Pulmonary Fibrosis And/or Bone Marrow Failure, Telomere-Related, 2

A number sign (#) is used with this entry because telomere-related pulmonary fibrosis and/or bone marrow failure-2 (PFBMFT2) is caused by heterozygous mutation in the TERC gene (602322) on chromosome 3q26.

For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742).

Clinical Features

Vulliamy et al. (2002) reported 5 unrelated patients with telomere-related bone marrow failure-2 causing aplastic anemia. Four patients were adults and ranged in age between 22 and 53 years, and 1 was a 5-year-old child. The patients were ascertained from a larger group of 41 patients with aplastic anemia.

Fogarty et al. (2003) assessed 2 families with onset of pancytopenia in adults and detected novel point mutations in the TERC gene in affected members of both families (see 602322.0007 and 602322.0008). Affected individuals in both families had no physical signs of dyskeratosis congenita and nearly normal blood counts, but all had severely shortened telomeres, reduced hematopoietic function, and elevated serum erythropoietin and thrombopoietin. Fogarty et al. (2003) concluded that bone marrow failure of variable severity can result from mutations in the TERC gene.

Armanios et al. (2007) reported a patient with adult-onset pulmonary fibrosis. There was a family history of pulmonary fibrosis spanning 4 generations. In addition, 3 family members had aplastic anemia and a fourth died of acute myeloid leukemia (AML), probably in the setting of aplastic anemia.

Kirwan et al. (2009) reported a boy with telomere-related bone marrow failure-2, manifest as severe aplastic anemia. His father later presented with myelodysplastic syndrome (MDS) at age 45 years. In vitro studies showed less than 1% telomerase activity, and telomeres in the father were very short. Family history revealed that the boy's paternal grandfather had anemia and thrombocytopenia.

Parry et al. (2011) demonstrated that a personal and family history of both aplastic anemia and pulmonary fibrosis is highly predictive for the presence of a germline mutation in the TERT or TERC genes. They performed a retrospective study of 10 patients referred for bone marrow failure or pulmonary fibrosis who had a family history of the other disorder. Six cases presented initially with aplastic anemia and 4 initially with interstitial lung disease. Six of the 10 were subsequently diagnosed with a second feature, including pulmonary or hepatic fibrosis, or hypoplastic marrow. The mean age at diagnosis for those who presented with aplastic anemia was significantly younger than those with pulmonary fibrosis (14 vs 51 years). All patients had at least 1 other first-degree relative with bone marrow failure or pulmonary disease, and the transmission pattern was consistent with autosomal dominant inheritance. In 8 of 10 families, there was phenotypic heterogeneity across generations: older generations first manifested with pulmonary fibrosis, whereas subsequent generations manifested with bone marrow failure at an earlier age. Although none had skin manifestations, most had premature graying of the hair before age 25 years. All 10 probands had a mutation in either the TERT (7 patients) (see, e.g., 187270.0018-187270.0020) or the TERC (3 patients) (see, e.g., 602322.0008 and 602322.0012) gene, and the mutations segregated with the disorder. The mutant genes were associated with very short telomerase lengths in patient lymphocytes (less than 1% of control). Parry et al. (2011) concluded that the complex of bone marrow failure and pulmonary fibrosis is highly specific for the presence of a germline telomerase defect.

Inheritance

The transmission pattern of PFBMFT2 in the family reported by Armanios et al. (2007) was consistent with autosomal dominant inheritance.

In 8 of 10 families with telomerase mutations, Parry et al. (2011) observed phenotypic heterogeneity across generations: older generations first manifested with pulmonary fibrosis, whereas subsequent generations manifested with bone marrow failure at an earlier age. These findings suggested that genetic anticipation due to telomere shortening is not only associated with early age of onset across generations, but also with a changing pattern of disease manifestations.

Molecular Genetics

Ball et al. (1998) found that patients with idiopathic aplastic anemia have shorter telomeres than normal controls. Because patients with the very rare autosomal dominant form of dyskeratosis congenita (127550), which is caused by mutation in the TERC gene, also have very short telomeres (Vulliamy et al., 2001), Vulliamy et al. (2002) performed mutation screens of the TERC gene in patients with aplastic anemia. They identified heterozygous TERC mutations in 2 of 17 patients with idiopathic aplastic anemia, in 3 of 27 patients with constitutional aplastic anemia, and in none of 214 normal controls. Furthermore, patients with TERC mutations had significantly shorter telomeres than age-matched controls. The 58G-A mutation (602322.0004) was found in 3 of the patients, 2 of whom were categorized as having idiopathic aplastic anemia and 1 as having constitutional aplastic anemia (associated with short stature and phimosis). This variability in the severity and age at onset in patients with the same mutation highlighted the role of other genetic or environmental factors in the clinical phenotype. Vulliamy et al. (2002) observed that in X-linked dyskeratosis congenita, which is also characterized by aplastic anemia, the recurrent mutation 1058C-T (300126.0006) is associated with a wide variation in the age at onset of aplastic anemia from 1 to 22 years.

Among 73 probands with familial idiopathic pulmonary fibrosis screened for mutation in the TERT or the TERC gene, Armanios et al. (2007) detected 1 patient with a heterozygous mutation in the TERC gene (602322.0009).

Alder et al. (2008) studied telomere length in 62 sporadic patients with idiopathic interstitial pneumonia, 50 (81%) of whom had been diagnosed with pulmonary fibrosis. They found that pulmonary fibrosis patients had shorter leukocyte telomeres than age-matched controls (p less than 0.0001). Screening the TERT and TERC genes in 100 consecutive patients, including the 62 individuals in whom telomere length had been measured, revealed a mutation in TERC in 1 patient (602322.0010). The authors noted that a subset of patients (10%) with no family history had telomere lengths in the range of known mutation carriers, even when mutations were not detected. In addition, from a total of 150 patients with pulmonary fibrosis, they detected a cluster of 4 (3%) patients, who also had cryptogenic liver cirrhosis, suggesting that the observed telomere shortening has consequences and can contribute to what appears clinically as 'idiopathic' progressive organ failure in the lung and the liver.

In a boy with aplastic anemia and his father with adult-onset myelodysplastic syndrome, Kirwan et al. (2009) identified a heterozygous mutation (602322.0013). The findings suggested that constitutional TERC mutations can be associated with the development of myelodysplastic syndrome even in the absence of aplastic anemia. Overall, Kirwan et al. (2009) identified TERT or TERC mutations in 4 of 20 families presenting with MDS/AML.