IllnessThrombocytopenias + thrombocytopathies, hereditary; differential diagnosis

NGS +

[Sanger]

Platelets stop the blood flow immediately after injury through fundamentally different mechanisms: activation, adhesion, aggregation, secretion and promotion of coagulation. The clinical complications in patients with thrombocyte disorders varies widely, even within the same type, ranging from almost insignificant to life-threatening. In thrombocytopenias (e.g. Wiskott-Aldrich syndrome) or thrombocytopathies (e.g. Bernard-Soulier syndrome, Glanzmann thrombasthenia), bleeding generally occurs immediately after injury, especially in the skin, mucous membranes, nose, gastrointestinal tract and urinary tract. Generally, the joints and muscles are not affected by the bleeding. Congenital disorders are rare and can easily be confused with acquired disorders, the latter being much more common in clinical practice. Thus the differential diagnosis is often complex. A lifelong tendency to bleed may indicate a congenital platelet dysfunction, often recognised in childhood, but occurrence in adulthood does not rule out a congenital defect. The hereditary platelet disorders comprise a heterogeneous group of >60 rare diseases caused by mutations in >70 genes. Inheritance patterns include autosomal dominant and recessive as well as X-linked transmission. The DNA diagnostic yield is highly dependent on the quality of clinical phenotyping and ranging <25% for thrombocytopenias and around 40% for thrombocytopathies. Therefore, a negative molecular genetic test result does not exclude the clinical diagnosis.

References: https://www.ncbi.nlm.nih.gov/books/NBK1178/

https://www.ncbi.nlm.nih.gov/books/NBK7014/

https://www.mdpi.com/1422-0067/22/9/4521/htm

• Allelic: Alzheimer disease, late-onset, susceptibility to (PLAU)
• Allelic: Amyotrophic lateral sclerosis-parkinsonism/dementia complex, susceptibility to (TRPM7)
• Allelic: Anemia, XL, with/without neutropenia and/or platelet abnormalities (GATA1)
• Allelic: Cardiac valvular dysplasia, XL (FLNA)
• Allelic: Colon cancer, advanced, somatic (SRC)
• Allelic: Deafness, AD 17 (MYH9)
• Allelic: Erythrokeratodermia variabilis et progressiva 4 (KDSR)
• Allelic: FG syndrome 2 (FLNA)
• Allelic: Frontometaphyseal dysplasia 1 (FLNA)
• Allelic: Hemolytic uremic syndrome, atypical, susceptibility to, 6 (THBD)
• Allelic: Heterotopia, periventricular, 1 (FLNA)
• Allelic: Leukemia, acute myeloid (RUNX1)
• Allelic: Leukemia, acute myeloid, somatic (ETV6)
• Allelic: Leukemia, megakaryoblastic, with/-out Down syndrome, somatic (GATA1)
• Allelic: Melnick-Needles syndrome (FLNA)
• Allelic: Metachondromatosis (PTPN11)
• Allelic: Myelofibrosis with myeloid metaplasia, somatic (MPL)
• Allelic: Myocardial infarction, susceptibility to (ITGB3)
• Allelic: Neutropenia, severe congenital, XL (WASP)
• Allelic: Nonarteritic anterior ischemic optic neuropathy, susceptibility to (GP1BA)
• Allelic: Otopalatodigital syndrome, type I (FLNA)
• Allelic: Otopalatodigital syndrome, type II (FLNA)
• Allelic: Purpura, posttransfusion (ITGB3)
• Allelic: Seizures, cortical blindness, microcephaly syndrome (DIAPH1)
• Allelic: Terminal osseous dysplasia (FLNA)
• Allelic: Thrombocytopenia, neonatal alloimmune (ITGB3)
• Allelic: Thrombocytopenia, neonatal alloimmune, BAK antigen related (ITGA2B)
• Allelic: Vesicoureteral reflux 8 (TNXB)
• Allelic: Wiskott-Aldrich syndrome (WASP)
• Bernard-Soulier syndrome, type B (GP1BB)
• Bernard-Soulier syndrome, type C (GP9)
• Bernard-Soulier syndrome, types A1 [AR] + A2 [AD] (GP1BA)
• Bleeding disorder, platelet-type, 1 [Bernard-Soulier syndrome] (GP9, GP1BA, GP1BB)
• Bleeding disorder, platelet-type, 11 (GP6)
• Bleeding disorder, platelet-type, 12 (PTGS1)
• Bleeding disorder, platelet-type, 13, susceptibility to (TBXA2R)
• Bleeding disorder, platelet-type, 15 (ACTN1)
• Bleeding disorder, platelet-type, 16, AD (ITGA2B)
• Bleeding disorder, platelet-type, 17 (GFI1B)
• Bleeding disorder, platelet-type, 18 (RASGRP)
• Bleeding disorder, platelet-type, 19 (PRKACG)
• Bleeding disorder, platelet-type, 20 (SLFN14)
• Bleeding disorder, platelet-type, 21 (FLI1)
• Bleeding disorder, platelet-type, 24, AD (ITGB3)
• Bleeding disorder, platelet-type, 7 [Scott syndrome] (ANO6)
• Bleeding disorder, platelet-type, 8 (P2RY12)
• Congenital short bowel syndrome (FLNA)
• Deafness, AD 1, with/-out thrombocytopenia (DIAPH1)
• Dominant macrothrombocytopenia, mild bleeding, disrupted cytoskeleton remodeling [lit.] (TPM4)
• Ehlers-Danlos syndrome due to tenascin X deficiency [panelapp] (TNXB)
• Ehlers-Danlos syndrome, classic-like, 1 (TNXB)
• Ehlers-Danlos syndrome, musculocontractural type 1 (CHST14)
• Gastrointestinal ulceration, recurrent, with dysfunctional platelets (PLA2G4A)
• Ghosal hematodiaphyseal syndrome (TBXAS1)
• Giant platelet disorder, isolated (GP1BB)
• Glanzmann thrombasthenia (ITGA2B, ITGB3)
• Gray platelet syndrome (NBEAL2)
• Hemophagocytic lymphohistiocytosis, familial, 3 (UNC13D)
• Hemophagocytic lymphohistiocytosis, familial, 5, with/-out microvillus inclusion disease (STXBP2)
• Hermansky-Pudlak syndrome 1, 3, 4, 5, 6 (HPS1, HPS3, HPS4, HPS5, HPS6)
• Hermansky-Pudlak syndrome 10 (AP3D1)
• Hermansky-Pudlak syndrome 2 (AP3B1)
• Hermansky-Pudlak syndrome 7 (DTNBP1)
• Hermansky-Pudlak syndrome 8, 9 (BLOC1S3, BLOC1S6)
• Immunodeficiency 71 with inflammatory disease + congenital thrombocytopenia (ARPC1B)
• Inherited Thrombocytopenia assiciated with mutation of UDP-Galactose-4-Epimerase (GALE)
• Intestinal pseudoobstruction, neuronal (FLNA)
• LEOPARD syndrome 1 (PTPN11)
• Leukocyte adhesion deficiency, type III (FERMT3)
• Macrothrombocytopenia + granulocyte incl. with/-out nephritis/sensorineural hearing loss (MYH9)
• Macrothrombocytopenia [panelapp] (TRPM7)
• Macrothrombocytopenia, AD, TUBB1-related (TUBB1)
• Myopathy associated with thrombocytopenia [panelapp] (GNE)
• Noonan syndrome 1 (PTPN11)
• Platelet disorder, familial, with associated myeloid malignancy (RUNX1)
• Purinergic receptor P2X, ligand-gated ion channel, 1 deficiency (P2RX1)
• Quebec platelet disorder (PLAU)
• Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 (HOXA11)
• Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 (MECOM)
• Recessive severe thrombocytopenia with progression to marrow fibrosis at young age [panelapp] (KDSR)
• Significant bruising/haematomas [panelapp] (TNXB)
• Sitosterolemia 1 (ABCG8)
• Sitosterolemia 2 (ABCG5)
• Stormorken syndrome [YORK platelet syndrome] (STIM1)
• Takenouchi-Kosaki syndrome (CDC42)
• Telangiectasia, hereditary hemorrhagic, type 1 (ENG)
• Telangiectasia, hereditary hemorrhagic, type 2 (ACVRL1)
• Thrombocythemia 1 (THPO)
• Thrombocythemia 2 (MPL)
• Thrombocytopenia 2 (ANKRD26)
• Thrombocytopenia 3 (FYB1)
• Thrombocytopenia 4 (CYCS)
• Thrombocytopenia 5 (ETV6)
• Thrombocytopenia 6 (SRC)
• Thrombocytopenia with beta-thalassemia, XL (GATA1)
• Thrombocytopenia, AD, 7 (IKZF5)
• Thrombocytopenia, XL (WASP)
• Thrombocytopenia, XL, intermittent (WASP)
• Thrombocytopenia, XL, with/-out dyserythropoietic anemia (GATA1)
• Thrombocytopenia, anemia + myelofibrosis (MPIG6B)
• Thrombocytopenia, congenital amegakaryocytic (MPL)
• Thrombocytopenia, neonatal alloimmune (ITGB3)
• Thrombocytopenia-absent radius syndrome (RBM8A)
• Thrombophilia due to thrombomodulin defect (THBD)
• Thrombotic thrombocytopenic purpura, hereditary (ADAMTS13)
• von Willebrand disease, platelet-type (GP1BA)
• von Willebrand disease, type 1 (VWF)
• von Willebrand disease, type 3 (VWF)
• von Willebrand disease, types 2A, 2B, 2M + 2N (VWF)