Clinical and laboratory findings in patients with the UNC13D intron 1 mutation, c.118-308C > T, and/or the 253-kb inversion
. | Patient A . | Patient B:1 . | Patient B:2 . | Patient C . | Patient D . | Patient E . | Patient F . | Patient G . | Patient H . | Patient I . | . | Patient J:1 . | Patient J:2 . | Patient K . | Patient L . | Patient M . | Patient N . | Patient O:1 . | Patient O:2 . | Patient P . | Patient Q . | Patient R . |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ethnical origin | Croatia | Slovenia | Slovenia | Sweden | Denmark/Ukraine | Croatia | Sweden | Denmark | Sweden | Finland | Ethnical origin | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden/USA | Sweden | Norway |
Familial disease | No | Yes | Yes | No | No | No | No | No | No | Familial disease | Yes | Yes | No | Yes | No | No | Yes | Yes | No | No | No | |
Parental consanguinity | No | No | No | No | No | No | No | No | No | No | Parental consanguinity | No | No | No | No | No | No | No | No | No | ||
Sex | Male | Male | Male | Male | Male | Female | Male | Female | Female | Male | Sex | Female | Female | Female | Female | Male | Female | Male | Female | Female | Female | Male |
Allele 1 | 753 + 1G, splice error | 2642T > C, Leu881Pro | 2642T > C, Leu881Pro | 532delC, Gln178ArgfsX71 | 2346_2349delGGAG, Arg782SerfsX12 | 118-308C > T | Inversion | Inversion | Inversion | Inversion | Allele 1 | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | ||
Allele 2 | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 2346_2349delGGAG, Arg782SerfsX12 | 2176C > T, Gln726X | Allele 2 | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | ||
Age at diagnosis of HLH, days | 55 | 195 | 229 | 57 | 150 | 133 | 87 | 198 | 104 | 148 | Age at diagnosis of HLH, days | 365 | 1 | 79 | 459 | 104 | 127 | 56 | 134 | 73 | 3 | 388 |
Fever | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Fever | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes |
Splenomegaly | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | Splenomegaly | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Hepatomegaly | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Hepatomegaly | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes |
Hb, g/L | 100 | 115 | 105 | 70 | 61 | 81 | 60 | 95 | 46 | 97 | Hb, g/L | 83 | 138 | 62 | 100 | 87 | 100 | 58 | 65 | 82 | 61 | 62 |
Neutrophils, × 109/L | 0.3 | 0.8 | 1.0 | 1.0 | 0.4 | 0.0 | 0.2 | 0.6 | 0.4 | 0.9 | Neutrophils, × 109/L | 2.9 | 2.9 | 1.4 | 0.8 | 0.7 | 0.4 | 0.1 | 0.7 | 0.2 | 0.3 | 0.8 |
Platelets, × 109/L | 28 | 143 | 34 | 13 | 22 | 3 | 31 | 72 | 17 | 59 | Platelets, × 109/L | 38 | 15 | 32 | 15 | 12 | 37 | 7 | 76 | 18 | 10 | 33 |
Triglycerides, mM | 2.8 | 12 | 4.5 | 2.3 | 7.3 | 3.9 | 2.4 | 6.1 | 4.2 | 5.4 | Triglycerides, mM | 3.0 | 2.7 | 11 | 2.6 | 3.4 | 2.7 | 3.4 | 17.3 | 5.5 | 1.9 | 4.4 |
Fibrinogen, g/L | 0.9 | 1.5 | 4.2 | 2.1 | 0.9 | 0.6 | 1.2 | 2.3 | 0.6 | Fibrinogen, g/L | 0.5 | 0.6 | 1.2 | 2.4 | 0.6 | 0.7 | < 0.5 | 1.7 | 0.8 | 0.7 | 2.9 | |
Hemophagocytosis | Yes | Yes | No | No | No | Yes | No | Yes | Yes | Yes | Hemophagocytosis | Yes | No | No | No | No | Yes | ND | No | Yes (CSF) | No | Yes |
Ferritin, μg/L | 5000 | 6482 | 315 | 2800 | 2399 | 1020 | 1540 | 437 | 4148 | 1858 | Ferritin, μg/L | 2920 | > 15 000 | 5433 | 6597 | 7828 | 2387 | 11 372 | 208 | 8100 | 1147 | 1162 |
sCD25, U/mL | ND | ND | ND | > 7500 | ND | ND | 20 380 | ND | ND | 30 486 | sCD25, U/mL | 21 976 | ND | 5666 | 14 110 | ND | 11 861 | ND | 8802 | > 7500 | > 7500 | Elevated |
NK cell activity* | Borderline (11 LU) | ND | Defective | Defective | Defective | Defective | ND | Defective | Borderline (13 LU) | Defective | NK cell activity* | Defective | Defective | Defective | Defective | Defective | Defective | ND | Defective | Defective | Defective | Defective |
NK cell degranulation | Defective | ND | Defective | Low | Defective | Defective | ND | Defective | Defective | ND | NK cell degranulation | Defective | Defective | Defective | Defective | Defective | ND | ND | ND | Defective | Defective | ND |
Neurologic manifestations† | Yes | No | No | No | Yes | No | No | No | No | Yes | Neurologic manifestations† | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | No | No |
Pathologic CSF | Yes | No | No | No | Yes | Yes | Yes | Yes | Yes | Yes | Pathologic CSF | Yes | ND | Yes | Yes | Yes | ND | Yes | Yes | Yes | ND | Yes |
Treatment active disease | HLH-2004 | HLH-2004 | HSCT | HLH-2004 | HLH-2004 | HLH-2004 | HLH-94 | HLH-2004 | HLH-2004 | HLH-94 | Treatment active disease | HLH-2004 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-94 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-94 |
Remission at 2 months | Remission, but possible CNS progression | No | NA | No | Remission, but possible CNS progression | Yes | No | No | Yes | No | Remission at 2 months | No | No | No | No | No | No | No | Yes | No | No | Yes |
Age at HSCT, days | 245 | 191 | 273 | 128 | 297 | 653 | 177 | 373 | 419 | 471 | Age at HSCT | 705 | No | 195 | No | 224 | 371/853 | No | 197 | 150 | 86 | 843 |
Outcome | Alive | Deceased 226 days | Deceased 289 days | Alive | Deceased 312 days | Alive | Alive | Deceased 460 days | Alive | Alive | Outcome | Alive | Deceased 71 days | Alive | Deceased | Alive | Alive | Deceased 143 days | Alive | Alive | Deceased | Alive |
. | Patient A . | Patient B:1 . | Patient B:2 . | Patient C . | Patient D . | Patient E . | Patient F . | Patient G . | Patient H . | Patient I . | . | Patient J:1 . | Patient J:2 . | Patient K . | Patient L . | Patient M . | Patient N . | Patient O:1 . | Patient O:2 . | Patient P . | Patient Q . | Patient R . |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Ethnical origin | Croatia | Slovenia | Slovenia | Sweden | Denmark/Ukraine | Croatia | Sweden | Denmark | Sweden | Finland | Ethnical origin | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden | Sweden/USA | Sweden | Norway |
Familial disease | No | Yes | Yes | No | No | No | No | No | No | Familial disease | Yes | Yes | No | Yes | No | No | Yes | Yes | No | No | No | |
Parental consanguinity | No | No | No | No | No | No | No | No | No | No | Parental consanguinity | No | No | No | No | No | No | No | No | No | ||
Sex | Male | Male | Male | Male | Male | Female | Male | Female | Female | Male | Sex | Female | Female | Female | Female | Male | Female | Male | Female | Female | Female | Male |
Allele 1 | 753 + 1G, splice error | 2642T > C, Leu881Pro | 2642T > C, Leu881Pro | 532delC, Gln178ArgfsX71 | 2346_2349delGGAG, Arg782SerfsX12 | 118-308C > T | Inversion | Inversion | Inversion | Inversion | Allele 1 | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | ||
Allele 2 | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 118-308C > T | 2346_2349delGGAG, Arg782SerfsX12 | 2176C > T, Gln726X | Allele 2 | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | Inversion | ||
Age at diagnosis of HLH, days | 55 | 195 | 229 | 57 | 150 | 133 | 87 | 198 | 104 | 148 | Age at diagnosis of HLH, days | 365 | 1 | 79 | 459 | 104 | 127 | 56 | 134 | 73 | 3 | 388 |
Fever | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Fever | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes |
Splenomegaly | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | Splenomegaly | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
Hepatomegaly | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Hepatomegaly | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | Yes | Yes |
Hb, g/L | 100 | 115 | 105 | 70 | 61 | 81 | 60 | 95 | 46 | 97 | Hb, g/L | 83 | 138 | 62 | 100 | 87 | 100 | 58 | 65 | 82 | 61 | 62 |
Neutrophils, × 109/L | 0.3 | 0.8 | 1.0 | 1.0 | 0.4 | 0.0 | 0.2 | 0.6 | 0.4 | 0.9 | Neutrophils, × 109/L | 2.9 | 2.9 | 1.4 | 0.8 | 0.7 | 0.4 | 0.1 | 0.7 | 0.2 | 0.3 | 0.8 |
Platelets, × 109/L | 28 | 143 | 34 | 13 | 22 | 3 | 31 | 72 | 17 | 59 | Platelets, × 109/L | 38 | 15 | 32 | 15 | 12 | 37 | 7 | 76 | 18 | 10 | 33 |
Triglycerides, mM | 2.8 | 12 | 4.5 | 2.3 | 7.3 | 3.9 | 2.4 | 6.1 | 4.2 | 5.4 | Triglycerides, mM | 3.0 | 2.7 | 11 | 2.6 | 3.4 | 2.7 | 3.4 | 17.3 | 5.5 | 1.9 | 4.4 |
Fibrinogen, g/L | 0.9 | 1.5 | 4.2 | 2.1 | 0.9 | 0.6 | 1.2 | 2.3 | 0.6 | Fibrinogen, g/L | 0.5 | 0.6 | 1.2 | 2.4 | 0.6 | 0.7 | < 0.5 | 1.7 | 0.8 | 0.7 | 2.9 | |
Hemophagocytosis | Yes | Yes | No | No | No | Yes | No | Yes | Yes | Yes | Hemophagocytosis | Yes | No | No | No | No | Yes | ND | No | Yes (CSF) | No | Yes |
Ferritin, μg/L | 5000 | 6482 | 315 | 2800 | 2399 | 1020 | 1540 | 437 | 4148 | 1858 | Ferritin, μg/L | 2920 | > 15 000 | 5433 | 6597 | 7828 | 2387 | 11 372 | 208 | 8100 | 1147 | 1162 |
sCD25, U/mL | ND | ND | ND | > 7500 | ND | ND | 20 380 | ND | ND | 30 486 | sCD25, U/mL | 21 976 | ND | 5666 | 14 110 | ND | 11 861 | ND | 8802 | > 7500 | > 7500 | Elevated |
NK cell activity* | Borderline (11 LU) | ND | Defective | Defective | Defective | Defective | ND | Defective | Borderline (13 LU) | Defective | NK cell activity* | Defective | Defective | Defective | Defective | Defective | Defective | ND | Defective | Defective | Defective | Defective |
NK cell degranulation | Defective | ND | Defective | Low | Defective | Defective | ND | Defective | Defective | ND | NK cell degranulation | Defective | Defective | Defective | Defective | Defective | ND | ND | ND | Defective | Defective | ND |
Neurologic manifestations† | Yes | No | No | No | Yes | No | No | No | No | Yes | Neurologic manifestations† | Yes | Yes | Yes | Yes | Yes | Yes | Yes | No | Yes | No | No |
Pathologic CSF | Yes | No | No | No | Yes | Yes | Yes | Yes | Yes | Yes | Pathologic CSF | Yes | ND | Yes | Yes | Yes | ND | Yes | Yes | Yes | ND | Yes |
Treatment active disease | HLH-2004 | HLH-2004 | HSCT | HLH-2004 | HLH-2004 | HLH-2004 | HLH-94 | HLH-2004 | HLH-2004 | HLH-94 | Treatment active disease | HLH-2004 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-94 | HLH-2004 | HLH-2004 | HLH-2004 | HLH-94 |
Remission at 2 months | Remission, but possible CNS progression | No | NA | No | Remission, but possible CNS progression | Yes | No | No | Yes | No | Remission at 2 months | No | No | No | No | No | No | No | Yes | No | No | Yes |
Age at HSCT, days | 245 | 191 | 273 | 128 | 297 | 653 | 177 | 373 | 419 | 471 | Age at HSCT | 705 | No | 195 | No | 224 | 371/853 | No | 197 | 150 | 86 | 843 |
Outcome | Alive | Deceased 226 days | Deceased 289 days | Alive | Deceased 312 days | Alive | Alive | Deceased 460 days | Alive | Alive | Outcome | Alive | Deceased 71 days | Alive | Deceased | Alive | Alive | Deceased 143 days | Alive | Alive | Deceased | Alive |
Patient B:1 and B:2 carried a novel missense mutation, c.2642T > C, p.Leu881Pro predicted to be pathogenic using 2 different protein prediction programs (PolyPhen, SIFT30,31 ), whereas the other mutations are previously described.9,25,32
ND indicates no data; NA, not applicable; CSF, cerebrospinal fluid; CNS, central nervous system; and HSCT, hematopoietic stem cell transplantation.
Defective: ≤ 10 lytic units.
Reported at some point during the course of the disease.