Introduction
Sebastian syndrome, also called Sebastian platelet syndrome, belongs to a heterogeneous group of macrothrombocytopenia (MTCP) disorders. These clusters of syndromes are hereditary in nature. They are caused due to genetic abnormality resulting in defective proteins that are functional in some specialized tissues such as platelets, white blood cells, renal tissue, and the inner ear. Hence individuals with specific genetic defects acquire clinical diseases related to the affected tissues and organs. Sebastian syndrome is one such disorder characterized by decreased platelets that are abnormal in shape along with altered white blood cells (leukocytes).
What Is Sebastian Syndrome?
Sebastian syndrome (SS) is a rare autosomal dominant inherited disease resulting in thrombocytopenia (reduced number of platelets) associated with giant platelets and granulocyte inclusions (abnormal proteins accumulated inside the cells). Neutrophils, basophils, and eosinophils are the commonly affected granulocytes. This syndrome is the most recently studied MYH9-related disease and is distinguished from other related disorders by the absence of renal impairment, hearing deficit, and eye abnormalities.
What Causes Sebastian Syndrome?
Sebastian syndrome is caused by the inheritance of a defective gene. Usually occurs in 6 to 11 members of a family with varying severity or sometimes remains asymptomatic (without any clinical disease). It shows an equal prevalence in both males and females. However, females are prone to increase bleeding complications in menstrual cycles or during pregnancy and childbirth.
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Pattern of Inheritance - Autosomal dominance. Autosomal means both mother and father have an equal chance of passing the gene to the child (not linked to sex chromosomes). Dominance means the presence of one gene (abnormal gene) is sufficient to express the phenotype (clinical disease). A child born to parents with defective genes has a 50 % risk percentage of developing Sebastian syndrome.
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Affected Gene - Mutation of MYH9 gene. Non-muscle myosins are motor proteins that play vital roles in several cellular processes in tissues like hematopoietic cells (precursor cells for the production of platelets and granulocytes), kidney, ear, and eye lens. This protein is coded in the MYH9 (myosin heavy chain 9) gene. Mutation (abnormal genetic disturbances) in this gene leads to functional impairment of the associated tissues. The resulting clinical disorders are grouped as MYH9-related diseases (MYH9-RD).
Characteristics of MYH9-Related Diseases (MYH9-RD):
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Autosomal dominant disorder.
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Macrothrombocytopenia (giant platelets with a reduced number in circulation).
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Abnormal leukocyte inclusion granules present from birth.
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Risk of developing functional disorders such as nephropathy, deafness, or cataracts in childhood or during adult life (late onset).
What Are the Clinical Manifestations of Sebastian Syndrome?
Individuals having Sebastian syndrome do not show symptoms of renal impairment, hearing problems, or signs of cataracts. The severity of bleeding symptoms varies from moderate bleeding episodes to completely asymptomatic bleeding tendencies even under hemostatic stress conditions (minor trauma or surgery). Some of the common bleeding symptoms reported in Sebastian syndrome are as follows:
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Bleeding diathesis (tendency to bleed easily) of unknown origin.
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Mucocutaneous bleeding such as bleeding from gums, oral cavity, and within the cheeks (buccal mucosa).
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Mild or recurrent bleeding episodes during minor trauma or injury.
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Easy bruising.
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Purpuric lesions especially in extremities (hands and legs).
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Menorrhagia (unusually heavy menstrual flow).
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Deep tissue bleeding.
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Bleeding during dental procedures or extractions.
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Ecchymoses (purplish discoloration under the skin).
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Petechiae (purple or brown hemorrhagic spots in legs, arms, or thighs due to subcutaneous bleeding).
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Epistaxis (nasal bleeding).
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In severe cases, intracranial bleeding in neonates with Sebastian syndrome.
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Moderate to excessive blood loss following surgical procedures.
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No symptoms related to renal impairment, cataract development, or auditory dysfunction.
What Are the Laboratory Investigations for Sebastian Syndrome?
Laboratory investigations play a crucial role in the diagnosis of Sebastian syndrome. Other forms of MYH9-related diseases are excluded by the absence of renal failure, hearing loss, and cataract development. Sebastian syndrome is closely related to the May-Hegglin anomaly which requires ultrastructural evaluation of neutrophil inclusions to confirm Sebastian syndrome. Due to the presence of only bleeding symptoms, Sebastian syndrome often gets misdiagnosed as idiopathic thrombocytopenia purpura (ITP) resulting in unsuccessful treatment interventions. The following laboratory investigations help in the accurate diagnosis of Sebastian syndrome.
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Detailed history to identify lifelong episodes of mild thrombocytopenia.
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Family history with the absence of any evidence of hearing loss, nephropathy, or cataracts proves beneficial.
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Detailed hemostatic tests show prolonged bleeding time.
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Demonstration of giant platelets in peripheral smear with Wright-Giemsa stain.
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Complete blood count (CBC) to detect Low platelet count.
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Platelet count ranges from 20,000 to 120,000 platelets/µl with a reduced mean platelet volume of 15 to 20 fl.
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Light microscopy, inclusions in the granulocytes have a similar morphological appearance to that of the May-Hegglin anomaly (another entity of macrothrombocytopenia).
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Electron microscopy, helps to differentiate between the two types by showing distinct inclusions characteristic of Sebastian syndrome. The leukocyte inclusions are more round and do not contain longitudinally arranged filaments as in the May-Hegglin anomaly.
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Leukocyte ultrastructural studies help in the confirmatory diagnosis of Sebastian syndrome.
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Platelet function studies show normal or near-to-normal functioning of platelets.
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The absence of platelet aggregation responses to epinephrine in platelet aggregation tests indicates a reduced number and abnormal shape of platelets.
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Platelet aggregometry, platelet flow cytometry, and PFA-100 testing are some of the automated instrumentations to assess platelet functions.
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Immunocytochemistry and immunofluorescence tests on blood films help in the detailed analysis of the leukocyte inclusions.
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Mutation screening is essential to assess the risk of acquiring genetic defects and serves as a guide for genetic counseling.
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A complete and extensive physical examination and laboratory investigations of renal function, visual capacity, fundoscopy, and auditory tests are needed to rule out other MYH9-related disorders.
What Are the Treatment Interventions for Sebastian Syndrome?
Most individuals do not require specific therapeutic intervention. Management of bleeding episodes and hemostatic maintenance is the primary objective in treating individuals with Sebastian syndrome. Misinterpretation of the diagnosis of Sebastian syndrome as chronic idiopathic thrombocytopenic purpura (ITP) could lead to unwanted harmful treatments and unnecessary drug exposure.
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Patients with Sebastian syndrome do not respond to treatment with steroids and immunosuppressants which are often prescribed for ITP.
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Active hemorrhagic episodes are controlled by the administration of antifibrinolytic agents.
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Preoperative administration of desmopressin reduces the risk of excessive bleeding.
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Platelet transfusions are considered in severe cases of bleeding following surgical procedures or trauma.
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Transfusion of platelet concentrates is found to increase platelet count.
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Non-peptide thrombopoietin mimetic agents are under trial in assessing their effectiveness in MYH9-related disorders.
Conclusion
Complete history and thorough examination of peripheral blood smear in individuals with thrombocytopenia play an important role in diagnosing Sebastian syndrome. This greatly reduces the misinterpreted diagnosis of chronic idiopathic thrombocytopenia purpura (ITP) thus preventing unnecessary and potentially harmful therapies. Genetic screening tests and genetic counseling help in the better management of Sebastian syndrome.
