Scott syndrome

Overview

Scott syndrome is an extremely rare inherited bleeding disorder characterized by a defect in platelet function, specifically in the externalization of phosphatidylserine (PS) on the surface of activated platelets. This impairment affects the coagulation cascade, resulting in delayed or insufficient clot formation. Unlike more common bleeding disorders such as hemophilia or von Willebrand disease, Scott syndrome does not involve deficiencies in clotting factors but rather a cellular mechanism crucial for efficient blood coagulation. The syndrome was first described in the 1970s and has since been identified in only a small number of human cases, although it has been more extensively studied in animal models such as dogs.

Causes

Scott syndrome is caused by mutations in the ANO6 gene (also known as TMEM16F), which encodes a protein involved in phospholipid scrambling. This protein enables phosphatidylserine (PS) to move from the inner to the outer leaflet of the platelet membrane upon activation, a critical step in providing a procoagulant surface for clotting factor complexes to assemble. In individuals with Scott syndrome, mutations in the ANO6 gene disrupt this process, impairing the ability of platelets to support thrombin generation and stable clot formation. The syndrome is inherited in an autosomal recessive manner, meaning two defective copies of the gene (one from each parent) are necessary to manifest the condition.

Symptoms

The clinical manifestations of Scott syndrome are related to defective blood clotting and can vary in severity. Common symptoms include:

• Easy bruising: Frequent or spontaneous bruises, often without a clear cause

• Prolonged bleeding: Extended bleeding times following injury, surgery, or dental procedures

• Menorrhagia: Heavy or prolonged menstrual bleeding in affected females

• Hematuria: Blood in the urine

• Epistaxis: Frequent or severe nosebleeds

• Mucocutaneous bleeding: Bleeding in the gums or gastrointestinal tract (less common)

Despite the defective platelet function, individuals with Scott syndrome do not typically experience spontaneous internal bleeding or joint bleeding as seen in classic hemophilia.

Diagnosis

Diagnosing Scott syndrome can be challenging due to its rarity and the nonspecific nature of its symptoms. Diagnosis involves specialized laboratory tests focused on platelet function and coagulation pathways. Diagnostic steps may include:

• Bleeding time: May be prolonged but not diagnostic alone

• Platelet aggregation studies: Typically normal, distinguishing it from other platelet function disorders

• Procoagulant activity assay: Shows impaired phosphatidylserine exposure on activated platelets

• Flow cytometry: To detect the absence of PS externalization on the platelet membrane following stimulation

• Genetic testing: Identification of pathogenic variants in the ANO6 gene confirms the diagnosis

A comprehensive hematologic evaluation and referral to a specialized center are often necessary to make a definitive diagnosis.

Treatment

There is no specific cure for Scott syndrome, and treatment focuses on preventing and controlling bleeding episodes. Management strategies include:

• Antifibrinolytic agents: Such as tranexamic acid to reduce bleeding during dental work, menstruation, or minor surgery

• Platelet transfusions: Used in more serious bleeding episodes or before major surgical procedures

• Avoidance of NSAIDs: Non-steroidal anti-inflammatory drugs should be avoided as they can worsen bleeding

• Hormonal therapy: For women with menorrhagia to regulate or suppress menstrual cycles

• Genetic counseling: Recommended for affected families to understand inheritance risks and family planning options

Patients with Scott syndrome should also wear medical alert identification and maintain regular follow-up with a hematologist experienced in rare bleeding disorders.

Prognosis

The long-term outlook for individuals with Scott syndrome is generally favorable, especially with appropriate management and avoidance of high-risk bleeding situations. Most patients can live normal lives with only occasional bleeding episodes, particularly if preventive strategies are in place. However, because the condition can lead to serious bleeding during surgery or trauma, early diagnosis and ongoing care are crucial. The rarity of the disorder means that many aspects of its natural history remain unclear, but with increasing awareness and better diagnostic tools, outcomes continue to improve.