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

ABSTRACT: 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.

SUBMITTER: Peca D

PROVIDER: S-EPMC4795107 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Peca Donatella D Boldrini Renata R Johannson Jan J Shieh Joseph T JT Citti Arianna A Petrini Stefania S Salerno Teresa T Cazzato Salvatore S Testa Raffaele R Messina Francesco F Onofri Alfredo A Cenacchi Giovanna G Westermark Per P Ullmann Nicola N Cogo Paola P Cogo Paola P Cutrera Renato R Danhaive Olivier O

European journal of human genetics : EJHG 20150318 8

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 ...[more]

PMID: 25782673

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Project description:ImportanceSurfactant protein C (SP-C) dysfunction is a rare disease associated with interstitial lung disease. Early therapies may improve outcomes but the diagnosis is often delayed owing to variability of manifestations.ObjectiveTo investigate the manifestations and outcomes of SP-C dysfunction.MethodsWe retrospectively analyzed the records of five pediatric patients who were diagnosed with SP-C dysfunction between February 2014 and April 2017 at Beijing Children's Hospital.ResultsThe five patients included two boys and three girls with a median age at diagnosis of 1.3 years. All patients presented with interstitial lung disease and had a heterozygous SFTPC mutation, including an I73T mutation in three patients, a V39L mutation in one patient, and a Y104H mutation in one patient. In addition to common respiratory manifestations, hemoptysis and anemia were observed in one patient with the I73T mutation. Elevated levels of autoantibodies and a large number of hemosiderin-laden macrophages in bronchoalveolar lavage fluid were found in two patients with the I73T mutation, suggesting the presence of diffuse alveolar hemorrage and autoimmunity. Chest high-resolution computed tomography features included ground-glass opacities, reticular opacities, cysts, and pleural thickening. Transbronchial lung biopsy was performed in one patient with the I73T mutation, which revealed the presence of some hemosiderin-laden macrophages in alveolar spaces. All patients received treatment with corticosteroids; two received combined treatment with hydroxychloroquine. During follow-up, the two patients who received hydroxychloroquine showed improved symptoms; of the remaining three patients, two died after their families refused further treatment, while the final patient was lost to follow-up.InterpretationThis is the first report to describe a new phenotype of diffuse alveolar hemorrhage with autoimmunity in patients with I73T SFTPC mutation. Treatment with hydroxychloroquine should be considered for patients with SP-C dysfunction.

Project description:ObjectiveSurfactant protein D (SP-D) is considered a serum biomarker of various forms of interstitial lung disease (ILD). In this study, we examined the utility of SP-D as a predictive biomarker for mortality in patients with ILD associated with polymyositis/dermatomyositis (PM/DM) using large-scale multicentre cohort data.MethodsWe enrolled 381 patients with incident PM/DM-associated ILD in a multicentre retrospective cohort based on the availability of serum SP-D at the baseline. Demographic and clinical characteristics as well as the presence of autoantibodies to melanoma differentiation-associated gene 5 (MDA5) and aminoacyl tRNA synthetase were measured at the time of diagnosis, and follow-up survival data were collected prospectively.ResultsSeventy-eight patients died during the median observation period of 18 months, and the majority of patients died of ILD. The SP-D levels at baseline were significantly lower (P = 0.02) in a non-survivor subset than in a survivor subset among the entire enrolled patients. However, the SP-D levels were higher in the non-survivor subset than in the survivor subset based on the stratification by anti-MDA5-positive, anti-ARS-positive and, double-negativity, although there was an only statistically significant difference (P = 0.01) in the double-negative group. Surprisingly, the SP-D levels were within the upper limit of normal, 110 ng/mL, in 54 (87%) of 62 anti-MDA5-positive patients who died. In the double-negative group, the mortality rates were significantly higher (P = 0.002) in a subset with SP-D ?127.6 ng/mL, the cut-off value for mortality calculated by the receiver operating characteristic curve, than the other subset. All of patients with SP-D <127.6 ng/mL survived.ConclusionSerum SP-D levels behave differently among patients with stratified by anti-MDA5 antibody, anti-ARS antibody and both negativity in PM/DM-associated ILD. Its use in clinical practice should be applied with caution on the basis of the presence or absence of anti-MDA5 antibody or anti-ARS antibody.

Dataset Information

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

Publications

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

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