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Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 1(PFBMFT1)

MedGen UID:
766531
Concept ID:
C3553617
Disease or Syndrome
Synonym: PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 1
 
Gene (location): TERT (5p15.33)
 
Monarch Initiative: MONDO:0013878
OMIM®: 614742

Definition

Dyskeratosis congenita and related telomere biology disorders (DC/TBD) are caused by impaired telomere maintenance resulting in short or very short telomeres. The phenotypic spectrum of telomere biology disorders is broad and includes individuals with classic dyskeratosis congenita (DC) as well as those with very short telomeres and an isolated physical finding. Classic DC is characterized by a triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia, although this may not be present in all individuals. People with DC/TBD are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome or acute myelogenous leukemia, solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), taurodontism, liver disease, gastrointestinal telangiectasias, and avascular necrosis of the hips or shoulders. Although most persons with DC/TBD have normal psychomotor development and normal neurologic function, significant developmental delay is present in both forms; additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome and Coats plus syndrome). Onset and progression of manifestations of DC/TBD vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. [from GeneReviews]

Additional description

From OMIM
Shortened telomeres can cause a wide variety of clinical features that constitute a phenotypic spectrum. The most severe form is dyskeratosis congenita (see, e.g., 127550), characterized by early childhood onset of skin abnormalities, bone marrow failure, predisposition to malignancy, and risk of pulmonary and hepatic fibrosis. Adult-onset pulmonary fibrosis is the most common manifestation of mutant telomerase genes, but hepatopulmonary syndrome may precede the pulmonary fibrosis. Other manifestations include aplastic anemia due to bone marrow failure, liver disease, hepatic fibrosis, and increased cancer risk, particularly myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and squamous cell carcinoma. Phenotype, age at onset, and severity are determined by telomere length, not just telomerase mutation (Armanios, 2009; Schratz et al., 2023). The genetic diagnosis of telomere-related bone marrow failure and pulmonary fibrosis has implications for treatment because affected individuals generally do not respond to immunosuppression and may be at increased risk for fatal complications after bone marrow or lung transplantation (Parry et al., 2011). Genetic Heterogeneity of Telomere-Related Pulmonary Fibrosis and/or Bone Marrow Failure Syndromes Also see PFBMFT2 (614743), caused by mutation in the TERC gene (602322) on chromosome 3q26; PFBMFT3 (616373), caused by mutation in the RTEL1 gene (608833) on chromosome 20q13; PFBMFT4 (616371), caused by mutation in the PARN gene (604212) on chromosome 16p13; PFBMFT5 (618674), caused by mutation in the ZCCHC8 gene (616381) on chromosome 12q24; PFBMFT6 (619767), caused by mutation in the RPA1 gene (179835) on chromosome 17p13; PFBMFT7 (620365), caused by mutation in the NAF1 gene (617868) on chromosome 4q32; PFBMFT8 (620367), caused by mutation in the POT1 gene (606478) on chromosome 7q31; and PFBMFT9 (620400), caused by mutation in the NOP10 gene (606471) on chromosome 15q14.  http://www.omim.org/entry/614742

Clinical features

From HPO
Myeloid leukemia
MedGen UID:
7320
Concept ID:
C0023470
Neoplastic Process
A leukemia that originates from a myeloid cell, that is the blood forming cells of the bone marrow.
Myelodysplasia
MedGen UID:
10231
Concept ID:
C0026985
Congenital Abnormality
Clonal hematopoietic stem cell disorders characterized by dysplasia (ineffective production) in one or more hematopoietic cell lineages, leading to anemia and cytopenia.
Clubbing of fingers
MedGen UID:
3129
Concept ID:
C0009080
Finding
Terminal broadening of the fingers (distal phalanges of the fingers).
Cirrhosis of liver
MedGen UID:
7368
Concept ID:
C0023890
Disease or Syndrome
A chronic disorder of the liver in which liver tissue becomes scarred and is partially replaced by regenerative nodules and fibrotic tissue resulting in loss of liver function.
Gastroesophageal reflux
MedGen UID:
1368658
Concept ID:
C4317146
Finding
A condition in which the stomach contents leak backwards from the stomach into the esophagus through the lower esophageal sphincter.
Obstructive sleep apnea syndrome
MedGen UID:
101045
Concept ID:
C0520679
Disease or Syndrome
Obstructive sleep apnea is a common, chronic, complex disease associated with serious cardiovascular and neuropsychologic sequelae and with substantial social and economic costs (Palmer et al., 2003).
Anemia
MedGen UID:
1526
Concept ID:
C0002871
Disease or Syndrome
A reduction in erythrocytes volume or hemoglobin concentration.
Aplastic anemia
MedGen UID:
8063
Concept ID:
C0002874
Disease or Syndrome
Aplastic anemia is a serious disorder of the bone marrow that affects between 2 and 5 persons per million per year. About 75% of these cases are classified as idiopathic (Young, 2000). In about 15% of cases a drug or infection can be identified that precipitates the aplasia, although why only some individuals are susceptible is unclear. In about 5 to 10% of patients, the aplastic anemia is constitutional--i.e., is familial or presents with one or more associated somatic abnormalities (summary by Vulliamy et al., 2002).
Pancytopenia
MedGen UID:
18281
Concept ID:
C0030312
Disease or Syndrome
An abnormal reduction in numbers of all blood cell types (red blood cells, white blood cells, and platelets).
Bone marrow hypocellularity
MedGen UID:
383749
Concept ID:
C1855710
Finding
A reduced number of hematopoietic cells present in the bone marrow relative to marrow fat.
Osteopenia
MedGen UID:
18222
Concept ID:
C0029453
Disease or Syndrome
Osteopenia is a term to define bone density that is not normal but also not as low as osteoporosis. By definition from the World Health Organization osteopenia is defined by bone densitometry as a T score -1 to -2.5.
Cough
MedGen UID:
41325
Concept ID:
C0010200
Sign or Symptom
A sudden, audible expulsion of air from the lungs through a partially closed glottis, preceded by inhalation.
Dyspnea
MedGen UID:
3938
Concept ID:
C0013404
Sign or Symptom
Difficult or labored breathing. Dyspnea is a subjective feeling only the patient can rate, e.g., on a Borg scale.
Pulmonary fibrosis
MedGen UID:
11028
Concept ID:
C0034069
Disease or Syndrome
Replacement of normal lung tissues by fibroblasts and collagen.
Crackles
MedGen UID:
11118
Concept ID:
C0034642
Finding
Crackles are discontinuous, explosive, and nonmusical adventitious lung sounds normally heard in inspiration and sometimes during expiration. Crackles are usually classified as fine and coarse crackles based on their duration, loudness, pitch, timing in the respiratory cycle, and relationship to coughing and changing body position.
Decreased DLCO
MedGen UID:
892993
Concept ID:
C4073175
Finding
Reduced ability of the lungs to transfer gas from inspired air to the bloodstream as measured by the diffusing capacity of the lungs for carbon monoxide (DLCO) test.
Reticular pattern on pulmonary HRCT
MedGen UID:
1386432
Concept ID:
C4476748
Finding
On pulmonary high-resolution computed tomography, reticular pattern is characterized by innumerable interlacing shadows suggesting a mesh.
Usual interstitial pneumonia
MedGen UID:
1662563
Concept ID:
C4721509
Disease or Syndrome
Temporal and spatial heterogeneity in lungs based on presence of fibrosis and honeycombing.
Mediastinal lymphadenopathy
MedGen UID:
451062
Concept ID:
C0520743
Disease or Syndrome
Swelling of lymph nodes within the mediastinum, the central compartment of the thoracic cavities that contains the heart and the great vessels, the esophagus, and trachea and other structures including lymph nodes.
Premature graying of hair
MedGen UID:
75524
Concept ID:
C0263498
Finding
Development of gray hair at a younger than normal age.
Short telomere length
MedGen UID:
1627435
Concept ID:
C4531138
Anatomical Abnormality
An abnormal reduction in telomere length. Telomeres are non-coding, repetitive sequences of DNA at the ends of the chromosomes of eukaryotic cells which become shorter as cells divide, and when telomere attrition reaches its limit, cell proliferation arrest, senescence, and apoptosis can occur.

Professional guidelines

PubMed

Rajan SK, Cottin V, Dhar R, Danoff S, Flaherty KR, Brown KK, Mohan A, Renzoni E, Mohan M, Udwadia Z, Shenoy P, Currow D, Devraj A, Jankharia B, Kulshrestha R, Jones S, Ravaglia C, Quadrelli S, Iyer R, Dhooria S, Kolb M, Wells AU
Eur Respir J 2023 Mar;61(3) Epub 2023 Mar 30 doi: 10.1183/13993003.03187-2021. PMID: 36517177Free PMC Article
Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, Kreuter M, Lynch DA, Maher TM, Martinez FJ, Molina-Molina M, Myers JL, Nicholson AG, Ryerson CJ, Strek ME, Troy LK, Wijsenbeek M, Mammen MJ, Hossain T, Bissell BD, Herman DD, Hon SM, Kheir F, Khor YH, Macrea M, Antoniou KM, Bouros D, Buendia-Roldan I, Caro F, Crestani B, Ho L, Morisset J, Olson AL, Podolanczuk A, Poletti V, Selman M, Ewing T, Jones S, Knight SL, Ghazipura M, Wilson KC
Am J Respir Crit Care Med 2022 May 1;205(9):e18-e47. doi: 10.1164/rccm.202202-0399ST. PMID: 35486072Free PMC Article
Thenappan T, Ormiston ML, Ryan JJ, Archer SL
BMJ 2018 Mar 14;360:j5492. doi: 10.1136/bmj.j5492. PMID: 29540357Free PMC Article

Recent clinical studies

Etiology

Strykowski R, Adegunsoye A
Immunol Allergy Clin North Am 2023 May;43(2):209-228. Epub 2023 Mar 3 doi: 10.1016/j.iac.2023.01.010. PMID: 37055085
Rajan SK, Cottin V, Dhar R, Danoff S, Flaherty KR, Brown KK, Mohan A, Renzoni E, Mohan M, Udwadia Z, Shenoy P, Currow D, Devraj A, Jankharia B, Kulshrestha R, Jones S, Ravaglia C, Quadrelli S, Iyer R, Dhooria S, Kolb M, Wells AU
Eur Respir J 2023 Mar;61(3) Epub 2023 Mar 30 doi: 10.1183/13993003.03187-2021. PMID: 36517177Free PMC Article
Cottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, Skowasch D, Park JS, Poonyagariyagorn HK, Wuyts W, Wells AU
Eur Respir Rev 2018 Dec 31;27(150) Epub 2018 Dec 21 doi: 10.1183/16000617.0076-2018. PMID: 30578335Free PMC Article
Hewlett JC, Kropski JA, Blackwell TS
Matrix Biol 2018 Oct;71-72:112-127. Epub 2018 Apr 3 doi: 10.1016/j.matbio.2018.03.021. PMID: 29625182Free PMC Article
Meyer KC
Expert Rev Respir Med 2017 May;11(5):343-359. Epub 2017 Apr 10 doi: 10.1080/17476348.2017.1312346. PMID: 28345383

Diagnosis

Koudstaal T, Funke-Chambour M, Kreuter M, Molyneaux PL, Wijsenbeek MS
Trends Mol Med 2023 Dec;29(12):1076-1087. Epub 2023 Sep 14 doi: 10.1016/j.molmed.2023.08.010. PMID: 37716906
Rajan SK, Cottin V, Dhar R, Danoff S, Flaherty KR, Brown KK, Mohan A, Renzoni E, Mohan M, Udwadia Z, Shenoy P, Currow D, Devraj A, Jankharia B, Kulshrestha R, Jones S, Ravaglia C, Quadrelli S, Iyer R, Dhooria S, Kolb M, Wells AU
Eur Respir J 2023 Mar;61(3) Epub 2023 Mar 30 doi: 10.1183/13993003.03187-2021. PMID: 36517177Free PMC Article
Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, Swigris JJ, Taniguchi H, Wells AU
Nat Rev Dis Primers 2017 Oct 20;3:17074. doi: 10.1038/nrdp.2017.74. PMID: 29052582
Richeldi L, Collard HR, Jones MG
Lancet 2017 May 13;389(10082):1941-1952. Epub 2017 Mar 30 doi: 10.1016/S0140-6736(17)30866-8. PMID: 28365056
Meyer KC
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Therapy

Koudstaal T, Wijsenbeek MS
Presse Med 2023 Sep;52(3):104166. Epub 2023 May 6 doi: 10.1016/j.lpm.2023.104166. PMID: 37156412
Glass DS, Grossfeld D, Renna HA, Agarwala P, Spiegler P, DeLeon J, Reiss AB
Clin Respir J 2022 Feb;16(2):84-96. Epub 2022 Jan 10 doi: 10.1111/crj.13466. PMID: 35001525Free PMC Article
Finnerty JP, Ponnuswamy A, Dutta P, Abdelaziz A, Kamil H
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Heukels P, Moor CC, von der Thüsen JH, Wijsenbeek MS, Kool M
Respir Med 2019 Feb;147:79-91. Epub 2019 Jan 9 doi: 10.1016/j.rmed.2018.12.015. PMID: 30704705
Liu T, De Los Santos FG, Phan SH
Methods Mol Biol 2017;1627:27-42. doi: 10.1007/978-1-4939-7113-8_2. PMID: 28836192

Prognosis

Shah Gupta R, Koteci A, Morgan A, George PM, Quint JK
BMJ Open Respir Res 2023 Jun;10(1) doi: 10.1136/bmjresp-2022-001291. PMID: 37308252Free PMC Article
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Maher TM, Bendstrup E, Dron L, Langley J, Smith G, Khalid JM, Patel H, Kreuter M
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Hutchinson J, Fogarty A, Hubbard R, McKeever T
Eur Respir J 2015 Sep;46(3):795-806. Epub 2015 May 14 doi: 10.1183/09031936.00185114. PMID: 25976683
Ley B, Collard HR, King TE Jr
Am J Respir Crit Care Med 2011 Feb 15;183(4):431-40. Epub 2010 Oct 8 doi: 10.1164/rccm.201006-0894CI. PMID: 20935110

Clinical prediction guides

Cottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, Skowasch D, Park JS, Poonyagariyagorn HK, Wuyts W, Wells AU
Eur Respir Rev 2018 Dec 31;27(150) Epub 2018 Dec 21 doi: 10.1183/16000617.0076-2018. PMID: 30578335Free PMC Article
Richeldi L
Eur Respir Rev 2013 Jun 1;22(128):103-5. doi: 10.1183/09059180.00001413. PMID: 23728863Free PMC Article
Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, Poletti V, Buccioli M, Elicker BM, Jones KD, King TE Jr, Collard HR
Ann Intern Med 2012 May 15;156(10):684-91. doi: 10.7326/0003-4819-156-10-201205150-00004. PMID: 22586007
Zisman DA, Keane MP, Belperio JA, Strieter RM, Lynch JP 3rd
Methods Mol Med 2005;117:3-44. doi: 10.1385/1-59259-940-0:003. PMID: 16130230Free PMC Article
Thannickal VJ, Toews GB, White ES, Lynch JP 3rd, Martinez FJ
Annu Rev Med 2004;55:395-417. doi: 10.1146/annurev.med.55.091902.103810. PMID: 14746528

Recent systematic reviews

Shah Gupta R, Koteci A, Morgan A, George PM, Quint JK
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Chen B, Yan Y, Wang H, Xu J
Aging Cell 2023 Jul;22(7):e13874. Epub 2023 May 26 doi: 10.1111/acel.13874. PMID: 37232505Free PMC Article
Finnerty JP, Ponnuswamy A, Dutta P, Abdelaziz A, Kamil H
BMC Pulm Med 2021 Dec 11;21(1):411. doi: 10.1186/s12890-021-01783-1. PMID: 34895203Free PMC Article
Dowman L, Hill CJ, May A, Holland AE
Cochrane Database Syst Rev 2021 Feb 1;2(2):CD006322. doi: 10.1002/14651858.CD006322.pub4. PMID: 34559419Free PMC Article
Hutchinson J, Fogarty A, Hubbard R, McKeever T
Eur Respir J 2015 Sep;46(3):795-806. Epub 2015 May 14 doi: 10.1183/09031936.00185114. PMID: 25976683

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