Pleuroparenchymal Fibroelastosis Associated with TERT Mutations

We thank Nunes and colleagues for their interest in our patients with telomere-related gene mutations associated with pleuroparenchymal fibroelastosis (PPFE)[1]. Their cohort of five patients with PPFE and rare variants in TERT is similar to ours with regard to its female predominance[2]. Here we provide additional details of our eight cases to point out additional similarities and differences between these two cohorts (Table).

Table.

Characteristics of patients with pleuroparechymal fibroelastosis (PPFE) and pathogenic rare variants in TERT, TERC, and RTEL1.

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8
Gender	Female	Male	Female	Female	Female	Female	Female	Female
Ethnicity	Caucasian	Caucasian	Caucasian	African American	Caucasian	Caucasian	Hispanic	Caucasian
Age at Diagnosis	60	65	60	30	33	57	64	66
Smoking Status	Never	Former	Never	Never	Never	Never	Never	Never
BMI	21.6	32	18.3	21.6	26.7	18.3	16.8	20.1
Pneumothorax/Pneumomediastinum	Pneumomediastinum				Pneumothorax		Pneumomediastinum
Family History of PF	Yes	Yes	Yes	No	Yes	Yes	Yes	Yes
Telomeropathy Manifestations	Transient LFT elevation	Macrocytosis	Pancytopenia, MDS	Anemia, thrombocytopenia	Macrocytosis	Anemia, Macrocytosis		Breast Cancer
Gene	RTEL1	RTEL1	TERC	TERT	TERT	TERT	TERT	TERT
DNA Change	c.2206_2208delGAC	c.2005C>T	r.182g>c	c.2539G>A	c.416T>G	c.1892G>A	c.2851C>T	c.430G>A
Impact on Protein	p.Asp736del	p.Gln669X		p.Gly847Ser	p.Leu139Arg	pArg631Gln	p.Arg951Trp	p.Val144Met
ExAC Frequency	Absent	Absent	Absent	Absent	Absent	Absent	8.29 × 10−6	Absent
Age-adjusted LTL (percentile)	<1st		<1st	6–7th	<1st	<1st
HRCT Features
Upper Zone	PPFE	Reticulations		Fibrocystic changes	PPFE with reticulations	PPFE	PPFE
Lower Zone	Reticulations	Reticulations		Reticulations, honeycombing	PPFE	PPFE	Reticulations, honeycombing
Biopsy Specimen	Explant	Surgical biopsy	Explant	Explant		Explant	Surgical biopsy	Surgical biopsy
Pathologic Diagnosis	PPFE	PPFE	PPFE	PPFE		PPFE	PPFE	PPFE
UIP Features	--	Fibroblastic Foci	Honeycombing	Honeycombing		--	Honeycombing	Honeycombing, Fibroblastic Foci
Outcome	Transplant	Death	Transplant	Transplant	Alive	Transplant	Death	Death

Abbreviations: BMI, body mass index; PF, pulmonary fibrosis; LFT, liver function test; MDS, myelodysplastic syndrome; ExAC, Exome Aggregation Consortium; LTL, leukocyte telomere length; HRCT, high resolution computed tomography

A diagnosis of PPFE was made by multidisciplinary diagnosis and histopathologic examination of lung tissue in 7 of the 8 cases in our cohort. While changes consistent with PPFE were seen in the upper lobes of CT scans in 4 of the 6 cases for which high resolution CT scans were available, the presence of lower lobe fibrosis resembling a usual interstitial pneumonia (UIP) lesion was also noted in four cases. Similar to the findings of Nunes, we often found the co-existence of PPFE with UIP-like features (fibroblastic foci, honeycombing) on pathologic evaluation. The women in our cohort also had a low BMI, with a mean BMI of 20.5 (range 16.8–26.7). We also note a high incidence of either spontaneous pneumothorax or pneumomediastinum (3/8), a high proportion of never smokers (7/8), and a wide range of the age at diagnosis (30–66 years). There was evidence of several manifestations of a short telomere syndrome including a family history of pulmonary fibrosis, macrocytosis, anemia, thrombocytopenia, pancytopenia, myelodysplastic syndrome or transient liver function test abnormalities in six individuals. All had evidence of progression of their interstitial lung disease (ILD), with seven patients expiring or undergoing lung transplantation.

Individuals with pathogenic variants in three different telomere-related genes (TERT, TERC, RTEL1) were included in our PPFE cohort, whereas only variants in TERT were described in the Nunes cohort. All variants were very rare with allele frequencies <10⁻⁵. Telomere lengths were not measured by Nunes. For those individuals in our cohort in which blood leukocytes were available, the age-adjusted leukocyte telomere lengths were all <10^th percentile, with most <1^st percentile. Two of the individuals in the Nunes cohort had a diagnosis of Sjogren’s syndrome. While we did not find evidence of autoimmune disease in our PPFE cohort, we did have two individuals of the 115 patients with mutations in one of four different telomere-related genes that met the diagnostic criteria for scleroderma, and neither of those patients had radiographic evidence of PPFE.

We agree with Nunes et al that a diagnosis of PPFE should bring to mind a short telomere syndrome especially if a positive family history of pulmonary fibrosis is obtained, given its relatively high prevalence (10.4%) in patients with telomere-related gene mutations. Short telomere length independently predicts worse transplant-free survival in patients with sporadic IPF[3], and the presence of a telomere-related mutation is associated with poor outcomes regardless of the specific diagnosis[1]. Therefore, the decline in lung function and poor survival described by Nunes and colleagues may not be related to the diagnosis of PPFE, but rather due to telomere dysregulation. Further investigation is warranted to determine the etiology of the injury and mechanisms that lead to extracellular deposition of elastin as opposed to collagen in these patients.