Patient characteristics and assays
| Donors (UPN) . | Gender (no. of patients) . | Age, y . | Mutation . | Phenotype . | Assays* . |
|---|---|---|---|---|---|
| Median (range) . | |||||
| TBD† | 8 M, 3 F (n = 11) | 14 (3-54) | |||
| Patient 1 NCI 6-2‡ | M | 16 | TERC | Mild thrombocytopenia, no DC, | CFE, adipo, SA-βG, transplant |
| Patient 2 NCI 156-1 | M | 3 | TINF2 | Nail dysplasia, SAA, femur FX age 7 | CFE, adipo, SA-βG, transplant |
| Patient 3 NCI 164-2 | M | 3 | RTEL1 | Severe phenotype (HH) | CFE, adipo, SA-βG, transplant |
| Patient 4 NCI 6-1‡ | F | 48 | TERC | DC, SAA, AVN femur head | CFE, adipo, SA-βG |
| Patient 5 NCI 26-1 | M | 29 | TERT | AVN femur head | Biopsy, CFE, adipo, PPARG, SA-βG transplant |
| Patient 6 NCI 180-1 | M | 8 | RTEL1 | Severe phenotype (HH), DC, FX of finger, bone age 14 | CFE, adipo, SA-βG, transplant |
| Patient 7 NHLBI 53-6§ | F | 54 | TERT | Pulmonary fibrosis, hypocellular marrow, normal CBC, early graying | Fibrosis |
| Patient 8 NHLBI-42-4§ | M | 52 | TERT | Hypocellular marrow, normal CBC | Fibrosis |
| Patient 9 NCI 202-1 | M | 14 | WRAP53 | Nail dysplasia, esophageal web, developmental delay, renal anomaly, SAA | CFE, adipo, PPARG, transplant |
| Patient 10 NCI 201-1 | F | 13 | No telomere-related mutation found to date | Mild thrombocytopenia and neutropenia, microcephaly | CFE, adipo, transplant |
| Patient 11 NCI 160-1 | M | 7 | TINF2 | Severe phenotype, DC, microcephaly, epiphora, SAA, FX of femur, humerus, clavicle, age 7 | CFE, adipo, transplant |
| SDS | 3 M, 1 F (n = 4) | 12 (6-15) | CFE | ||
| NCI 11-1 | |||||
| NCI 46-1 | |||||
| NCI 178-1 | |||||
| NCI 173-1 | |||||
| DBA | 2 M, 2 F (n = 4) | 34.5 (8-58) | CFE | ||
| NCI 193-1 | |||||
| NCI 193-2 | |||||
| NCI R2-072-1, | |||||
| NCI 150-1 | |||||
| AAA | 6 M, 2 F (n = 8) | 27 (5-61) | CFE, transplant | ||
| NHLBI 64-1 | |||||
| NHLBI 02-9 | |||||
| NHLBI 73-0 | |||||
| NHLBI 65-3 | |||||
| NHLBI 28-1 | |||||
| NHLBI 65-3 | |||||
| NHLBI 93-0 | |||||
| NHLBI 43-7 | |||||
| Normal donors (N) | 8 M, 5 F (n = 13) | 20 (18-59) | Used for all assays | ||
| Donors related to patients 7, 8§ | |||||
| Donor A | M | 44 | No TERT mutation | Normal marrow and CBC, TL – 6.2 kb (between first and fifth percentile) | Fibrosis |
| NHLBI 21-3 | |||||
| Donor B | F | 54 | No TERT mutation | Borderline hypocellular marrow, normal CBC, early graying, TL – 6.1 kb (between first and fifth percentile) | Fibrosis |
| NHLBI 56-1 | |||||
| Donor C | M | 52 | No TERT mutation | Borderline hypocellular marrow, normal CBC, TL – 5.4 kb (between first and fifth percentile) | Fibrosis |
| NHLBI 09-8 |
| Donors (UPN) . | Gender (no. of patients) . | Age, y . | Mutation . | Phenotype . | Assays* . |
|---|---|---|---|---|---|
| Median (range) . | |||||
| TBD† | 8 M, 3 F (n = 11) | 14 (3-54) | |||
| Patient 1 NCI 6-2‡ | M | 16 | TERC | Mild thrombocytopenia, no DC, | CFE, adipo, SA-βG, transplant |
| Patient 2 NCI 156-1 | M | 3 | TINF2 | Nail dysplasia, SAA, femur FX age 7 | CFE, adipo, SA-βG, transplant |
| Patient 3 NCI 164-2 | M | 3 | RTEL1 | Severe phenotype (HH) | CFE, adipo, SA-βG, transplant |
| Patient 4 NCI 6-1‡ | F | 48 | TERC | DC, SAA, AVN femur head | CFE, adipo, SA-βG |
| Patient 5 NCI 26-1 | M | 29 | TERT | AVN femur head | Biopsy, CFE, adipo, PPARG, SA-βG transplant |
| Patient 6 NCI 180-1 | M | 8 | RTEL1 | Severe phenotype (HH), DC, FX of finger, bone age 14 | CFE, adipo, SA-βG, transplant |
| Patient 7 NHLBI 53-6§ | F | 54 | TERT | Pulmonary fibrosis, hypocellular marrow, normal CBC, early graying | Fibrosis |
| Patient 8 NHLBI-42-4§ | M | 52 | TERT | Hypocellular marrow, normal CBC | Fibrosis |
| Patient 9 NCI 202-1 | M | 14 | WRAP53 | Nail dysplasia, esophageal web, developmental delay, renal anomaly, SAA | CFE, adipo, PPARG, transplant |
| Patient 10 NCI 201-1 | F | 13 | No telomere-related mutation found to date | Mild thrombocytopenia and neutropenia, microcephaly | CFE, adipo, transplant |
| Patient 11 NCI 160-1 | M | 7 | TINF2 | Severe phenotype, DC, microcephaly, epiphora, SAA, FX of femur, humerus, clavicle, age 7 | CFE, adipo, transplant |
| SDS | 3 M, 1 F (n = 4) | 12 (6-15) | CFE | ||
| NCI 11-1 | |||||
| NCI 46-1 | |||||
| NCI 178-1 | |||||
| NCI 173-1 | |||||
| DBA | 2 M, 2 F (n = 4) | 34.5 (8-58) | CFE | ||
| NCI 193-1 | |||||
| NCI 193-2 | |||||
| NCI R2-072-1, | |||||
| NCI 150-1 | |||||
| AAA | 6 M, 2 F (n = 8) | 27 (5-61) | CFE, transplant | ||
| NHLBI 64-1 | |||||
| NHLBI 02-9 | |||||
| NHLBI 73-0 | |||||
| NHLBI 65-3 | |||||
| NHLBI 28-1 | |||||
| NHLBI 65-3 | |||||
| NHLBI 93-0 | |||||
| NHLBI 43-7 | |||||
| Normal donors (N) | 8 M, 5 F (n = 13) | 20 (18-59) | Used for all assays | ||
| Donors related to patients 7, 8§ | |||||
| Donor A | M | 44 | No TERT mutation | Normal marrow and CBC, TL – 6.2 kb (between first and fifth percentile) | Fibrosis |
| NHLBI 21-3 | |||||
| Donor B | F | 54 | No TERT mutation | Borderline hypocellular marrow, normal CBC, early graying, TL – 6.1 kb (between first and fifth percentile) | Fibrosis |
| NHLBI 56-1 | |||||
| Donor C | M | 52 | No TERT mutation | Borderline hypocellular marrow, normal CBC, TL – 5.4 kb (between first and fifth percentile) | Fibrosis |
| NHLBI 09-8 |
Comparison by age: TBD vs SDS, P = .468; TBD vs DBA, P = .322; TBD vs AAA, P = .238; TBD vs N, P = .186.
AAA, acquired aplastic anemia, characterized by nonfamilial acquired immunosuppression-responsive pancytopenia; adipo, adipogenesis confirmed by Oil Red O staining; AVN, avascular necrosis; CBC, complete blood count; CFE, colony-forming efficiency assays, primary and/or secondary; DBA, Diamond-Blackfan anemia, characterized by congenital erythroid aplasia, with normal levels of other blood cells; DC, dyskeratosis congenita, characterized by the classical triad of oral leukoplakia, skin hypo/hyperpigmentation, nail dysplasia; F, female; FX, fracture; HH, Hoyeraal-Hreidarsson syndrome: includes microcephaly, cerebellar hypoplasia, developmental delay, immune deficiency, aplastic anemia, intrauterine growth retardation; M, male; MAA, moderate aplastic anemia; NCI, National Cancer Institute; NHLBI, National Heart, Lung, and Blood Institute; PPARG, qRT-PCR measurement of PPARG mRNA; SAA, severe aplastic anemia; SA-βG, measured for senescence-associated β-galactosidase staining; SDS, Shwachman-Diamond syndrome, characterized by exocrine pancreatic insufficiency, BM dysfunction, skeletal abnormalities and short stature; TBD, telomere biology disorders; TL, telomere length, as determined by automated multicolor flow fluorescence in situ hybridization6,58,59 ; transplant, cells were used to generate transplants by attachment to HA/TCP scaffolds and placed subcutaneously into immunocompromised mice; UPN, unique patient number.
All cultures were examined for morphologic changes (fibrosis, formation of adipocytes, cell shape changes) by standard inverted microscopy during culture.
All TBD patients had short telomeres compared with normal age-matched controls as determined by automated multicolor flow fluorescence in situ hybridization.6,58,59
Family members.
Siblings of the proband; sample from the proband was unavailable.