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Letters to the Editor
Clinical diagnostic value of telomere length measurement in inherited bone marrow failure syndromes
Bone marrow failure (BMF) is characterized by a hypocellular marrow and encompasses a diverse group of inherited and acquired disorders. Inherited bone marrow failure syndromes (IBMFS) occur in approximately 5%– 30% of patients with BMF in pediatric cohorts and con- sist of more than 25 defined disease entities, including dyskeratosis congenita (DC), Fanconi anemia (FA), Diamond–Blackfan anemia (DBA), and Shwachman– Diamond syndrome (SDS).1 IBMFS are a heterogeneous group of disorders in which BMF is usually associated with physical abnormalities. The diagnosis of IBMFS pre- viously relied on the recognition of characteristic clinical features. Recent diagnostic advances using next-genera- tion sequencing have revealed that some patients initially diagnosed with idiopathic aplastic anemia (AA) had cryp- tic presentations of IBMFS.2 This issue is important as a more accurate diagnosis may improve treatment out- comes.
Telomeres are the end segments of chromosomes: they are composed of long DNA repeats and a protein com- plex, and are essential for genome integrity. Germline mutations in genes involved in telomere biology can result in significantly short telomere length (TL) in
peripheral blood lymphocytes in patients with DC.3 Although there is a consensus on the usefulness of TL for screening for DC, but not for other IBMFS, several inves- tigators have demonstrated that TL is excessively short in patients with AA4 and non-DC IBMFS,5 including FA, SDS, and DBA. To assess the diagnostic value of TL, we measured TL in 133 patients with BMF and compared it to that in patients with DC, non-DC IBMFS, and AA.
We retrospectively studied 133 patients (68 male and 65 female) with BMF in Japan between 2013 and 2018. We collected peripheral blood samples at diagnosis from all patients, measured TL from peripheral blood lympho- cytes, and performed targeted sequencing analysis cover- ing 184 genes associated with IBMFS (Online Supplementary Table S1), as described in our previous studies.2,4 TL was measured by flow-fluorescence in situ hybridization (flow-FISH) using a Telomere PNA Kit (Dako Cytomation, Glostrup, Denmark) according to the manufacturer’s instructions. We calculated the age- adjusted relative TL in terms of the standard deviation (SD) from 71 normal, age-matched, healthy controls (median age, 29 years; range, 1-47 years) as previously described.4 In 112 of 133 (84%) patients, paroxysmal nocturnal hemoglobinuria-type granulocytes and red blood cells were also evaluated by flow cytometry.4 As thresholds for determining the presence of minor paroxysmal nocturnal hemoglobinuria clones, we defined >0.020% and >0.037% for CD11b+ CD55-
Table 1. Clinical characteristics and laboratory findings of patients with bone marrow failure.
All patients DC Non-DC IBMFS AA (N=133) (n=11) (n=15) (n=107)
P
0.675 0.851
<0.001
0.024
0.374 0.011 0.065 0.307 0.121 0.106
0.632
<0.001
<0.001
<0.001
Age, years, median (range) Gender, n (%)
Male
Female Cytopenia, n (%)
Unilineage cytopenia Bicytopenia Pancytopenia
Severity, n (%)* Moderate Severe
Very severe
WBC, ×109/L, median (range) ANC, ×109/L, median (range) ALC, ×109/L, median (range)
Hb, g/dL, median (range) Platelets, ×109/L, median (range) ARC, ‰, median (range)
Minor PNH clones, n (%) Positive
Negative
Not done
Very short TL, < -2.19 SD, n (%)
RelativelyshortTL, <-1.71SD,n(%)
TL, SD, median (range)
7 (0-22)
68 (51) 65 (49)
4 (3) 24 (18) 105 (79)
67 (52)
35 (27)
27 (21) 2.8 (0.3-12.8) 0.6 (0.0-5.4) 1.8 (0.1-8.2) 8.0 (2.7-14.3) 2.5 (0.2-40.9) 11.5 (0.0-57.0)
42 (32) 70 (53) 21 (15) 31 (23) 44 (33)
-0.96 (-5.73 to +4.00)
7 (1-19)
5 (45) 6 (55)
1 (9) 3 (27) 7 (64)
7 (70)
2 (20)
1 (10)
2.7 (1.7-5.3) 0.8 (0.6-1.7) 1.3 (0.5-4.3) 8.4 (3.1-14.3) 2.5 (0.3-7.5) 15.5 (4.0-32.0)
3 (27) 5 (46) 3 (27) 10 (91) 10 (91)
-3.50 (-5.73 to +0.83)
6 (0-15)
7 (47) 8 (53)
3 (20) 3 (20) 9 (60)
10 (83)
2 (17)
0 (0)
3.1 (1.7-7.8) 0.9 (0.2-5.4) 2.1 (1.2-5.9) 6.6 (3.7-11.3) 3.6 (0.2-40.9) 12.7 (1.2-39.1)
3 (20)
10 (67)
2 (13)
4 (25)
9 (60)
-1.89 (-4.74 to +2.05)
7 (0-22)
56 (52) 51 (48)
0 (0) 18(17) 89 (83)
50 (47)
31 (29)
26 (24) 2.8 (0.3-12.8) 0.5 (0-5.2) 1.8 (0.1-8.2) 8.1 (2.7-14.0) 2.3 (0.2-38.0) 10.0 (0.0-57.0)
36 (34)
55 (51)
16 (15) 17(16)
25 (23)
-0.84 (-4.27 to +4.00)
DC: dyskeratosis congenital; IBMFS: inherited bone marrow failure syndromes; AA: aplastic anemia; WBC: white blood cell count; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; Hb: hemoglobin; ARC: absolute reticulocyte count; PNH: paroxysmal nocturnal hemoglobinuria; TL: telomere length; SD: standard deviation; *excluding patients with unilineage cytopenia.
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