Clinical cohort of individuals with A91V/pLOF genotype
| ID . | Patient information . | PRF1 variant in trans to A91V (c.272 C>T) . | Clinical characteristics . | Therapy and outcome . | Reference . | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Sex, age (at last clinical information in y) . | Reason for genetic testing . | Protein change . | Genetic variant . | First clinical manifestation (age at onset) . | Second clinical manifestation (age at onset) . | Third clinical manifestation (age at onset) . | Information on disease trigger . | HSCT (age) . | Outcome at last clinical information (cause of death) . | ||
| 1 | M, 18 | HLH (≥5/8) | L17Rfs∗34 | c.50del | HLH (≥5/8) (18 y) | None | Allogeneic (19 y) | Alive and well | PNR | ||
| 2 | M, 47 | Other clinical symptoms | R28C | c.82C>T | CNS inflammatory disorder (CLIPPERS) (42 y) | n/a | No | Alive | 19 | ||
| 3 | M, 62 | Other clinical symptoms | P39H | c.116C>A | CNS inflammatory disorder (CLIPPERS) (52 y) | n/a | No | Alive | 19 | ||
| 4 | M, 23 | HLH-like systemic disease (<5/8) | R54C | c.160C>T | HLH-like systemic disease (<5/8) (22 y) | None | No | Dead (HLH activity) | 20 | ||
| 5 | M, 0.1 | HLH-like systemic disease (<5/8) | G71S | c.211G>A | HLH-like systemic disease (<5/8) (0.1 y) | None | No | Dead (HLH activity) | PNR | ||
| 6 | M, 17 (iv) | HLH (≥5/8) | L80fsY∗27 | c.238del | HLH (≥5/8), CNS-HLH (17 y) | EBV infection (17 y) | Allogeneic (19 y) | Alive and well | PNR | ||
| 7 | M, 21 (iv) | Family screening | L80fsY∗27 | c.238del | Disease free | n/a | Alive and well | PNR | |||
| 8 | M, 23 (iv) | Family screening | L80fsY∗27 | c.238del | Disease free | n/a | Alive and well | PNR | |||
| 9 | F, 20 | HLH (≥5/8) | R104C | c.310C>T | HLH (≥5/8) (20 y) | None | Allogeneic (21 y) | Dead (HSCT related) | 21 | ||
| 10 | F, 15 | HLH-like systemic disease including CNS | I125T | c.374T>C | Recurrent episodes of fever, pancytopenia, and splenomegaly (11 y) | HLH-like systemic disease (<5/8) (13 y) | None | No | Alive and well | 22 | |
| 11 | M, 25 | HLH (≥5/8) | G149S | c.445G>A | HLH (≥5/8); granuloma sinus cavernous (25 y) | None | No | Alive with severe sequelae | PNR | ||
| 12 | M, 25 | HLH (≥5/8) | G149S | c.445G>A | HLH (≥5/8) (25 y) | None | Unknown | PNR | |||
| 13 | F, 72 | HLH (≥5/8) | G149S | c.445G>A | Bladder carcinoma (66 y) | HLH (≥5/8) (72 y) | CNS-HLH (72 y) | CNS-HLH triggered by EBV reactivation | No | Dead (MOF) | 23 |
| 14 | F, 21 | HLH (≥5/8) | G149S | c.445G>A | HLH (≥5/8) (21 y) | T-cell lymphoma (21 y) | Lymphoma | No | Dead (MOF) | PNR | |
| 15 | F, 31 | Family screening | G149S | c.445G>A | Disease free | n/a | Alive and well | 24 | |||
| 16 | F, 9 | HLH-like systemic disease including CNS | S150∗ | c.449C>A | CNS-HLH, EBV-encephalitis (8 y) | First EBV infection | Allogeneic (9 y) | Alive and well | PNR | ||
| 17 | M, 1.5 (iii) | HLH (≥5/8) | R177C | c.529C>T | HLH (≥5/8) (neonatal) | Enterovirus meningitis | No | Alive and well | PNR | ||
| 18 | M, 4 (iii) | Family screening | R177C | c.529C>T | Disease free | n/a | Alive and well | PNR | |||
| 19 | F, 19 | HLH (≥5/8) | P188L | c.563C>T | HLH (≥5/8) (19 y) | Nr | Unknown | 7 (P10) | |||
| 20 | F, 4 | Other clinical symptoms | P188L | c.563C>T | Recurrent febrile episodes, persistent neutropenia, lymphadenopathy, leg abscesses, microcephaly, and failure to thrive (3 y) | n/a | No | Alive with severe sequelae | PNR | ||
| 21 | F, 6.5 | HLH-like systemic disease (<5/8) | Y219∗ | c.657C>A | HLH-like systemic disease (<5/8) (0.2 y) | None | Allogeneic (0.5 y) | Alive and well | PNR | ||
| 22 | M, 41 | Family screening | G220S | c.658G>A | Disease free | n/a | Alive and well | PNR | |||
| 23 | F, 42 | HLH (≥5/8) | H222Q | c.666C>A | HLH (≥5/8) (42 y) | Acute liver failure (42 y) | Nr | Unknown | PNR | ||
| 24 | M, 44 | HLH (≥5/8) | H222Q | c.666C>A | HLH (≥5/8) (44 y) | Nr | Unknown | PNR | |||
| 25 | F, 42 | Family screening | H222Q | c.666C>A | Disease free | n/a | Alive and well | PNR | |||
| 26 | F, 13 | Other clinical symptoms | R232H | c.695G>A | Anaplastic large cell lymphoma (13 y) | n/a | Unknown | 25 (P44) 26 (P4) | |||
| 27 | F, 1 | HLH (≥5/8) | R232H | c.695G>A | HLH (≥5/8) (1 y) | Mycoplasma infection (1 y) | Allogeneic | Unknown | PNR | ||
| 28 | M, 13 | HLH (≥5/8) | R232H | c.695G>A | HLH (≥5/8) (4.5 y) | CNS-HLH (6 y) | EBV infection (4.5 y) | Allogeneic (7 y) | Alive and well | PNR | |
| 29 | F, 13 (vii) | HLH (≥5/8) | [A91V; R232H] | c.[272C>T; 695G>A] | HLH (≥5/8) (13 y) | None | No | Dead (HLH activity) | 27 (II-4) | ||
| 30 | F, 13 (vii) | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | 27 (II-3) | |||
| 31 | F, 39 (vi) | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | PNR | |||
| 32 | M, 27 (vi) | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | PNR | |||
| 33 | M, 1.5 | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | PNR | |||
| 34 | Nr, 0.4 | HLH (≥5/8) | [C279Y; R373C] | c.[836G>A; 1117C>T] | HLH (≥5/8) (5 mo) | Nr | Unknown | 28 (P73) | |||
| 35 | F, 20 | Other clinical symptoms | K285del | c.853_855del | Granulomatous interstitial lung disease (6 y) | CNS-HLH (10 y) | None | Allogeneic (10 y) | Alive and well | PNR | |
| 36 | M, 5 | HLH (≥5/8) | K285del | c.853_855del | CNS-HLH (0.3 y) | None | Allogeneic (5 y) | Dead (HSCT related) | PNR | ||
| 37 | F, 5 | HLH (≥5/8) | K284_K285del | 850_855del | CNS-HLH (0.2 y) | CMV-infection (0.2 y) | Allogeneic (2 y) | Alive and well | PNR | ||
| 38 | F, 49 | HLH (≥5/8) | Q324_A437delinsP | c.971_1309del | HLH (≥5/8) (40 y) | EBV infection (40 y) | Unknown | PNR | |||
| 39 | M, 18 | HLH (≥5/8) | V348M | c.1042G>A | HLH (≥5/8) (18 y) | Persisting neutropenia (18 y) | Nr | Unknown | 7 (P7) | ||
| 40 | M, 36 (i) | HLH-like systemic disease including CNS | W374∗ | c.1122G>A | HLH-like systemic disease including CNS (hemiplegia, somnolence, and multifocal demyelination) (22 y) | HLH (≥5/8) with cushingoid features (24 y) | HLH (≥5/8) (29 y) | None | No | Dead (HLH activity with severe CNS involvement) | 20,26,29 |
| 41 | F, 37 (i) | HLH-like systemic disease (<5/8) | W374∗ | c.1122G>A | HLH-like systemic disease (<5/8) (21 y) | T-cell lymphoma (21 y) | HLH (≥5/8) (37 y) | Lymphoma (21 y) | Autologous (21 y) Allogeneic (37 y) | Dead (HSCT related) | 20,26,29 |
| 42 | F, 9 | HLH (≥5/8) | W374∗ | c.1122G>A | CNS-HLH (5 y) | EBV infection (5 y) | Allogeneic (7 y) | Alive and well | PNR | ||
| 43 | M, 0.7 | HLH (≥5/8) | W374∗ | c.1122G>A | CNS-HLH (0.3 y) | None | Allogeneic (0.7 y) | Unknown | PNR | ||
| 44 | M, 21 (v) | HLH-like systemic disease including CNS | W374∗ | c.1122G>A | HLH-like systemic disease, CNS-HLH (21 y) | None | Allogeneic (22 y) | Dead (HSCT related) | PNR | ||
| 45 | M, 55 (v) | Family screening | W374∗ | c.1122G>A | Disease free | n/a | PNR | ||||
| 46 | M, 43 | HLH-like systemic disease (<5/8) | R385W | c.1153C>T | HLH-like systemic disease (<5/8) (42 y) | EBV-, Aspergillus-, Klebsiella p.-infections (42 y) | No | Dead (infection) | PNR | ||
| 47 | F, 30 | HLH (≥5/8) | Q405∗ | c.1213C>T | HLH (≥5/8) (25 y) | HLH (≥5/8) (27 y) | None | Allogeneic (29 y) | Dead (HSCT related) | PNR | |
| 48 | F, 53 | HLH (≥5/8) | Q405∗ | c.1213C>T | HLH (≥5/8) (5 y) | None | No | Alive and well | PNR | ||
| 49 | F, 43 (ii) | HLH (≥5/8) | R410W | c.1228C>T | HLH (≥5/8) (43 y) | EBV infection (43 y) | No | Dead (MOF) | 30 (II-1) | ||
| 50 | F, 35 (ii) | Family screening | R410W | c.1228C>T | Disease free | n/a | Alive and well | 30 (II-5) | |||
| 51 | M, 81 (ii) | Family screening | R410W | c.1228C>T | Disease free for FHL2 phenotypes. Other diseases: renal (54 y), prostate (71 y), gastric carcinoma (77 y), AML (81 y) | n/a | No | Dead (other) | 30 (I-1) | ||
| 52 | F, 7 | HLH (≥5/8) | F421C | c.1262T>G | HLH-like systemic disease (<5/8) (7 y) | SPTCL (7 y) | Liver disease (7 y) | Lymphoma (7 y) | No | Dead (HLH activity) | 31 (P3) 26 (P3) |
| ID . | Patient information . | PRF1 variant in trans to A91V (c.272 C>T) . | Clinical characteristics . | Therapy and outcome . | Reference . | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Sex, age (at last clinical information in y) . | Reason for genetic testing . | Protein change . | Genetic variant . | First clinical manifestation (age at onset) . | Second clinical manifestation (age at onset) . | Third clinical manifestation (age at onset) . | Information on disease trigger . | HSCT (age) . | Outcome at last clinical information (cause of death) . | ||
| 1 | M, 18 | HLH (≥5/8) | L17Rfs∗34 | c.50del | HLH (≥5/8) (18 y) | None | Allogeneic (19 y) | Alive and well | PNR | ||
| 2 | M, 47 | Other clinical symptoms | R28C | c.82C>T | CNS inflammatory disorder (CLIPPERS) (42 y) | n/a | No | Alive | 19 | ||
| 3 | M, 62 | Other clinical symptoms | P39H | c.116C>A | CNS inflammatory disorder (CLIPPERS) (52 y) | n/a | No | Alive | 19 | ||
| 4 | M, 23 | HLH-like systemic disease (<5/8) | R54C | c.160C>T | HLH-like systemic disease (<5/8) (22 y) | None | No | Dead (HLH activity) | 20 | ||
| 5 | M, 0.1 | HLH-like systemic disease (<5/8) | G71S | c.211G>A | HLH-like systemic disease (<5/8) (0.1 y) | None | No | Dead (HLH activity) | PNR | ||
| 6 | M, 17 (iv) | HLH (≥5/8) | L80fsY∗27 | c.238del | HLH (≥5/8), CNS-HLH (17 y) | EBV infection (17 y) | Allogeneic (19 y) | Alive and well | PNR | ||
| 7 | M, 21 (iv) | Family screening | L80fsY∗27 | c.238del | Disease free | n/a | Alive and well | PNR | |||
| 8 | M, 23 (iv) | Family screening | L80fsY∗27 | c.238del | Disease free | n/a | Alive and well | PNR | |||
| 9 | F, 20 | HLH (≥5/8) | R104C | c.310C>T | HLH (≥5/8) (20 y) | None | Allogeneic (21 y) | Dead (HSCT related) | 21 | ||
| 10 | F, 15 | HLH-like systemic disease including CNS | I125T | c.374T>C | Recurrent episodes of fever, pancytopenia, and splenomegaly (11 y) | HLH-like systemic disease (<5/8) (13 y) | None | No | Alive and well | 22 | |
| 11 | M, 25 | HLH (≥5/8) | G149S | c.445G>A | HLH (≥5/8); granuloma sinus cavernous (25 y) | None | No | Alive with severe sequelae | PNR | ||
| 12 | M, 25 | HLH (≥5/8) | G149S | c.445G>A | HLH (≥5/8) (25 y) | None | Unknown | PNR | |||
| 13 | F, 72 | HLH (≥5/8) | G149S | c.445G>A | Bladder carcinoma (66 y) | HLH (≥5/8) (72 y) | CNS-HLH (72 y) | CNS-HLH triggered by EBV reactivation | No | Dead (MOF) | 23 |
| 14 | F, 21 | HLH (≥5/8) | G149S | c.445G>A | HLH (≥5/8) (21 y) | T-cell lymphoma (21 y) | Lymphoma | No | Dead (MOF) | PNR | |
| 15 | F, 31 | Family screening | G149S | c.445G>A | Disease free | n/a | Alive and well | 24 | |||
| 16 | F, 9 | HLH-like systemic disease including CNS | S150∗ | c.449C>A | CNS-HLH, EBV-encephalitis (8 y) | First EBV infection | Allogeneic (9 y) | Alive and well | PNR | ||
| 17 | M, 1.5 (iii) | HLH (≥5/8) | R177C | c.529C>T | HLH (≥5/8) (neonatal) | Enterovirus meningitis | No | Alive and well | PNR | ||
| 18 | M, 4 (iii) | Family screening | R177C | c.529C>T | Disease free | n/a | Alive and well | PNR | |||
| 19 | F, 19 | HLH (≥5/8) | P188L | c.563C>T | HLH (≥5/8) (19 y) | Nr | Unknown | 7 (P10) | |||
| 20 | F, 4 | Other clinical symptoms | P188L | c.563C>T | Recurrent febrile episodes, persistent neutropenia, lymphadenopathy, leg abscesses, microcephaly, and failure to thrive (3 y) | n/a | No | Alive with severe sequelae | PNR | ||
| 21 | F, 6.5 | HLH-like systemic disease (<5/8) | Y219∗ | c.657C>A | HLH-like systemic disease (<5/8) (0.2 y) | None | Allogeneic (0.5 y) | Alive and well | PNR | ||
| 22 | M, 41 | Family screening | G220S | c.658G>A | Disease free | n/a | Alive and well | PNR | |||
| 23 | F, 42 | HLH (≥5/8) | H222Q | c.666C>A | HLH (≥5/8) (42 y) | Acute liver failure (42 y) | Nr | Unknown | PNR | ||
| 24 | M, 44 | HLH (≥5/8) | H222Q | c.666C>A | HLH (≥5/8) (44 y) | Nr | Unknown | PNR | |||
| 25 | F, 42 | Family screening | H222Q | c.666C>A | Disease free | n/a | Alive and well | PNR | |||
| 26 | F, 13 | Other clinical symptoms | R232H | c.695G>A | Anaplastic large cell lymphoma (13 y) | n/a | Unknown | 25 (P44) 26 (P4) | |||
| 27 | F, 1 | HLH (≥5/8) | R232H | c.695G>A | HLH (≥5/8) (1 y) | Mycoplasma infection (1 y) | Allogeneic | Unknown | PNR | ||
| 28 | M, 13 | HLH (≥5/8) | R232H | c.695G>A | HLH (≥5/8) (4.5 y) | CNS-HLH (6 y) | EBV infection (4.5 y) | Allogeneic (7 y) | Alive and well | PNR | |
| 29 | F, 13 (vii) | HLH (≥5/8) | [A91V; R232H] | c.[272C>T; 695G>A] | HLH (≥5/8) (13 y) | None | No | Dead (HLH activity) | 27 (II-4) | ||
| 30 | F, 13 (vii) | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | 27 (II-3) | |||
| 31 | F, 39 (vi) | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | PNR | |||
| 32 | M, 27 (vi) | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | PNR | |||
| 33 | M, 1.5 | Family screening | [A91V; R232H] | c.[272C>T; 695G>A] | Disease free | n/a | Alive and well | PNR | |||
| 34 | Nr, 0.4 | HLH (≥5/8) | [C279Y; R373C] | c.[836G>A; 1117C>T] | HLH (≥5/8) (5 mo) | Nr | Unknown | 28 (P73) | |||
| 35 | F, 20 | Other clinical symptoms | K285del | c.853_855del | Granulomatous interstitial lung disease (6 y) | CNS-HLH (10 y) | None | Allogeneic (10 y) | Alive and well | PNR | |
| 36 | M, 5 | HLH (≥5/8) | K285del | c.853_855del | CNS-HLH (0.3 y) | None | Allogeneic (5 y) | Dead (HSCT related) | PNR | ||
| 37 | F, 5 | HLH (≥5/8) | K284_K285del | 850_855del | CNS-HLH (0.2 y) | CMV-infection (0.2 y) | Allogeneic (2 y) | Alive and well | PNR | ||
| 38 | F, 49 | HLH (≥5/8) | Q324_A437delinsP | c.971_1309del | HLH (≥5/8) (40 y) | EBV infection (40 y) | Unknown | PNR | |||
| 39 | M, 18 | HLH (≥5/8) | V348M | c.1042G>A | HLH (≥5/8) (18 y) | Persisting neutropenia (18 y) | Nr | Unknown | 7 (P7) | ||
| 40 | M, 36 (i) | HLH-like systemic disease including CNS | W374∗ | c.1122G>A | HLH-like systemic disease including CNS (hemiplegia, somnolence, and multifocal demyelination) (22 y) | HLH (≥5/8) with cushingoid features (24 y) | HLH (≥5/8) (29 y) | None | No | Dead (HLH activity with severe CNS involvement) | 20,26,29 |
| 41 | F, 37 (i) | HLH-like systemic disease (<5/8) | W374∗ | c.1122G>A | HLH-like systemic disease (<5/8) (21 y) | T-cell lymphoma (21 y) | HLH (≥5/8) (37 y) | Lymphoma (21 y) | Autologous (21 y) Allogeneic (37 y) | Dead (HSCT related) | 20,26,29 |
| 42 | F, 9 | HLH (≥5/8) | W374∗ | c.1122G>A | CNS-HLH (5 y) | EBV infection (5 y) | Allogeneic (7 y) | Alive and well | PNR | ||
| 43 | M, 0.7 | HLH (≥5/8) | W374∗ | c.1122G>A | CNS-HLH (0.3 y) | None | Allogeneic (0.7 y) | Unknown | PNR | ||
| 44 | M, 21 (v) | HLH-like systemic disease including CNS | W374∗ | c.1122G>A | HLH-like systemic disease, CNS-HLH (21 y) | None | Allogeneic (22 y) | Dead (HSCT related) | PNR | ||
| 45 | M, 55 (v) | Family screening | W374∗ | c.1122G>A | Disease free | n/a | PNR | ||||
| 46 | M, 43 | HLH-like systemic disease (<5/8) | R385W | c.1153C>T | HLH-like systemic disease (<5/8) (42 y) | EBV-, Aspergillus-, Klebsiella p.-infections (42 y) | No | Dead (infection) | PNR | ||
| 47 | F, 30 | HLH (≥5/8) | Q405∗ | c.1213C>T | HLH (≥5/8) (25 y) | HLH (≥5/8) (27 y) | None | Allogeneic (29 y) | Dead (HSCT related) | PNR | |
| 48 | F, 53 | HLH (≥5/8) | Q405∗ | c.1213C>T | HLH (≥5/8) (5 y) | None | No | Alive and well | PNR | ||
| 49 | F, 43 (ii) | HLH (≥5/8) | R410W | c.1228C>T | HLH (≥5/8) (43 y) | EBV infection (43 y) | No | Dead (MOF) | 30 (II-1) | ||
| 50 | F, 35 (ii) | Family screening | R410W | c.1228C>T | Disease free | n/a | Alive and well | 30 (II-5) | |||
| 51 | M, 81 (ii) | Family screening | R410W | c.1228C>T | Disease free for FHL2 phenotypes. Other diseases: renal (54 y), prostate (71 y), gastric carcinoma (77 y), AML (81 y) | n/a | No | Dead (other) | 30 (I-1) | ||
| 52 | F, 7 | HLH (≥5/8) | F421C | c.1262T>G | HLH-like systemic disease (<5/8) (7 y) | SPTCL (7 y) | Liver disease (7 y) | Lymphoma (7 y) | No | Dead (HLH activity) | 31 (P3) 26 (P3) |
CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CMV, cytomegalovirus; CNS, central nervous system; F, female; i-vii, individuals with similar signs belong to the same family; ID, patient identification number; M, male; MOF, multiorgan failure; n/a, not applicable; Nr, not reported; PNR, previously not reported; I-1, II-1, II-5, patient IDs in reference 30; II-3, II-4, patient IDs in reference 27.