Scott Syndrome

A number sign (#) is used with this entry because of evidence that Scott syndrome (SCTS) is caused by homozygous mutation in the TMEM16F gene (608663) on chromosome 12q12.

Description

Scott syndrome is a mild platelet-type bleeding disorder characterized by impaired surface exposure of procoagulant phosphatidylserine (PS) on platelets and other blood cells, following activation with Ca(2+)-elevating agents (Munnix et al., 2003).

Clinical Features

In 4 generations of a family (with 1 instance of male-to-male transmission), Robinson et al. (1967) described a mild bleeding disorder with no spontaneous hemorrhage. Analysis of blood coagulation in 2 generations revealed normal values for all clotting factors and other hemostatic systems except prothrombin consumption and thromboplastin inactivation. Robinson et al. (1967) demonstrated the presence of what they termed an 'inactivator' of active factor X (F10; 613872) in the plasma of these patients which accelerated the decay of blood thromboplastin. The inhibitor resembled that commonly observed in systemic lupus erythematosus; a similar agent was found in normal plasma but in much smaller amounts.

Parry et al. (1980) studied 10 individuals from 3 unrelated Welsh families who had reduced prothrombin conversion as shown by a grossly abnormal prothrombin consumption index (PCI). Male-to-male transmission was reported. All known plasma coagulation factors were present in adequate concentrations; some affected persons had mild postoperative or postpartum bleeding but none suffered spontaneous bleeding. In therapeutic trials both plasma and platelet transfusions were needed to correct the abnormality. This finding, together with in vitro and other in vivo studies, suggested to Parry et al. (1980) that the abnormality was associated with an inhibitor of the interaction between plasma and phospholipid during blood coagulation. Parry et al. (1980) considered the abnormality similar but not identical to that in several members of the family reported by Robinson et al. (1967).

Weiss (1994) reviewed the disorder of platelet coagulant activity known as Scott syndrome.

Kojima et al. (1994) demonstrated that the coagulant nonresponder phenotype observed in platelets and erythrocytes in Scott syndrome is expressed by all of the EBV-transformed lymphoblasts derived from the B cells of the patient, and that the unique phenotype of the defective cells can be isolated by single cell cloning and propagated in culture through many generations. The continuous expression of the aberrant phenotype through in vitro culture confirmed that the Scott syndrome defect represents a gene deletion or mutation that is passed to daughter cells through mitosis. Furthermore, they demonstrated by heterokaryon hybridoma fusion that the abnormal Scott phenotype can be corrected by fusion with a cell exhibiting the normal coagulant-responder phenotype, and that the normal phenotype is sustained when these hybridomas are subsequently propagated through many generations. Taken together with the results of previous studies, these data suggested that the cellular defect in Scott syndrome reflects a mutation or deletion of a gene required for normal Ca(2+)-dependent transbilayer migration of phosphatidylserine to the plasma membrane surface and that this defect is shared among the blood cells of lymphoid, megakaryocytic, and erythroid lineages.

Toti et al. (1996) characterized a familial instance of Scott syndrome and confirmed that it is a genetic disorder affecting the outward transmembrane migration of phosphatidylserine. Low prothrombin consumption in the serum of the proposita, a 71-year-old woman, and 2 of her children was the sole abnormal hemostasis parameter. The degree of exposure of procoagulant phospholipids, chiefly phosphatidylserine, was reduced in stimulated platelets, erythrocytes, and EBV-infected B lymphocytes, indicating that multiple hematologic lineages are affected in this disorder. The data were considered compatible with homozygous status of the proposita and heterozygous status of her children. Toti et al. (1996) concluded that Scott syndrome is transmitted as an autosomal recessive trait, reflecting the deletion or mutation of a putative outward phosphatidylserine translocase.

Biochemical Features

Miletich et al. (1977, 1978) demonstrated that each platelet has about 200 binding sites with high affinity specifically for activated factor X (factor Xa). Bound factor Xa is 300,000 times more active than free factor Xa in generating thrombin from prothrombin and is protected from inactivation by antithrombin III. Factor V (612309) is also essential for the binding process. The important physiologic role of the platelet receptor for factor X was indicated by the studies (Miletich et al., 1979) of a woman with a hemorrhagic diathesis due to deficiency of the platelet receptor who was first reported by Weiss et al. (1979). Receptors in the parents were normal; however, Miletich et al. (1979) did not exclude autosomal recessive inheritance. Since the patient's value for factor X binding was 25% of normal, the heterozygous state might be characterized by values 75% of normal, which would be indistinguishable from the normal range. Rosing et al. (1985) confirmed the deficiency in capacity to promote prothrombin activation in this patient and demonstrated a deficiency in the ability to promote factor X activation as well. Rosing et al. (1985) also showed that the platelets were defective in the capacity to expose phosphatidylserine at the outer surface of stimulated platelets. In further studies of the same patient, Ahmad et al. (1989) described findings suggesting impairment of factor VIIIa binding.

Phospholipid scramblase (see 604170) is a plasma membrane protein purified by Basse et al. (1996) that mediates accelerated transbilayer migration of phospholipids upon binding calcium ions, facilitating rapid mobilization of phosphatidylserine to the cell surface upon elevation of internal Ca(2+). In patients with Scott syndrome, circulating blood cells show decreased cell surface exposure of phosphatidylserine at elevated cytosolic levels of calcium ion, implying an underlying defect or deficiency of phospholipid scramblase. To gain insight into the molecular basis of Scott syndrome, Stout et al. (1997) compared PL scramblase in Scott erythrocyte membranes to those of normal controls. Whereas membranes of Scott cells were unresponsive to Ca(2+)-induced activation of PL scramblase at neutral pH, apparently normal PL scramblase activity was induced at pH less than 6.0. After extraction with octylglucoside, a membrane protein was isolated from the Scott cells that exhibited normal PL scramblase activity when reconstituted in vesicles with exogenous PLs. Like PL scramblase from normal red cells, PL scramblase from Scott red cells was maximally activated by addition of calcium ion (at pH 7.4) or by acidification to pH less than 6.0, and similar apparent affinities for calcium ion and rates of transbilayer transfer of PLs were observed. Stout et al. (1997) suggested that the defect in Scott syndrome is related to an altered interaction of calcium ion with PL scramblase on the endofacial surface of the cell membrane, due either to an intrinsic constraint upon the protein preventing interaction with calcium ion in situ, or to an unidentified inhibitor or cofactor in the Scott cell that is dissociated by detergent.

Munnix et al. (2003) analyzed the relationship between Ca(2+) flux and phosphatidylserine exposure in platelets and B lymphocytes derived from the original Scott syndrome patient (Weiss et al., 1979), a patient from 1 of the Welsh families reported by Parry et al. (1980), and 2 controls. The 34-year-old Welsh woman, who had a history of excessive bleeding after dental extractions since childhood, suffered life-threatening postpartum hemorrhage after an uncomplicated forceps delivery. Munnix et al. (2003) found that although she had normal levels of coagulation factors and normal platelet aggregation, her collagen-activated platelets showed only 52% of the prothrombinase activity of a control and had markedly reduced phosphatidylserine exposure, confirming the phenotype of Scott syndrome. Ca(2+) entry into platelets and lymphoblasts from both patients was normal, and elevated intracellular free Ca(2+) concentrations resulting from store-mediated Ca(2+) entry was not sufficient to trigger phosphatidylserine exposure.

Molecular Genetics

Suzuki et al. (2010) identified homozygosity for a splice site mutation in TMEM16F (608663.0001) in the patient reported by Kojima et al. (1994) and by Weiss et al. (1979).

Nomenclature

The bleeding disorder in the patient studied by Weiss et al. (1979) was referred to as Scott syndrome, presumably on the basis of the patient's surname (Ahmad et al., 1989).

Animal Model

Brooks et al. (2002) discovered a novel canine hereditary bleeding disorder with the characteristic features of Scott syndrome. Affected dogs were from a single, inbred colony and experienced clinical signs of epistaxis, hyphema (hemorrhage into the anterior chamber of the eye), intramuscular hematoma, and prolonged bleeding with cutaneous bruising after surgery. The hemostatic abnormalities were restricted to tests of platelet procoagulant activity, whereas platelet count, platelet morphology under light microscopy, bleeding time, clot retraction, and platelet aggregation and secretion in response to thrombin, collagen, and adenosine diphosphate stimulation were all within normal limits. Washed platelets from the affected dogs demonstrated approximately twice normal clotting times in a platelet factor-3 availability assay and, in a prothrombinase assay, generated only background levels of thrombin in response to calcium ionophore, thrombin, or combined thrombin plus collagen stimulation. These studies indicated recessive inheritance.

History

In a patient with Scott syndrome, Albrecht et al. (2005) identified a heterozygous missense mutation (arg1925 to gln) in the ABCA1 gene (600046), which was not found in unaffected family members or controls. However, both mutant and wildtype alleles were reduced in mRNA expression, and the authors found no causative mutation for this phenomenon in the ABCA1 gene or its proximal promoter. Albrecht et al. (2005) suggested that a putative second mutation in a trans-acting regulatory gene might be involved in the disorder in this patient.