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Management of suspected monogenic lung fibrosis in a specialised centre

Raphael Borie, Caroline Kannengiesser, Flore Sicre de Fontbrune, Laurent Gouya, Nadia Nathan, Bruno Crestani
European Respiratory Review 2017 26: 160122; DOI: 10.1183/16000617.0122-2016
Raphael Borie
1Service de Pneumologie A, Centre de Compétence des Maladies Pulmonaires Rares, Paris, France
2DHU FIRE, Hôpital Bichat, APHP, Paris, France
3INSERM, Unité 1152, Paris, France
4Université Paris Diderot, Paris, France
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  • For correspondence: raphael.borie@aphp.fr
Caroline Kannengiesser
4Université Paris Diderot, Paris, France
5Laboratoire de Génétique, APHP, Hôpital Bichat, Paris, France
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Flore Sicre de Fontbrune
6Service d'Hématologie Greffe de Moelle, CMRM Aplasies médullaires, Hôpital Saint Louis, APHP, Paris, France
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Laurent Gouya
4Université Paris Diderot, Paris, France
7Centre Français des Porphyries, Hôpital Louis Mourier, AP-HP, Colombes, France
8Laboratory of Excellence, GR-Ex, Paris, France
9INSERM UMR1149, Paris, France
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Nadia Nathan
10Service de Pneumologie Pédiatrique, Centre National de Référence des Maladies Respiratoires Rares, Hôpital Armand-Trousseau, APHP, Paris, France
11INSERM Unité Mixte de Recherche S933, Sorbonne Universités, Université Pierre et Marie Curie, Paris, France
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Bruno Crestani
1Service de Pneumologie A, Centre de Compétence des Maladies Pulmonaires Rares, Paris, France
2DHU FIRE, Hôpital Bichat, APHP, Paris, France
3INSERM, Unité 1152, Paris, France
4Université Paris Diderot, Paris, France
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  • Article
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  • FIGURE 1
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    FIGURE 1

    a) Main genes and b) corresponding pathways identified in 2016 as a Mendelian cause of suspected monogenic pulmonary fibrosis in adults.

  • FIGURE 2
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    FIGURE 2

    Typical pedigree of a family suggestive of a TERC mutation with autosomal dominant transmission and anticipation. Ages are those reported at diagnosis. ILD: interstitial lung disease. The arrow indicates the proband.

  • FIGURE 3
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    FIGURE 3

    Representative computed tomography scans of carriers of a) RTEL1 and b) TERC mutations. Usual interstitial pneumonia is the most frequent pattern seen (a), but a pattern suggestive of pleuro-parenchymal fibroelastosis diagnosis seems unexpectedly frequent (b).

  • FIGURE 4
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    FIGURE 4

    Representative computed tomography scans of carriers of a) SFTPC, b) SFTPA1, c) ABCA3, d) NFKX2-1 and e) NF1 pathogenic mutations, all inconsistent with usual interstitial pneumonia.

  • FIGURE 5
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    FIGURE 5

    Significance of the principal genetic variants associated with familial pulmonary fibrosis by their strength and frequency. For example, TERT mutations are rare but have a powerful effect with great penetrance, whereas polymorphism of the MUC5B promoter is frequent but with a weaker effect. Modified from [117, 118, 119].

  • FIGURE 6
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    FIGURE 6

    Simplified diagram of the multidisciplinary process to diagnose interstitial lung disease, including a clinician, radiologist, pathologist and also a geneticist: a first path to personalised medicine. CT: computed tomography.

  • FIGURE 7
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    FIGURE 7

    Diagram of genetic and somatic evaluation offered for asymptomatic relatives. Somatic evaluation includes chest computed tomography scan, pulmonary function test, complete blood count and liver blood test.

Tables

  • Figures
  • Supplementary Materials
  • TABLE 1

    Main genes with rare variants associated with pulmonary fibrosis

    FunctionGeneTransmissionAge of onset of pulmonary manifestationAssociated signs
    TelomeraseTERT-TERCADAdults, average 55 yearsTelomeropathy;
    combined pulmonary fibrosis and emphysema
    TINF2ADChildren, rare adults <50 yearsTelomeropathy [31]
    DKC1XChildren, rare adults <50 yearsTelomeropathy [120]
    HelicaseRTEL1ADAdults 35–60 yearsTelomeropathy
    RNA regulationPARNADAdults 47–81 yearsPulmonary granulomatosis;
    telomeropathy [33]
    NAF1ADAdults 45–60 yearsTelomeropathy [5]
    SurfactantSFTPA1-SFTPA2ADFrom newborn to 72 yearsLung cancer [90, 121]
    SFTPBARNewborn[122]
    SFTPCADChildren, rare adults <50 yearsCombined pulmonary fibrosis and emphysema [123]
    ABCA3ARChildren, rare adults <50 yearsCombined pulmonary fibrosis and emphysema [83]
    NFKX2-1 (TITF1)ADChildren, rare adults <50 yearsChorea, hypothyroidism [93]
    Tumour suppressorNF1ADAdultsType 1 neurofibromatosis [124]
    LysosomeHPS-1 to HPS-8/AP-3B1ARAdultsHermansky–Pudlak syndrome [125]
    Stimulation of interferon synthesisTMEM173ADChildren, rare adults <50 yearsRecurrent fever;
    alopecia; skin rash;
    antinuclear antibodies;
    vasculitis [95, 100]
    Endoplasmic reticulum stressCOPAADChildren, rare adults <25 yearsArthritis, antinuclear antibodies and ANCA [8]
    UnknownFAM111BAD7–30 yearsMyopathy, poikiloderma [6]
    MitochondriaNDUFAF6AR19–50 yearsAcadian variant of Fanconi syndrome [126]
    Zinc finger transcription factorsGATA2AD4–76 yearsAlveolar proteinosis;
    myeloid disease;
    monoMAC syndrome [10]
    • AD: autosomal dominant; X: X-linked; AR: autosomal recessive; ANCA: anti-neutrophil cytoplasmic antibodies.

  • TABLE 2

    Patients with interstitial lung disease (ILD) for whom we propose genetic testing

    Idiopathic or non-idiopathic ILD with at least one of the following:
     Familial ILD
     Cryptogenic pulmonary fibrosis <50 years old
     Rare syndrome (table 1) or telomeropathy assessed as personal, or familial history of:
      Bone-marrow failure, thrombocytopenia or myelodysplasia
      Dyskeratosis congenita
      Cryptogenic cirrhosis

Supplementary Materials

  • Figures
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  • Supplementary Material

    R. Borie ERR-0122-2016_Borie

    B. Crestani ERR-0122-2016_Crestani

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European Respiratory Review: 26 (144)
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Management of suspected monogenic lung fibrosis in a specialised centre
Raphael Borie, Caroline Kannengiesser, Flore Sicre de Fontbrune, Laurent Gouya, Nadia Nathan, Bruno Crestani
European Respiratory Review Jun 2017, 26 (144) 160122; DOI: 10.1183/16000617.0122-2016

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Management of suspected monogenic lung fibrosis in a specialised centre
Raphael Borie, Caroline Kannengiesser, Flore Sicre de Fontbrune, Laurent Gouya, Nadia Nathan, Bruno Crestani
European Respiratory Review Jun 2017, 26 (144) 160122; DOI: 10.1183/16000617.0122-2016
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  • Article
    • Abstract
    • Abstract
    • Introduction
    • Pulmonary fibrosis associated with genetic mutations
    • Indication for genetic diagnosis
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