The known hereditary myeloid malignancy syndromes
| Class . | Hematologic malignancy risk . | Gene . | Disorder . | Hematologic phenotype . | Other phenotype . | Inheritance . | OMIM no. . | Key . |
|---|---|---|---|---|---|---|---|---|
| Familial MDS/AL syndrome | MDS AML ALL NHL CML | ANKRD26 | Thrombocytopenia 2 | Chronic thrombocytopenia with normal platelet size, easy bruising, increased plasma thrombopoietin, platelet dysfunction | NA | AD* | 188 000 | A |
| ETV6 | Thrombocytopenia 5 | Chronic thrombocytopenia with normal platelet size is present in nearly all mutation carriers, macrocytosis, easy bleeding/bruising | Esophageal dysmotility? Colon cancer? | AD | 616 216 | B | ||
| RUNX1 | FPD/AML | Mild to moderate chronic thrombocytopenia with normal platelet size, easy bleeding/bruising, epistaxis; platelet function may be abnormal on platelet aggregation studies | Eczema | AD | 601 399601 626 | C | ||
| DDX41 | Familial MDS/AML with mutated DDX41 | None until development of hematologic malignancy; MDS/AML often hypocellular with prominent erythroid dysplasia or erythroleukemia morphology | Autoimmune disorders? | AD | 153 550616 871 | D | ||
| CEBPA | Familial AML with CEBPA mutation | None until development of AML | NA | AD | 601 626 | E | ||
| GATA2 | Familial MDS/AML with GATA2 mutation | Mild cytopenias including chronic neutropenia, B-/NK-cell lymphopenia, monocytopenia are common | Anogenital or cutaneous warts, congenital sensorineural deafness, lymphedema, opportunistic infections (eg, atypical mycobacterial infections), pulmonary alveolar proteinosis immunodeficiency | AD | 614 038 | F | ||
| ATG2B/GSKIP | Myeloid neoplasms with germ line predisposition | Primary myelofibrosis, essential thrombocythemia | NA | AD | 601 626 | G | ||
| TERC/TERT | Telomere syndromes with familial MDS/AL presentation | Mild asymptomatic cytopenias, especially thrombocytopenia or macrocytosis, are common; if cytopenias are progressive or severe, AA or hematologic malignancy likely | Early-onset anogenital cancer, early onset head and neck cancer, esophageal stricture, hepatic cirrhosis, hepatopulmonary syndrome, osteoporosis, premature gray hair, pulmonary fibrosis or emphysema; lymphocyte subset telomere lengths <1st percentile for age. The classical triad of reticulated pigmentation, leukoplakia, and nail dystrophy less likely | AD, AR* | 601 626613 989614 742615 134 | H | ||
| SRP72 | Familial aplastic anemia/MDS with SRP72 mutation | None until development of MDS or aplastic anemia | Congenital sensorineural deafness | AD | 614 675 | I | ||
| IBMFSs | MDS AML ALL* Other* | ACD CTC1 DKC1 NHP2 NOP10 PARN RTEL1 TERC TERT TINF2 WRAP53 | Telomere syndromes | Cytopenias, macrocytosis, elevated hemoglobin F; if cytopenias are progressive or severe, AA or hematologic malignancy likely | Abnormal dentition, cerebellar hypoplasia, dental caries, developmental delay, early-onset head and neck cancer, esophageal stenosis, liver fibrosis, epiphora, intrauterine growth retardation, microcephaly, osteoporosis, premature gray hair, pulmonary fibrosis, testicular atrophy. The classical triad of reticulated pigmentation, leukoplakia, and nail dystrophy; lymphocyte subset telomere lengths <1st percentile for age | AD AR X-linked | 224 230268 130606 471608 833612 661613 987613 988613 990615 190616 353616 371616 373616 553 | J |
| FANCA FANCB FANCC FANCD1/BRCA2 FANCD2 FANCE FANCF FANCG FANCI FANCJ FANCL FANCM FANCN FANCS/BRCA1 | Fanconi anemia | Cytopenias, macrocytosis, elevated hemoglobin F; if cytopenias are progressive or severe, AA or hematologic malignancy likely | Anal atresia, absent kidney, cafe-au-lait spots, cleft palate, congenital heart defects, cryptorchidism, developmental delay, duplicated kidney, esophageal atresia, horseshoe kidney, hypergonadotrophic hypogonadism, kidney malformation, limb anomalies, microcephaly, nail dystrophy, radial ray anomalies, short neck, skin pigmentation abnormalities, small stature, strabismus, tracheoesophageal fistula, severe toxicity with cytotoxic exposures. Spontaneous and induced chromosomal instability | AR, X-linked | 227 645227 646227 650300 514600 901603 467605 724609 053609 054610 832614 082614 083 | K | ||
| Cancer predisposition syndromes | MDS AML ALL NHL HL MM | TP53 | Li-Fraumeni syndrome | None until development of hematologic malignancy; 6% of tumors in individuals with Li-Fraumeni syndrome are hematologic malignancies; therapy-related leukemias possible34,35 | Adrenocortical carcinoma, brain cancer, breast cancer, choroid plexus carcinoma, colon cancer, lung carcinoma, sarcoma, any tumor possible | AD | 137 800151 623601 626 | L |
| BRCA1 BRCA2 | Hereditary breast and ovarian cancer syndrome | None until development of hematologic malignancy.34,35 Therapy-related leukemias possible | Breast cancer, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, male breast cancer, melanoma | AD | 604 370612 555 | M | ||
| EPCAM MLH1 MSH2 MSH6 PMS2 | Lynch syndrome | None until development of hematologic malignancy | Colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, hepatobiliary cancers, microsatellite instability of tumor cells, ovarian cancer, sebaceous adenomas, sebaceous carcinoma, sebaceous epitheliomas, small bowel cancer, transitional cell carcinoma; also cafe-au-lait lesions and early-onset hematologic malignancies or brain tumors in MMR deficiency | AD AR (MMR deficiency) | 114 500120 435158 320276 300609 310613 244614 337614 350 | N | ||
| Familial MPNs | CML AML | ATG2B/GSKIP | Myeloid neoplasms with germ line predisposition | Primary myelofibrosis, essential thrombocythemia | NA | AD | 601 626 | O |
| RBBP6 | MPNs with germ line RBBP6 mutation | Primary myelofibrosis, essential thrombocythemia | Glioma | AD | 601 626 |
| Class . | Hematologic malignancy risk . | Gene . | Disorder . | Hematologic phenotype . | Other phenotype . | Inheritance . | OMIM no. . | Key . |
|---|---|---|---|---|---|---|---|---|
| Familial MDS/AL syndrome | MDS AML ALL NHL CML | ANKRD26 | Thrombocytopenia 2 | Chronic thrombocytopenia with normal platelet size, easy bruising, increased plasma thrombopoietin, platelet dysfunction | NA | AD* | 188 000 | A |
| ETV6 | Thrombocytopenia 5 | Chronic thrombocytopenia with normal platelet size is present in nearly all mutation carriers, macrocytosis, easy bleeding/bruising | Esophageal dysmotility? Colon cancer? | AD | 616 216 | B | ||
| RUNX1 | FPD/AML | Mild to moderate chronic thrombocytopenia with normal platelet size, easy bleeding/bruising, epistaxis; platelet function may be abnormal on platelet aggregation studies | Eczema | AD | 601 399601 626 | C | ||
| DDX41 | Familial MDS/AML with mutated DDX41 | None until development of hematologic malignancy; MDS/AML often hypocellular with prominent erythroid dysplasia or erythroleukemia morphology | Autoimmune disorders? | AD | 153 550616 871 | D | ||
| CEBPA | Familial AML with CEBPA mutation | None until development of AML | NA | AD | 601 626 | E | ||
| GATA2 | Familial MDS/AML with GATA2 mutation | Mild cytopenias including chronic neutropenia, B-/NK-cell lymphopenia, monocytopenia are common | Anogenital or cutaneous warts, congenital sensorineural deafness, lymphedema, opportunistic infections (eg, atypical mycobacterial infections), pulmonary alveolar proteinosis immunodeficiency | AD | 614 038 | F | ||
| ATG2B/GSKIP | Myeloid neoplasms with germ line predisposition | Primary myelofibrosis, essential thrombocythemia | NA | AD | 601 626 | G | ||
| TERC/TERT | Telomere syndromes with familial MDS/AL presentation | Mild asymptomatic cytopenias, especially thrombocytopenia or macrocytosis, are common; if cytopenias are progressive or severe, AA or hematologic malignancy likely | Early-onset anogenital cancer, early onset head and neck cancer, esophageal stricture, hepatic cirrhosis, hepatopulmonary syndrome, osteoporosis, premature gray hair, pulmonary fibrosis or emphysema; lymphocyte subset telomere lengths <1st percentile for age. The classical triad of reticulated pigmentation, leukoplakia, and nail dystrophy less likely | AD, AR* | 601 626613 989614 742615 134 | H | ||
| SRP72 | Familial aplastic anemia/MDS with SRP72 mutation | None until development of MDS or aplastic anemia | Congenital sensorineural deafness | AD | 614 675 | I | ||
| IBMFSs | MDS AML ALL* Other* | ACD CTC1 DKC1 NHP2 NOP10 PARN RTEL1 TERC TERT TINF2 WRAP53 | Telomere syndromes | Cytopenias, macrocytosis, elevated hemoglobin F; if cytopenias are progressive or severe, AA or hematologic malignancy likely | Abnormal dentition, cerebellar hypoplasia, dental caries, developmental delay, early-onset head and neck cancer, esophageal stenosis, liver fibrosis, epiphora, intrauterine growth retardation, microcephaly, osteoporosis, premature gray hair, pulmonary fibrosis, testicular atrophy. The classical triad of reticulated pigmentation, leukoplakia, and nail dystrophy; lymphocyte subset telomere lengths <1st percentile for age | AD AR X-linked | 224 230268 130606 471608 833612 661613 987613 988613 990615 190616 353616 371616 373616 553 | J |
| FANCA FANCB FANCC FANCD1/BRCA2 FANCD2 FANCE FANCF FANCG FANCI FANCJ FANCL FANCM FANCN FANCS/BRCA1 | Fanconi anemia | Cytopenias, macrocytosis, elevated hemoglobin F; if cytopenias are progressive or severe, AA or hematologic malignancy likely | Anal atresia, absent kidney, cafe-au-lait spots, cleft palate, congenital heart defects, cryptorchidism, developmental delay, duplicated kidney, esophageal atresia, horseshoe kidney, hypergonadotrophic hypogonadism, kidney malformation, limb anomalies, microcephaly, nail dystrophy, radial ray anomalies, short neck, skin pigmentation abnormalities, small stature, strabismus, tracheoesophageal fistula, severe toxicity with cytotoxic exposures. Spontaneous and induced chromosomal instability | AR, X-linked | 227 645227 646227 650300 514600 901603 467605 724609 053609 054610 832614 082614 083 | K | ||
| Cancer predisposition syndromes | MDS AML ALL NHL HL MM | TP53 | Li-Fraumeni syndrome | None until development of hematologic malignancy; 6% of tumors in individuals with Li-Fraumeni syndrome are hematologic malignancies; therapy-related leukemias possible34,35 | Adrenocortical carcinoma, brain cancer, breast cancer, choroid plexus carcinoma, colon cancer, lung carcinoma, sarcoma, any tumor possible | AD | 137 800151 623601 626 | L |
| BRCA1 BRCA2 | Hereditary breast and ovarian cancer syndrome | None until development of hematologic malignancy.34,35 Therapy-related leukemias possible | Breast cancer, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, male breast cancer, melanoma | AD | 604 370612 555 | M | ||
| EPCAM MLH1 MSH2 MSH6 PMS2 | Lynch syndrome | None until development of hematologic malignancy | Colorectal cancer, endometrial cancer, gastric cancer, glioblastoma, hepatobiliary cancers, microsatellite instability of tumor cells, ovarian cancer, sebaceous adenomas, sebaceous carcinoma, sebaceous epitheliomas, small bowel cancer, transitional cell carcinoma; also cafe-au-lait lesions and early-onset hematologic malignancies or brain tumors in MMR deficiency | AD AR (MMR deficiency) | 114 500120 435158 320276 300609 310613 244614 337614 350 | N | ||
| Familial MPNs | CML AML | ATG2B/GSKIP | Myeloid neoplasms with germ line predisposition | Primary myelofibrosis, essential thrombocythemia | NA | AD | 601 626 | O |
| RBBP6 | MPNs with germ line RBBP6 mutation | Primary myelofibrosis, essential thrombocythemia | Glioma | AD | 601 626 |
AD, autosomal dominant; AR, autosomal recessive; MMR, mismatch repair; NA, not applicable; NK, natural killer.
Indicates that association is less established and is an area of ongoing investigation.