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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Pulmonary Fibrosis, Familial

Synonyms: Adult Familial Cryptogenic Fibrosing Alveolitis, Familial Interstitial Pneumonia. Includes: SFTPC-Related Familial Pulmonary Fibrosis, TERC-Related Familial Pulmonary Fibrosis, TERT-Related Familial Pulmonary Fibrosis

, MS, CGC and , MD.

Author Information
, MS, CGC
National Jewish Health
Denver, Colorado
, MD
National Jewish Health
Denver, Colorado

Initial Posting: ; Last Update: October 19, 2010.

Summary

Disease 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). 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). 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. Mutations in TERT, TERC, and SFTPC 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 immunotherapy therapy, have significant functional impairment, and have no other major illnesses that would preclude transplantation.

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) over 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; up to 50% of unaffected at-risk family members have a positive screen (i.e., possibly have pulmonary fibrosis) and require further evaluation (positive screen: 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).

Other: Pharmacologic interventions have not been shown to alter the course of idiopathic pulmonary fibrosis (IPF) or FPF; however, immunosuppressive therapy is occasionally beneficial.

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

Diagnosis

Clinical Diagnosis

The diagnosis of an idiopathic interstitial pneumonia (IIP) is established by the presence of all of the following findings, based on criteria published as a consensus statement [American Thoracic Society 2000, Travis et al 2002] and approved by the American Thoracic Society, the American College of Chest Physicians, and the European Respiratory Society:

  • 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
  • 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, anti-depressants) 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])
  • 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, nonspecific interstitial pneumonia [NSIP], acute interstitial pneumonia, cryptogenic organizing pneumonia, respiratory bronchiolitis interstitial lung disease, or desquamative interstitial pneumonia) and cultures of the biopsies that are negative for bacteria, mycobacterium, and fungi
    • A transbronchial biopsy or bronchoalveolar lavage (BAL) that excludes alternative diagnoses
  • 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 greater than or equal to three months
    • Bibasilar, inspiratory crackles (dry or "velcro"-type in quality)

The diagnosis of familial pulmonary fibrosis (FPF) is established in an individual with IIP who has at least one other first-degree relative (parent, sib, or offspring) with IIP.

The different forms of IIP 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. 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 [Travis et al 2002].

Molecular Genetic Testing

Genes. The three genes in which mutation is known to cause familial pulmonary fibrosis (FPF) are TERT, TERC, and SFTPC.

Mutations in TERT and TERC have been reported in 8%-15% of families with IPF. Germline mutations in TERT and TERC are present in 1%-3% of simplex cases of IPF [Armanios 2009]. In a more recent study, Diaz de Leon et al [2010] reported that 18% of FPF kindreds had heterozygous mutations in TERT alone.

To date, the contribution of SFTPC mutations to different types of adult interstitial lung diseases (e.g., IPF, FPF) is thought to be 1% or less for FPF and simplex cases. The range of phenotypes associated with SFTPC mutations is unknown. Mutations in SFTPC appear to be more prevalent in children with lung disease than in adults. Of note, pediatric interstitial lung disease (ILD) does not usually fit the definition of adult-onset of ILD. Three studies have reported SFTPC mutations in familial IPF [Nogee et al 2001, Thomas et al 2002, Guillot et al 2009]. In a study of more than 100 adults with IPF, only one person had an SFTPC mutation. In simplex cases of IPF, SFTPC mutations appear to be rare [Lawson et al 2004].

Evidence for further locus heterogeneity. No other genes are definitely known to be associated with FPF; however, the following observations suggest possible roles for other genes in FPF causation.

  • In a cohort from Mexico, mutations in the genes encoding surfactant protein A1 (SFTPA1) and surfactant protein B (SFTPB) have been shown to be associated with IPF in nonsmokers and smokers, respectively [Selman et al 2003].
  • Normal allelic variants of the genes encoding various cytokines (IL-1RA, TNF-alpha, and IL-6) have been reported to be associated with the development of IPF [Whyte et al 2000, Pantelidis et al 2001]. An additional study showed significant association of IPF with TNF [Riha et al 2004].
  • Normal allelic variants of various candidate genes for IIP include TGFB1, FN1, IGF1, complement receptor-1 (CR1), IFNG, HLA genotypes, SERPINA1, TP53, and ACE. Replication of these studies is warranted to evaluate the significance of these findings [Schwartz 2008].
  • ELMOD2 was identified as a candidate gene for FPF in a genomic screen of six multiplex families from southeastern Finland [Hodgson et al 2006].
  • Mutations 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 mutations were not found in 3557 population-based controls [Wang et al 2009].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Familial Pulmonary Fibrosis

Gene 1% of FPF Attributed to Mutations in This GeneTest MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
TERT~15%Sequence analysisSequence variants 4~97%-99%
TERC~2%Sequence analysisSequence variants 4~97%-99%
SFTPC~1%Sequence analysisSequence variants 4~99%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

4. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband

  • The diagnosis of familial pulmonary fibrosis (FPF) in a proband is based on established clinical diagnostic criteria for an idiopathic interstitial pneumonia (IIP) and a positive family history (in ≥ first-degree relatives [parent, sib, or offspring] with IIP).
  • Mutations in the three genes known to be associated with FPF account for a small proportion of FPF and the predictive value of such test results is as yet unclear.
  • A TERT or TERC mutation may be suspected in probands with a personal or family history that includes pulmonary fibrosis, aplastic anemia, cryptogenic hepatic cirrhosis, dyskeratosis congenita, and unexplained bone marrow failure. However, the variable expressivity of phenotype associated with a mutation in one of these genes and the high likelihood of reduced penetrance means that the absence of these disorders in the family history does not eliminate the possibility that a mutation in one of these two genes is causative.

An SFTPC mutation may be suspected in probands with a family history that includes infantile or childhood onset of a pediatric interstitial lung disease; however, an SFTPC mutation is infrequently observed in adults with IPF [Lawson et al 2004].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

The clinical symptoms, radiographic changes, pulmonary function testing abnormalities, and histopathologic findings of familial pulmonary fibrosis (FPF) need further definition; little of this information is known for familial cases as compared to simplex cases (i.e., a single occurrence in a family).

In a comparison of simplex (often called sporadic) cases and familial IPF cases, individuals from families with FPF were found to have clinical, pathologic, and radiologic features similar to those of simplex IPF [Lee et al 2005]. Within a family with FPF, however, multiple family members may have been given different idiopathic interstitial pneumonia diagnoses (i.e., not just IPF). Although fulminant interstitial lung disease (ILD) during infancy has been reported, it is likely that this early-onset ILD, also known as diffuse lung disease, is distinct pathogenically from adult-onset FPF [Deutsch et al 2007].

Steele et al [2005] found that 45% of pedigrees had several subtypes of idiopathic interstitial pneumonias (IPF, NSIP, COP).

Mutations in SFTPC were associated with the development of an inflammatory form of IIP in one family [Nogee et al 2001] and what appears to be both idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP) in another large family [Thomas et al 2002].

Like simplex cases, individuals with FPF usually present between ages 50 and 70 years. The most common symptoms are shortness of breath upon exertion and a dry cough. Some affected individuals may experience fever, weight loss, fatigue, and muscle and joint pain. Average survival of individuals with IPF is three years from diagnosis. Cause of death is usually respiratory failure.

The clinical presentations and outcomes of lung disease associated with SFTPC mutations are significantly variable within families known to be segregating a mutation [Hamvas et al 2007]. The clinical spectrum in heterozygotes for a SFTPC mutation ranges in age at diagnosis from infancy to adulthood and from asymptomatic to respiratory failure requiring lung transplantation.

Like IPF, 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].

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known.

In families with a mutation in TERT or TERC, mutations 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) are often 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 mutations appear more likely to be associated with the phenotypes of dyskeratosis congenita (DC) and bone marrow failure than FPF [Garcia et al 2007].

The clinical variability seen in SFTPC mutations could be related to genotype; this is yet to be determined. The clinical presentations and outcomes of lung disease associated with SFTPC mutations are significantly more variable than for lung disease associated with TERT and TERC mutations, even within a family segregating the same mutation [Hamvas et al 2007].

Penetrance

Penetrance for the phenotype associated with mutations in TERC, TERT, and SFTPC 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 mutations and variable phenotype ranging from lung disease to liver disease to bone marrow dysfunction. .

Prevalence

The prevalence of idiopathic pulmonary fibrosis (IPF) is approximately 20.2:100,000 in men and 13.2:100,000 in women; IPF affects at least five million persons worldwide [Meltzer & Noble 2008]. 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 1.34:1,000,000 population.

Recent studies suggest that 0.5%-3.7% of IPF is familial with up to 19% of persons with IPF reporting a family history significant for interstitial lung disease [Lawson & Loyd 2006]. 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.

Although familial pulmonary fibrosis (FPF) is rare, its overlap with IPF enhances the value of FPF kindred studies because they may provide insights into the etiology and pathogenesis of IPF. Several lines of evidence suggest that inherited genetic factors play a role in the development of pulmonary fibrosis, at least in a subset of individuals. The role of genetic factors in the development of PF is supported by: (a) the occurrence of forms of pulmonary fibrosis that appear to be inherited (familial pulmonary fibrosis and pulmonary fibrosis associated with pleiotropic genetic disorders); (b) the apparent variation in individual susceptibility to fibrogenic dusts that are known to cause pulmonary fibrosis; and (c) the differences in development of pulmonary fibrosis observed between inbred strains of mice following experimental exposure to fibrogenic agents [Schwartz 2008].

Interstitial lung disease is observed in a number of genetic disorders. Although these genetic disorders are distinct clinically and pathologically, they are all associated with PF, pointing toward a genetic basis influencing this association.

Other inherited diffuse parenchymal lung diseases:

  • 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. Inheritance is autosomal recessive. Seven genes are known to cause HPS: HPS1, HPS3, HPS4, HPS5, HPS6, AP3B1, DTNBP1, and BLOC1S3.
  • 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.

    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. Inheritance is autosomal dominant.
  • 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), 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. Two causative genes, TSC1 and TSC2, have been identified. Two thirds of affected individuals have TSC as the result of a de novo gene mutation. Inheritance is autosomal dominant.
  • Niemann-Pick disease type B (acid sphinomyelinase deficiency) is a lipid storage disease characterized by the accumulation of sphingomyelin in the central nervous system and the reticuloendothelial system. It can present in infants, children, or adults. Neonates can present with ascites and severe liver disease from infiltration of the liver and/or respiratory failure from infiltration of the lungs; children and adults present with neurologic findings of ataxia, gaze palsy, dementia, dystonia, and seizures.

    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.

    Niemann-Pick disease type B is caused by mutation in the sphingomyelin phosphodiesterase-1 gene (SMPD1). Inheritance is autosomal recessive.
  • 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 mutations in GBA. Inheritance is autosomal recessive.
  • Familial hypocalciuric hypercalcemia 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 in CASR, encoding the calcium-sensing receptor.

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with idiopathic interstitial pneumonia (IIP), the following evaluations are recommended:

  • Clinical history
  • Chest radiograph
  • Pulmonary function studies

In cases that could represent a form of IIP:

  • High-resolution computed tomography (HRCT) scan

To establish a definite diagnosis of IIP:

  • Lung biopsy

Treatment of Manifestations

The management of the individual with familial pulmonary fibrosis (FPF) is similar to that for IIP and depends on the type of IIP diagnosed for each individual within the family [American Thoracic Society 2000, Travis et al 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.

Oxygen therapy may improve exercise tolerance in patients with hypoxemia.

Surveillance

The frequency of follow-up evaluations for persons with FPF depends largely on the patient's individual diagnosis and status. Those who are stable may be evaluated every three to six months, while others may need more frequent follow up.

Agents/Circumstances to Avoid

Cigarette smoking places individuals at increased risk of developing idiopathic pulmonary fibrosis (IPF) and FPF as well [Steele et al 2005].

Evaluation of Relatives at Risk

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]. In previous studies, these simple screening tests have been found to be sensitive for establishing the diagnosis [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]. Up to 50% of unaffected at-risk family members have a positive screen and require further evaluation.

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

Therapies Under Investigation

Antifibrotic agents such as interferon gamma and perfenidone are currently being tested to determine their efficacy in treating IPF. If they are found to be effective in treating IPF, these agents may also be effective in treating FPF.

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

Other

Pharmacologic interventions have not been shown to alter the course of IPF.

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. 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.

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) because of reduced penetrance.

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 disease-causing mutation on the basis of family history, the risk to the sibs of inheriting the mutation is 50%. Because the penetrance is likely reduced, the risk to sibs of being affected is less than 50%.

Offspring of a proband. Each child of an individual with FPF has a 50% chance of inheriting the disorder; however, because penetrance is likely reduced in FPF, the risk to offspring of being affected is less than 50%.

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].

Family planning

  • The optimal time for determination of genetic risk 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation). The predictive value of such tests is as yet unclear.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

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 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 disease-causing mutation 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.

  • Coalition for Pulmonary Fibrosis
    1659 Branham Lane
    Suite F, #227
    San Jose CA 95118-5226
    Phone: 888-222-8541 (toll-free)
    Email: info@coalitionforpf.org
  • Pulmonary Fibrosis Foundation
    811 West Evergreen Avenue
    Suite 303
    Chicago IL 60622-2642
    Phone: 888-733-6741 (toll-free)
    Fax: 866-587-9158 (toll-free)
    Email: info@pulmonaryfibrosis.org

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 symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name 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
187270TELOMERASE REVERSE TRANSCRIPTASE; TERT
602322TELOMERASE RNA COMPONENT; TERC

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

Molecular Genetic Pathogenesis

Short telomeres have been reported as a potential risk factor in familial pulmonary fibrosis and simplex cases in absence of TERT and TERC mutations [Alder et al 2008, Cronkhite et al 2008] and have been proposed as a potential marker for IPF/FPF. Note: A test for short telomeres as a biomarker for pulmonary fibrosis has not yet been developed. A more recent study by Diaz de Leon et al [2010] showed that family members within kindreds who do not inherit a TERT mutation may have shorter telomere lengths than controls, demonstrating that factors other than mutations in TERT (e.g., mutations in other genes, epigenetic inheritance) can affect telomere length.

While the finding of short telomeres is promising and suggests that telomere length may play a role in the pathogenesis of IIP, further studies are needed to understand the biologic consequences of telomere shortening in pulmonary fibrosis and its contributions to the development of progressive lung scarring.

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 (hTERT) and the telomerase RNA component (hTERC), which functions as a template to synthesize telomere DNA. Other proteins involved with the telomerase complex include dyskerin, H/ACA ribonucleoprotein complex subunit 1, H/ACA ribonucleoprotein complex subunit 2, and H/ACA ribonucleoprotein complex subunit 3 [Armanios 2009, Calado & Young 2009].

Telomerase is normally repressed in postnatal somatic cells, resulting in progressive shortening of telomeres; hTERT is only highly expressed in specific germline cells, proliferative stem cells of renewal tissues, and immortal cancer cells. hTERC is expressed in all tissues [Garcia et al 2007].

Mutations 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 mutations in DKC1 (the gene 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. Mutations 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].

Pulmonary fibrosis is a pleiotropic finding of the autosomal dominant form of DC. Armanios et al [2007] observed that pulmonary fibrosis was a prominent feature in one of their families with autosomal dominant DC, leading them to hypothesize that TERC and TERT may be candidate genes in familial IPF in which the inheritance pattern is also known to be autosomal dominant. A candidate gene approach was taken by Armanios et al [2007], leading to identification in a subset of families with IPF of germline mutations in the genes encoding both of these components of telomerase. In a separate genome-wide linkage study Tsakiri et al [2007] identified mutations in TERT and TERC in families with pulmonary fibrosis. Collectively these studies identified loss-of-function hTERT and hTERC in 8%-15% of families with IPF. Germline mutations in these genes are also present in 1%-3% of simplex cases (i.e., single occurrence in a family) of IPF [Armanios 2009]. In a more recent expanded follow-up study of the Tsakiri study, Diaz de Leon et al [2010] included additional family members and more unrelated kindreds. This study found that 18% of families had heterozygous TERT mutations.

Since telomere shortening can result from mutations 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 mutations in the genes that encode telomerase [Cronkhite et al 2008]. Furthermore, Diaz de Leon et al [2010] showed that family members can inherit short telomeres and not the mutation present in other family members, a finding that may suggest the presence of other as-yet unidentified genetic abnormalities in persons with pulmonary fibrosis.

TERT

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

Pathogenic allelic variants. Mutations 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 mutations in TERT.

A total of 24 TERT mutations for pulmonary fibrosis have been reported through these studies. The mutations found thus far are spread across the three domains of TERT but cluster in conserved regions. Diaz de Leon et al [2010] reported two mutations that were found in different unrelated families. No other common mutations 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 Symbol.

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

Normal gene product. Telomerase is a ribonucleoprotein polymerase that maintains telomere ends by addition of the telomere repeat TTAGGG. The enzyme 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. Mutations for 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 telomerase from repairing 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 Symbol.

Pathogenic allelic variants. Multiple mutations 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 mutations associated with FPF have been described.

  • 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 460+1G>A mutation (genomic DNA base 1728) in the splice donor site of intron 4, resulting in a dominant-negative effect.
  • Thomas et al [2002] reported a mutation in one large kindred in both adult and childhood onset of interstitial lung disease.
  • Guillot et al [2009] identified a novel mutation 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.

The Ile73Thr mutation, the most prevalent SFTPC mutation reported to date in the pediatric age group, can be de novo or inherited.

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 mutations causing diffuse lung disease include alteration of SP-C metabolism or complete SP-C deficiency.

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 was educated at the University of Rochester (BA) and the University of California at San Diego (MD). Following a residency and chief residency in Internal Medicine at Boston City Hospital, he completed a fellowship in Occupational Medicine at the Harvard School of Public Health, where he received an MPH and a Pulmonary and Critical Care Fellowship at the University of Washington in Seattle. In addition, while at the University of Washington, he completed a research fellowship in the Robert Wood Johnson Clinical Scholars Program. Dr. Schwartz was a faculty member at the University of Iowa for 12 years where he completed a sabbatical in molecular genetics with Dr. Jeff Murray. He joined Duke University in 2000, where he served as a Professor of Medicine and Genetics, Director of the Division of Pulmonary and Critical Care Medicine, and Director of the Program in Environmental Genomics. Dr. Schwartz was funded to establish three NIH Centers at Duke: a Center focusing on Environmental Genomics, a Program Project in Environmental Asthma, and an Environmental Health Sciences Research Center. He has served on several study sections and editorial boards, is a member of the American Society for Clinical Investigation and the Association of American Physicians, and was awarded the Scientific Accomplishment Award from the American Thoracic Society in 2003. In May 2005, he became the Director of the National Institute of Environmental Health Sciences (NIEHS) at the NIH and the National Toxicology Program. In May 2008, he became Director of the Center for Genes, Environment, and Health at National Jewish Health.

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 Diplomate of the American Board of Genetic Counselors (ABGC) in 2009. After several years spent in laboratories 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 coordinating the Familial Pulmonary Fibrosis study and providing genetic counseling services for the institution and to patients and families with IPF. In addition she manages the Familial Pulmonary Fibrosis Genetic Counseling line supported by the Coalition for Pulmonary Fibrosis (CPF) and the Pulmonary Fibrosis Foundation (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 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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