Surfactant Protein C Mutations Are the Basis of a Significant Portion of Adult Familial Pulmonary Fibrosis in a Dutch Cohort

Moorsel, Coline H.M. van; Oosterhout, Matthijs F.M. van; Barlo, Nicole P.; Jong, Pim A. de; Vis, Joanne J. van der; Ruven, Henk J.T.; Es, Hendrik W. van; Bosch, Jules M.M. van den; Grutters, Jan C.

doi:10.1164/rccm.200906-0953oc

Cited by 261 publications

(201 citation statements)

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“…17 Focal or diffuse reticulonodular patterns, centrolobular and subpleural nodules and cystic lesions are described in adults. 29,30 We did not observe specific differences in lung histology between our cases, in whom lung biopsy was obtained at a median age of 6 months. We observed a combination of DIP with features of PAP, a pattern common to most genetic surfactant deficiencies in infants.…”

Section: Polarized Light Microscopymentioning

confidence: 50%

“…8,20,23,28 In this paper the youngest subject, a 28-week preterm triplet carrying the p.(Pro173His) mutation was identified by comparing RDS severity with his two siblings with wild-type SP-C alleles. Conversely, in the literature, SP-C mutations have been found in adults with familial idiopathic pulmonary fibrosis 29 and in adults 14-68 year-old in one pedigree, 30 Figure 1 Lung tissue morphology and surfactant protein immunohistochemistry. Immunohistochemistry staining for SP-B (columns 1 and 2, 10 × and 40 × magnification, respectively) and pro-SP-C (columns 3 and 4) in a 3-month-old control (row 1), three linker domain mutants (row 2-4) and one BRICHOS domain mutant (row 5).…”

Section: Polarized Light Microscopymentioning

confidence: 99%

“…We observed a combination of DIP with features of PAP, a pattern common to most genetic surfactant deficiencies in infants. 1 In the literature, older children and adults with SP-C mutations display patchy fibrotic lesions of usual interstitial pneumonia or diffuse nonspecific interstitial pneumonia, in combination with nodular septa thickening and clustered cystic lesions, 29,30 suggesting lung tissue morphology is more age-specific rather than disease-specific.…”

Section: Polarized Light Microscopymentioning

confidence: 99%

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Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

et al. 2015

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Genetic defects of surfactant metabolism are associated with a broad range of clinical manifestations, from neonatal respiratory distress syndrome to adult interstitial lung disease. Early therapies may improve symptoms but diagnosis is often delayed owing to phenotype and genotype variability. Our objective was to characterize the cellular/ultrastructural correlates of surfactant protein C (SP-C) mutations in children with idiopathic diffuse lung diseases. We sequenced SFTPC -the gene encoding SP-C -SFTPB and ABCA3, and analyzed morphology, ultrastructure and SP expression in lung tissue when available. We identified eight subjects who were heterozygous for SP-C mutations. Median age at onset and clinical course were variable. None of the mutations were located in the mature peptide-encoding region, but were either in the pro-protein BRICHOS or linker C-terminal domains. Although lung morphology was similar to other genetic surfactant metabolism disorders, electron microscopy studies showed specific anomalies, suggesting surfactant homeostasis disruption, plus trafficking defects in the four subjects with linker domain mutation and protein misfolding in the single BRICHOS mutation carrier in whom material was available. Immunolabeling studies showed increased proSP-C staining in all cases. In two cases, amyloid deposits could be identified. Immunochemistry and ultrastructural studies may be useful for diagnostic purposes and for genotype interpretation.

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Section: Polarized Light Microscopymentioning

confidence: 50%

Section: Polarized Light Microscopymentioning

confidence: 99%

Section: Polarized Light Microscopymentioning

confidence: 99%

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Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

et al. 2015

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“…Patterns of combined emphysema and pulmonary fibrosis have been described in children [30] and adults who never smoked [31]. Findings that have consistently been reported in SFTPC mutations are ground-glass opacity, multiple lung cysts of varying sizes, and septal thickening [8,13,32]. Two different reports described a spectrum of progression from initial diffuse ground-glass opacity to multiple lung cysts and pulmonary fibrosis [11,30].…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Neuroendocrine Cell Hyperplasia Associated With Surfactant Protein C Gene Mutation

Jiramethee

Khoór

Erasmus

2016

Chest

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Familial interstitial lung disease (ILD) is defined as presence of ILD in 2 or more family members. Surfactant protein C (SFTPC) gene mutations are rare, but well-known cause of familial ILD. We reported a 20-year-old male, who was referred for lung transplantation. He was symptomatic at age 3 and underwent surgical lung biopsy at age 6, which revealed a nonspecific interstitial pneumonia (NSIP) pattern. Genetic workup revealed a novel SFTPC mutation in the first intron with a C to A transversion. At age 21, he underwent bilateral lung transplantation. Explanted lung histology suggested NSIP. In addition there was pulmonary neuroendocrine cell (PNEC) hyperplasia and carcinoid tumorlets. His mother had undergone lung transplantation several years earlier, and her explanted lung showed similar pathology. SFTPC mutations are inherited in an autosomal dominant pattern. Various types of ILD have been associated with SFTPC mutation including NSIP, usual interstitial pneumonia (UIP), and desquamative interstitial pneumonia (DIP). PNEC hyperplasia has been described to occur in association with lung inflammation but has not been previously described with familial ILD associated with SFTPC mutation.

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“…[18][19][20][21] Mutations in TERT and TERC genes, and in genes coding for surfactant proteins A and C, have been detected in up to 20 and 3% of familial UIP patients, respectively, and telomere shortening has been noted in about one fourth of sporadic UIP in the absence of detectable genetic mutations. [22][23][24][25][26][27] It has been proposed that these abnormalities may predispose the lung epithelium to acute injury from environmental exposures that ordinarily would not be damaging in persons with normal genetic composition. 23 Given the current focus on acute lung injury and abnormal wound healing in the pathogenesis of UIP, there are several potential treatment approaches, as summarized in Table 4.…”

Section: Current Concepts Of Pathogenesis and Treatment Of Uipmentioning

confidence: 99%

Smoking-related interstitial fibrosis (SRIF), pathogenesis and treatment of usual interstitial pneumonia (UIP), and transbronchial biopsy in UIP

Katzenstein

2012

Modern Pathology

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This review focuses on three selected topics of current interest that are related to chronic fibrosing lung disorders and are important for pathologists. First, the clinical and pathologic features of smoking-related interstitial fibrosis (SRIF) are highlighted. SRIF is a common finding in smokers that has striking histologic changes but only mild associated clinical manifestations. It is characterized by marked alveolar septal fibrosis composed of a distinct form of hyalinized collagen deposition. The process is present mainly in subpleural and centrilobular parenchyma and is associated with emphysema and respiratory bronchiolitis. Second, important aspects of the pathogenesis and treatment of usual interstitial pneumonia (UIP) are reviewed. The current theory proposes that UIP is caused by tiny foci of acute lung injury (manifest pathologically by fibroblast foci) that occur and recur in the interstitium over many years. Inflammation may be present as a secondary phenomenon, but is not the primary cause, and therefore anti-inflammatory agents have little effect. The recurrent injury leads to permanent fibrosis, through a process that is considered to represent a form of abnormal wound healing. Multiple therapies have been attempted that are aimed largely at interrupting the fibrosing process, but none have been successful. The cause of the injury is unknown, but a role for aspiration due to gastroesophageal reflux is a popular current theory, and there is some evidence that anti-reflux therapy may be beneficial. Genetic predisposition has been implicated in the etiology of familial cases, and there is evidence that telomere shortening may be important in sporadic cases. Third, the use of transbronchial biopsy (TBB) in diagnosing UIP is reviewed. TBB can provide a surprising amount of information and is especially useful in certain situations, such as elderly or very sick patients in whom surgical lung biopsy carries increased morbidity and mortality.

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Surfactant Protein C Mutations Are the Basis of a Significant Portion of Adult Familial Pulmonary Fibrosis in a Dutch Cohort

Abstract: Mutations in SFTPC are a frequent cause of FPF in adult patients in our cohort. Nonclassifiable radiological patterns with cystic changes and histopathological patterns of usual interstitial pneumonia are characteristics of adult SFTPC mutation carriers.

Cited by 261 publications

References 35 publications

Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

Clinical and ultrastructural spectrum of diffuse lung disease associated with surfactant protein C mutations

Pulmonary Neuroendocrine Cell Hyperplasia Associated With Surfactant Protein C Gene Mutation

Smoking-related interstitial fibrosis (SRIF), pathogenesis and treatment of usual interstitial pneumonia (UIP), and transbronchial biopsy in UIP

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