Related Thrombocytopenia and Predisposition to Leukemia

CLINICAL CHARACTERISTICS

Individuals with related thrombocytopenia and predisposition to leukemia most often present with a lifelong history of thrombocytopenia, which is usually in the mild-to-moderate range. No syndromic features or associations are consistently shared across pedigrees. Affected individuals also have a high risk of developing a hematologic malignancy (with B-cell acute lymphoblastic leukemia [B-ALL] being the most common) and possibly other benign and malignant solid tumors.

DIAGNOSIS/TESTING: The diagnosis of related thrombocytopenia and predisposition to leukemia is established in a proband by identification of a heterozygous germline pathogenic variant in by molecular genetic testing.

MANAGEMENT

For clinical bleeding, local measures with consideration of antifibrinolytic agents, desmopressin, and/or platelet transfusion if bleeding is moderate to severe. For individuals with a history of moderate or severe bleeding, antifibrinolytic agents or desmopressin may be considered prior to surgical procedures to reduce bleeding complications. Platelet transfusions should be used judiciously, particularly in women of childbearing age, to reduce the risk of alloimmunization. For neoplasm, standard neoplasm-specific therapy with extra consideration of indications for stem cell transplantation, eligibility, and available donors. Complete blood count (CBC) with differential every six to 12 months and consideration of bone marrow aspirate and biopsy every one to three years. The frequency of such screening must be weighed against the burden of the screening protocol, particularly in young children. The exact frequency of CBC and bone marrow evaluations should be determined on a case-by-case basis by the physician and with consideration of patient/family preferences. For those with a history of bleeding, avoidance of medications that decrease platelet function (e.g., aspirin, nonsteroidal anti-inflammatory drugs) and avoidance of participation in contact sports are recommended. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of clinical surveillance for malignancy and management of potential significant thrombocytopenia. Platelet counts should be monitored during pregnancy and prior to delivery. Platelet transfusions prior to invasive procedures (e.g., epidural analgesia or cesarean section) or at the time of delivery may be considered in those with a history of bleeding or severe thrombocytopenia on a case-by-case basis.

GENETIC COUNSELING

-related thrombocytopenia and predisposition to leukemia is inherited in an autosomal dominant manner. To date, most individuals diagnosed with related thrombocytopenia and predisposition to leukemia inherited a pathogenic variant from a parent either known to be heterozgyous based on molecular genetic testing or presumed to be heterozgyous based on pedigree analysis or reported history of thrombocyotpenia. The heterozygous parent may not have any known clinical findings associated with related thrombocytopenia and predisposition to leukemia. Each child of proband has a 50% chance of inheriting the pathogenic variant. Once the pathogenic variant has been identified in an affected family member, predictive testing for at-risk asymptomatic family members and prenatal/preimplantation genetic testing are possible.