A novel, homozygous mutation in GFI1B causing inherited thrombocytopenia with Glanzmann-like platelet dysfunction

Introduction Inherited platelet disorders (IPD) are rare. To date mutations in around 80 genes have been identified as causes of IPD with heterogeneous clinical manifestations [1] [2]. Recognizing IPD can be difficult but is advisable in order to provide patients with proper counseling and treatment in bleeding situations [3]. Novel mutations are frequently found and require an accurate platelet diagnostic work-up to confirm their clinical relevance and pathogenic role [4]. We report a female patient with lifelong hemorrhagic diathesis.

Method Clinical assessment, platelet phenotyping by flow-cytometry, immunofluorescence microscopy, standard aggregometry, DNA analysis as well as a platelet reactive antibody screening using MAIPA were performed.

Results The patient was a 46-year-old woman with congenital, moderate thrombocytopenia (range 55-76,000/µl) and substantial spontaneous and provoked bleeding symptoms. A diagnosis of Glanzmann Thrombasthenia (GT) had been previously made at another institution, and the patient was consequently treated on-demand with platelet concentrates. Family history strongly suggested an autosomal-dominant inherited bleeding disorder. By standard aggregometry, a GT-like platelet dysfunction (absence of platelet aggregation after stimulation with all agonists except ristocetin at high concentration) was found. However, the expression of platelet glycoprotein receptor GPIIbIIIa and GPIbIX was normal. No platelet autoantibodies potentially causing acquired GT were detected. By light-microscopy, we found partially degranulated large platelets and rarely giant platelets. A mild alpha-storage pool disorder was detected by immunofluorescence-microscopy as well as expression of the stem cell antigen CD34 on platelet surfaces. The combination of autosomal-dominant macro-thrombocytopenia with reduced alpha granule markers and expression of CD34 strongly indicated a mutation in GFI1B gene [5]. Genetic testing confirmed a hitherto non-reported GFI1B variant, p.His181Leu, which was present in a homozygous state. Alternative splicing results in two GFI1B isoforms. The identified missense variant was predicted to affect the function of the longer isoform, which is required for megakaryopoiesis and platelet production but not of the short one which is essential for erythroid differentiation. Because of the highly consistent platelet phenotype, we interpreted this variant as pathogenic. In addition, we suggest that the particular homozygous state of the mutation can lead to the GT-like platelet dysfunction, which is unusual in patients with GFI1B-related thrombocytopenia. No mutations were present in ITGA2B and ITGB3.

Conclusion In patients presenting with platelet dysfunction immunofluorescence on the blood smear allows extended platelet phenotyping. This can guide further diagnostic steps and, together with genetic testing, result in a final diagnosis

Conflict of Interest

The authors have no conflicts of interests to declare.

• References

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Publication History

Article published online:
20 February 2023