Autoimmunity in Down’s Syndrome: Another Possible Mechanism of Moyamoya Disease
To the Editor:
The presence of Down’s syndrome (DS) associated with moyamoya disease has been increasingly noted in the last years. Several reports suggest that the incidence of moyamoya disease is higher in children with DS than in other children. Since 1977, when this association was described for the first time, more than twenty cases have been reported.1 2 3 However, the reason of this association is unknown. Furthermore, DS is associated with autoimmune disorders.4 We describe a child with trisomy 21 affected by moyamoya and Graves’ disease, associated with anti-thyroid microsome antibodies and antiphospholipid antibodies (aPL). This patient was included in the prospective study of stroke in young adults in Cantabria, Spain.5 6
A 21-year-old man was admitted to the hospital on May 27, 1986. Thirteen days before, his mother noticed a sudden muscle weakness in his left arm; 3 days later she also noted that he had difficulty in walking because of a weakness in his left leg. The patient was the eighth pregnancy of a mother who was 39 years of age at the time of delivery. When he was a baby, a mental deficiency was noted, and he also suffered from an incomplete acquisition of the language, with use only of monosyllables.
His blood pressure was 110/50 mm Hg and his pulse was 130. On general physical examination a mongoloid face, bilateral exophthalmos, and diffuse goiter were present. On neurological examination a moderate left hemiparesis with increased deep tendon reflexes of the left extremities was found.
Except for an increase of serum gamma globulin (23%), routine laboratory investigations were normal. A serologic test for syphilis and tests for antinuclear antibodies were negative. A lumbar puncture yielded normal cerebrospinal fluid. A x-ray examination of chest showed no abnormalities. An ECG and 24-hour Holter monitoring revealed sinus tachycardia at a rate of 130. An echocardiographic study demonstrated hyperdynamic systolic left ventricular function. A diagnosis of trisomy 21, clinically suspected, was confirmed by karyotyping. Thyroid function tests showed the total thyroxine 21.2 μg/dL (normal value, 4.0 to 12.5), the total T3 583 ηg/dL (80 to 210), the resin T3 uptake index 1.34 (0.85 to 1.15), the thyrotropin <0.5 mUI/L (0.15 to 4.5), negative antithyroglobulin antibodies, and positive antimicrosomal antibodies (titer of 1:400). The thyroid scintigraphy with 99mTc demonstrated a thyroid gland uniformly increased in size, with a regular distribution of the tracer. The coagulation studies revealed slight positive lupus anticoagulant (LA). Positive IgG anticardiolipin antibodies (ACA) were disclosed in plasma.
A CT scan of the cranial contents demonstrated a septum pellucidum cyst, slight calcifications in the basal ganglia, and right paraventricular frontal infarct. Right vertebral and internal carotid angiography showed marked stenosis of the supraclinoid portion of the carotid artery, important decreased flow in the middle cerebral artery, and nonvisualization of the anterior cerebral artery. Lenticulostriate arteries were prominently shown. The vertebrobasilar territory was normal, and there was a transcortical anastomosis from posterior cerebral arteries to anterior cerebral arteries. Left internal carotid angiography demonstrated a very poor visualization of anterior cerebral arteries.
A diagnosis of DS, Graves’ disease, and moyamoya disease was established. The patient was treated with antithyroid agents and 250 mg acetylsalicylic acid daily. As a result of the cerebral infarction, the patient suffered a moderate disability in his left limbs. Antithyroid treatment was stopped in 1991; however, thyroid function continued to be normal from that point. Neither other cerebrovascular disorders nor other major diseases have since been detected in the patient. The last laboratory exams, which were carried out in January and August 1997, showed slight positive LA, positive ACA ELISA test (50 UGPL/mL), positive antimicrosomal antibodies (1:1000), and serum hypergammaglobulinemia of 31%.
This patient was diagnosed of Graves’ disease and presence of thyroid autoantibodies. Patients with DS are known to have an altered immune system. In particular, they have an increased prevalence of autoimmune disorders, such as autoimmune thyroid disease.4 The high prevalence of thyroid autoantibodies found in DS patients (39.3%)4 supports the recognized association between thyroid dysfunction and DS.
Our patient also had aPL. The report of a woman with autoimmune hyperthyroidism and the presence of LA, antimicrosomal antibodies, and ACA has been described.7 Also reported has been the case of a child with trisomy 21 affected by hypothyroidism associated with antithyroglobulin and anti-thyroid microsome antibodies in the blood.8 Moreover, this patient was affected by multiple arterial thromboses in association with ACA, thus suggesting the antiphospholipid syndrome.8 This observed association does not seem a casual fact: on the contrary, it would possibly be related to unknown exogenous factors acting on subjects genetically predisposed to autoimmunity.8
Furthermore, our DS patient had clinical and radiological features consistent with the diagnosis of moyamoya disease. At present, the etiology of this disease is still unknown. It is not clear whether moyamoya disease represents a congenital arterial displasia or is a syndrome caused by nonspecific vascular reaction. Recently, it has been postulated that a protein encoded on chromosome 21 may be related to the pathogenesis of moyamoya disease.1 However, the presence in trisomy 21 patients of autoimmune processes and autoantibodies make us suspect that the higher frequency of moyamoya disease in DS could be also result from an immune disturbance. Moreover, moyamoya disease itself has been associated with aPL.9
We conclude that different autoantibodies may be produced in DS. In subjects genetically predisposed to autoimmunity, these or other unknown antibodies could be associated with moyamoya disease. We believe that testing for plasma aPL is important in DS associated with moyamoya disease.
- Copyright © 1998 by American Heart Association
Cramer SC, Robertson RL, Dooling EC, Scott RM. Moyamoya and Down syndrome: clinical and radiological features. Stroke. 1996;27:2131–2135.
Schrager GO, Cohen SJ, Vigman MP. Acute hemiplegia and cortical blindness due to Moyamoya disease: report of a case in a child with Down’s syndrome. Pediatrics. 1977;60:33–37.
Leno C, Berciano J, Combarros O, Polo JM, Pascual J, Quintana F, Merino J, Sedano C, Martín-Durán R, Alvarez C, Llorca J. A prospective study of stroke in young adults in Cantabria, Spain. Stroke. 1993;24:792–795.
Leno C, Berciano J, Combarros O, Sedano C, Alvarez C, Merino J, Quintana F, Martín-Durán R, Rebollo M, Pascual J, Polo JM. Etiologic study of stroke in 95 young adults. Neurología. 1995;10:283–287.