Main features of inherited thrombocytopenias classified according to their clinical picture
| Disease (abbreviation, OMIM entry) . | Inheritance . | Gene (locus) . | Thrombocytopenia*/platelet size . | Bleeding† . | Additional features to thrombocytopenia . |
|---|---|---|---|---|---|
| Forms with only thrombocytopenia | |||||
| Bernard-Soulier syndrome (bBSS, mBSS, 231200/153670) | |||||
| Biallelic18 | AR | GP1BA (17p13) GPIBB (22q11) | ++,+++/giant, large | S | Impaired platelet function. |
| Monoallelic15 | AD | GP9 (3q21) | +/large | A/Mi | |
| Gray platelet syndrome (GPS, 139090)3 | AR | NBEAL2 (3p21) | ++,+++/large | Mi/S | Impaired platelet function. Severely reduced content of α granules. Platelet count decreases over time. Development of progressive bone marrow fibrosis and splenomegaly. Elevated serum vitamin B12 levels. |
| ACTN1-related thrombocytopenia (ACTN1-RT, 615193)19 | AD | ACTN1 (14q24) | +/large | A/Mi | — |
| Platelet-type von Willebrand disease (PTvWD, 177820)20 | AD | GP1BA (17p13) | +,+++/ normal, slightly increased | A/Mi | Platelet count is normal in most patients but may decrease greatly under stressful conditions (pregnancy, surgery, and infection). |
| ITGA2B/ITGB3-related thrombocytopenia (ITGA2B/ITGB3-RT (187800)21 | AD | ITGA2B (17q21) | +,++/large | Mi/Mo | Impaired platelet function. |
| ITGB3 (17q21) | |||||
| TUBB1-related thrombocytopenia (TUBB1-RT, 613112)22 | AD | TUBB1 (20q13) | +/large | A/Mo | — |
| CYCS-related thrombocytopenia (CYCS-RT or THC4, 612004)23 | AD | CYCS (7p15) | +/ normal, slightly reduced | A | — |
| GFI1b-related thrombocytopenia (GFI1b-RT, 187900)5 | AD | GFI1B (9q34) | +,++/large | Mo/S | Impaired platelet function. Reduced α granules. Red cell anisocytosis. |
| PRKACG-related thrombocytopenia (PRKACG-RT, 616176)4 | AR | PRKACG (9q21) | +++/large | S | Impaired platelet function. |
| FYB-related thrombocytopenia (FYB-RT, na)7 | AR | FYB (5p13.1) | ++,+++/ normal, slightly reduced | Mi/Mo | — |
| SLFN14-related thrombocytopenia (SLFN14-RT, na)8 | AD | SLFN14 (17q12) | +,++/normal, large | Mi/S | Impaired platelet function. |
| FLI1-related thrombocytopenia (FLI1-RT, na)24 | AR | FLI1 (11p24.3) | ++/large | Mi/Mo | Impaired platelet function. Giant α granules. |
| Inherited thrombocytopenia from monoallelic THPO mutation (na, na)25 | AD | THPO (3q27.1) | +/ normal, slightly increased | A | — |
| TRPM7-related thrombocytopenia (TRPM7-RT)26 | AD | TRPM7 (15q21.2) | +,++/large | A/Mi | Aberrant distribution of granules, increased number and anarchic organization of microtubules. |
| Tropomyosin 4-related thrombocytopenia (TPM4-RT, na)17 | AD | TPM4 (19p13.1) | +/large | Mi | — |
| Forms with additional clinically relevant congenital defects/syndromic forms | |||||
| Wiskott-Aldrich syndrome (WAS, 301000)27 | XL | WAS (Xp11) | +++/ normal, slightly reduced | S | Severe immunodeficiency leading to early death. Eczema. Increased risk of malignancies and autoimmunity. |
| X-linked thrombocytopenia (XLT, 313900)28 | XL | WAS (Xp11) | ++,+++/ normal, slightly reduced | A/Mo | Mild immunodeficiency. Mild transient eczema. Increased risk of malignancies and autoimmunity. Nonsyndromic patients with only thrombocytopenia are described. |
| Paris-Trousseau thrombocytopenia (TCPT, 188025), Jacobsen syndrome (JBS, 147791)29 | AD | Deletions in 11q23 | +++/ normal, slightly increased | Mo/S | Growth retardation, cognitive impairment, facial and skull dysmorphisms, malformations of the cardiovascular system, CNS, gastrointestinal apparatus, kidney, and/or urinary tract; other malformations. Impaired platelet function. Giant α-granules and reduced dense granules. Thrombocytopenia may resolve over time. |
| FLNA-related thrombocytopenia (FLNA-RT, na)30 | XL | FLNA (Xq28) | ++/large | Mi/Mo | Periventricular nodular heterotopia (OMIM 300049). Nonsyndromic patients with only thrombocytopenia are described. |
| GATA1-related diseases: X-linked thrombocytopenia with thalassemia (XLTT, 314050), X-linked thrombocytopenia with dyserythropoietic anemia (XLTDA, 300367)31 | XL | GATA1 (Xp11) | +++/ normal, slightly increased | Mi/S | Hemolytic anemia with laboratory abnormalities resembling β-thalassemia, splenomegaly, and dyserythropoietic anemia. Congenital erythropoietic porphyria. |
| Thrombocytopenia-absent radius syndrome (TAR, 274000)32 | AR | RBM8A (1q21) | +++/ normal, slightly reduced | S | Bilateral radial aplasia +/− additional upper and lower limb abnormalities. Possible kidney, cardiac, and/or CNS malformations. Possible intolerance to cow’s milk that can be associated with exacerbation of thrombocytopenia. Reduced megakaryocytes in bone marrow. Platelet count may rise over time. |
| Stormorken syndrome (STRMK,185070)6 | AD | STIM1 (11p15) | ++,+++/na | Mi | Myopathy with tubular aggregates, congenital miosis, functional or anatomical asplenia, ichthyosis, headache, mild anemia, facial dysmorphisms, defects in physical growth, and cognitive impairment. |
| York platelet syndrome (YPS, na)33 | AD | STIM1 (11p15) | ++,+++/normal | A | Myopathy, platelet ultrastructural abnormalities, such as moderately decreased α granules, increased vacuoles, and giant electron dense and targeted-like bodies. |
| Forms with increased risk of acquiring additional illnesses/predisposing forms | |||||
| MYH9-related disease (MYH9-RD (na)14 | AD | MYH9 (22q12) | +,+++/giant, large | A/Mi | Possible development of sensorineural deafness, nephropathy, and/or cataract. Half of the patients present with elevated liver enzymes without developing liver dysfunction. |
| DIAPH1-related thrombocytopenia (DIAPH1-RT, na)10 | AD | DIAPH1 (5q31.3) | +,+++/large | A | Risk of sensorineural deafness during infancy. Possible mild transient leukopenia. |
| Congenital amegakaryocytic thrombocytopenia (CAMT, 604498)34 | AR | MPL (1p34.2) | +++/normal, slightly reduced | S | Reduced/absent megakaryocytes. Evolution to severe bone marrow aplasia in infancy in all patients. |
| Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT, 605432, 616738)35,36 | AD/AR | HOXA11 (7p15) or MECOM (3q26.2) | +++/ normal, slightly increased | S | Bilateral radio-ulnar synostosis +/− other malformations. Reduced/absent megakaryocytes in bone marrow. Possible progression to bone marrow aplasia. The hematological phenotype is more severe in the AR form because of MECOM mutations. |
| Familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML, 601399)37 | AD | RUNX1 (21q22) | ++/ normal, slightly increased | A/Mo | Over 40% of patients acquire acute myelogenous leukemia or myelodysplastic syndromes. Increased risk of T acute lymphoblastic leukemia. Impaired platelet function. |
| ANKRD26-related thrombocytopenia (ANKRD26-RT (or THC2, 188000)16 | AD | ANKRD26 (10p12) | ++,+++/ normal, slightly increased | A/Mi | About 8% of patients acquire myeloid malignancies. Some patients have increased levels of hemoglobin and/or leukocytes. Reduced α granules in some patients. |
| ETV6-related thrombocytopenia (ETV6-RT, na)9 | AD | ETV6 (12p13) | +,++/ normal, slightly increased | A/Mo | About 25% of patients acquire acute lymphoblastic leukemia and other hematological malignancies. |
| SRC-related thrombocytopenia (SRC-RT)11 | AD | SRC (20q11.23) | ++,+++/large | Mo/S | Congenital facial dysmorphism, juvenile myelofibrosis and splenomegaly, severe osteoporosis, premature edentulism. Platelets hypogranular or agranular. Abundant vacuoles. |
| Disease (abbreviation, OMIM entry) . | Inheritance . | Gene (locus) . | Thrombocytopenia*/platelet size . | Bleeding† . | Additional features to thrombocytopenia . |
|---|---|---|---|---|---|
| Forms with only thrombocytopenia | |||||
| Bernard-Soulier syndrome (bBSS, mBSS, 231200/153670) | |||||
| Biallelic18 | AR | GP1BA (17p13) GPIBB (22q11) | ++,+++/giant, large | S | Impaired platelet function. |
| Monoallelic15 | AD | GP9 (3q21) | +/large | A/Mi | |
| Gray platelet syndrome (GPS, 139090)3 | AR | NBEAL2 (3p21) | ++,+++/large | Mi/S | Impaired platelet function. Severely reduced content of α granules. Platelet count decreases over time. Development of progressive bone marrow fibrosis and splenomegaly. Elevated serum vitamin B12 levels. |
| ACTN1-related thrombocytopenia (ACTN1-RT, 615193)19 | AD | ACTN1 (14q24) | +/large | A/Mi | — |
| Platelet-type von Willebrand disease (PTvWD, 177820)20 | AD | GP1BA (17p13) | +,+++/ normal, slightly increased | A/Mi | Platelet count is normal in most patients but may decrease greatly under stressful conditions (pregnancy, surgery, and infection). |
| ITGA2B/ITGB3-related thrombocytopenia (ITGA2B/ITGB3-RT (187800)21 | AD | ITGA2B (17q21) | +,++/large | Mi/Mo | Impaired platelet function. |
| ITGB3 (17q21) | |||||
| TUBB1-related thrombocytopenia (TUBB1-RT, 613112)22 | AD | TUBB1 (20q13) | +/large | A/Mo | — |
| CYCS-related thrombocytopenia (CYCS-RT or THC4, 612004)23 | AD | CYCS (7p15) | +/ normal, slightly reduced | A | — |
| GFI1b-related thrombocytopenia (GFI1b-RT, 187900)5 | AD | GFI1B (9q34) | +,++/large | Mo/S | Impaired platelet function. Reduced α granules. Red cell anisocytosis. |
| PRKACG-related thrombocytopenia (PRKACG-RT, 616176)4 | AR | PRKACG (9q21) | +++/large | S | Impaired platelet function. |
| FYB-related thrombocytopenia (FYB-RT, na)7 | AR | FYB (5p13.1) | ++,+++/ normal, slightly reduced | Mi/Mo | — |
| SLFN14-related thrombocytopenia (SLFN14-RT, na)8 | AD | SLFN14 (17q12) | +,++/normal, large | Mi/S | Impaired platelet function. |
| FLI1-related thrombocytopenia (FLI1-RT, na)24 | AR | FLI1 (11p24.3) | ++/large | Mi/Mo | Impaired platelet function. Giant α granules. |
| Inherited thrombocytopenia from monoallelic THPO mutation (na, na)25 | AD | THPO (3q27.1) | +/ normal, slightly increased | A | — |
| TRPM7-related thrombocytopenia (TRPM7-RT)26 | AD | TRPM7 (15q21.2) | +,++/large | A/Mi | Aberrant distribution of granules, increased number and anarchic organization of microtubules. |
| Tropomyosin 4-related thrombocytopenia (TPM4-RT, na)17 | AD | TPM4 (19p13.1) | +/large | Mi | — |
| Forms with additional clinically relevant congenital defects/syndromic forms | |||||
| Wiskott-Aldrich syndrome (WAS, 301000)27 | XL | WAS (Xp11) | +++/ normal, slightly reduced | S | Severe immunodeficiency leading to early death. Eczema. Increased risk of malignancies and autoimmunity. |
| X-linked thrombocytopenia (XLT, 313900)28 | XL | WAS (Xp11) | ++,+++/ normal, slightly reduced | A/Mo | Mild immunodeficiency. Mild transient eczema. Increased risk of malignancies and autoimmunity. Nonsyndromic patients with only thrombocytopenia are described. |
| Paris-Trousseau thrombocytopenia (TCPT, 188025), Jacobsen syndrome (JBS, 147791)29 | AD | Deletions in 11q23 | +++/ normal, slightly increased | Mo/S | Growth retardation, cognitive impairment, facial and skull dysmorphisms, malformations of the cardiovascular system, CNS, gastrointestinal apparatus, kidney, and/or urinary tract; other malformations. Impaired platelet function. Giant α-granules and reduced dense granules. Thrombocytopenia may resolve over time. |
| FLNA-related thrombocytopenia (FLNA-RT, na)30 | XL | FLNA (Xq28) | ++/large | Mi/Mo | Periventricular nodular heterotopia (OMIM 300049). Nonsyndromic patients with only thrombocytopenia are described. |
| GATA1-related diseases: X-linked thrombocytopenia with thalassemia (XLTT, 314050), X-linked thrombocytopenia with dyserythropoietic anemia (XLTDA, 300367)31 | XL | GATA1 (Xp11) | +++/ normal, slightly increased | Mi/S | Hemolytic anemia with laboratory abnormalities resembling β-thalassemia, splenomegaly, and dyserythropoietic anemia. Congenital erythropoietic porphyria. |
| Thrombocytopenia-absent radius syndrome (TAR, 274000)32 | AR | RBM8A (1q21) | +++/ normal, slightly reduced | S | Bilateral radial aplasia +/− additional upper and lower limb abnormalities. Possible kidney, cardiac, and/or CNS malformations. Possible intolerance to cow’s milk that can be associated with exacerbation of thrombocytopenia. Reduced megakaryocytes in bone marrow. Platelet count may rise over time. |
| Stormorken syndrome (STRMK,185070)6 | AD | STIM1 (11p15) | ++,+++/na | Mi | Myopathy with tubular aggregates, congenital miosis, functional or anatomical asplenia, ichthyosis, headache, mild anemia, facial dysmorphisms, defects in physical growth, and cognitive impairment. |
| York platelet syndrome (YPS, na)33 | AD | STIM1 (11p15) | ++,+++/normal | A | Myopathy, platelet ultrastructural abnormalities, such as moderately decreased α granules, increased vacuoles, and giant electron dense and targeted-like bodies. |
| Forms with increased risk of acquiring additional illnesses/predisposing forms | |||||
| MYH9-related disease (MYH9-RD (na)14 | AD | MYH9 (22q12) | +,+++/giant, large | A/Mi | Possible development of sensorineural deafness, nephropathy, and/or cataract. Half of the patients present with elevated liver enzymes without developing liver dysfunction. |
| DIAPH1-related thrombocytopenia (DIAPH1-RT, na)10 | AD | DIAPH1 (5q31.3) | +,+++/large | A | Risk of sensorineural deafness during infancy. Possible mild transient leukopenia. |
| Congenital amegakaryocytic thrombocytopenia (CAMT, 604498)34 | AR | MPL (1p34.2) | +++/normal, slightly reduced | S | Reduced/absent megakaryocytes. Evolution to severe bone marrow aplasia in infancy in all patients. |
| Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT, 605432, 616738)35,36 | AD/AR | HOXA11 (7p15) or MECOM (3q26.2) | +++/ normal, slightly increased | S | Bilateral radio-ulnar synostosis +/− other malformations. Reduced/absent megakaryocytes in bone marrow. Possible progression to bone marrow aplasia. The hematological phenotype is more severe in the AR form because of MECOM mutations. |
| Familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML, 601399)37 | AD | RUNX1 (21q22) | ++/ normal, slightly increased | A/Mo | Over 40% of patients acquire acute myelogenous leukemia or myelodysplastic syndromes. Increased risk of T acute lymphoblastic leukemia. Impaired platelet function. |
| ANKRD26-related thrombocytopenia (ANKRD26-RT (or THC2, 188000)16 | AD | ANKRD26 (10p12) | ++,+++/ normal, slightly increased | A/Mi | About 8% of patients acquire myeloid malignancies. Some patients have increased levels of hemoglobin and/or leukocytes. Reduced α granules in some patients. |
| ETV6-related thrombocytopenia (ETV6-RT, na)9 | AD | ETV6 (12p13) | +,++/ normal, slightly increased | A/Mo | About 25% of patients acquire acute lymphoblastic leukemia and other hematological malignancies. |
| SRC-related thrombocytopenia (SRC-RT)11 | AD | SRC (20q11.23) | ++,+++/large | Mo/S | Congenital facial dysmorphism, juvenile myelofibrosis and splenomegaly, severe osteoporosis, premature edentulism. Platelets hypogranular or agranular. Abundant vacuoles. |
AD, autosomal dominant; AR, autosomal recessive; CNS, central nervous system; na, not available; OMIM, online Mendelian inheritance in man; vWD, von Willebrand disease; XL, X-linked.
Degrees of thrombocytopenia: + indicates > 100 × 109 platelets/L; ++, 50 × 109 to 100 × 109 platelets/L; +++, < 50 × 109 platelets/L.
Severity of bleeding tendency in most patients reported for each form: A indicates absent; Mi, mild; Mo, moderate; and S, severe.