythematosus); and no previous exposure to drugs associated with pulmonary fibrosis (e.g., bleomycin, methotrexate, cyclophosphamide, nitrofurantoin) in an individual who is immunocompetent
  • Abnormal pulmonary function studies that include evidence of restriction (reduced VC with an increase in FEV1/FVC ratio) and/or impaired gas exchange (increased P(A-a)O2 with rest or exercise or decreased carbon monoxide diffusing capacity [DLCO])
  • A high-resolution computed tomography (HRCT) scan in the prone position (one 1.5-mm image every 2 cm from the apex to the base of the lungs) that demonstrates bibasilar reticular abnormalities with or without ground glass opacities
  • Either of the following criteria:
    • A surgical lung biopsy that demonstrates a histologic pattern consistent with one of the forms of IIP (i.e., usual interstitial pneumonia [UIP], nonspecific interstitial pneumonia [NSIP], acute interstitial pneumonia [AIP], cryptogenic organizing pneumonia [COP], respiratory bronchiolitis interstitial lung disease [RB-ILD], or desquamative interstitial pneumonia [DIP]) and cultures of the biopsies that are negative for bacteria, mycobacterium, and fungi
    • A transbronchial biopsy or bronchoalveolar lavage (BAL) that excludes alternative diagnoses

Multidisciplinary team discussion to include radiologists, pathologists, and pulmonologists is strongly recommended.

The different forms of IIP that can be associated with FPF are as follows (listed in order of relative frequency):

  • Idiopathic pulmonary fibrosis (IPF)/cryptogenic fibrosing alveolitis (CFA)
  • Nonspecific interstitial pneumonitis (NSIP)
  • Cryptogenic organizing pneumonia (COP)
  • Acute interstitial pneumonia (AIP; also called Hamman-Rich syndrome)
  • Respiratory bronchiolitis associated interstitial lung disease (RB-ILD)
  • Desquamative interstitial pneumonitis (DIP)
  • Lymphocytic interstitial pneumonitis (LIP)

Idiopathic pulmonary fibrosis (IPF) is the most common form of IIP and is present in approximately 55% of families with FPF. Approximately 45% of families with FPF are heterogeneous for the other subtypes of IIP [Steele et al 2005]. Achieving a correct diagnosis is a dynamic process based on the criteria listed above. The final diagnosis should be rendered only after the pulmonologist, radiologist, and pathologist have reviewed all of the clinical, radiologic, and pathologic data obtained from the patient [American Thoracic Society & European Respiratory Society 2002, Raghu et al 2011].

Establishing the Diagnosis of Familial Pulmonary Fibrosis (FPF)

The diagnosis of familial pulmonary fibrosis (FPF) is established in a proband with IIP who has

Approaches to molecular genetic testing can include:

  • Serial single-gene testing of TERT, TERC, SFTPC, and SFTPA2 based on family history, age of onset, phenotypes suggestive of a telomerase syndrome, or the presence of lung cancer:
    • TERT and TERC account for the majority of families with a pathogenic variant and may or may not show clinical features of a “telomerase syndrome” as described below.
    • If age of onset is younger than 50 in affected family members and/or pediatric interstitial lung disease is present, mutation of SFTPC may be suspected.
    • Pathogenic variants in SFTPA2, described in two families with bronchoalveolar cell (BAC) cancer, represent a smaller contribution to families with pathogenic variants.
    • Sequence analysis is performed first. If no pathogenic variant is found, deletion/duplication analysis can be considered, although large deletions/duplications have not been reported to date in the genes associated with FPF.
  • Use of a multi-gene panel that includes TERT, TERC, SFTPC, SFTPA2, and other genes of interest (see Differential Diagnosis). Note: The genes included in multi-gene panels vary by laboratory and over time.

Table 1.

Summary of Molecular Genetic Testing Used in Familial Pulmonary Fibrosis

Gene 1 Proportion of Familial Pulmonary Fibrosis Attributed to Mutation of This GeneTest Method
TERT ~18% 2, 3Sequence analysis 4
Deletion/duplication analysis 5
TERC ~1% 2, 3Sequence analysis 4
Deletion/duplication analysis 5
SFTPC ~1-25% 2, 6Sequence analysis 4
Deletion/duplication analysis 5
SFTPA2 <1% 7Sequence analysis 4
Deletion/duplication analysis 5
Unknown 8NANA
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2.

Estimated frequencies as summarized by Diaz de Leon et al [2010] and Garcia [2011] reported that 18% of FPF kindreds had heterozygous pathogenic variants in TERT

3.

Germline pathogenic variants in TERT and TERC are present in 1%-3% of simplex cases of IPF [Armanios 2009].

4.

Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6.

In a Dutch cohort, van Moorsel et al [2010] reported that 5 of 20 unrelated individuals with FPF had SFTPC pathogenic variants, the highest frequency of SFTPC pathogenic variants yet reported.

7.

Wang et al [2009] reported pathogenic variants in SFTPA2 in two families with FPF and lung cancer.

8.

No other genes with rare pathogenic variants are definitely known to be associated with FPF; however, several observations suggest possible roles for other genes in FPF causation (click here for information on evidence for further locus heterogeneity).

Clinical Characteristics

Clinical Description

Age of diagnosis. Individuals with familial pulmonary fibrosis (FPF) usually present between ages 50 and 70 years. For individuals with mutation of SFTPC, age at diagnosis can range from infancy to adulthood even within families [Hamvas et al 2007].

Presentation. The most common symptoms are shortness of breath on exertion and a dry cough regardless of the type of underlying IIP. Digital clubbing may be present. Some affected individuals may experience fever, weight loss, fatigue, and muscle and joint pain.

Pulmonary findings. Bibasilar, inspiratory crackles (dry or "velcro"-type in quality) on auscultation.

Pulmonary function studies inclusive of forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), and the six-minute walk test (6-MWT) distance and oxyhemoglobin saturation change at baseline are vital measurements to serially monitor disease course.

  • Reduced VC with an increase in FEV1/FVC ratio and/or impaired gas exchange (increased P(A-a)O2 with rest or exercise or decreased diffusion capacity of the lung for carbon monoxide [DLCO]) are findings of an abnormal pulmonary function study .
  • Longitudinal declines in these measurements have been associated with predictors of mortality.

Rate of progression varies among patients and is unpredictable at the time of diagnosis. The majority of patients have a slow, progressive decline but some can be stable or progress rapidly. Some may have acute worsening. Other comorbidities may affect the disease course. Need for oxygen is based on clinically significant resting hypoxemia [Raghu et al 2011].

Steele et al [2005] found that 45% of pedigrees showed phenotypic heterogeneity with several subtypes of idiopathic interstitial pneumonias (IPF, NSIP, COP) occurring within a family.

Pulmonary findings in individuals with mutation of SFTPC may vary from asymptomatic to having respiratory failure requiring lung transplantation [Hamvas et al 2007].

Other. Patients with FPF may have other comorbidities that include pulmonary hypertension, obstructive sleep apnea, emphysema, gastroesophageal reflux disease (GERD), and obesity [Raghu et al 2011].

Cancer risk. FPF may be complicated by lung cancer. Bronchoalveolar cell carcinoma, small-cell carcinoma, and adenocarcinoma have been described [Ozawa et al 2009, Wang et al 2009].

Life span. Average survival of individuals with IPF is two to three years from diagnosis. FPF survival is thought not to differ from IPF survival. Cause of death is usually respiratory failure.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

In families with mutation of TERT or TERC, pathogenic variants have been observed in relatives with bone marrow dysfunction and/or fibrosis in the lung and liver. Of note, diseases related to telomerase dysfunction (see Molecular Genetics, Molecular Genetic Pathogenesis) can be seen in different family members rather than in the same individual especially in kindreds segregating a TERT mutation [Diaz de Leon et al 2010]. TERC pathogenic variants appear more likely to be associated with the phenotypes of dyskeratosis congenita (DC) and bone marrow failure than FPF [Garcia et al 2007].

The range of phenotypes associated with mutation of SFTPC is unknown. Pathogenic variants in SFTPC appear to be more prevalent in children with interstitial lung disease than in adults. Of note, pediatric interstitial lung disease does not usually fit the definition of adult-onset IIP. Multiple studies have reported SFTPC pathogenic variants in familial IPF [Nogee et al 2001, Thomas et al 2002, Guillot et al 2009, van Moorsel et al 2010]. In a study of more than 100 adults with sporadic IPF, only one person had an SFTPC pathogenic variant [Lawson et al 2004].

Pathogenic variants in SFTPA2 were reported to show a causal relationship between familial IPF and adenocarcinoma of the lung and bronchioalveolar cell carcinoma (BAC) of the lung. These same pathogenic variants were not found in 3557 population-based controls [Wang et al 2009].

Penetrance

Penetrance for the phenotype associated with pathogenic variants in TERC, TERT, SFTPC, and SFTPA2 is unknown but thought to be incomplete. In the first report of penetrance, Diaz de Leon et al [2010] observed incomplete penetrance (~40%) in families with pulmonary fibrosis and TERT pathogenic variants and variable phenotype ranging from lung disease to liver disease to bone marrow dysfunction.

Nomenclature

Idiopathic pulmonary fibrosis has also been referred to as adult familial cryptogenic fibrosing alveolitis.

Prevalence

Marshall et al [2000] estimated that familial cases account for 0.5%-2.2% of all cases of IPF and reported the prevalence of FPF as 1.34 per 106 in the UK population.

Recent studies suggest that 0.5%-3.7% of IPF is familial with up to 19%-20% of persons with IPF reporting a family history significant for interstitial lung disease [Hodgson et al 2002, Lawson & Loyd 2006, García-Sancho et al 2011]. Therefore, the prevalence may be higher. More studies on prevalence are needed.

Differential Diagnosis

Idiopathic pulmonary fibrosis (IPF) is an incurable disease with a five-year survival of 30%-50% from the time of diagnosis [American Thoracic Society 2000]. Although progress has been made in understanding the molecular and cellular events involved in idiopathic pulmonary fibrosis, the exact pathogenesis has yet to be determined. The initiating stimulus is unknown in the majority of individuals, and only a subset of individuals (5%-20%) exposed to known fibrogenic agents actually develop PF. IPF is distinguished from FPF by lack of other affected family members.

Other inherited disorders that exhibit diffuse parenchymal lung disease as a clinical feature:

  • Hermansky-Pudlak syndrome (HPS) is a multisystem disorder characterized by tyrosinase-positive oculocutaneous albinism, a bleeding diathesis resulting from a platelet storage pool deficiency, and, in some cases, pulmonary fibrosis or granulomatous colitis. Pulmonary fibrosis typically causes symptoms in the early thirties and progresses to death within a decade. Hermansky-Pudlak syndrome is known to be associated with a defect in five-hydroxytryptamine and lysosomal metabolism. In Hermansky-Pudlak syndrome, the release of PDGF-B by alveolar macrophages is enhanced. This growth factor is thought to play a pathogenic role in idiopathic pulmonary fibrosis. Pathogenic variants in HPS1, AP3B1 (HPS2), HPS3, HPS4, HPS5, HPS6, DTNBP1 (HPS7), BLOC1S3 (HPS8), and BLOC1S6 (PLDN) are known to cause HPS. Inheritance is autosomal recessive.
  • Neurofibromatosis type 1 (NF1) is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris Lisch nodules. Learning disabilities are common. Less common but potentially more serious manifestations include plexiform neurofibromas, optic and other central nervous system gliomas, malignant peripheral nerve sheath tumors, osseous lesions, and vasculopathy. NF1 is caused by pathogenic variants in NF1. Inheritance is autosomal dominant.

    Pulmonary fibrosis is an occasional finding, though the association of pulmonary fibrosis with NF1 is somewhat controversial today [Ryu et al 2005]. The symptomatic onset of lung disease, when it occurs, is usually between ages 35 and 60 years, although symptomatic pulmonary fibrosis has developed as early as the second decade. Dyspnea is the usual presenting symptom. Pulmonary function tests show restrictive or obstructive lung defect with a reduced carbon monoxide diffusing capacity (DLCO). The natural history of interstitial lung disease in NF1 is unclear. Progression to respiratory failure, pulmonary hypertension, and cor pulmonale may occur. No effective treatment is known. Like IPF, the interstitial lung disease in NF1 is sometimes complicated by scar carcinoma.

    Radiographic findings include diffuse interstitial pulmonary fibrosis and bullae. The bullae are usually apical, may appear with or without fibrosis, and are often large. A chest roentgenogram early in the course of the disease may show patchy airspace disease and may even be normal despite interstitial pulmonary fibrosis documented by lung biopsy. Pleural disease and mediastinal adenopathy are not known features of this disease, although neurofibromas can sometimes simulate pleural thickening or a mediastinal mass.

    The pathologic features of interstitial lung disease in NF1 are nonspecific. Since these were described prior to the currently evolved understanding of specific histologic subgroups, it is unclear if the fibrotic pattern is unclassifiable or represents one of the precisely defined histologic subgroups.

    Other thoracic radiographic manifestations are caused by the direct effect of neurofibromas. Intrathoracic meningomyeloceles may present as a posterior mediastinal mass. 'Twisted ribbon' rib deformities caused by the pressure of intercostal fibromas, vertebral defects, and scoliosis have been described.
  • Tuberous sclerosis complex (TSC) involves abnormalities of the skin (hypomelanotic macules, facial angiofibromas, shagreen patches, fibrous facial plaques, ungual fibromas), brain (cortical tubers, subependymal nodules, seizures, intellectual disability/developmental delay), kidney (angiomyolipomas, cysts, renal cell carcinomas), and heart (rhabdomyomas, arrhythmias). Pulmonary lymphangioleiomyomatosis (LAM) occurs in a small proportion of premenopausal women with TSC. Individuals with LAM typically present with symptoms of dyspnea on exertion and progressive loss of lung function that may resemble some of the presenting symptoms of FPF.

    The diagnosis of TSC is based on clinical findings. Pathogenic variants in TSC1 and TSC2 are causative. Two thirds of affected individuals have TSC as the result of de novo mutation. Inheritance is autosomal dominant.
  • Niemann-Pick disease type B (acid sphinomyelinase deficiency) is characterized by hepatosplenomegaly with progressive hypersplenism and stable liver dysfunction, gradual deterioration in pulmonary function, and atherogenic lipid profile. Progressive and/or clinically significant neurologic manifestations occur infrequently. Survival to adulthood can occur. Niemann-Pick disease type B is caused by pathogenic variants in SMPD1. Inheritance is autosomal recessive.

    The incidence of lung involvement is unknown. Chest radiography may show a reticulonodular or miliary pattern; progression to honeycombing has been described. Reticuloendothelial cells filled with sphingomyelin may fill the alveolar spaces and interstitium and can be recovered with bronchoalveolar lavage. No effective treatment is known.
  • Gaucher disease encompasses a continuum of five clinical subtypes that range from a perinatal-lethal form to an asymptomatic form. The pulmonary manifestations of Gaucher disease type 1 are caused by Gaucher cells infiltrating the interstitium, filling the alveoli or obstructing pulmonary capillaries. Obliteration of pulmonary capillaries may result in pulmonary hypertension and cor pulmonale. Acute fatal bone marrow embolization of Gaucher cells to the lungs has been described. Pulmonary infections occur with increased frequency.

    Histopathologic examination shows Gaucher cell infiltration, but inflammation and fibrosis are not usual features. The Gaucher cells stain positively with PAS and autofluoresce. Gaucher cells may be found in the sputum or in the bronchial washes. Chest radiographic findings are not specific. Diffuse interstitial infiltrates that occasionally have a miliary appearance have been described, as has mediastinal adenopathy. Pulmonary function tests reveal typical restrictive lung defect with a reduced DLCO.

    The diagnosis of Gaucher disease relies on demonstration of deficient glucosylceramidase enzyme activity in peripheral blood leukocytes or other nucleated cells. Gaucher disease is caused by mutation of GBA. Inheritance is autosomal recessive.
  • Familial hypocalciuric hypercalcemia type 1 (OMIM 145980) is a very rare disorder characterized by hypocalciuric hypercalcemia, interstitial lung disease (ILD) / pulmonary fibrosis, and recurrent respiratory tract infections caused by granulocyte dysfunction associated with a relative deficiency in myeloperoxidase. The disease usually presents in the fourth decade. Reticulonodular infiltrates that may progress to honeycombing on chest radiograph and restrictive pulmonary physiology are typical findings. Disease progression appears to be slow: survival after diagnosis is approximately ten years. The mode of inheritance is probably autosomal dominant manner, based on the report of one family with three sibs clinically affected by ILD. In this relatively large family, 45% of 38 family members studied had a reduced DLCO, suggesting subclinical disease. Several asymptomatic individuals also had abnormalities of BAL fluid cell count, suggesting active alveolitis. In addition, 60% had recurrent respiratory tract infections. The disorder is caused by mutation of CASR (which encodes the calcium-sensing receptor).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with familial pulmonary fibrosis (FPF), the following evaluations are recommended:

  • Clinical history
  • Chest radiograph
  • High-resolution computed tomography (HRCT) scan of the chest
  • Pulmonary function studies
  • Evaluation by a pulmonologist, preferably one with experience in IPF
  • Medical genetics consultation

Treatment of Manifestations

The management of the individual with familial pulmonary fibrosis (FPF) is similar to that for interstitial idiopathic pneumonia (IIP) and depends on the type of IIP diagnosed for each individual within the family [American Thoracic Society 2000, American Thoracic Society & European Respiratory Society 2002].

Lung transplantation may be a consideration in selected individuals with FPF. In general, those who are unresponsive to therapy, have significant functional impairment, and have no other major illnesses that would preclude transplantation are good candidates. Five-year survival rates post transplant in IPF have been estimated at 50%-56% [Raghu et al 2011].

Non-pharmologic treatments:

  • Oxygen therapy may improve exercise tolerance in patients with hypoxemia.
  • Pulmonary rehabilitation is a recommended option for patients who would benefit.

Pharmacologic interventions have not generally been shown to alter the course of IPF. Treatments have been categorized into classes such as corticosteroids, immunosuppressive/cytotoxic agents, and antifibrotic agents. However, at least two antifibrotic pharmacologic interventions recently approved may be an option for patients with FPF to slow the decline of lung function. See Therapies Under Investigation.

Prevention of Secondary Complications

The following are recommended:

  • Prevention and prompt treatment of acute exacerbations
  • Treatment of coexisting comorbidities if appropriate including:
    • Pulmonary hypertension
    • Gastroesophageal reflux disease (GERD)
    • Pulmonary embolism
    • Lung cancer
    • Coronary artery disease
    • Respiratory infections
    • Pneumothorax
    • Aspiration

Surveillance

The frequency of follow-up evaluations for persons with FPF depends largely on the patient's individual diagnosis and status. Surveillance would follow the guidelines for IPF [Raghu et al 2011] or the specific type of IIP. Those who are stable may be evaluated every three to six months, while others may need more frequent follow up.

  • Pulmonary function studies including the following to serially monitor disease course [Raghu et al 2011]:
    • Forced vital capacity (FVC)
    • Diffusion capacity of the lung for carbon monoxide (DLCO)
    • The six-minute walk test (6-MWT) distance and oxyhemoglobin saturation change at baseline
  • Monitoring for progression of disease by HRCT of the chest
  • Oxygen saturation by resting pulse oximetry
  • Serologic monitoring for connective tissue disease (CTD) in patients suspected of an underlying possibility for CTD-related ILD
  • Monitoring for any side effects known from pharmacologic treatments
  • Symptom control

Agents/Circumstances to Avoid

Cigarette smoking is a risk factor for developing idiopathic pulmonary fibrosis (IPF) and was shown to be an independent risk factor in families with FPF [Steele et al 2005].

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment.

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, simple screening tests have been found to be sensitive for establishing the diagnosis in relatives at risk [Watters et al 1986, Hartley et al 1994] and prognosis of pulmonary fibrosis [Watters et al 1986, Schwartz et al 1994a, Schwartz et al 1994b].
    • It is recommended that every five years, asymptomatic first-degree relatives (of individuals with FPF) older than age 50 years undergo pulmonary function tests, obtain an HRCT scan of the chest to detect early abnormalities, and complete a standardized questionnaire to assess the presence of respiratory symptoms.
    • Family members are considered to have a positive screening evaluation (i.e., to possibly have pulmonary fibrosis) if they have at least class 2 dyspnea (breathlessness when hurrying on a level surface or walking up a slight hill), a DLCO below 80% of predicted, or presence of at least ILO category 1 findings on chest x-ray [International Labour Office 2011]. Family members who have a positive screen require further evaluation (see Diagnosis).
  • A study of asymptomatic at-risk family members in a FPF cohort by Kropski et al [2015] identified more than 25% of subjects with subtle radiologic and histopathologic abnormalities suggestive of possible early interstitial lung disease. It is unknown if these findings would become symptomatic FPF in the subjects.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Several therapies remain under investigation for the treatment of IPF. Agents targeted to fibroblast proliferation, pulmonary hypertension, anti-inflammatory, anticoagulation, and various chemokine and monoclonal antibodies among other targets remain under investigation as potential treatments. Two antifibrotic agents recently approved by the FDA for use in IPF as of October 2014 include pirfenidone [King et al 2014] and nintedanib [Richeldi et al 2014]; the former has been available in Japan and Europe for several years as a therapy for IPF.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The inheritance of familial pulmonary fibrosis (FPF) is not clear. Complex inheritance (including multifactorial inheritance and autosomal dominant inheritance with reduced penetrance) appears likely though autosomal recessive inheritance remains a possibility. The largest study of families with FPF to date [Steele et al 2005] supports an autosomal dominant mode of inheritance with reduced penetrance. Subsequent family studies support this model as well [Lawson & Loyd 2006]. The study by Marshall et al [2000] investigating 25 families with FPF also supports this model but cannot exclude autosomal recessive inheritance. Further studies are warranted to delineate all inheritance patterns.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals diagnosed with FPF have an affected parent.
  • Although most individuals diagnosed with FPF have an affected parent, the disorder may appear to have skipped a generation (i.e., the individual diagnosed has an affected grandparent related through an unaffected parent) because of reduced penetrance.
  • A proband with FPF may have the disorder as the result of de novo mutation. However, the overall proportion of cases caused by de novo mutation is unknown.

Note: The family history of some individuals diagnosed with FPF may appear to be negative because of reduced penetrance, failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate evaluations have been performed on the parents of the proband (see Evaluation of Relatives at Risk).

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or known to have a TERT, TERC, SFTPC, or SFTPA2 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. Because penetrance is likely reduced, the risk to sibs of being affected is less than 50%.

Offspring of a proband In families with an autosomal dominant pattern of FPF inheritance and/or a TERT, TERC, SFTPC, or SFTPA2 pathogenic variant, offspring have a 50% chance of inheriting a pathogenic variant. However, the risk of developing FPF is less than 50% due to reduced penetrance.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment

Other modes of inheritance. Autosomal recessive inheritance may need to be considered in simplex cases (i.e., cases with only one affected individual in a family) and in families with only affected sibs [Marshall et al 2000]. X-linked inheritance may also be possible [Kropski et al 2014].

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the TERT, TERC, SFTPC, or SFTPA2 pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

Requests for prenatal testing for adult-onset conditions which (like familial pulmonary fibrosis) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing are the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the TERT, TERC, SFTPC, or SFTPA2 pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Pulmonary Fibrosis, Familial: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B.

OMIM Entries for Pulmonary Fibrosis, Familial (View All in OMIM)

178500PULMONARY FIBROSIS, IDIOPATHIC; IPF
178620SURFACTANT, PULMONARY-ASSOCIATED PROTEIN C; SFTPC
178642SURFACTANT, PULMONARY-ASSOCIATED PROTEIN A2; SFTPA2
187270TELOMERASE REVERSE TRANSCRIPTASE; TERT
602322TELOMERASE RNA COMPONENT; TERC

Not all of the loci/genes associated with familial pulmonary fibrosis are known.

Molecular Genetic Pathogenesis

Telomeres are DNA-protein structures that protect chromosome ends and provide chromosomal integrity. They consist of TTAGGG repeats that are bound by a specialized protein complex known as shelterin. The asymmetric replication of DNA during mitosis and the ensuing “end-replication problem” leaves newly synthesized DNA strands shorter than the original template, and ultimately causes telomeres to shorten successively with each cell division, activating a p53-dependent cell-cycle checkpoint that signals the arrest of cell proliferation, senescence, and apoptosis.

The enzyme telomerase solves this end-replication problem by providing a repetitive template for enzymatic repair of the ends of chromosomes by synthesizing new telomeres and providing telomere elongation. The enzyme telomerase is made up of telomerase reverse transcriptase (encoded by TERT) and the telomerase RNA component (product of TERC), which functions as a template to synthesize telomere DNA. Telomerase is normally repressed in postnatal somatic cells, resulting in progressive shortening of telomeres; telomerase reverse transcriptase is only highly expressed in specific germline cells, proliferative stem cells of renewal tissues, and immortal cancer cells. Telomerase RNA component is expressed in all tissues [Garcia et al 2007].

Pathogenic variants in telomerase components were first described in dyskeratosis congenita (DC), characterized by abnormal skin findings, bone marrow failure, and interstitial lung disease (e.g., pulmonary fibrosis). Telomere shortening is a common feature of DC and bone marrow failure syndromes, two diseases previously associated with pathogenic variants in DKC1 (encoding dyskerin), TERT, TERC, or TINF2 (a shelterin component). All persons with DC have short telomeres in their circulating leukocytes regardless of which gene is mutated. Pathogenic variants in TERT are present in up to 4% of individuals with acquired aplastic anemia and yet short telomere lengths are found in 34% of persons with that disease [Cronkhite et al 2008].

Since telomere shortening can result from pathogenic variants in the genes encoding the telomerase complex, it is hypothesized that telomere shortening may play a role in the development of both familial and idiopathic pulmonary fibrosis. The presence of short telomeres may explain the increased occurrence of pulmonary fibrosis in older individuals. However, it has been shown that a significant fraction of individuals with pulmonary fibrosis (20%-25%) have short telomere lengths that cannot always be explained by pathogenic variants in the genes that encode telomerase [Cronkhite et al 2008]. Diaz de Leon et al [2010] showed that family members within kindreds who do not inherit a TERT pathogenic variant may have shorter telomere lengths than controls, demonstrating that factors other than pathogenic variants in TERT (e.g., pathogenic variants in other genes, epigenetic inheritance) can affect telomere length.

TERT

Gene structure. TERT consists of 16 exons and 15 introns spanning 35 kb. Alternatively spliced transcript variants encode different isoforms of telomerase. For a detailed summary of gene and protein information, see Table A, Gene .

Pathogenic allelic variants. Pathogenic variants in TERT have been shown to associate with the FPF/IPF phenotype, but have yet to be demonstrated to cause disease.

Tsakiri et al [2007] found two frameshift deletions and five missense mutations in persons with pulmonary fibrosis. Armanios et al [2007] found two missense, two splice-junction, and one frameshift mutation in their cohort of individuals with pulmonary fibrosis. Cronkhite et al [2008] found six novel mutations. Diaz de Leon et al [2010] expanded upon the familial cohorts of Tsakiri and Cronkhite and found six additional pathogenic variants in TERT. Dai et al [2015] found four novel mutations in Chinese individuals with sporadic IPF, the first study to evaluate telomerase mutations in that population.

At least 28 TERT pathogenic variants for pulmonary fibrosis have been reported through these and other studies listed in the Telomerase Database. The pathogenic variants found thus far are spread across the three domains of TERT but cluster in conserved regions. Diaz de Leon et al [2010] reported two pathogenic variants that were found in different unrelated families. No other common pathogenic variants have been reported.

More information can be found in the Telomerase Database.

Normal gene product. Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The protein is made up of 1132 amino acids and three domains: the N-terminal extension, the reverse transcriptase, and the C-terminal extension.

Abnormal gene product. It is thought that loss-of-function mutations in TERT impair the ability of telomerase to repair telomeres after cell division. Short dysfunctional telomeres then signal the arrest of cell proliferation, ultimately leading to cell death and organ failure. In addition, TERT is only highly expressed in specific germline cells, proliferative stem cells of renewal tissues, and immortal cancer cells. The bronchoalveolar epithelium is thought to be constantly replaced and may rely on a supply of local progenitor reserves that may be limited by short telomeres [Armanios et al 2007].

TERC

Gene structure. TERC comprises one exon (consisting of 451 bp of DNA) that encodes the telomerase RNA component. TERC contains the template that encodes for telomeric repeats and binds to telomerase reverse transcriptase (TERT) for DNA synthesis. For a detailed summary of gene and protein information, see Table A, Gene .

Pathogenic allelic variants. Pathogenic variants in TERC have been shown to associate with the FPF/IPF phenotype, but have yet to be determined to be the cause of disease. The following TERC pathogenic variants have been reported to date in persons with pulmonary fibrosis (see Telomerase Database).

  • Tsakiri et al [2007] found a pathogenic variant in the terminal residue of the P1b helix of the pseudoknot region in one proband. This change was not found in 94 ethnically matched controls but had been reported previously in one person with severe aplastic anemia who was a compound heterozygote for variants in TERC.
  • Armanios et al [2007] found one pathogenic variant in the pseudoknot region in a proband.
  • Marrone et al [2007] found a deletion in one person with a history of aplastic anemia and pulmonary fibrosis and a family history of pulmonary fibrosis.
  • Alder et al [2008] described a previously unreported germline mutation in conserved regions 4 and 5 in a simplex IIP case as well as the individual’s younger asymptomatic siblings.
  • Dai et al [2015] found three novel mutations in Chinese persons with sporadic IPF, the first study to evaluate telomerase mutations in that population.

Normal gene product. Telomerase consists of a protein component with reverse transcriptase activity (TERT), and an RNA component (TERC), encoded by this gene, that serves as a template for the telomere repeat. Three domains characterize TERC: a pseudoknot that includes the template, conserved regions 4 and 5 (CR4-CR5), and ScaRNA domain for nuclear recruitment. Pathogenic variants associated with pulmonary fibrosis have been found in the pseudoknot and CR4-CR5 regions.

Abnormal gene product. It is thought that loss-of-function mutations in TERC impair repair of telomeres after cell division. Short dysfunctional telomeres then signal the arrest of cell proliferation, ultimately leading to cell death and organ failure. This is especially true in cells with high turnover.

SFTPC

Gene structure. SFTPC consists of six exons and spans approximately 3.5 kb. Alternatively spliced transcript variants encoding different protein isoforms have been identified. For a detailed summary of gene and protein information, see Table A, Gene .

Pathogenic allelic variants. Multiple pathogenic variants in this gene cause pulmonary surfactant metabolism dysfunction type 2 (also called pulmonary alveolar proteinosis) resulting from surfactant protein C deficiency, and are associated with interstitial lung disease in older infants, children, and less often in adults. Only a few pathogenic variants associated with FPF have been described.

  • The p.Ile73Thr pathogenic variant, the most prevalent SFTPC pathogenic variant reported to date in children, can be de novo or inherited.
  • In an infant and mother with respiratory insufficiency resulting from surfactant metabolism dysfunction and surfactant protein C deficiency, Nogee et al [2001] identified a heterozygous pathogenic variant in the splice donor site of intron 4, resulting in a dominant-negative effect.
  • Thomas et al [2002] reported a pathogenic variant in one large kindred in both adult and childhood onset of interstitial lung disease.
  • Guillot et al [2009] identified a novel pathogenic variant in affected members of a family with surfactant protein C deficiency. The proband had onset of interstitial lung disease at age two months; adults developed pulmonary fibrosis.
  • In a Dutch cohort, van Moorsel et al [2010] reported that five of 20 unrelated individuals with FPF had SFTPC pathogenic variants, the highest frequency of SFTPC pathogenic variants yet reported.

Normal gene product. Pulmonary-associated surfactant protein C (SPC) is an extremely hydrophobic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC, and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. SPC is synthesized as a 197 amino-acid proprotein (proSP-C) that undergoes multiple processing steps to the mature SP-C peptide of 35 amino acids, to be finally released in the alveoli associated with the other surfactant proteins and phospholipids [Guillot et al 2009].

Abnormal gene product. Mechanisms proposed for SFTPC pathogenic variants causing diffuse lung disease include alteration of SP-C metabolism or complete SP-C deficiency.

SFTPA2

Gene structure. SFTPA2 consists of five exons and encodes an isoform of surfactant-associate protein, SPA. SFTPA2 shares greater than 90% of identity across coding and noncoding regions with nearby SFTPA1 which codes for the other isoform of protein SPA, known as SPA1. For a detailed summary of gene and protein information, see Table A, Gene .

Pathogenic allelic variants. Wang et al [2009] used linkage in a family with FPF and lung cancer resulting in the finding of a rare heterozygous missense mutation c.692G>T (Gly231Val) in SFTPA2, which segregated in family members with FPF and/or lung cancer. Further interrogation of 58 probands within their familial cohort revealed another heterozygous mutation in SFTPA2 in a proband with IPF and lung cancer (c.593T>C, Phe198Ser). No other affected family members of this proband were available for testing. In an analysis of more than 1,000 ethnically matched subjects, neither of these mutations was found.

Normal gene product. SFTPA2 encodes a protein of 248 amino acids; it includes a collagen-like region, a neck domain, and a C-terminal carbohydrate-recognition domain.

Abnormal gene product. Wang et al [2009] showed that the two missense mutations were in a highly conserved region of the C-terminal carbohydrate recognition lectin domain (CRD) and most likely interrupted proper protein folding and cellular trafficking.

References

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Suggested Reading

  1. Armanios M, Chen JL, Chang YP, Brodsky RA, Hawkins A, Griffin CA, Eshleman JR, Cohen AR, Chakravarti A, Hamosh A, Greider CW. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenita. Proc Natl Acad Sci U S A. 2005;102:15960–4. [PMC free article: PMC1276104] [PubMed: 16247010]
  2. Hamvas A. Inherited surfactant protein-B deficiency and surfactant protein-C associated disease: clinical features and evaluation. Semin Perinatol. 2006;30:316–26. [PubMed: 17142157]

Chapter Notes

Author Notes

David Schwartz is a professor of medicine and immunology at the University of Colorado and National Jewish Health, and is serving as the Robert Schrier Chair of the Department of Medicine at the University of Colorado. Throughout his career, Dr. Schwartz has made numerous contributions toward understanding the role that biological and genetic determinants play in the onset of diseases that are influenced by the environment. These efforts have provided new insights into the genetics, epigenetics, and genomics of interstitial lung disease, asthma, and innate immunity. His work has led to the recognition that genetic susceptibility, and specifically MUC5B, plays a role in the etiology of pulmonary fibrosis. Dr. Schwartz’s lab was the first to clone the humanTLR4 gene and demonstrate that variation in this gene decreased immune responsiveness to endotoxin, enhanced the risk of Gram negative sepsis, and protected individuals from the development of coronary artery disease. In addition, the Schwartz lab demonstrated the potential importance of locus-specific DNA methylation in the development of allergic airway disease in mice and young children by directing the maturation of T lymphocytes toward a Th2 phenotype. Prior to moving to Denver, Dr. Schwartz served as Director of the National Institute of Environmental Health Sciences at the NIH. While at the NIH, he developed the Genes, Environment and Health Initiative, the Epigenomics Roadmap Initiative, and a program in translational research in environmental sciences. Between 2000 and 2005, Dr. Schwartz served at Duke University, where he held concurrent positions as Vice Chair for Research and Director of Pulmonary and Critical Care Medicine. While at Duke, Dr. Schwartz established three interdisciplinary Centers in Environmental Health Sciences, Environmental Genomics, and Environmental Asthma, illustrating his commitment to critical biomedical concerns and public health issues. He is a member of the American Society for Clinical Investigation, the Association of American Physicians, and the American Clinical and Climatological Association, and a recipient of the 2003 ATS Scientific Accomplishment Award, the 2013 ATS Amberson Lectureship Award, and the 2014 Bonfils-Stanton Science and Medicine Award.

Janet Talbert earned her Bachelor of Science (BS) at Tennessee Technological University and her Master of Science (MS) in Biophysics and Genetics at the University of Colorado Denver Health Sciences Center. She became a certified genetic counselor through board certification by the Diplomate of the American Board of Genetic Counselors (ABGC) in 2009. She is a member of the National Society of Genetic Counselors (NSGC). After laboratory experience for genetic identity testing and genetic research, she turned her focus to clinical research. She has been part of the Interstitial Lung Disease Program at National Jewish Health since 2003 in roles that include coordinating a Familial Pulmonary Fibrosis study and providing genetic counseling services for the institution at large and to patients and families with IPF. She is the director of the Familial Pulmonary Fibrosis Genetic Counseling telephone line at National Jewish Health which is supported by the Coalition for Pulmonary Fibrosis (CPF) and the Pulmonary Fibrosis Foundation (PFF). She serves on the medical advisory board of the PFF and is part of an education outreach Ambassador Program for the PFF.

Author History

Janet Talbert, MS, CGC (2010-present)
David Schwartz, MD (2005-present)
Anastasia Wise, PhD; National Jewish Health (2005-2010)

Revision History

  • 19 March 2015 (me) Comprehensive update posted live
  • 19 October 2010 (me) Comprehensive update posted live
  • 3 February 2009 (cd) Revision: prenatal testing for TERT and TERC mutations available clinically
  • 2 October 2007 (cd) Revision: mutations in TERT and TERC reported to "increase susceptibility to adult-onset IPF" [Armanios et al 2007, Tsakiri et al 2007]; molecular testing for TERT and TERC mutations available on a clinical basis but the predictive value of the tests is as yet unclear.
  • 11 June 2007 (me) Comprehensive update posted to live Web site
  • 21 January 2005 (me) Review posted to live Web site
  • 8 April 2004 (ds) Original submission
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