Hematological abnormalities and 22q11.2 deletion syndrome

Abstract

The 22q11.2 deletion syndrome (22q11DS) is a common genetic disease characterized by broad phenotypic variability. Despite the small number of studies describing hematological alterations in individuals with 22q11DS, it appears that these abnormalities are more frequent than previously imagined. Thus, the objective of our study was to report on a patient with 22q11DS presenting thrombocytopenia and large platelets and to review the literature. The patient, a 13-year-old boy, was originally evaluated due to craniofacial dysmorphia and speech delay. He also had a history of behavioral changes, neuropsychomotor delay and recurrent otitis/sinusitis. The identification of a 22q11.2 microdeletion by fluorescent in situ hybridization diagnosed the syndrome. Despite his hematological alterations, he only had a history of epistaxis and bruising of the upper and lower limbs. Assessments of the prothrombin time, thrombin time, partial thromboplastin time, bleeding time, fibrinogen levels and platelet aggregation (including the ristocetin induced platelet aggregation test) were all normal. Hematological alterations observed in 22q11DS are directly related to the genetic disorder itself (especially in respect to deletion of the GPIb gene) and secondary to some clinical findings, such as immunodeficiency. Macrothrombocytopenia is increasingly being considered a feature of the broad spectrum of 22q11DS and may potentially be a clinical marker for the syndrome.

Hemizygosity for the gene encoding glycoprotein Ibβ is not responsible for macrothrombocytopenia and bleeding in patients with 22q11 deletion syndrome

“…Our findings also challenge the prevailing view that GPIBB hemizygosity is the cause of macrothrombocytopenia and a bleeding tendency in patients with 22q11DS . This view is not based on proof of a causal relationship, but is instead founded on the overlap of features observed in 22q11DS with the phenotype observed in individuals with Bernard–Soulier syndrome attributable to hemizygosity or homozygosity for pathogenic variants of GPIBB (Tables S2 and S3).…”

“…Only 25% of the patients with 22q11DS in our study had both large platelets and low platelet counts, suggesting that macrothrombocytopenia may not be as representative a feature of the wide spectrum of 22q11DS as has been previously supposed . This supposition is based, in part, on case reports, all of which described patients with large platelets (when platelet size was reported) and platelet counts that dropped below normal on at least one occasion (Table S4).…”

“…These findings reveal that mild macrothrombocytopenia and a mild bleeding diathesis are characteristic of incompletely overlapping subsets of patients, and that neither GPIBB copy number nor GPIBB sequence variation accounts for either macrothrombocytopenia or excessive bleeding in patients with 22q11DS. Only 25% of the patients with 22q11DS in our study had both large platelets and low platelet counts, suggesting that macrothrombocytopenia may not be as representative a feature of the wide spectrum of 22q11DS as has been previously supposed [32,36,39,41,54,55]. This supposition is based, in part, on case reports, all of which described patients with large platelets (when platelet size was reported) and platelet counts that dropped below normal on at least one occasion (Table S4).…”

“…MPVs of >10 fL and platelet counts of <150 000 μL −1 would justify sequencing of GPIBB to molecularly assess for Bernard–Soulier syndrome; if no pathogenic variant of GPIBB is identified, another genetic cause of congenital macrothrombocytopenia should be considered. The degree of thrombocytopenia is the biggest predictor for the risk of bleeding in patients with 22q11DS ; therefore, the types of bleeding expected in patients with 22q11DS would depend on the patient's platelet count. Patients with platelet counts of > 50 000 μL −1 might show mild to moderate bleeding symptoms, whereas those with platelet counts of < 50 000 μL −1 might show severe bleeding.…”

Effect of 22q11.2 deletion on bleeding and transfusion utilization in children with congenital heart disease undergoing cardiac surgery

“…Patients with 22q11.2 DS have been described as “Bernard Soulier-like” in that they have an increased prevalence of macrothrombocytopenia (24–27), decreased levels of platelet surface expression of GPIb-V-IX and/or decreased levels of total platelet GPIbβ (25,28), and platelet function defects (25,28). In addition, patients with 22q11.2 DS have symptoms consistent with a mild hemostatic disorder such as easy bruising, epistaxis and menorrhagia (28,29). The extent to which patients with 22q11.2 DS bleed excessively in association with cardiac surgery is not known.…”