Genetic interstitial lung disease

Abstract

The interstitial lung diseases (ILDs), or diffuse parenchymal lung diseases, are a heterogeneous collection of more than 100 different pulmonary disorders that affect the tissue and spaces surrounding the alveoli. Patients affected by ILD usually present with shortness of breath or cough; for many, there is evidence of pulmonary restriction, decreased diffusion capacity, and radiographic appearance of alveolar and/or reticulonodular infiltrates. This article reviews the inherited ILDs, with a focus on the diseases that may be seen by pulmonologists caring for adult patients. The authors conclude by briefly discussing the utility of genetic testing in this population.

Figure 1. Characteristics of ILD associated with telomerase (TERT) mutations

(A) Penetrance of self-reported pulmonary fibrosis is shown for men (yellow) and women (blue bars) of different ages. Penetrance of pulmonary fibrosis for men vs. women 40–49, 50–59 and >60 years of age is 14% vs. 2%, 38% vs. 14% and 60% vs. 50%. (B) Kaplan-Meier survival curve of 47 different TERT mutation carriers with ILD demonstrate a mean survival of three years after diagnosis. (C) Computed tomography (CT) scans of three different TERT mutation carriers with ILD. Representative cases are shown with a pattern typical of Usual Interstitial Pneumonia (UIP) with peripheral, basal-predominant fibrosis and moderate to severe honeycombing (a,b), a pattern consistent with UIP except for the absence of honeycombing (c,d) and a pattern atypical of UIP with fibrosis predominantly affecting the upper lobes and along the bronchi (e,f). Scans are shown at the level of the carina (a, c, e) and the lung base (b, d, f). The majority of carriers (74%) had a CT scan typical of UIP, 13% had a CT scan consistent with UIP except for the absence of honeycombing and 13% had a CT scan atypical of UIP. (D) Histology of surgical lung biopsies from TERT mutation carriers with ILD. The majority of cases (86%) of TERT mutation carriers with lung specimens available for review had diagnostic histologic features of UIP. In this low magnification view of UIP (g), typical variegated honeycomb areas are seen alternating with normal areas and scarred lung. The cases shown in (h) shows increased inflammation and a small, loosely aggregated non-necrotizing granuloma (arrows) that is characterized by a cluster of epitheloid histiocytes and multinucleated giant cells surrounded by chronic inflammation in the interstitium. Panels g and h are shown at 40 and 100-fold magnification, respectively. Adapted from figures originally published in reference.

Figure 2. Birt-Hogg-Dubé (BHD) syndrome presenting as recurrent spontaneous pneumothoraces

(A) Condensed pedigree of kindred F42 presenting with familial spontaneous pneumothorax. Circles represent females; squares represent males. Individuals with a pneumothorax, lung cysts as detected by high resolution CT scans of the chest, fibrofolliculomas, and renal cancer are indicated by blue, green, yellow and red symbols, respectively. The presence of a heterozygous frameshift mutation in the gene encoding folliculin (FLCN) predicting the premature termination of the protein is indicated by the plus signs. The sequence variant is described according to recommended guidelines. Of the four mutation carriers, only the two elder family members had histopathologic evidence of multiple fibrofolliculomas, the characteristic skin lesion of BHD syndrome. The proband, her sister and mother have evidence of at least one pulmonary cyst by high resolution computed tomograph (HRCT). A 3 cm renal mass was detected in the proband's sister and she was referred for partial nephrectomy. (B) HRCT scan of the proband reveals multiple subcentimeter cysts (indicated by the arrows) within the lower lobes.