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September 08, 2017

Disease synonyms


Inheritance pattern

Autosomal recessive, autosomal dominant, X-linked recessive, somatic

Clinical features

Thrombocytopenia is a disorder of haematopoetic cells with predominant defects of platelets and it is defined as having a platelet count of less than 150,000 in mL of circulating blood, while the normal number of platelets ranges between 150,000 and 450,000 cells per mL of blood 1. Platelets are haemopoetic cells that play a primary role in haemostasis, interacting with subendothelium-bound von Willebrand factor (vWF) via the membrane glycoprotein complexes.

Platelet adhesion is the initial interaction in blood coagulation and control of bleeding. The estimated incidence of X-linked thrombocytopenia and Wiskott-Aldrich Syndrome is between 1 and 10 per million males worldwide 2. The prevalence of thrombocytopenia absent radius syndrome is estimated at 1:200,000-1:100,000 3. Causes of thrombocytopenia include decreased platelet production, increased platelet destruction, increased splenic sequestration, and dilution.

The major clinical signs and symptoms of thrombocytopenia may include the following:

  • Easy or excessive bruising (“purpura”)
  • Superficial bleeding into the skin (“petechiae”) (typically most evident on the lower legs)
  • Scattered small ecchymosis at sites of minor trauma
  • Prolonged bleeding
  • Bleeding from gums or nose
  • Blood in urine or stool
  • Fatigue
  • Enlarged spleen
  • Jaundice.

Thrombocytopenia usually presents in infancy or early childhood, most commonly with intensive and frequent mucosal bleeding, bloody diarrhea, intermittent petechiae and purpura, and recurrent bacterial and viral infections 4. At least 40% of affected individuals also develop one or more autoimmune conditions, including hemolytic anemia, immune thrombocytopenic purpura, immune-mediated neutropenia, rheumatoid arthritis, vasculitis, and immune-mediated damage to the kidneys and liver 1, 4.

Clinical expression of thrombocytopenia has broad spectrum of variations ranging from asymptomatic to life-threatening bleeding conditions. Various syndromes and diseases are associated with thrombocytopenia, including the following:

Wiskott-Aldrich syndrome caused by mutations in the WAS gene should be suspected in males affected with:

  • Profound thrombocytopenia (<70,000 platelets/mL)
  • Small platelet size (>2 SD below the mean)
  • Recurrent bacterial or viral infection
  • Eczema
  • Autoimmune disorder
  • Lymphoma
  • Family history of one or more maternally related males with a WAS-related phenotype or disorder.

X-linked thrombocytopenia (XLT) also caused by mutations in the WAS gene 4 should be suspected in affected males with:

  • Congenital thrombocytopenia (5,000-50,000 platelets/mL) 4
  • Small platelet size
  • Absence of other clinical findings of Wiskott-Aldrich syndrome
  • Family history of one or more maternally related males with a WAS-related phenotype or disorder.

X-linked congenital neutropenia (XLN) also caused by mutation in the WAS gene 5 characterized with the following clinical features in affected males:

  • Recurrent bacterial or viral infections
  • Persistent neutropenia
  • Arrested development of the bone marrow in the absence of other clinical findings of Wiskott-Aldrich syndrome TAR syndrome is thrombocytopenia-related disorder characterized by thrombocytopenia and absence of radius 6.

TAR syndrome is caused by mutations in RBM8A, encoding RNA regulatory protein. Diagnosis of TAR syndrome is established in a patient who has both of the following features:

  • Bilateral absence of the radii with the presence of both thumbs
  • Thrombocytopenia (usually <50,000 platelets/mL) 6.

Bernard Soulier syndrome (BSS) is an inherited platelet disorder characterized by mild to severe bleeding tendency, macrothrombocytopenia and absent ristocetin-induced platelet agglutination. BSS is caused by mutations in the GP1BA, GP1BB, or GP9 genes 7.

Glanzmann thrombasthenia platelet-type bleeding disorder is a congenital macrothrombocytopenia associated with platelet anisocytosis mildly increased bleeding tendency. Glanzmann thrombasthenia can be caused by mutations in the integrin-related genes ITGA2B or ITGB3 8.

Thrombocytopenia with beta-thalassemia is a hereditary thrombocytopenia caused by mutations in the GATA1 gene, encoding transcription factor GATA binding protein 9. The major clinical features of this thrombocytopenia subtype include variable thrombocytopenia, hemolytic anemia, splenomegaly, and abnormalities in hemoglobin chain synthesis.

Additional thrombocytopenia-related conditions are caused by mutations in MYH9, encoding nonmuscular myosin heavy chain 9 protein:

Epstein syndrome is an autosomal dominant disorder characterized by thrombocytopenia, giant platelets, nephritis, and deafness 10.

Fechtner syndrome is an autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and Dohle-like body inclusions in peripheral blood leukocytes, with the additional features of nephritis, hearing loss, and eye abnormalities, mostly cataracts 10.

Sebastian syndrome is an autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and inclusions in peripheral blood leukocytes 10.

May-Hegglin anomaly is an autosomal dominant disorder characterized by the triad of thrombocytopenia, giant platelets, and Dohle-like body inclusions in peripheral blood leukocytes. About 25-50% of affected individuals have mild to moderate episodic bleeding 11.

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance
ABCB7 300135 Anemia, Sideroblastic, and Spinocerebellar Ataxia XLR
ACTN1 102575 Bleeding disorder, platelet-type, 15 AD
ADAMTS13 604134 thrombotic thrombocytopenic purpura AR
AK2 103020 Reticular dysgenesis AR
ALAS2 301300 X-linked sideroblastic anemia; Protoporphyria, erythropoietic, X-linked XL, XLR
AMN 605799 AR
ANK1 612641 Spherocytosis, type 1 AD, AR
ANKRD26 610855 thrombocytopenia type 2 AD
AP3B1 603401 Hermansky-Pudlak syndrome type 2 AR
ATM 607585 familial breast-ovarian cancer type 2; ataxia-telangiectasia AD, AR
ATRX 300032 Alpha-Thalassemia Myelodysplasia Syndrome; Alpha-Thalassemia/Mental Retardation Syndrome, X-Linked; Mental retardation-hypotonic facies syndrome, X-linked XLD, XLR
BLM 604610 Bloom syndrome AR
BLOC1S3 609762 Hermansky-Pudlak syndrome 8 AR
BRCA1 113705 familial breast-ovarian cancer type 1; pancreatic cancer type 4; Fanconi anemia, complementation group S AD, AR
BRCA2 600185 familial breast-ovarian cancer type 2; Medulloblastoma; Prostate Cancer; Wilms tumor, type 1; Fanconi anemia complementation group D1; pancreatic cancer type 2 AD, AR
BRIP1 605882 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group J AD
CASP10 601762 Autoimmune lymphoproliferative syndrome, type II; Lymphoma, non-Hodgkin; Gastric Cancer AD
CBL 165360 Leukemia, juvenile myelomonocytic; Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia AD
CBLIF 609342 Intrinsic factor deficiency AR
CD36 173510 Platelet glycoprotein IV deficiency; resistance to malaria AR
CD40LG 300386 Immunodeficiency With Hyper-Igm, Type 1 XLR
CDAN1 607465 congenital dyserythropoietic anemia 1 AR
CDIN1 615626 congenital dyserythropoietic anemia 1b AR
CENPJ 609279 primary microcephaly 6; Seckel syndrome 4 AR
CEP152 613529 Seckel syndrome 5; primary microcephaly 9 AR
CLCN7 602727 Osteopetrosis, autosomal dominant 2; Osteopetrosis, autosomal recessive 4 AD, AR
CLPB 616254 3-methylglutaconic aciduria type VII with cataracts, neurologic involvement and neutropenia AR
CSF3R 138971 Neutropenia, severe congenital, 7, autosomal recessive AR
CTC1 613129 Cerebroretinal microangiopathy with calcifications and cysts AR
CUBN 602997 megaloblastic anemia 1 AR
CXCR4 162643 WHIM syndrome AD
CYB5R3 613213 methemoglobinemia type I AR
CYCS 123970 Thrombocytopenia 4 AD
DHFR 126060 AR
DIAPH1 602121 Deafness, autosomal dominant 1; Seizures, cortical blindness, microcephaly syndrome AD, AR
DKC1 300126 X-linked dyskeratosis congenita XLR
DTNBP1 607145 Hermansky-Pudlak syndrome 7 AR
ELANE 130130 Neutropenia, cyclic; Neutropenia, severe congenital 1, autosomal dominant AD
EPB42 177070 Spherocytosis, type 5
ERCC4 133520 xeroderma pigmentosum complementation group F; XFE prpgeroid syndroem; Fanconi anemia of complementation group Q AR
FANCA 607139 Fanconi anemia complementation group A AR
FANCB 300515 Fanconi anemia of complementation group B XLR
FANCC 613899 Fanconi anemia of complementation group C AR
FANCD2 613984 Fanconi anemia of complementation group D2 AR
FANCE 613976 Fanconi anemia of complementation group E AR
FANCF 613897 Fanconi anemia of complementation group F
FANCG 602956 Fanconi anemia of complementation group G
FANCI 611360 Fanconi anemia of complementation group I AR
FANCL 608111 Fanconi anemia of complementation group L AR
FANCM 609644 Spermatogenic failure 28 AR
FAS 134637 Autoimmune lymphoproliferative syndrome AD
FASLG 134638 Lung Cancer; Autoimmune lymphoproliferative syndrome AD
G6PC3 611045 Neutropenia, severe congenital 4, autosomal recessive AR
G6PD 305900 glucose-6-phosphate dehydrogenase deficiency; resistance to malaria XLD
GATA1 305371 X-linked congenital dyserythropoietic anemia with thrombocytopenia; Anemia, X-linked, with/without neutropenia and/or platelet abnormalities; beta-thalassemia - X-linked thrombocytopenia XLR
GFI1 600871 Neutropenia, severe congenital 2, autosomal dominant AD
GFI1B 604383 Bleeding disorder, platelet-type, 17 AD, AR
GLRX5 609588 Anemia, sideroblastic, 3, pyridoxine-refractory AR
GNE 603824 Sialuria; Nonaka myopathy AD, AR
GP1BA 606672 Bernard-Soulier syndrome, type A2 (dominant); platelet type von Willebrand disease; Bernard-Soulier syndrome, type C AD, AR
GP1BB 138720 Bernard-Soulier syndrome, type C AR
GP9 173515 Bernard-Soulier syndrome, type C AR
GPI 172400 nonspherocytic hemolytic anemia due to glucose phosphate isomerase deficiency AR
GSS 601002 Glutathione synthetase deficiency AR
HAX1 605998 autosomal recessive severe congenital neutropenia type 3 AR
HBA1 141800 Heinz Body Anemias; alpha-Thalassemia; Hemoglobin H Disease AD
HBA2 141850 Heinz Body Anemias; alpha-Thalassemia; Hemoglobin H Disease AD
HBB 141900 Heinz Body Anemias; Delta-beta thalassemia; dominantly inherited inclusion body beta-thalassemia; sickle cell anemia; resistance to malaria; beta-thalassemia AD, AR
HFE 613609 Alzheimer Disease; hepatoerythropoietic porphyria; variegate porphyria; hemochromatosis type 1; susceptibility to microvascular complications of diabetes type 7; Transferrin serum level QTL2 AD, AR
HOXA11 142958 Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 AD
HPS1 604982 Hermansky-Pudlak syndrome type 1 AR
HPS3 606118 Hermansky-Pudlak syndrome type 3 AR
HPS4 606682 Hermansky-Pudlak syndrome type 4 AR
HPS5 607521 Hermansky-Pudlak syndrome type 5 AR
HPS6 607522 Hermansky-Pudlak syndrome type 6 AR
HSPA9 600548 Sideroblastic anemia type 4 AD, AR
IL2RG 308380 Severe X-linked combined immunodeficiency; moderate X-linked combined immunodeficiency XLR
ITGA2B 607759 Bleeding disorder, platelet-type, 16, autosomal dominant; Glanzmann thrombasthenia AD, AR
ITGB3 173470 Bleeding disorder, platelet-type, 16, autosomal dominant; Glanzmann thrombasthenia; Myocardial infarction, decreased susceptibility to AD, AR
ITK 186973 Lymphoproliferative syndrome 1 AR
JAGN1 616012 Neutropenia, severe congenital, 6, autosomal recessive AR
KLF1 600599 Blood group--lutheran inhibitor; Fetal hemoglobin quantitative trait locus 6; Anemia, congenital dyserythropoietic, type iv AD
KRAS 190070 Arteriovenous malformations of the brain; Bladder Cancer; familial breast-ovarian cancer type 2; Gastric Cancer, Hereditary Diffuse; Schimmelpenning-Feuerstein-Mims Syndrome; Lung Cancer; Pancreatic Cancer; acute myeloid leukemia; Noonan syndrome 3; Autoimmune lymphoproliferative syndrome type IV; Cardiofaciocutaneous syndrome 2 AD
LIG4 601837 LIG4 syndrome AR
LPIN2 605519 Majeed syndrome
LYST 606897 Chediak-Higashi syndrome AR
MLH1 120436 Muir-Torre syndrome; mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-2 AD, AR
MPL 159530 somatic myelofibrosis with myeloid metaplasia; thrombocythemia type 2; congenital amegakaryocytic thrombocytopenia AD, AR
MRE11 600814 Ataxia-telangiectasia-like disorder type 1 AR
MSH2 609309 Lynch syndrome; Muir-Torre syndrome; mismatch repair cancer syndrome AD, AR
MSH6 600678 mismatch repair cancer syndrome; endometrial cancer; hereditary nonpolyposis colorectal cancer-5 AD, AR
MTR 156570 homocystinuria-megaloblastic anemia, cblG complementation type; folate-sensitive neural tube defects AR
MTRR 602568 Homocystinuria-Megaloblastic Anemia, Cble Complementation Type; folate-sensitive neural tube defects AR
MYH9 160775 Fechtner syndrome; Macrothrombocytopenia and progressive sensorineural deafness; May-Hegglin anomaly; Sebastian syndrome; deafness type 17 AD
NBN 602667 Nijmegen breakage syndrome; Aplastic Anemia; Acute lymphoblastic leukemia AR
NF1 613113 neurofibromatosis type 1; Neurofibromatosis-Noonan syndrome; Leukemia, juvenile myelomonocytic AD
NHP2 606470 Dyskeratosis Congenita, Autosomal Recessive, 2 AR
NOP10 606471 Dyskeratosis Congenita, Autosomal Recessive, 1 AR
NRAS 164790 colorectal cancer; Melanocytic nevus syndrome, congenital, somatic; Nevus, Epidermal; Schimmelpenning-Feuerstein-Mims Syndrome; Thyroid Carcinoma, Follicular; Neurocutaneous melanosis, somatic; Noonan syndrome 6; Autoimmune lymphoproliferative syndrome type IV AD
PALB2 610355 familial breast-ovarian cancer type 2; Fanconi anemia of complementation group N; Pancreatic cancer, susceptibility to, 3 AD
PARN 604212 Dyskeratosis congenita, autosomal recessive 6; telomere-related pulmonary fibrosis and/or bone marrow failure type 4 AD, AR
PC 608786 pyruvate carboxylase deficiency AR
PDHA1 300502 Pyruvate dehydrogenase E1-alpha deficiency XLD
PDHX 608769 Lacticacidemia due to PDX1 deficiency AR
PKLR 609712 pyruvate kinase deficiency AD, AR
PMS2 600259 mismatch repair cancer syndrome; hereditary nonpolyposis colorectal cancer-4 AR
PRF1 170280 familial hemophagocytic lymphohistiocytosis 2; Lymphoma, non-Hodgkin; Aplastic Anemia AR
PTPN11 176876 LEOPARD syndrome 1; Noonan syndrome 1; Leukemia, juvenile myelomonocytic AD
PUS1 608109 myopathy, lactic acidosis and sideroblastic anemia type 1 AR
RAC2 602049 Neutrophil immunodeficiency syndrome
RAD51C 602774 Fanconi anemia of complementation group O; Breast-ovarian cancer, familial, susceptibility to, 3 AR
RBBP8 604124 Jawad syndrome / Microcephaly with mental retardation and digital anomalies; Seckel syndrome 2 AR
RBM8A 605313 Thrombocytopenia-absent radius syndrome AR
RIT1 609591 Noonan syndrome 8 AD
RPL11 604175 Diamond-Blackfan anemia 7 AD
RPL15 604174 Diamond-Blackfan anemia 12 AD
RPL26 603704 Diamond-Blackfan anemia 11 AD
RPL27 607526 AD
RPL35A 180468 Diamond-Blackfan anemia 5 AD
RPL5 603634 Diamond-Blackfan anemia 6 AD
RPS10 603632 Diamond-Blackfan anemia 9 AD
RPS17 180472 Diamond-Blackfan anemia 4 AD
RPS19 603474 Diamond-Blackfan anemia 1 AD
RPS24 602412 Diamond-blackfan anemia type 3 AD
RPS26 603701 Diamond-Blackfan anemia 10 AD
RPS27 603702 Diamond-Blackfan anemia 17 AD
RPS28 603685 Diamond-Blackfan anemia 15 with mandibulofacial dysostosis AD
RPS29 603633 Diamond-Blackfan anemia 13 AD
RPS7 603658 Diamond-Blackfan anemia 8 AD
RTEL1 608833 dyskeratosis congenita; that telomere-related pulmonary fibrosis and/or bone marrow failure type 3 AD, AR
RUNX1 151385 Platelet disorder, familial, with associated myeloid malignancy; acute myeloid leukemia AD
SAMD9 610456 normophosphatemic familial tumoral calcinosis; MIRAGE syndrome AD, AR
SBDS 607444 Shwachman-Bodian-Diamond syndrome; Aplastic Anemia AR
SEC23B 610512 congenital dyserythropoietic anemia 2; Cowden syndrome 7 AD, AR
SH2D1A 300490 Lymphoproliferative Syndrome, X-Linked, 1 XLR
SLC19A2 603941 Thiamine-responsive megaloblastic anemia syndrome AR
SLC19A3 606152 biotin-thiamine-responsive basal ganglia disease AR
SLC25A19 606521 Microcephaly, Amish type; Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type) AR
SLC25A38 610819 Anemia, sideroblastic, 2, pyridoxine-refractory AR
SLC4A1 109270 Autosomal dominant distal renal tubular acidosis; resistance to malaria; Renal tubular acidosis, distal, with hemolytic anemia; Spherocytosis, type 4 AD, AR
SLX4 613278 Fanconi anemia of complementation group P AR
SPTA1 182860 Elliptocytosis type 2; Pyropoikilocytosis; Spherocytosis, type 3 AD, AR
SPTB 182870 Spherocytosis, type 2; Elliptocytosis 3 AD
SRP72 602122 Bone marrow failure, familial AD
STIM1 605921 Myopathy, tubular aggregate, 1; Immunodeficiency 10 AD, AR
STX11 605014 Hemophagocytic lymphohistiocytosis, familial, 4 AR
STXBP2 601717 Hemophagocytic lymphohistiocytosis, familial, 5
TCN2 613441 Transcobalamin II deficiency AR
TERT 187270 acute myeloid leukemia; Dyskeratosis congenita 4; Bone marrow failure, telomere-related, 1 AD, AR
TINF2 604319 Revesz syndrome; Dyskeratosis congenita, autosomal dominant 3 AD
TP53 191170 familial breast-ovarian cancer type 2; colorectal cancer; Hepatocellular Carcinoma; Glioma susceptibility 1; Li-Fraumeni syndrome 1; Osteogenic Sarcoma; Pancreatic Cancer AD
TPK1 606370 Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) AR
TRNT1 612907 Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay AR
UBE2T 610538 Fanconi anemia of complementation group T AR
UNC13D 608897 familial hemophagocytic lymphohistiocytosis 3 AR
VPS13B 607817 Cohen syndrome AR
VPS45 610035 Severe congenital neutropenia type 5 AR
WAS 300392 Neutropenia, severe congenital, X-linked; Wiskott-Aldrich syndrome; Thrombocytopenia 1 XLR
WRAP53 612661 Autosomal recessive dyskeratosis congenita type 3 AR
XIAP 300079 X-linked lymphoproliferative disease 2 XLR
XRCC2 600375 Fanconi anemia, complementation group U AR
YARS2 610957 Myopathy, lactic acidosis, and sideroblastic anemia 2 AR

Treatment of thrombocytopenia usually includes platelet transfusion used to provide an immediate platelet increase. Furthermore, treatment should be focused on the etiology of thrombocytopenia (e.g. discontinuation of the drug that caused the thrombocytopenia, treatment of the underlying infection, chemotherapy, and others). Hematopoietic cell transplantation (HCT) is the only known curative treatment. Topical steroids and antibiotics should be considered for infected eczema. Immunosuppressants should be used for autoimmune disease and granulocyte colony stimulating factor and appropriate antibiotics for neutropenia.

CENTOGENE offers sequencing and deletion/duplication analysis for the genes in the Thrombocytopenia panel (ADAMTS13, ANKRD26, CYCS, GATA1, GP1BA, GP1BB, GP9, ITGA2B, ITGB3, MASTL, MPL, MYH9, RUNX1, WAS).

Differential diagnosis

The differential diagnosis of thrombocytopenia-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Disseminated intravascular coagulation liver disease
  • Thrombotic Thrombocytopenic Purpura (TTP)
  • Drug-induced immune thrombocytopenia (alcohol, heparin, quinine/quinidine, sulfonamides)
  • Infection/sepsis
  • Acute leukemia, myelodysplastic syndrome or related malignancy
  • Megaloblastic anemia.

Testing strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free whole genome sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and providing sequencing of the entire gene with more uniform coverage

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for thrombocytopenia using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire gene (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Thrombocytopenia panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the thrombocytopenia panel, we further recommend continuing the bioinformatics analysis of the data with whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for thrombocytopenia testing:

  • Individuals with a family history of thrombocytopenia and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling thrombocytopenia
  • Individuals with a negative but suspected family history of thrombocytopenia, in order to perform proper genetic counseling.

Test utility

Sequencing, deletion/duplication of the panel genes should be performed in all individuals suspected of having thrombocytopenia and suspected phenotypes. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the thrombocytopenia and related disorders identify at-risk family members, provide disease risks as well as appropriate referral for patient support and/or resources.