brosis with upper lung predominance, centrilobular brosis, or a pleuroparenchymal fbroelastosis (PPFE) pattern [17, 19, 32]. In patients with TRG mutation, IPF is the most frequent ILD diagnosis (45–86%) [9, 30, 38], but other ILD diagnoses are frequent: PPFE (up to 10%), chronic HP (7–11%), and unclassi able brosis (19–30%) [17, 19, 32, 33]. Alternative diagnosis, such as pneumoconiosis, rheumatoid arthritis associated ILD, and alveolar lipoproteinosis are very rare in patients with FPF due to TRG mutations.

Carriers of rare TRG variants have a more rapid decline in forced vital capacity (FVC) than patients without TRG variants [17, 43]. Newton et al. reported a 300 mL/year decline in FVC independent of the type of TRG (TERC, TERT, RTEL1, or PARN), or of the ILD diagnosis (IPF vs. non-IPF) [17].

The mean survival after ILD diagnosis is 2.8– 5.2 years [44] in TRG-related FPF. However, disease progression varies and the ILD histopathology may modify the prognosis [33, 45].

Other Lung Disease

Hepatopulmonary Syndrome

Hepatopulmonary syndrome (HPS) should be suspected in patients carriers of a TRG mutation presenting with hypoxemia, especially when the ILD is mild [46]. Liver involvement must be actively searched for, because blood liver abnormalities can be subtle or absent. In a series of 42 patients with telomere syndrome who complained of dyspnea, nine patients had a hepatopulmonary syndrome, de ned as the combination of liver disease, evidence of intrapulmonary vascular dilatation, and hypoxemia. TRG mutations implicated in HPS include TERT (n = 4), RTEL1 (n = 1), or DKC1 (n = 1) [46].

Emphysema

Several lines of evidence suggest an increased risk of emphysema in TRG mutation carriers. The KO TERC mice with short telomeres develop emphysema when exposed to tobacco smoke, but no lung brosis [47]. In female smokers with severe chronic obstructive pulmonary disease and emphysema, TERT and NAF1 mutations have been found [15, 48, 49]. The prevalence of combined pulmonary fbrosis and emphysema (CPFE) in cohorts of TRG mutation carriers is reported to be 13–15%, in line with the usual prevalence of emphysema in IPF cohorts [17, 32, 33, 50].

Immunodefciency

Immunodefciency and opportunistic infections have been mainly been described in children. A Pneumocystis jirovecii infection has been reported in an adult carrying a TERC

mutation without any immunosuppressive therapy [51, 52]. Although the exact prevalence of immunode ciency and its impact for lung transplantation need to be evaluated, patients with TRG mutations appear to be at an increased risk of CMV infection after lung transplantation [53].

Extrapulmonary Manifestations

Pulmonary and extrapulmonary manifestations associated with TRG mutations lack a consensus de nition and have been variably reported as “telomere syndrome,” “telomeropathy,” or “short telomere syndrome.”

Mucocutaneous Involvement

Dyskeratosis congenita (DKC) was the rst telomeropathy associated with TRG mutations [54, 55]. DKC is de ned by the mucocutaneous triad: reticular skin pigmentation, nail dystrophy, and oral mucosal leukoplakia [56]. Mucocutaneous involvement appears in childhood, and bone marrow failure usually appears after the age of 10 [56]. Lung brosis may spontaneously appear in DKC, although after hematopoietic stem cell transplantation, patients with DKC may develop severe pulmonary complications, including lung brosis [57].

Adult patients with TRG mutation and pulmonary brosis usually do not present the mucocutaneous triad, but 15–40% present premature hair graying (before the age of 30) [32, 58]. The same gene mutation can be associated with different phenotypes, likely as a consequence of genetic anticipation and telomere shortening. For instance, descendants of patients with pulmonary brosis without DKC features may present with typical DKC [17].

Hematological Involvement

TRG mutations have been associated with bone marrow failure, myelodysplasia, or acute leukemia [59–61]. The coexistence of pulmonary brosis and bone marrow failure, particularly in a young patient, increases the probability of an underlying TRG mutation (Table 24.3) [62, 63]. The coexistence of myelodysplasia and lung brosis in older patients is probably more coincidental [62].

Table 24.3  French Proposal for Indication of a Genetic Testing (RESPIFIL)

Idiopathic or non-idiopathic ILD with at least one of the following: