test . These values indicated that his pulmonary function remained relatively stable on nintedanib therapy .
DISCUSSION
When pulmonary fibrosis occurs in two or more relatives of the same family , it is termed familial pulmonary fibrosis ( FPF ). 1 It is an autosomal dominant progressive scarring lung disease of unknown etiology , with incomplete penetrance . 2 Germline mutations involving the telomerase complex genes ( TERT , TERC ) and shortened telomeres have been identified in one-third of cases of FPF . 3 Telomerase is responsible for maintaining chromosome ends . When its components are altered , its ends shorten , causing a premature aging syndrome . Telomere shortening is the suggested pathophysiological mechanism underlying idiopathic pulmonary fibrosis ( IPF ). 4
Furthermore , variants in surfactant-related genes and mucin ( MUC5B ) promoters have been identified as factors contributing to the pathogenesis of FPF . 5 Often , those with mutations of the telomerase complex have pulmonary fibrosis and other complications related to telomere shortening , including bone marrow failure , cryptogenic liver cirrhosis , and cutaneous diseases . 4 , 6 Notably , the true prevalence of FPF may be underestimated . For instance , one study found that one in six family members of patients with sporadic pulmonary fibrosis has unrecognized interstitial lung disease . 7
The clinical presentation of FPF is closely mirrors that of IPF , causing symptoms such as dyspnea on exertion progressing to dyspnea at rest , dry cough , inspiratory crackles on lung auscultation , and clubbing of the fingernails , which aligns with our patient ’ s case . However , FPF usually presents in the fifth decade , occurring slightly earlier than the onset of IPF . 8 This earlier presentation of FPF is thought to be associated with the inheritance of shorter telomeres .
The diagnosis of FPF typically begins with PFTs , which show a restrictive lung disease pattern , characterized by reduced DLCO and TLC values . Accordingly , our patient ’ s PFTs revealed a restrictive lung defect . Moreover , a HRCT scan of the chest will display fibrotic changes , represented by honeycombing of the lung periphery and traction bronchiectasis in the lower lobes , which was consistent with our patient ’ s imaging findings . 9 Although lung biopsy showing a usual interstitial pneumonia pattern is considered confirmatory , it is not necessary for diagnosis when there is a clear clinical presentation of FPF . 4 In addition , a biopsy of the lung was not performed on our patient given the risk of complications . Furthermore , it is necessary to rule out connective tissue disease as the underlying etiology for progressive interstitial lung disease . The mean survival following an FPF diagnosis is typically three years . 8
The rapidly progressive respiratory underscores the profound impact of the disease . Unfortunately , FPF does not respond to immunosuppressive therapy . No current treatments improve life expectancy , but the progression of the disease may be slowed with anti-fibrotic agents , such as pirfenidone and nintedanib . In our patient ’ s case , nintedanib likely played a pivotal role in maintaining his respiratory function , evident in the stabilization of his PFTs within
10 , 11
three months of nintedanib initiation . As patients progress toward respiratory failure , oxygen is typically required . Ultimately , many patients require lung transplantation as it is the only curative treatment .
As our understanding of FPF continues to advance , there is potential for tailoring future therapies to individuals based on their specific genetic mutations . Given the paucity of treatment options and known genetic components of FPF , genomic sequencing would allow for the identification of telomerase mutations present in the individual . This information could prevent other family members from experiencing sudden respiratory dysfunction and related comorbidities of FPF .
For instance , dyskeratosis congenita ( DC ) is a rare telomere-mediated syndrome . The X-linked form of DC is caused by DKC1 gene mutations , while the autosomal dominant form is caused by hTERT and hTR mutations . It is known to manifest as FPF and presents with reticular skin pigmentation , nail dystrophy , and oral mucosal leukoplakia , often complicated by bone marrow failure . 12 In individuals with autosomal dominant short telomere syndromes , bone marrow failure can develop
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B
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FIGURE 2
High-resolution computed tomography scan of the chest showing increased interstitial markings ( yellow arrows ), honeycombing of the lung periphery ( red arrows ), and traction bronchiectasis ( blue arrows ) in the upper ( a ), middle ( b ), and lower ( c ) lung lobes , respectively . Note the small overall size of the lungs .
from genetic anticipation . 4 Consequently , future generations may be at risk of experiencing more severe diseases that would be passed on to their successors . The early identification of genetic risk factors may impact prognosis and the process of listing for lung transplantation . Namely , telomerase-related genes should be identified as these mutations increase the incidence of hematologic complications after lung transplant . 13 It is unknown if an associated genetic complication contributed to the
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