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The pathogenesis of arterial dissection is incompletely understood, but a primary arteriopathy is frequently suspected, especially in younger patients. The possibility of a genetic predisposition to such an arteriopathy is supported by the familial occurrence of arterial dissections6,7,8,9 and their association with various heritable connective-tissue disorders.10,11 In our experience with cervical-artery dissections, the nature of the arteriopathy is identified in only a small fraction of patients.12,13
Among approximately 240 patients with spontaneous cervical-artery dissections who were seen at the Mayo Clinic between 1970 and 1992, 8 had a documented family history of arterial dissection. We describe two of these patients and their families, whose main clinical features were arterial dissection occurring at an early age and the presence of multiple lentigines. The arterial media and melanocytes are derived from neural-crest cells, suggesting that a neural-crest defect may be the underlying abnormality in these families.
Case Reports
Family A
Propositus
A left temporal headache and amaurosis fugax of the left eye followed by dysphasia and right hemiparesis developed in a 33-year-old man (Subject II-8 in Figure 1). He had undergone surgical repair of an aortic coarctation just distal to the left subclavian artery at the age of 19 years.
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Family History
There was no evidence of consanguinity in the patient's family, which was of German origin. At the time of his birth, his mother was 31 years of age and his father was 35.
One of his brothers (Subject II-7 in Figure 1) had died suddenly at the age of 22 years. Autopsy revealed a hemopericardium caused by dissection and rupture of the ascending aorta. Extensive cystic medial necrosis of the aorta was also noted. The remainder of the cardiovascular system was normal. Like his brother, Subject II-7 had numerous hyperpigmented skin lesions mainly affecting the skin of the extremities, as confirmed by examination of photographs. No other relatives had a history of arterial dissection or hyperpigmented skin lesions compatible with a diagnosis of lentigines.
Family B
Propositus
An occipital headache and right hemifacial numbness developed in a previously healthy 24-year-old woman (Subject VI-3 in Figure 1) shortly after a downhill-skiing accident in which she fractured her right radius but sustained no head or neck injury. Neurologic examination showed right hemiparesis and left Horner's syndrome. Angiography demonstrated a dissection of the left cervical vertebral artery, resulting in occlusion. Six and a half years later, six weeks post partum, the patient had a sudden right occipital headache while breast-feeding. Right hemicorporal numbness and transient dysphagia developed shortly thereafter.
On examination, the patient's blood pressure was 125/70 mm Hg. Multiple small (2 to 3 mm in diameter) maculae that were dark brown and uniformly colored were present on the trunk as well as the arms and legs, particularly the fingers and toes. Areas exposed to the sun as well as areas protected from the sun were affected. The face and mucous membranes were not involved, and the skin lesions did not darken with exposure to the sun. These skin lesions had first been noted in childhood and had increased in number until early adulthood. There were no café au lait spots. The patient did not have ocular hypertelorism or deafness and was of normal stature (height, 175 cm; weight, 76 kg). Neurologic examination showed dysarthria, left-beating nystagmus, and truncal ataxia. A computed tomographic scan of the head and examination of the cerebrospinal fluid revealed no abnormalities, nor did ophthalmologic, electrocardiographic, and echocardiographic examinations. Angiography revealed a dissection of the right cervical vertebral artery and the previously identified occlusion of the left vertebral artery. Both carotid arteries were normal. A saphenous-vein graft was placed between the left occipital artery and the left posterior inferior cerebellar artery because multiple episodes of transient quadriparesis had developed despite anticoagulation. At surgery, the left occipital artery was found to be discolored and blue, with a very weak pulse. The artery was opened, and a dissection was found. The artery proximal to the dissection was used for the bypass. The occipital-artery dissection was believed to be related to the operation. Microscopical examination of the resected artery showed an acute medial dissection with focal cystic degeneration of the media. Biopsy of an upper-arm lesion confirmed the diagnosis of lentigines.
No vascular events have occurred and the lentigines have faded during eight years of follow-up. Analysis of the type III procollagen gene13 in cultured skin fibroblasts showed no abnormalities.
Family History
The patient's family was of English and Swedish origin. Her parents (Subjects V-1 and V-2 in Figure 1) were half third cousins (Wright's coefficient of inbreeding, 1/512). Her parents were 33 years of age when she was born.
At the age of 25 years, one of her brothers (Subject VI-1 in Figure 1) had a severe headache followed by a right hemiparesis. There was no history of trauma. Angiography revealed an area of smooth stenosis of the left extracranial internal carotid artery beginning 2.5 cm from its origin, a finding consistent with the occurrence of dissection. Like his sister, Subject VI-1 has multiple skin lesions that are dark brown to black on his trunk and extremities, especially the lower legs, as confirmed by examination of photographs. The lesions appeared in childhood.
The patient's father (Subject V-1 in Figure 1) had a left hemiparesis at the age of 43 years and died suddenly two years later. His medical records were not available. He had no hyperpigmented skin lesions, as confirmed by examination of photographs. No other relatives had a history of arterial dissection or hyperpigmented skin lesions compatible with a diagnosis of lentigines.
Discussion
These two families have a constellation of findings consisting of arterial dissections, multiple lentigines, and cystic medial necrosis. We consider this syndrome to be genetic in origin. The absence of documented vertical transmission in the families and the history of consanguinity in Family B suggest autosomal recessive inheritance. However, autosomal dominant inheritance with variable penetrance or expression remains a possibility, since we did not directly examine any of the other family members, with possibly more subtle manifestations of the syndrome, and although well documented, the consanguinity in Family B was distant.
The affected members of these families tended to be younger than patients with cervical-artery or aortic dissections in general.1,2,12 Acute dissection of an occipital artery while it was exposed during surgery, as occurred in one of the patients, is unique in our experience. Other features of the arterial dissections in the families, however, such as multivessel involvement, recurrent dissection, and the presence of carotid loops, are regularly encountered in patients with cervical-artery dissections.2,12
The presence of multiple lentigines was the most readily apparent clinical finding in the families. Lentigines are flat or slightly raised isolated areas of brown-to-black skin pigmentation, approximately 2 to 4 mm in diameter. They usually appear in childhood and increase in number through early adulthood; they may subsequently fade or disappear completely. Clinically, lentigines are distinguished from freckles (ephelides) by their darker color, their presence in areas not exposed to the sun, the fact that they do not darken appreciably or increase in number during exposure to the sun, and their relative uncommonness in red-haired and fair-skinned people.14,15 Histologically, lentigines have an increased number of melanocytes at the dermoepidermal junction and elongation of the rete ridges, whereas freckles have a normal or slightly decreased number of melanocytes and no elongation of the rete ridges.14,15 General lentiginosis is a component of several syndromes, some of which have some of the features found in the families we studied. Carney's complex is an autosomal dominant syndrome whose main clinical features are cardiac myxomas and multiple lentigines.16,17,18,19 Affected persons also may have cutaneous myxomas, endocrine overactivity, and schwannomas.20,21,22,23 This syndrome can be ruled out in the families we studied, because none of the family members had any evidence of cardiac myxoma on echocardiography or autopsy, nor did they have any of the associated features. In addition, the lentigines associated with cardiac myxomas often involve mucous membranes,16,23 whereas in our patients the mucous membranes were spared. Multiple lentigines can also occur in the syndrome of lentiginosis and hypertrophic cardiomyopathy, or LEOPARD (lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and deafness) syndrome.24,25,26 The congenital heart disease associated with this autosomal dominant syndrome includes subaortic stenosis and valvular or infundibular pulmonary-artery stenosis, but aortic coarctation, as was found in one of our patients, is not a recognized feature, and none of the other components of the LEOPARD syndrome were observed in the syndrome we describe. Moreover, spontaneous arterial dissections have not been noted in any of the above-mentioned syndromes, and previous reports on the familial occurrence of arterial dissections have not mentioned the presence of hyperpigmented skin lesions.
In both of the families we studied, cystic medial necrosis was detected on microscopical examination of arterial segments that were available because of surgical resection or autopsy. Cystic medial necrosis is a nonspecific disorder of the arterial media that is found at autopsy in approximately 2 percent of the population, especially in the elderly.27 In young persons, cystic medial necrosis has been described in various heritable disorders that are associated with arterial dissections, including the Marfan syndrome,28 Ehlers–Danlos syndrome,29 and autosomal dominant polycystic kidney disease.9 There was no clinical evidence of any of these disorders in our patients. Cystic medial necrosis has also been described in patients with arterial dissection in the absence of a known phenotypic syndrome, including patients with familial arterial dissections.8,30,31 There was no evidence of a mutation in the type III procollagen gene (the underlying defect in Ehlers–Danlos syndrome type IV32) in the propositus from Family B.
An abnormality of cells derived from the neural crest (neurocristopathy) could explain the findings in the families we studied. The neural crest is a transient structure that occurs at a very early stage of embryogenesis.33 It is divided into two regions, the trunk neural crest and the cranial neural crest.33 The trunk neural crest gives rise to various types of cells in all parts of the body, including melanocytes.33 These pigment cells are involved in the pathogenesis of lentigines, and this could account for the cutaneous manifestations in the two families. The entire tunica media of the aortic arch and its branches is composed of cells originating in the cranial neural crest,34 which could explain the findings of cystic medial necrosis and the subsequent development of arterial dissection in the two families. After ablating a portion of the cranial neural crest in chick embryos, Rosenquist et al.35 detected marked coarsening and disarray of elastin fibers in the arterial wall, findings similar to the changes of cystic medial necrosis. Aortic coarctation, observed in one of our patients, has also been hypothesized to result from a migration disorder of cells derived from the neural crest.36 Aortic coarctation is associated with aortic dissection and cystic medial necrosis1 and has also been described in a child with intracranial arterial dissection.37
In conclusion, we describe a familial syndrome of arterial dissection, multiple lentigines, and cystic medial necrosis. This syndrome may represent a neurocristopathy.
Source Information
From the Departments of Neurologic Surgery (W.I.S., D.G.P.), Medical Genetics (V.V.M.), Neurology (B.M.), and Dermatology (H.O.P.), Mayo Clinic, Rochester, Minn.
Address reprint requests to Dr. Schievink at the Mayo Clinic, Department of Neurologic Surgery, 200 First St., SW, Rochester, MN 55905.
References
1-Antitrypsin deficiency in intracranial aneurysms and cervical artery dissection. Lancet 1994;343:452-453. [CrossRef][Medline]
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