|Year : 2022 | Volume
| Issue : 4 | Page : 280-284
GNE – related severe congenital macrothrombocytopenia: A case report and literature review
Muhammad Matloob Alam1, Abdulrhman Alathaibi1, Muhammad Kashif2, Mohammed Zakaria1, Ruwayd Adel Attar1, Hamdan Saeed Al-Ghamdi3, Abdullah Obaid Al Harbi3
1 Department of Hematology/Oncology, Armed Forces Hospital, Alhada, Taif, Saudi Arabia
2 Department of Laboratory, Armed Forces Hospital, Alhada, Taif, Saudi Arabia
3 Department of Pediatric, Armed Forces Hospital, Alhada, Taif, Saudi Arabia
|Date of Submission||08-May-2022|
|Date of Decision||01-Jun-2022|
|Date of Acceptance||22-Jun-2022|
|Date of Web Publication||18-Oct-2022|
Dr. Muhammad Matloob Alam
Department of Hematology/Oncology, Armed Forces Hospital, Alhada, Taif
Source of Support: None, Conflict of Interest: None
Congenital thrombocytopenia results from genetic mutations in genes implicated in megakaryocyte differentiation and/or platelet formation and clearance. We report the case of an 11-month-old girl who presented with severe macrothrombocytopenia since birth and subsequently developed an intracranial bleed. She was diagnosed to have GNE gene mutation. GNE gene encodes the key enzyme in sialic acid biosynthesis, glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE/MNK). Its mutation is responsible for the reduction in sialic acid biosynthesis and consequently leads to severe congenital thrombocytopenia and/or myopathy. Although no sign of myopathy is observed in our patient; it is possible myopathy can be developed later, thus long-term follow-up with neurology is highly advisable. We recommend the genetic counseling and a segregation analysis of this variant in other affected individuals in the family.
Keywords: Congenital, GNE gene mutation, macro/thrombocytopenia, myopathy, intracranial bleeding, sialic acid
|How to cite this article:|
Alam MM, Alathaibi A, Kashif M, Zakaria M, Attar RA, Al-Ghamdi HS, Al Harbi AO. GNE – related severe congenital macrothrombocytopenia: A case report and literature review. J Appl Hematol 2022;13:280-4
|How to cite this URL:|
Alam MM, Alathaibi A, Kashif M, Zakaria M, Attar RA, Al-Ghamdi HS, Al Harbi AO. GNE – related severe congenital macrothrombocytopenia: A case report and literature review. J Appl Hematol [serial online] 2022 [cited 2022 Dec 3];13:280-4. Available from: https://www.jahjournal.org/text.asp?2022/13/4/280/358710
| Introduction|| |
Congenital thrombocytopenia is a group of hereditary disorders characterized by a low platelet count as the main feature, and often with abnormal platelet function, which can consequently lead to impaired hemostasis., Congenital thrombocytopenia results from genetic mutations in genes implicated in megakaryocyte differentiation and/or platelet formation and clearance. The identification of the underlying causative gene of congenital thrombocytopenia is challenging given the high degree of heterogeneity, but important due to the presence of various clinical presentations and prognoses, where some defects can lead to myopathy and hematological malignancies.,,,
Hereditary thrombocytopenias have been classified into three groups depending on platelet volume. About fourteen clinical entities of inherited macrothrombocytopenias have been described. Bernard–Soulier syndrome, gray platelet syndrome, and May–Hegglin anomaly are the most common giant platelet thrombocytopenias. Many of which cause moderate-to-severe bleeding tendencies and are often underrecognized and are frequently misdiagnosed as immune thrombocytopenia purpura.
Diagnostic strategies to date have included a predominant phenotypic approach. Clinical manifestations, hematological parameters, and traditional platelet function tests allow for an initial diagnosis., However, employing next-generation sequencing, such as whole-genome sequencing and whole-exome sequencing can be an efficient methods for discovering causal genetic variants in both known and novel genes not previously implicated in congenital thrombocytopenia.,,, The individual processes involved in platelet production and hemostasis are genetically controlled; to date, mutations of more than 50 genes have been implicated to cause many different forms of congenital thrombocytopenia.
In this study, we report the case of an 11-month-old girl who presented with severe macrothrombocytopenia and intracranial bleed. We used a whole-exome sequencing approach to elucidate the genetic basis of a severe form of congenital thrombocytopenia in our patient. She was diagnosed to have a homozygous GNE gene mutation. GNE gene mutation is causing the reduction in sialic acid biosynthesis and consequently leads to severe congenital thrombocytopenia and/or myopathy.
| Case Report|| |
We present a Saudi girl, who initially presented to our hospital at the age of 9 months with intracranial bleeding and severe thrombocytopenia.
She was born by spontaneous vaginal delivery at 38 weeks of gestation without a history of pre- or postnatal complications. She received intramuscular Vitamin K at birth without noticeable bruising or bleeding. Her first complete blood count including platelets count at birth was unremarkable. She was discharged from the nursery on the 3rd day of life with routine follow-up. She received routine vaccination without bleeding symptoms.
At the age of 9 months, she was admitted to the hospital with a history of sudden onset of seizure activity. On arrival, her clinical and systemic examination was essentially normal. She had no dysmorphic features, her developmental milestones were appropriate for her age. Gross motor examinations were unremarkable with no muscle weakness noted. Her complete blood count on presentation revealed low hemoglobin (Hb – 7.8 g/dl [10.5–13.5 g/dl]) and severe thrombocytopenia (platelets count: 8 × 109/L [150–450 × 109/L]) with normal white blood cells and differential counts. Peripheral blood smear showed markedly reduced platelets count with the presence of giant platelet [Figure 1]. No other abnormalities were noticed in the other blood counts and morphology. Neuroimaging showed a large left frontoparietal extra-axial hematoma associated with mass effect on the adjacent cortical sulci and left lateral ventricle with mild midline shift [Figure 2]. Investigations and key findings are summarized in [Table 1].
|Figure 1: Peripheral blood smear showing markedly reduced platelets with the presence of giant platelets|
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|Figure 2: (a-c) Computed tomography scan of brain showing large left frontoparietal extra-axial hematoma associated with mass effect on the adjacent cortical sulci and left lateral ventricle with mild midline shift|
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Due to her recent history of CNS bleed and severe thrombocytopenia, she was initially stabilized with neuro-supportive care and platelets were transfused to keep platelets count at a safe level (>100 × 109/L). She was kept NPO, head of the bed elevated to 30°, normovolemic, normoglycemic, and normotensive status was maintained, hydration and electrolytes were checked regularly and corrected accordingly, and her oxygenation, hemoglobin, and platelets count were optimized and monitored for high intracranial pressure and seizure. She did not require any neurosurgical intervention. As there was an initial impression of immune thrombocytopenia, intravenous immunoglobulin was given and a pulse steroid was also started after bone marrow aspirate and trephine. The bone marrow aspirate and trephine showed a normocellular specimen with normal megakaryocyte numbers and morphology [Figure 3]a and [Figure 3]b.
|Figure 3: (a and b) Bone marrow aspirate and trephine showing a normocellular specimen with adequate megakaryocyte numbers and morphology|
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The exome of our patients was sequenced, and the alignment of the sequencing reads revealed homozygous and pathogenic variations; c. 1732G>A, p.(Gly578Ser) at Chr9:36220012; Gene isoform; GNE (NM_001128227.3) (Phenotype MIM number; 605820; AR).
She received platelet transfusions every 1–2 weeks for the first 3 months after intracranial hemorrhage. After stabilization of CNS bleed, the frequency of platelets transfusion was gradually decreased. Protective counseling to avoid NSAID medications, IM injection, and contact sports was done and she was discharged from the hospital in stable condition with follow-up with a hematologist and neurosurgery.
On follow-up visits, her baseline platelet count has remained <5 × 109/L on multiple occasions without bleeding symptoms. The shared decision between physician and parents was not to transfuse platelets regularly until indicated if bleeding symptoms appear or any surgical procedures planned to avoid the development of antibodies and platelet transfusion reactiveness.
Family history revealed that her 7-year-old elder brother also has severe thrombocytopenia since birth and his platelet count remained in the range of 1 × 109/L to 5 × 109/L without bleeding symptoms. He has no signs/symptoms of myopathy. There is one another 4-year-old sibling; he is healthy with a normal platelet count. Furthermore, both parents had no bleeding symptoms and have normal platelet counts as well. Her two first-degree cousins from the maternal side also had a history of severe thrombocytopenia since birth, now aged 19-year-old girl and 14-year-old boy. Both of them stopped following up with hematology at the age of 2–3 years. Both do not have any bleeding symptoms nor have any sign of myopathy at present. We recommend a segregation analysis of this variant in other affected individuals in the family.
| Discussion|| |
Mutations in the GNE gene have been reported worldwide in approximately 4,000 patients although the incidence of the disease has been estimated to be 1–9/100,000 individuals., The GNE gene is localized on chromosome 9p13.3,,,, that encodes glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase, a bifunctional enzyme. It is involved in cell surface sialylation and a critical regulator of cell surface adhesion molecules, GNE is also expressed in the bone marrow.,,
GNE gene mutation decreases the enzymatic activity and consequently, sialylation, or reduces the incorporation of sialic acid to glycoproteins and glycolipids. Sialic acid is located in the platelet membrane, forming during glycosylation, and is known to play a significant role in platelet functions. Several studies have reported that platelets deficient in sialylation are removed from circulation by hepatic Ashwell–Morell receptor, resulting in shortened platelet survival and thrombocytopenia., Many studies showed that the Ashwell–Morell receptor binds with hyposialylated platelets, and removal of only 8%–10% of sialic acid residues by neuraminidase treatment in vivo leads to increased platelet clearance rates.
Mutations in the GNE gene have also been identified in both hereditary inclusion body myopathy and Nonaka myopathy, which is also termed as distal myopathy with rimmed vacuoles., More than 10 GNE gene mutations have been reported in human distal myopathy with rimmed vacuoles. However, the exact mechanisms behind GNE defects, leading to distal myopathy with rimmed vacuoles are still not fully understood.
In other studies, two families were reported as distal myopathy with rimmed vacuoles associated with mild-to-moderate thrombocytopenia and no obvious bleeding thrombocytopenia., Other dominant mutations in the GNE gene have been associated with sialuria., It is important to note that recessive patients presented with severe body myopathy as a primary symptom, whereas the patient in our study did not display signs of myopathy, although this is possible because of her early age.
More recent literature reports the variant similar to our patient in patients with hereditary thrombocytopenia. The variant is found in 0.00091% of the overall population with a varied ethnic and clinical backgrounds. These GNE gene variant mutations can cause thrombocytopenia without associated myopathy. A study reported two cousins in a consanguineous family presented with moderate-to-severe bleeding associated with severe thrombocytopenia and required regular platelet transfusions.
In 2018, Revel-Vilk et al. summarized nine patients from unrelated three families, all exhibiting compound homozygous or heterozygous mutations in GNE. All of them had thrombocytopenia and mild-to-moderate bleeding symptoms; however, none of them showed evidence of neuromuscular symptoms associated with GNE myopathy. Although no sign of myopathy is observed in our patient, it can be developed later thus long-term follow-up with neurology is highly advisable. We recommend genetic counseling and segregation analysis of this variant in other affected individuals in the family is also important. Targeted molecular genetic testing and, if indicated, prenatal analysis can be offered to family members of the patient.
| Conclusion|| |
In summary, the homozygous GNE gene mutation identified here is responsible for severe thrombocytopenia in our patients. GNE gene mutation is causing the reduction in sialic acid biosynthesis and consequently leads to severe congenital thrombocytopenia and/or myopathy. As myopathy can be developed later in life thus long-term follow-up with neurology is highly advisable. We also recommend genetic counseling, targeted molecular genetic testing in other affected individuals in the family and, if indicated, prenatal analysis can be offered to family members of the patient.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]