Table 1. Leukemia susceptibility... | American Society of Hematology

Table 1.

Leukemia susceptibility disorders

Underlying biology	Disease/syndrome	Gene(s)	Inheritance pattern		Cytopenias and nonmalignant hematologic features	Nongenetic diagnostic testing	Other manifestations
DNA repair	Fanconi anemia	FANCA through FANCW (n = 22)*	AR (1 XLR, 1 AD)	AML	Single or pancytopenia, elevated HbF, macrocytosis	Increased chromosome breakage	Short stature, radial ray anomalies, microcephaly, café au lait spots*
	Nijmegen breakage syndrome	NBN	AR	ALL	Immunodeficiency	Ionizing radiation sensitivity of lymphocytes	Microcephaly, microgenia, bird-like facies
	Ataxia telangiectasia	ATM	AR	ALL	Immunodeficiency		Cerebellar ataxia, conjunctival telangiectasias choreoathetosis, oculomotor apraxia
	Bloom syndrome	BLM (RECQL3)	AR	ALL or AML			Growth deficiency, sun sensitivity, reflux, insulin resistance
	CMMRDS (Turcot)	MSH1, MSH2, MSH6, PMS2, EPCAM	AR	ALL or AML			Heterozygous form leads to Lynch syndrome
Ribosome biogenesis	Shwachman Diamond syndrome	SDBS, DNAJC21, EFL1†	AR	AML	Neutropenia	Low serum isoamylase and trypsinogen	Exocrine pancreatic insufficiency, neurodevelopmental and skeletal abnormalities*
	Diamond Blackfan anemia	RPLs, RPSs, TSR2, GATA1 (n = 20)*	AD	AML	Erythroid hypoplasia, elevated HbF	Elevated erythroid ADA	Short stature, craniofacial anomalies, bifid thumbs*
Telomere biology	Dyskeratosis congenita	Telomerase and shelterin components (n = 14)*	AR, AD, XLR	AML	Single or pancytopenia, elevated HbF, macrocytosis	Very short telomeres	Skin pigmentation, nail dysplasia, oral leukoplakia, pulmonary fibrosis*
Hematopoietic transcription factors	Familial platelet disorder	RUNX1	AD	AML	Thrombocytopenia
	GATA2 deficiency	GATA2	AD	AML	Monocytopenia; low NK, dendritic, and/or B cells		Lymphedema, warts, nontuberculous mycobacterial infections, alveolar proteinosis
	Familial AML	CEBPA	AD	AML
	Thrombocytopenia, type 5	ETV6	AD	ALL, rarely AML	Thrombocytopenia, macrocytosis
	Susceptibility to ALL-3	PAX5	AD	ALL
Tumor suppressors	Li-Fraumeni syndrome	TP53	AD	AML or ALL		Clinically based on personal and family history	Other cancers, including brain tumors, sarcomas, breast and adrenocortical carcinomas
	Neurofibromatosis type 1	NF1	AD	JMML		Clinically based on personal and family history	Café au lait spots, Lisch nodules, neurofibromas
	Noonan syndrome	PTPN11	AD	JMML	Bleeding diathesis		Short stature, facial dysmorphism, congenital heart defects
Neutrophil development	Severe congenital neutropenia	ELA2, GFI1, G6PC3, GCSFR, HAX1	AD, AR	AML	Neutropenia		Severe bacterial infections
Other cell processes	DDX41-related myeloid neoplasia	DDX41	AD	AML	Thrombocytopenia
	MIRAGE	SAMD9	AD	AML	Thrombocytopenia, anemia		Infections, growth restriction, adrenal hypoplasia, genital malformations, enteropathy
	Ataxia-pancytopenia syndrome	SAMD9L	AD	AML	Thrombocytopenia, anemia		Cerebellar ataxia
	Thrombocytopenia, type 2	ANKRD26	AD	AML	Thrombocytopenia, hypogranular platelets
	Familial ALL with germline SH2B3 mutation	SH2B3	AR	ALL
Chromosomal aneuploidies	Down syndrome	Trisomy 21		ALL or AMKL	Transient myeloproliferative disorder		Congenital heart defects, intellectual disability, characteristic facies, gastrointestinal tract malformations, hearing loss
	Myelodysplasia and leukemia syndrome with monosomy 7	Monosomy 7		AML	Macrocytosis

Underlying biology	Disease/syndrome	Gene(s)	Inheritance pattern		Cytopenias and nonmalignant hematologic features	Nongenetic diagnostic testing	Other manifestations
DNA repair	Fanconi anemia	FANCA through FANCW (n = 22)*	AR (1 XLR, 1 AD)	AML	Single or pancytopenia, elevated HbF, macrocytosis	Increased chromosome breakage	Short stature, radial ray anomalies, microcephaly, café au lait spots*
	Nijmegen breakage syndrome	NBN	AR	ALL	Immunodeficiency	Ionizing radiation sensitivity of lymphocytes	Microcephaly, microgenia, bird-like facies
	Ataxia telangiectasia	ATM	AR	ALL	Immunodeficiency		Cerebellar ataxia, conjunctival telangiectasias choreoathetosis, oculomotor apraxia
	Bloom syndrome	BLM (RECQL3)	AR	ALL or AML			Growth deficiency, sun sensitivity, reflux, insulin resistance
	CMMRDS (Turcot)	MSH1, MSH2, MSH6, PMS2, EPCAM	AR	ALL or AML			Heterozygous form leads to Lynch syndrome
Ribosome biogenesis	Shwachman Diamond syndrome	SDBS, DNAJC21, EFL1†	AR	AML	Neutropenia	Low serum isoamylase and trypsinogen	Exocrine pancreatic insufficiency, neurodevelopmental and skeletal abnormalities*
	Diamond Blackfan anemia	RPLs, RPSs, TSR2, GATA1 (n = 20)*	AD	AML	Erythroid hypoplasia, elevated HbF	Elevated erythroid ADA	Short stature, craniofacial anomalies, bifid thumbs*
Telomere biology	Dyskeratosis congenita	Telomerase and shelterin components (n = 14)*	AR, AD, XLR	AML	Single or pancytopenia, elevated HbF, macrocytosis	Very short telomeres	Skin pigmentation, nail dysplasia, oral leukoplakia, pulmonary fibrosis*
Hematopoietic transcription factors	Familial platelet disorder	RUNX1	AD	AML	Thrombocytopenia
	GATA2 deficiency	GATA2	AD	AML	Monocytopenia; low NK, dendritic, and/or B cells		Lymphedema, warts, nontuberculous mycobacterial infections, alveolar proteinosis
	Familial AML	CEBPA	AD	AML
	Thrombocytopenia, type 5	ETV6	AD	ALL, rarely AML	Thrombocytopenia, macrocytosis
	Susceptibility to ALL-3	PAX5	AD	ALL
Tumor suppressors	Li-Fraumeni syndrome	TP53	AD	AML or ALL		Clinically based on personal and family history	Other cancers, including brain tumors, sarcomas, breast and adrenocortical carcinomas
	Neurofibromatosis type 1	NF1	AD	JMML		Clinically based on personal and family history	Café au lait spots, Lisch nodules, neurofibromas
	Noonan syndrome	PTPN11	AD	JMML	Bleeding diathesis		Short stature, facial dysmorphism, congenital heart defects
Neutrophil development	Severe congenital neutropenia	ELA2, GFI1, G6PC3, GCSFR, HAX1	AD, AR	AML	Neutropenia		Severe bacterial infections
Other cell processes	DDX41-related myeloid neoplasia	DDX41	AD	AML	Thrombocytopenia
	MIRAGE	SAMD9	AD	AML	Thrombocytopenia, anemia		Infections, growth restriction, adrenal hypoplasia, genital malformations, enteropathy
	Ataxia-pancytopenia syndrome	SAMD9L	AD	AML	Thrombocytopenia, anemia		Cerebellar ataxia
	Thrombocytopenia, type 2	ANKRD26	AD	AML	Thrombocytopenia, hypogranular platelets
	Familial ALL with germline SH2B3 mutation	SH2B3	AR	ALL
Chromosomal aneuploidies	Down syndrome	Trisomy 21		ALL or AMKL	Transient myeloproliferative disorder		Congenital heart defects, intellectual disability, characteristic facies, gastrointestinal tract malformations, hearing loss
	Myelodysplasia and leukemia syndrome with monosomy 7	Monosomy 7		AML	Macrocytosis

AD, autosomal dominant; ADA, adenosine deaminase; ALL, acute lymphoblastic leukemia; AMKL, acute megakaryoblastic leukemia; AML, acute myeloid leukemia; AR, autosomal recessive; CMMRDS, congenital mismatch repair deficiency syndrome; HbF, fetal hemoglobin; JMML, juvenile myelomonocytic leukemia; MIRAGE, myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy; NK, natural killer; XLR, X-linked recessive.

Additional detail can be seen in Alter (in this book⁴⁸).

†

Leukemia has not been reported in patients with Shwachman Diamond syndrome attributable to mutations in EFL1.

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