A Novel Homozygous GFI1B Mutation in Siblings With Thrombocytopenia and Bleeding Tendency

ABSTRACT

Platelet type bleeding disorder 17 (OMIM #187900) is a type of “gray platelet syndrome” and occurs due to a mutation in the GFI1B gene on chromosome 9q34.13. Patients usually present with a history of easy bleeding tendencies, recurrent epistaxis or gum bleeding, and rarely with severe hemorrhage, and they may often be misdiagnosed. We herein report a novel autosomal recessive bleeding disorder in two sisters of the same family caused by a mutation in GFI1B, where both sisters, 13 and 8 years old, respectively presented with a history of recurrent episodes of epistaxis, firstly misdiagnosed and treated as ITP. Later, the final diagnosis was made with whole genome sequencing. The identification of GFI1B mutations in patients with thrombocytopenia and bleeding disorders highlights the importance of genetic testing in the diagnostic workup of these conditions. The cases reported here presented with mild to moderate thrombocytopenia and were initially misdiagnosed as ITP. Whole exome sequencing has proven to be a valuable tool in identifying mutations, as demonstrated in this case. This case report underscores the significance of evaluating for inherited platelet disorders in instances of recurrent bleeding.

Pedigree chart showing affected siblings.

Summary.

• Platelet type bleeding disorder 17 (OMIM #187900) is a type of “gray platelet syndrome” and occurs due to a mutation in the GFI1B gene on chromosome 9q34.13.

• These disorders are rare but clinically important since they can cause recurrent mucocutaneous bleeding and may be misdiagnosed.

• The final diagnosis is made with whole exome sequencing.

Abbreviations

BMI

body mass index

CDC

Centers for Disease Control and Prevention

ER

emergency room

GPS

gray platelet syndrome

IPDs

inherited platelet disorders

ITP

immune thrombocytopenic purpura

SPDs

storage pool diseases

TUTH

Tribhuvan University Teaching Hospital

1. Introduction

Inherited platelet disorders (IPDs) are a heterogeneous group of diseases caused by molecular anomalies in genes involved in platelet formation and/or function [1]. It is broadly classified into platelet membrane receptor defects and storage pool diseases (SPDs). Although rare, these disorders are clinically important since they can cause recurrent mucocutaneous hemorrhage [2]. 17 (OMIM #187900) is a type of storage pool defect due to a mutation in the GFI1B gene on chromosome 9q34.13. Patients usually present with a history of easy bleeding tendencies, recurrent epistaxis, or gum bleeding, and rarely with severe hemorrhage [3].

We herein report a novel autosomal recessive bleeding disorder in two sisters of the same family caused by a mutation in GFI1B.

2. Case Presentation

2.1. Case 1

2.1.1. Case History and Examination

A 13‐year‐old developmentally normal, pre‐menarchal female born to a non‐consanguineously married couple from north‐east Nepal presented to the pediatric emergency room (ER) of Tribhuvan University Teaching Hospital (TUTH) with chief complaints of epistaxis from the right nostril for 3 h which did not stop after nasal compression and required anterior nasal packing. She did not give any history of fever, trauma, nose picking, rash, or bleeding from other sites.

On reviewing her history, she had a history of intermittent appearance of bluish patches over the body with easy bruising tendencies from the age of 2 years and multiple episodes of epistaxis and gum bleeding from the age of 5 years for which she was evaluated at various centers and misdiagnosed as chronic immune thrombocytopenic purpura (ITP) for which she was prescribed corticosteroids; however, her thrombocytopenia persisted, with the lowest being 19,000 × 10⁹/L. At the age of 9 years, she underwent splenectomy for persistent thrombocytopenia, despite which her bleeding tendencies and thrombocytopenia persisted.

On family history, her younger sister also has a history of recurrent epistaxis and gum bleeding with petechiae (discussed in detail in case 2). Her father has a history of easy bruising and bleeding tendencies with trivial trauma, which on investigation, blood parameters were normal but had not undergone other additional investigations. There is a history of the death of her two female siblings from seizure‐like episodes at the age of 9 and 10 months, the details of which are unknown.

The pedigree chart of the family is shown in Figure 1.

FIGURE 1.

Pedigree chart showing affected siblings.

On examination, she was alert and non‐dysmorphic. There was no pallor, petechiae, ecchymosis, or lymphadenopathy. Vitals were stable. On abdominal examination, there was a 10 cm scar on the left subcostal region; there was no organomegaly, and all the other systemic examinations were normal. On anthropometry, her weight was 30 kg (lies below the 5th centile in CDC growth chart for weight for age for a girl of 2 to 20 years), height was 140 cm (lies below the 5th centile in CDC growth chart for height for age for a girl of 2 to 20 years), and her body mass index (BMI) was 15.30 kg/m².

2.1.2. Investigation

Her blood investigations showed thrombocytopenia (89,000 × 10⁹/L) and anemia (Hb 11.7 g/dL) with a normal leucocyte count, PT, and APTT. Peripheral blood smear showed microcytic hypochromic RBCs with target cells and pencil cells with reduced platelets on the smear.

Bone marrow aspiration showed megakaryocytic thrombocytopenia. The vWF activity was within the normal limit (93.6%).

In the view of recurrent epistaxis with a similar history in a sibling with bone marrow aspiration showing megakaryocytic thrombocytopenia, an inherited platelet functional defect was suspected, for which whole exome sequencing was sent. This showed homozygous c.622G>T (p.Glu208Ter) in Exon 5 of GFI1B, causative of platelet type bleeding disorder‐17 (OMIM#1879000), which is a type of “gray platelet syndrome.”

2.2. Case 2

2.2.1. Case History and Examination

An 8‐year‐old developmentally normal female (younger sister of the patient in case 1), presented to the pediatric ER of TUTH with complaints of gum bleeding for 9 h which occurred spontaneously. On reviewing her history, she had a history of easy bruising, recurrent epistaxis, and gum bleeding since the age of 4 years of age, for which she had been evaluated in multiple centers and treated for ITP with corticosteroids but without improvement. On her past evaluations, she had thrombocytopenia with the lowest platelets being 24,000 × 10⁹/L.

She has received anti‐fibrinolytic and blood transfusions multiple times during bleeding episodes.

On examination, there was no pallor, petechiae, ecchymosis, or lymphadenopathy. Vitals were stable; there was no organomegaly, and all the systemic examinations were normal.

2.2.2. Investigation

On investigation she had thrombocytopenia (66,000 × 10⁹/L) and anemia (Hb 10.2 g/dL) with a normal leucocyte count, PT, and APTT. The vWF activity was within the normal limit (135%). PBS showed reduced and large platelets.

Sanger sequencing for the GFI1B gene was sent, and it showed the same mutation (homozygous c.622G>T (p.Glu208Ter) in Exon 5 of GFI1B), similar to her sister.

3. Conclusion and Results

The final diagnosis of both patients was made with whole exome sequencing. This case report underscores the significance of evaluating for inherited platelet disorders in instances of recurrent bleeding, particularly when conventional therapeutic interventions are ineffective in managing the hemorrhage or when there is a documented familial history of bleeding diathesis.

4. Discussion

GFI1B gene (Growth factor Independent 1B) is a gene that encodes a zinc finger protein crucial for the development and differentiation of megakaryocytes and erythrocytes. Functional studies have demonstrated that mutation in GFI1B disrupts the DNA binding domain, leading to impaired megakaryocyte development and production of abnormally large platelet precursors in reduced numbers [4]. Clinically, patients present with varying severity of recurrent mucocutaneous bleeding, with investigations showing macrothrombocytopenia, gray platelets with reduced amounts of alpha granules, aberrant platelet expression of the stem cell marker CD34, and red cell anisopoikilocytosis [5]. Both of our cases had thrombocytopenia at presentation and bone marrow showing megakaryocytic thrombocytopenia in the first case.

A cohort study done by Gunay‐Aygun et al. in 25 patients with gray platelet syndrome found that among the available data of patients, ITP was the initial diagnosis in 8 of 15 patients (53%), which is similar to our cases [6]. A similar case of homozygous GFI1B mutation has been reported in two sisters presented with thrombocytopenia and bleeding tendency [5].

The identification of GFI1B mutations in patients with thrombocytopenia and bleeding disorders highlights the importance of genetic testing in the diagnostic workup of these conditions. The cases reported here presented with mild to moderate thrombocytopenia and were initially misdiagnosed as ITP. However, we identified a c.622G>T homozygous likely pathogenic variant in GFI1B as the cause of recurrent mucocutaneous bleeding with thrombocytopenia in both cases. Had the genetic testing been done earlier, the prolonged ineffective treatment could have been avoided. Whole exome sequencing has proven to be a valuable tool in identifying variants, as demonstrated in this case.

There has been limited data in platelet‐type bleeding disorders, and further research is essential to elucidate the full spectrum of clinical phenotypes associated with GFB1B mutations and to explore potential therapeutic interventions.

Author Contributions

Shova Aryal: conceptualization, data curation, project administration, resources, writing – original draft, writing – review and editing. Surabhi Aryal: conceptualization, project administration, supervision, writing – original draft, writing – review and editing. Sangit Adhikari: conceptualization, data curation, project administration, software, writing – original draft, writing – review and editing. Punam Adhikari: conceptualization, writing – original draft, writing – review and editing.

Ethics Statement

The study is exempt from ethical approval in our institution as this includes anonymized patient details causing no harm to the patient after obtaining her consent. A copy of written consent can be made available to the editor in chief of this journal upon request.

Consent

Written informed consent was obtained from the patient's parents for publication and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal on request.

Conflicts of Interest

The authors declare no conflicts of interest.

Aryal S., Aryal S., Adhikari S., and Adhikari P., “A Novel Homozygous GFI1B Mutation in Siblings With Thrombocytopenia and Bleeding Tendency,” Clinical Case Reports 13, no. 10 (2025): e71075, 10.1002/ccr3.71075.

Data Availability Statement

All the data generated or analyzed during this study is included in the manuscript.