CASE REPORT Familial occurrence of cerebral arteriovenous malformation in sisters: case report* and review of the literature R. Herziga, S. Burvalb, V. Vladykac, L. Janouskovad, P. Krivaneke, B. Krupkaa, I. Vlachovaa and K. Urbaneka a Stroke Centre, Clinic of Neurology, Faculty Hospital, Olomouc, Czech Republic, bClinic of Radiology, Faculty Hospital, Olomouc, Czech Republic, cDepartment of Stereotactic and Radiation Neurosurgery, Na Homolce Hospital, Prague, Czech Republic, dRadiodiagnostic Department, Na Homolce Hospital, Prague, Czech Republic, and eDepartment of Neurosurgery, Na Homolce Hospital, Prague, Czech Republic Keywords: arteriovenous malformations, brain, genetics, therapy Received 3 March 1999 Accepted 17 September 1999 Cerebral arteriovenous malformations (AVMs) are considered to be congenital disorders. However, their familial occurrence has so far been described in only 19 families in the literature. The authors report on two cases in one family and review the literature. A 45-year-old female subject with sudden onset of headache and vomiting due to a subarachnoid haemorrhage from a small AVM in the posterior part of the corpus callosum near the midline on the left side was studied. Irradiation of the AVM using Leksell's gamma knife led to its complete obliteration. Her older sister presented with temporal seizures at the age of 49 and later also with left hemiparesis, left hemihypaesthesia and dizziness ] caused by a large AVM in the right temporal lobe. This AVM was treated by a combination of embolization and irradiation by the Leksell's gamma knife. Introduction Cerebral arteriovenous malformations (AVMs) are considered to result from aberrant differentiation of the mesoderm during embryonic development (Olivecrona and Ladenheim, 1957; Kaplan et al., 1961; Hatva et al., 1996). They display abnormal vascular development (McCormick, 1966; Martin and Vinters, 1995) and dysautoregulation of blood flow (Spetzler et al., 1978; Nornes and Grip, 1980; Muraszko et al., 1990). Familial occurrence of cerebral AVMs is very uncommon, although they are held to be congenital disorders. As well as reviewing the literature, the authors report on two patients with cerebral AVM in one family. Case Reports Case 1 The first Caucasian female had a sudden onset of headache and vomiting in February 1992, at the age of 45. Evaluation of cerebrospinal fluid (CSF) showed subarachnoid haemorrhage (SAH). Angiography, comCorrespondence: Roman Herzig, MD, Stroke Centre, Clinic of Neurology, Faculty Hospital, I. P. Pavlova 6, CZ-775 20 Olomouc, Czech Republic (fax: + 420/68/5852528, 414201). *The case report was presented as a poster at the XXVth International Czech and Slovak Neurovascular Symposium in ZlõÂ n, Czech Republic in September 1997. ã 2000 EFNS puted tomography (CT) and magnetic resonance imaging (MRI) revealed a small AVM (7 3 8 mm) in the posterior part of the corpus callosum near the midline on the left side. The AVM was fed by pericallosal artery and drained to the cerebral internal vein (Figure 1a,b). Later, paroxysmal vertigo and fainting were present once a month. Irradiation of the AVM using Leksell's gamma knife (volume 350 mm3, total dose of 40 Gy) was performed in November 1993; the neurological finding was normal. In November 1994 the angiography demonstrated complete obliteration of the AVM; the neurological finding was again normal. Case 2 The second Caucasian female, the older sister of Case 1, presented with increasing frequency of occurrence of temporal seizures since 1993 (at the age of 49). In December 1996, the neurological finding was normal; a CT demonstrated AVM (30 3 40 3 28 mm) in the right temporal lobe with light right lateral ventricle compression and a 4-mm mid-line shift. Left hemiparesis, left hemihypaesthesia and dizziness occurred in January 1997; angiography showed extensive AVM in the right temporal lobe, draining to the dilated and tortuous deep cerebral veins (Figure 2a,b). Left hemiparesis progressed in April 1997; CT and MRI demonstrated no bleeding to the AVM. An attempt to embolize the AVM was made in May 1997. However, this was not successful because of right internal carotid artery (RICA) tortuosity. Another angiography (in 95 96 R. Herzig et al. Figure 1 Case 1. (a) Cerebral angiogram. Small AVM in the posterior part of the corpus callosum near the mid-line on the left side. (b) Cranial MRI scan ] PD weighted TR 2.0, TE 15. Small AVM (7 3 8 mm) in the posterior part of corpus callosum near the midline on the left side. June 1997) revealed feeding of the AVM by the branches of the right posterior cerebral artery and by numerous branches of the RICA (e.g. branches of right middle cerebral artery and lenticulostriate artery) and of the right external carotid artery (e.g. middle meningeal artery, branches of superficial temporal artery and occipital artery). Embolization of the right middle meningeal artery was performed at the same time, without neurological complications. The last angiography, taken in July 1997, demonstrated an AVM fed by many branches of the RICA ] without the Figure 2 Case 2. Cerebral angiogram: Extensive AVM in the right temporal lobe, draining to the dilated and tortuous deep cerebral veins. dominant feeding artery. The frequency of temporal seizures increased in August and September 1997. However, there was no left hemiparesis progression. In February 1998, by which time there was still no neurological progression, MRI and angiography demonstrated the AVM (23 3 29 3 33 mm, volume 16.2 cm3) localized in the basal part of the right temporal lobe. Irradiation of the AVM using Leksell's gamma knife (total dose of 32 Gy, at the AVM nidus margin in 50% isodose of 16 Gy) was performed without complications. Because of the large volume of ã 2000 EFNS European Journal of Neurology 7, 95]100 Case Report: Cerebral AVM in sisters the AVM, its obliteration will probably take three years. MRI was performed in five relatives, and ultrasound examination of the carotid and vertebral arteries in combination with transcranial Doppler sonography in one member of this family. No AVM was found in these family members (Figure 3). Discussion AVMs are held to be formed as congenital developmental anomalies of the blood vessels ] from a persistent direct connection between the arterial and venous portions of the primitive vascular plexus in the embryo, prior to the fourth week of gestation; however, their genetic origin has not been clarified yet. Some authors suggest an autosomal dominant mode of transmission with variable penetrance (Snead et al., 1979; Aberfeld and Rao, 1981; Boyd et al., 1985; Larsen et al., 1997) or X-linked recessive inheritance pattern (Brilli et al., 1995). Tandan et al. have reported two brothers with myotonic muscular dystrophy (gene for this dominantly inherited disease is probably located on chromosome 19) and cerebral AVMs; the simultaneous occurrence of these two disorders could either be due to chance associations or to a common Figure 3 Pedigree. ã 2000 EFNS European Journal of Neurology 7, 95]100 97 causative mechanism, possibly a membrane abnormality (Grey et al., 1980; Tandan et al., 1991). Familial occurrence of cerebral AVMs is found in von Hippel]Lindau disease, Osler]Weber]Rendu disease, and Sturge]Weber]Dimitri disease. Including the two sisters in this article, only 44 cases of familial occurrence of cerebral AVMs unassociated with these diseases have been reported in the literature in 20 families (Tables 1 and 2) (ToÈnnis and Large-Cosack, 1953; Bannerman et al., 1970; Laing and Smith, 1974; Stoll and Wolfram, 1977; Barre et al., 1978; Snead et al., 1979; Aberfeld and Rao, 1981; Boyd et al., 1985; Zellen and Buchkeit, 1985; Bucci et al., 1986; Tandan et al., 1991; Yokoyama et al., 1991; Goto et al., 1994; Brilli et al., 1995; Larsen et al., 1997). The average age of 41 patients (the age was not reported in three cases) was 27.7 years. The nationwide Japanese survey on cerebrospinal vascular anomalies indicated that brain AVMs become manifest most frequently in the 20- to 39-year-old age group (Yokoyama et al., 1991). However, patients with familial cerebral AVMs become symptomatic earlier ] most frequently in the 10- to 19-year-old age group (13 cases in this age group in our survey). The same Japanese survey indicated that the male : female ratio of AVM cases is about 2 : 1 (Yokoyama et al., 1991). There is male : female ratio 98 R. Herzig et al. Table 1 Summary of 44 familial cerebral AVM cases in 20 families Authors Year Sex Age (years) Family relationship AVM site Presenting symptoms ToÈnnis and Large-Cosack 1953 Hunt (Bannerman et al., 1970) Laing and Smith 1966 Stoll and Wolfram 1977 Barre et al. 1978 Snead et al. 1979 Aberfeld and Rao 1981 Yamamoto et al. (Yokoyama et al., 1991) Yamamoto et al. (Yokoyama et al., 1991) Boyd et al. 1983 Zellen and Buchkeit 1985 Bucci et al. 1986 Yokoyama et al. 1991 Yokoyama et al. 1991 Yokoyama et al. 1991 Tandan et al. 1991 Goto et al. 1994 Brilli et al. 1995 Larsen et al. 1997 Herzig et al. 2000 M M F F F F M F M M M M M F M F F F F M M M M F M F M M M M F F M M M F F M M M F F F F ? ? 41 20 16 19 66 37 31 39 11 14 17 23 32 19 36 28 49 45 16 18 20 36 ? 16 36 16 50 11 24 21 18 31 46 24 23 2 13 52 21 6 45 49 Brother Brother Mother Daughter Sister Sister Father Daughter Brother Brother Brother Brother Brother Sister Brother Mother Daughter Mother Daughter Father Son Son Son Cousin Cousin Niece Uncle Father Son Cousin Cousin Mother Son Brother Brother Sister Sister Brother Brother Grandfather Mother Daughter Sister Sister ? ? Right temporal Right occipito-parietal Right parietal Right temporal Left temporal Left parietal Left basal ganglia Right fronto-temporal Bilateral thalamus Right lateral ventricle Left parietal Left frontal Left parieto-occipital Right frontal Left occipital Left occipital Right parieto-occipital Right occipital Right temporal Right temporal Left cerebello-pontine angle Left frontal, right Sylvian fissure ? Right thalamus, left frontal Left parietal, right temporal Right parietal Left parietal Right cerebellum Left lateral ventricle Right temporal Left parietal Left frontal, left occipital Left parietal Right frontal Left fronto-parietal Right pons Left occipital Right parieto-occipital Left frontal Right frontal Left corpus callosum Right temporal ICH ICH ? ? ICH ICH Headache Seizures ICH Seizures Asymptomatic ICH ICH ICH Seizures ICH SAH ICH ICH Headache Headache Seizures Asymptomatic Tinnitus, headache ? Left hemiparesis Headache Seizures Seizures ICH ICH ICH Seizures Aphasia ICH ICH ICH ICH ICH Asymptomatic Seizures Asymptomatic SAH Seizures 1974 1983 1985 AVM, arteriovenous malformation; SAH, subarachnoid haemorrhage; ICH, intracranial haemorrhage; ?, not reported. 1.2 : 1 in our survey ] it indicates that familial cerebral AVMs have a tendency to occur with similar frequency in both sexes. Familial cerebral AVMs were observed in parent]child and grandparent]parent]child combination, in siblings, in cousins, and in uncle-niece combination. The grandfather]mother]daugter combination and brother]brother (with stepfathers) combination can support either an autosomal dominant or (for the stepfathers) X-linked recessive inheritance pattern of familial cerebral AVMs (Brilli et al., 1995). However, we cannot find a specific familial relationship, although there is some tendency for the same sex to be affected by familial AVMs (Yokoyama et al., 1991). Multiple AVMs were present in four of 41 reported patients. The presenting symptoms were mainly intracranial haemorrhage, seizures, and headache. The preponderance of AVMs among Asian subjects ã 2000 EFNS European Journal of Neurology 7, 95]100 Case Report: Cerebral AVM in sisters Number of cases Criteria Age (years) Sex Family relationship 1]9 10]19 20]29 30]39 40]49 50]59 60]69 Male Female Parent]child Grandparent] parent]child Siblings Presenting symptoms Table 2 Age, sex, site distribution, family relationship and presenting symptoms compared with Caucasians seems to demonstrate that some ethnic groups have a genetic predisposition for the development of AVMs (Tay et al., 1971). In the fairly isolated Hida district of Japan, which has a population of about 150 000, 24 patients with AVMs have been encountered in a 10-year period; six of those 24 cases were in three families (Yokoyama et al., 1991). Although only very few familial cerebral AVMs have been described so far, MRI has facilitated the screening of asymptomatic AVMs, and may reveal in the future that the incidence of familial cerebral AVMs is higher than that previously thought. We think that in the case of familial occurrence of cerebral AVMs, all family members (including asymptomatic ones) should be screened by MRI. This screening also allows the detection of small asymptomatic AVMs, treatable with better results than when they are found later to have grown or when they present with haemorrhage or other clinical symptoms. References Aberfeld DC, Rao KR (1981). Familial arteriovenous malformation of the brain. Neurology 31:184]186. Bannerman RM, Ingall GB, Graf CJ (1970). 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