Clinical features associated with MDS predisposition syndromes
| Hematologic abnormalities . | Syndrome . | Hematologic malignancy . | Other malignancy . | Variably associated abnormalities . |
|---|---|---|---|---|
| Marrow failure | Dyskeratosis congenita/telomere biology disorder | MDS, AML | Squamous cell carcinoma of head/neck/GI tract/skin, hepatic cancers | Nail dystrophy, skin hypo-/hyperpigmentation, mucous membrane leukoplakia, idiopathic pulmonary fibrosis, liver disease (cirrhosis, steatosis, portal hypertension), arteriovenous malformations, early gray hair, stenosis of lacrimal duct/esophagus/urethra, GI/enteropathy, avascular necrosis, osteoporosis, immunodeficiency/immune dysregulation, endocrinopathies, dental anomalies, exudative retinopathy (Coats disease/Revesz syndrome), CNS abnormalities/cerebellar hypoplasia, hypogonadism, Hoyeraal-Hreidarsson syndrome (IUGR, microcephaly, cerebellar hypoplasia, combined immune deficiency), short stature |
| Fanconi anemia | MDS, AML; ALL has been associated with FANCD1/BRCA2 | Squamous cell carcinoma: oral, GI, vulvar; hepatocellular carcinoma, hepatic adenoma | Short stature; hyper-/hypopigmentation (café au lait spots); facial dysmorphologies; skeletal anomalies, including radial ray anomalies, thumb hypoplasia, and hypoplastic thenar eminences; osteopenia; hypogonadism; cardiac malformations; gastrointestinal malformations; urogenital anomalies/malformations; renal malformations; endocrinopathies Increased toxicity with chemotherapy and radiation | |
| GATA2 spectrum disorders | MDS, AML, CMML, JMML, T-lymphoblastic leukemia | MonoMAC syndrome (monocytopenia with mycobacterial infections); DCML deficiency (dendritic cell, monocyte, B-cell, NK cell deficiency); susceptibility to mycobacterial, fungal, viral infections; warts; molluscum; pulmonary alveolar proteinosis; Emberger syndrome (lymphedema, sensorineural hearing loss) | ||
| Shwachman-Diamond syndrome | MDS, AML | Short stature; exocrine pancreatic dysfunction; pancreatic lipomatosis/atresia; skeletal dysplasias, including thoracic dystrophy or metaphyseal dysostosis; osteopenia; eczema; transient transaminitis/hepatomegaly in early childhood; dental anomalies; immunodeficiencies; endocrinopathies; neurocognitive and other variable congenital anomalies | ||
| SDS-like | Possibly AML | |||
| SAMD9 | MDS, AML | MIRAGE syndrome: infections, immunodeficiencies, failure to thrive, IUGR, adrenal insufficiency, genital anomalies, enteropathy | ||
| SAMD9L | MDS, AML | Ataxia, cerebellar hypoplasia | ||
| Bone marrow failure syndrome 1 (SRP72) | MDS | Sensorineural hearing loss | ||
| Bone marrow failure syndrome 2 (ERCC6L2) | MDS, AML | |||
| Thrombocytopenia, platelet dysfunction | Thrombocytopenia 2 (ANKRD26) | MDS, AML, CMML, CLL | Platelet dysfunction | |
| Familial platelet disorder with propensity to myeloid malignancy (RUNX1) | MDS, AML, T-ALL, hairy cell leukemia | Platelet dysfunction | ||
| Thrombocytopenia 5 (ETV6) | MDS, AML, CMML, ALL, MM | Platelet dysfunction | ||
| Red cell aplasia | Diamond-Blackfan anemia | MDS, AML | Osteosarcoma, soft tissue sarcomas, GI/colon cancer | Short stature, facial dysmorphisms, radial ray anomalies, skeletal anomalies, cardiac malformations, renal malformations Neutropenia and immunodeficiencies associated with RPL35a |
| Neutropenia, cyclic neutropenia | ELANE | MDS, AML | Osteopenia, monocytosis, eosinophilia | |
| Neutropenia | SCN (HAX1) | Seizures, neurologic abnormalities | ||
| SCN (GFI1) | Lymphopenia | |||
| SCN (G6PC3) | Structural heart disease, urogenital anomalies, prominent veins, deafness, skeletal anomalies, immune dysregulation, colitis, poor growth, thrombocytopenia | |||
| SCN (JAGN1) | Skeletal, dental anomalies | |||
| X-linked neutropenia (WAS) | MDS, AML | |||
| Bloom syndrome | MDS, AML, ALL, lymphoma | Carcinomas | Short stature, sun-sensitive rash, pulmonary disease, immunodeficiency | |
| Constitutional mismatch repair deficiency syndrome (Lynch syndrome) | MDS, AML, ALL, lymphoma | GI (colon), ovarian, uterine, CNS, other | ||
| Down syndrome | ALL, AML, transient myeloproliferative disorder | Mental retardation, short stature, facial dysmorphisms, palmar crease, cardiac anomalies, endocrinopathies, gastrointestinal anomalies | ||
| ERBB3 | Erythroid MDS, erythroleukemia | |||
| Familial AML (CEBPA) | AML | Eosinophilia | ||
| Li-Fraumeni syndrome | MDS, AML, ALL, lymphoma | Breast cancer, osteosarcoma, soft tissue sarcomas, brain tumors, adrenocortical carcinoma | ||
| Ligase IV syndrome | MDS, lymphoma, ALL | Short stature, microcephaly, facial dysmorphism, bone hypoplasia, congenital hip dysplasia, photosensitivity, plantar warts, hypopigmentation, eczema, immunodeficiency, developmental delay | ||
| MBD4 | MDS, AML | |||
| Neurofibromatosis 1 | MDS, JMML | Melanoma, optic gliomas, brain tumors, malignant peripheral nerve sheath tumors | Café au lait spots, axillary freckling, Lisch nodules, neurofibromas | |
| Nijmegen breakage syndrome | AML, ALL, lymphoma | Brain tumors, sarcomas | Microcephaly, short stature, café au lait macules, facial abnormalities, retrognathia, immunodeficiency | |
| Noonan syndrome | MDS, AML, JMML, ALL, MPN | Brain tumors | Facial dysmorphisms, short stature, cardiac anomalies, broad neck, thoracic anomalies, cryptorchidism | |
| Noonan-like (CBL) | JMML, MDS | |||
| Susceptibility to acute myeloid leukemia (DDX41) | MDS, AML, CML, lymphoma | |||
| Trisomy 8 mosaicism | MDS, AML, CML | Facial anomalies (wide-set eyes; broad, upturned nose; micrognathia; eye anomalies), cleft palate, shortened neck, renal anomalies, cardiac anomalies, brain malformations, absent kneecap | ||
| Werner syndrome | MDS, AML | Thyroid cancer, melanoma, meningioma, sarcomas | Thin/early graying hair, skin findings, short stature, cataracts, premature aging |
| Hematologic abnormalities . | Syndrome . | Hematologic malignancy . | Other malignancy . | Variably associated abnormalities . |
|---|---|---|---|---|
| Marrow failure | Dyskeratosis congenita/telomere biology disorder | MDS, AML | Squamous cell carcinoma of head/neck/GI tract/skin, hepatic cancers | Nail dystrophy, skin hypo-/hyperpigmentation, mucous membrane leukoplakia, idiopathic pulmonary fibrosis, liver disease (cirrhosis, steatosis, portal hypertension), arteriovenous malformations, early gray hair, stenosis of lacrimal duct/esophagus/urethra, GI/enteropathy, avascular necrosis, osteoporosis, immunodeficiency/immune dysregulation, endocrinopathies, dental anomalies, exudative retinopathy (Coats disease/Revesz syndrome), CNS abnormalities/cerebellar hypoplasia, hypogonadism, Hoyeraal-Hreidarsson syndrome (IUGR, microcephaly, cerebellar hypoplasia, combined immune deficiency), short stature |
| Fanconi anemia | MDS, AML; ALL has been associated with FANCD1/BRCA2 | Squamous cell carcinoma: oral, GI, vulvar; hepatocellular carcinoma, hepatic adenoma | Short stature; hyper-/hypopigmentation (café au lait spots); facial dysmorphologies; skeletal anomalies, including radial ray anomalies, thumb hypoplasia, and hypoplastic thenar eminences; osteopenia; hypogonadism; cardiac malformations; gastrointestinal malformations; urogenital anomalies/malformations; renal malformations; endocrinopathies Increased toxicity with chemotherapy and radiation | |
| GATA2 spectrum disorders | MDS, AML, CMML, JMML, T-lymphoblastic leukemia | MonoMAC syndrome (monocytopenia with mycobacterial infections); DCML deficiency (dendritic cell, monocyte, B-cell, NK cell deficiency); susceptibility to mycobacterial, fungal, viral infections; warts; molluscum; pulmonary alveolar proteinosis; Emberger syndrome (lymphedema, sensorineural hearing loss) | ||
| Shwachman-Diamond syndrome | MDS, AML | Short stature; exocrine pancreatic dysfunction; pancreatic lipomatosis/atresia; skeletal dysplasias, including thoracic dystrophy or metaphyseal dysostosis; osteopenia; eczema; transient transaminitis/hepatomegaly in early childhood; dental anomalies; immunodeficiencies; endocrinopathies; neurocognitive and other variable congenital anomalies | ||
| SDS-like | Possibly AML | |||
| SAMD9 | MDS, AML | MIRAGE syndrome: infections, immunodeficiencies, failure to thrive, IUGR, adrenal insufficiency, genital anomalies, enteropathy | ||
| SAMD9L | MDS, AML | Ataxia, cerebellar hypoplasia | ||
| Bone marrow failure syndrome 1 (SRP72) | MDS | Sensorineural hearing loss | ||
| Bone marrow failure syndrome 2 (ERCC6L2) | MDS, AML | |||
| Thrombocytopenia, platelet dysfunction | Thrombocytopenia 2 (ANKRD26) | MDS, AML, CMML, CLL | Platelet dysfunction | |
| Familial platelet disorder with propensity to myeloid malignancy (RUNX1) | MDS, AML, T-ALL, hairy cell leukemia | Platelet dysfunction | ||
| Thrombocytopenia 5 (ETV6) | MDS, AML, CMML, ALL, MM | Platelet dysfunction | ||
| Red cell aplasia | Diamond-Blackfan anemia | MDS, AML | Osteosarcoma, soft tissue sarcomas, GI/colon cancer | Short stature, facial dysmorphisms, radial ray anomalies, skeletal anomalies, cardiac malformations, renal malformations Neutropenia and immunodeficiencies associated with RPL35a |
| Neutropenia, cyclic neutropenia | ELANE | MDS, AML | Osteopenia, monocytosis, eosinophilia | |
| Neutropenia | SCN (HAX1) | Seizures, neurologic abnormalities | ||
| SCN (GFI1) | Lymphopenia | |||
| SCN (G6PC3) | Structural heart disease, urogenital anomalies, prominent veins, deafness, skeletal anomalies, immune dysregulation, colitis, poor growth, thrombocytopenia | |||
| SCN (JAGN1) | Skeletal, dental anomalies | |||
| X-linked neutropenia (WAS) | MDS, AML | |||
| Bloom syndrome | MDS, AML, ALL, lymphoma | Carcinomas | Short stature, sun-sensitive rash, pulmonary disease, immunodeficiency | |
| Constitutional mismatch repair deficiency syndrome (Lynch syndrome) | MDS, AML, ALL, lymphoma | GI (colon), ovarian, uterine, CNS, other | ||
| Down syndrome | ALL, AML, transient myeloproliferative disorder | Mental retardation, short stature, facial dysmorphisms, palmar crease, cardiac anomalies, endocrinopathies, gastrointestinal anomalies | ||
| ERBB3 | Erythroid MDS, erythroleukemia | |||
| Familial AML (CEBPA) | AML | Eosinophilia | ||
| Li-Fraumeni syndrome | MDS, AML, ALL, lymphoma | Breast cancer, osteosarcoma, soft tissue sarcomas, brain tumors, adrenocortical carcinoma | ||
| Ligase IV syndrome | MDS, lymphoma, ALL | Short stature, microcephaly, facial dysmorphism, bone hypoplasia, congenital hip dysplasia, photosensitivity, plantar warts, hypopigmentation, eczema, immunodeficiency, developmental delay | ||
| MBD4 | MDS, AML | |||
| Neurofibromatosis 1 | MDS, JMML | Melanoma, optic gliomas, brain tumors, malignant peripheral nerve sheath tumors | Café au lait spots, axillary freckling, Lisch nodules, neurofibromas | |
| Nijmegen breakage syndrome | AML, ALL, lymphoma | Brain tumors, sarcomas | Microcephaly, short stature, café au lait macules, facial abnormalities, retrognathia, immunodeficiency | |
| Noonan syndrome | MDS, AML, JMML, ALL, MPN | Brain tumors | Facial dysmorphisms, short stature, cardiac anomalies, broad neck, thoracic anomalies, cryptorchidism | |
| Noonan-like (CBL) | JMML, MDS | |||
| Susceptibility to acute myeloid leukemia (DDX41) | MDS, AML, CML, lymphoma | |||
| Trisomy 8 mosaicism | MDS, AML, CML | Facial anomalies (wide-set eyes; broad, upturned nose; micrognathia; eye anomalies), cleft palate, shortened neck, renal anomalies, cardiac anomalies, brain malformations, absent kneecap | ||
| Werner syndrome | MDS, AML | Thyroid cancer, melanoma, meningioma, sarcomas | Thin/early graying hair, skin findings, short stature, cataracts, premature aging |
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CMML, chronic myelomonocytic leukemia; CNS, central nervous system; DCML, loss of dendritic cells, monocytes, and B and natural killer lymphoid cells; GI, gastrointestinal; IUGR, intrauterine growth restriction; JMML, juvenile myelomonocytic leukemia; MDS, myelodysplastic syndrome; MIRAGE, myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy; MM, multiple myeloma; MPN, myeloproliferative neoplasm; NK, natural killer; SCN, severe congenital neutropenia; SDS, Shwachman-Diamond syndrome; T-ALL, T-cell acute lymphoblastic leukemia.