Management of suspected monogenic lung fibrosis in a specialised centre

Abstract

At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team.

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

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

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

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

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

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

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.