Legal Medicine 17 (2015) 309–312
Contents lists available at ScienceDirect
Legal Medicine journal homepage: www.elsevier.com/locate/legalmed
Case report
Subarachnoid hemorrhage due to aneurysm rupture in a young woman with Alagille syndrome – A rare cause of sudden death E. Doberentz a, K. Kuchelmeister b, B. Madea a,⇑ a b
Institute of Legal Medicine, University of Bonn, Stiftsplatz 12, 53111 Bonn, Germany Institute of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
a r t i c l e
i n f o
Article history: Received 16 December 2014 Received in revised form 25 February 2015 Accepted 2 March 2015 Available online 14 March 2015 Keywords: Alagille syndrome Arteriohepatic dysplasia Subarachnoid aneurysm Subarachnoid hemorrhage
a b s t r a c t The Alagille syndrome (AGS) or arteriohepatic dysplasia is a rare, autosomal dominant inherited disease with a prevalence of approximately 1:100,000. AGS was first described in 1969 and affects liver, heart, arterial blood vessels, skeleton and the eyes. The expression of AGS is variable. In severe cases a liver transplantation is required. Presented is the case of a 25-year-old woman with AGS. At the age of 7 and 8 years she had liver transplantations. Other typical findings associated with Alagille syndrome (e.g. pulmonary or renal anomalies) were also present. The young woman apparently died suddenly and unexpectedly in a good health condition despite regular medical treatment. Cause of death was a subarachnoid hemorrhage with invasion of the hemorrhage into the ventricle system caused by a rupture of previously unknown large aneurysm in the terminal basilary artery. Intracranial vascular malformations are a common finding in patients with AGS and cause death in up to 16% of them. Life expectancy in AGS patients depends on the severity of changes of the affected liver. But AGS is also responsible for various vascular abnormalities in several other organs which can cause lethal complications. Due to the high rate of vascular complications and intracranial hemorrhage with the leading cause of mortality in patients with AGS, vascular screening by the use of noninvasive imaging techniques (CT or MR angiography) is required to avoid unexpected sudden death. Ó 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Case report
Alagille syndrome (AGS) or arteriohepatic dysplasia was first described by the French pediatrician Daniel Alagille in 1969 [1]. The prevalence of AGS has been reported as 1 in 100,000 live births [2]. AGS is an autosomal dominantly inherited disorder and it is mainly characterized by the reduction of the number of bile ducts leading to cholestasis and by multiple organ system involvement: cardiovascular system (peripheral pulmonary artery stenosis), eyes (posterior embryotoxon), skeleton (butterfly-like vertebral arch defects) and kidneys. It is associated with characteristic facial features with a small face, prominent forehead and hypertelorism of the deep set eyes [3–5]. An affection of the nervous and endocrine system has also been described [2,3]. Intracranial vessel abnormalities and other vascular lesions are also present in AGS [6–8]. One case with lethal cerebral vascular lesion is presented.
A 25-year-old woman with AGS was unexpectedly found dead in her bed. At the age of 7 and 8 she had liver transplantations. Facial dysplasia, peripheral pulmonary artery stenosis (state following balloon dilatation and stent implantation) and vertebral anomalies as well as renal dysplasia were already diagnosed. The young woman had been in a comparatively good health condition over the last few years and led a normal life. She consulted a doctor for routine diagnostic procedures regularly. 4 weeks before death, she was hospitalized for one night due to vomiting, diarrhea, headache and vertigo. A checkup was inconspicuous and she was dismissed from hospital.
⇑ Corresponding author at: Institute of Forensic Medicine, University of Bonn, Stiftsplatz 12, D-53111 Bonn, Germany. Tel.: +49 228 738315; fax: +49 228 738368. E-mail address: [email protected] (B. Madea). http://dx.doi.org/10.1016/j.legalmed.2015.03.004 1344-6223/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
2.1. Autopsy findings Forensic autopsy of the 25-year-old women with a body weight of 54.2 kg and height of 148 cm was performed. Facial dysplasia with a prominent forehead and widely spaced eyes were noted. The young woman had numerous scars on her chest, abdominal skin and extremities. The base of the oedematous swollen brain showed subarachnoid hemorrhage (Fig. 1) and a severely invasive
310
E. Doberentz et al. / Legal Medicine 17 (2015) 309–312
The woman had renal aplasia on the right side. The urinary bladder was well filled (250 ml). The young women furthermore had a scoliosis of the spine. 2.2. Histopathological findings The aneurysm was excised for histological examination. After fixation in formalin and embedding in paraffin wax, the aneurysm was laminated in thin slices in the sagittal plane and the sections were stained with H&E, Ferric, Elastica van Gieson and SMA (smooth muscle actin) stain. The internal elastic lamina of the aneurysm appeared degenerated or even absent (Figs. 3 and 4). Smooth muscle cells were degenerated and especially in the aneurysmal dome smooth muscle cells were absent (Fig. 5). Focal arteriosclerotic alterations of the vessel wall were seen. Signs of previous hemorrhage were not found. In the histological examination of further organs the liver tissue showed a normal lobular structure without pathological alterations (Fig. 6). The brain tissue was oedematous. Alveolar pulmonary oedema was also noted. 2.3. Cause of death
Fig. 1. Subarachnoid hemorrhage on the base of the brain in the region of the circle of Willis.
hemorrhage in the cerebral ventricle system was detected. The hemorrhage was caused by a large saccular ruptured aneurysm of the terminal basilar artery (Fig. 2). The lungs were massively oedematous with a rest of foam around her mouth. A stent in the pulmonary trunk was found. The lungs and the heart showed very thin arteries. Adhesions of the heart to the pericardium were seen. Multiple adhesions in the abdominal cavity and of the small liver (1050 g) to the stomach and the intestine were found. The liver capsule was thickened and the liver tissue was of increased density, however with normal structure. The gallbladder was missing.
The cause of death was a subarachnoidal hemorrhage with invasion in the ventricular system due to a ruptured aneurysm of the terminal basilary artery. 3. Discussion AGS is the most common inherited disorder that causes liver disease in children caused by mutations of the JAG1 gene that encodes Jagged1 which is a ligand in the Notch receptor signaling pathway [9–11]. The Notch receptor is involved in the fetal development of various organs, which explains the multisystemic appearance. The receptor plays an important role in the organ and the vascular development [8–10]. Mutations are especially associated with an impaired development of the bile duct and of
Fig. 2. 2 cm saccular aneurysm of the terminal basilar artery.
E. Doberentz et al. / Legal Medicine 17 (2015) 309–312
Fig. 3. The ruptured aneurysmal dome (upper right corner of the image), coronal section (elastica van Gieson stain, 4).
Fig. 4. Fragmentation of the aneurysmal internal elastic lamina. Elastica van Gieson stain 10.
Fig. 5. Arterio-aneurysmal junction. Smooth muscle cells colored brownish, increasing disappearance of the smooth muscle cells (SMA stain, 1,25) from left to right.
311
Fig. 6. Inconspicuous liver tissue, H&E 10.
the cardiovascular system [12]. Up to 90% of the patients show pulmonary artery involvement with peripheral pulmonary artery stenosis which is the most common feature in AGS [13,14]. Other vascular abnormalities affect the renal arteries (total obstruction or stenosis with renovascular hypertension), mesenteric vessels, aorta (aortic coarctations), and intra- and extracranial carotid arteries [14–16]. In this way, AGS patients have an increased risk of intracranial hemorrhage. The incidence of intracranial hemorrhage is 14–16% of all patients with AGS [3,13,15,17,18] in comparison to the incidence of subarachnoid hemorrhage due to aneurysmal rupture in the normal population of 10/100.000 which typically occurs at an age of 50 [19]. The cause of subarachnoid hemorrhage in the normal population is usually a congenital or degenerative aneurysm of the circle of Willis. In the presented case, the aneurysm was also located in the circle of Willis – a large basilary terminus aneurysm. In adults, aneurysm are typically located in the area of the anterior communicating arteries [20]. In the recent literature about AGS, reports describe 3 cases of subarachnoidal hemorrhage (Table 1), and one patient died [6]. In these cases and in the presented case the oldest patient was 30 years. Aneurysms are divided into small (25 mm) ones [21]. In contrast to the other reported cases with aneurysms less than 1 cm [6–8], in the presented case the aneurysm was large with approx. 2 cm in diameter. This large aneurysm was apparently without significant clinical symptoms and it was not pre-diagnosed. The 25-year-old woman obviously did not show typical symptoms of subarachnoid hemorrhage with headache, nausea and vomiting. She was in a good state of health following the liver transplantations during childhood. She was integrated into normal life with obviously good life expectancy. The symptoms which have lead to hospitalization 4 weeks prior to death were not imperatively indicating a life-threatening cerebral lesion. Lethal intracranial vascular abnormalities was not expected, but most cerebral aneurysms remain asymptomatic. Since the Ferric stain of the aneurysm was negative symptoms 4 weeks prior to death are not due to rupture of the vessel. Obviously the degeneration of smooth muscle cells and focal arteriosclerotic alterations predisposed to the vessel rupture. However, the reason of the aneurysm rupture often remains unclear. The disappearance of smooth muscle cells in the aneurysm in the present case is well illustrated in Fig. 5. Obviously the missing smooth muscle cells were the morphologic equivalent of a Locus minoris resistentiae. Life expectancy in AGS patients depends primarily on the severity of the affected liver and cardiac involvement, but also on
312
E. Doberentz et al. / Legal Medicine 17 (2015) 309–312 Table 1 Reported aneurysmal subarachnoid haemorrhage in AGS patients. Authors
Age, sex
Aneurysm location
Aneurysm diameter
Outcome
Schlosser et al. [8] Cowan et al. [7] Tumialán et al. [6]
30, f 23, f 21, f
Internal carotid artery Posterior communicating artery Terminal basilar artery
0.8 cm 0.5 cm 0.9 cm
Survived Survived Died
multiple and various vascular lesions which can lead to lethal complications. The expression of the autosomal dominant disease is quite variable; probably it is never diagnosed in a mild form and in the absence of severe hepatic disease [22]. 86% of the affected infants show symptoms of cholestasis and pruritus up to progressive liver failure before the age of 6 months. 15% of these patients require liver transplantation (2% of all pediatric liver transplantations) [4]. Noncardiac vascular complications are the most common cause of death in patients with AGS in up to 34%. AGS is also limited by heart disease (21%), liver disease (10%), and septical complications (7%), [15]. In case of clinical suspicion of a cerebral aneurysm or even a ruptured aneurysm, a cranial CT scan angiography is essential for the diagnosis. Therapeutic attempts of the aneurysm surgery are vascular clips being placed on the aneurysm neck (clipping), or the aneurysm can be filled with platinum coils and closed (coiling embolization). Depending on the location of the affected vessel also a bypass can be inserted. The prognosis of aneurysms of the posterior circulation of the circle of Wills is poor, because the access is significantly worse than to the anterior circulation [23,24]. In the forensic context it is of special importance that in cases of diagnosed AGS a vascular screening is carried out. If a vascular screening is omitted medical malpractice may be claimed by relatives and a very detailed multidisciplinary expert report may be necessary. Intracranial hemorrhage is one of the leading causes of mortality in AGS. Treating physicians have to be aware of this. According to the literature aneurysmal subarachnoid hemorrhage is one major cause of intracranial hemorrhage in AGS. However, there seem to be still other causes which require further investigations [6]. References [1] Alagille D, Borde J, Habid EC, Thomassin N. L´atresie des voies biliaires intrahépatiques avec voies biliaires extrahepatiques perméable chez l‘enfant. Arch Fr Pediatr 1969;26:51–71. [2] Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997;34:152–7. [3] Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of intralubular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995;127:220–4. [4] Tzakis AG, Reyes J, Tepetes K, Tzoracoleftherakis V, Todo S, Starzl TE. Liver transplantation for Alagille‘s syndrom. Liver Transpl 1993;128:337–9.
[5] Alagille D. Splenectomy in hereditary hemolytic disorders in children. Acquis Med Recent 1969:41–50. [6] Tumialán LM, Dhall SS, Tomak PR, Barrow DL. Alagille syndrome and aneurysmal subarachnoid hemorrhage. Pediatr Neurosurg 2006;42:57–61. [7] Cowan JA, Barkhoudarian G, Yang LJS, Thompson BG. Progression of a posterior communicating artery infundibulum into an aneurysm in a patient with Alagille syndrome. J Neurosurg 2004;101:694–6. [8] Schlosser HG, Kerner T, Woiciechowsky, Benndorf G. Multiple cerebral aneurysms and subarachnoid haemorrhage in a patient with Alagille syndrome. AJNR Am J Neuroradiol 2004;25:1366–7. [9] Ropke A, Kujat A, Garber M, Giannakudis J, Hansmann I. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 2003;21:100. [10] Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 2001;108:161–4. [11] Lindner V, Booth C, Prudovsky I, Small D, Maciag T, Liaw L. Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cel matrix and cell–cell interaction. Am J Pathol 2001;159:875–83. [12] Jacquet A, Guichon-Mantel A, Noel LH, Sqalli T, Bedossa P, Hadchouel M, et al. Alagille syndrome in adult patients: it is never too late. Am J Kidney Dis 2007;49:705–9. [13] Emerick KM, Rabd EB, Goldmuntz E, Krantz ID, Spinner NB, Piccolin DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999;29:822–9. [14] Moreau S, Bourdon N, Jokie M, de Rugy MG, Babin E, Valdazo A, et al. Alagille syndrome with cavernous carotid artery aneurysm. Int J Pediatr Otorhinolaryngol 1999;50:139–43. [15] Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccolin DA, et al. Vasculcar anomalies in Alagille syndrome. A significant cause of morbidity and mortality. Circulation 2004;23:1354–8. [16] Connor SEJ, Hewes D, Ball C, Jarosz JM. Alagille syndrome associated with angiographic moyamoya. Childs Nerv Syst 2002;18:186–90. [17] Bérard E, Triolo V. Intracranial haemorrhages in Alagille syndrome. J Pediatr 2000;136:708–9. [18] Lykavieris P, Crosnier C, Trichet C, Meunier-Rotival M, Hadchouel M. Bleeding tendency in children with Alagille syndrome. Pediatrics 2003;111:167–70. [19] Linn FH, Rinkel GJ, Algra A, et al. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke 1996;27:625–9. [20] Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations. Based on 6368 cases in the cooperative study. J Neurosurg 1966;25:219–23. [21] Malisch TW, Guglielmi G, Vinuela F, Duckwiler G, Gobin YP, Martin NA, et al. Intracranial aneurysms treated with the Guglielmi detachable coil: midterm clinical results in a consecutive series of 100 patients. J Neurosurg 1997;87:176–83. [22] Yucel H, Hoorntje SJ, Bravenboer B. Renal abnormalities in a family with Alagille syndrome. Neth J Med 2010;68:38–9. [23] Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Hall T, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr 1999;29:431–7. [24] Ostergaard JR, Volsdby B. Intracranial arterial aneurysms in children and adolescents. J Neurosurg 1983;58:832–7.
Contents lists available at ScienceDirect
Legal Medicine journal homepage: www.elsevier.com/locate/legalmed
Case report
Subarachnoid hemorrhage due to aneurysm rupture in a young woman with Alagille syndrome – A rare cause of sudden death E. Doberentz a, K. Kuchelmeister b, B. Madea a,⇑ a b
Institute of Legal Medicine, University of Bonn, Stiftsplatz 12, 53111 Bonn, Germany Institute of Neuropathology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany
a r t i c l e
i n f o
Article history: Received 16 December 2014 Received in revised form 25 February 2015 Accepted 2 March 2015 Available online 14 March 2015 Keywords: Alagille syndrome Arteriohepatic dysplasia Subarachnoid aneurysm Subarachnoid hemorrhage
a b s t r a c t The Alagille syndrome (AGS) or arteriohepatic dysplasia is a rare, autosomal dominant inherited disease with a prevalence of approximately 1:100,000. AGS was first described in 1969 and affects liver, heart, arterial blood vessels, skeleton and the eyes. The expression of AGS is variable. In severe cases a liver transplantation is required. Presented is the case of a 25-year-old woman with AGS. At the age of 7 and 8 years she had liver transplantations. Other typical findings associated with Alagille syndrome (e.g. pulmonary or renal anomalies) were also present. The young woman apparently died suddenly and unexpectedly in a good health condition despite regular medical treatment. Cause of death was a subarachnoid hemorrhage with invasion of the hemorrhage into the ventricle system caused by a rupture of previously unknown large aneurysm in the terminal basilary artery. Intracranial vascular malformations are a common finding in patients with AGS and cause death in up to 16% of them. Life expectancy in AGS patients depends on the severity of changes of the affected liver. But AGS is also responsible for various vascular abnormalities in several other organs which can cause lethal complications. Due to the high rate of vascular complications and intracranial hemorrhage with the leading cause of mortality in patients with AGS, vascular screening by the use of noninvasive imaging techniques (CT or MR angiography) is required to avoid unexpected sudden death. Ó 2015 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
2. Case report
Alagille syndrome (AGS) or arteriohepatic dysplasia was first described by the French pediatrician Daniel Alagille in 1969 [1]. The prevalence of AGS has been reported as 1 in 100,000 live births [2]. AGS is an autosomal dominantly inherited disorder and it is mainly characterized by the reduction of the number of bile ducts leading to cholestasis and by multiple organ system involvement: cardiovascular system (peripheral pulmonary artery stenosis), eyes (posterior embryotoxon), skeleton (butterfly-like vertebral arch defects) and kidneys. It is associated with characteristic facial features with a small face, prominent forehead and hypertelorism of the deep set eyes [3–5]. An affection of the nervous and endocrine system has also been described [2,3]. Intracranial vessel abnormalities and other vascular lesions are also present in AGS [6–8]. One case with lethal cerebral vascular lesion is presented.
A 25-year-old woman with AGS was unexpectedly found dead in her bed. At the age of 7 and 8 she had liver transplantations. Facial dysplasia, peripheral pulmonary artery stenosis (state following balloon dilatation and stent implantation) and vertebral anomalies as well as renal dysplasia were already diagnosed. The young woman had been in a comparatively good health condition over the last few years and led a normal life. She consulted a doctor for routine diagnostic procedures regularly. 4 weeks before death, she was hospitalized for one night due to vomiting, diarrhea, headache and vertigo. A checkup was inconspicuous and she was dismissed from hospital.
⇑ Corresponding author at: Institute of Forensic Medicine, University of Bonn, Stiftsplatz 12, D-53111 Bonn, Germany. Tel.: +49 228 738315; fax: +49 228 738368. E-mail address: [email protected] (B. Madea). http://dx.doi.org/10.1016/j.legalmed.2015.03.004 1344-6223/Ó 2015 Elsevier Ireland Ltd. All rights reserved.
2.1. Autopsy findings Forensic autopsy of the 25-year-old women with a body weight of 54.2 kg and height of 148 cm was performed. Facial dysplasia with a prominent forehead and widely spaced eyes were noted. The young woman had numerous scars on her chest, abdominal skin and extremities. The base of the oedematous swollen brain showed subarachnoid hemorrhage (Fig. 1) and a severely invasive
310
E. Doberentz et al. / Legal Medicine 17 (2015) 309–312
The woman had renal aplasia on the right side. The urinary bladder was well filled (250 ml). The young women furthermore had a scoliosis of the spine. 2.2. Histopathological findings The aneurysm was excised for histological examination. After fixation in formalin and embedding in paraffin wax, the aneurysm was laminated in thin slices in the sagittal plane and the sections were stained with H&E, Ferric, Elastica van Gieson and SMA (smooth muscle actin) stain. The internal elastic lamina of the aneurysm appeared degenerated or even absent (Figs. 3 and 4). Smooth muscle cells were degenerated and especially in the aneurysmal dome smooth muscle cells were absent (Fig. 5). Focal arteriosclerotic alterations of the vessel wall were seen. Signs of previous hemorrhage were not found. In the histological examination of further organs the liver tissue showed a normal lobular structure without pathological alterations (Fig. 6). The brain tissue was oedematous. Alveolar pulmonary oedema was also noted. 2.3. Cause of death
Fig. 1. Subarachnoid hemorrhage on the base of the brain in the region of the circle of Willis.
hemorrhage in the cerebral ventricle system was detected. The hemorrhage was caused by a large saccular ruptured aneurysm of the terminal basilar artery (Fig. 2). The lungs were massively oedematous with a rest of foam around her mouth. A stent in the pulmonary trunk was found. The lungs and the heart showed very thin arteries. Adhesions of the heart to the pericardium were seen. Multiple adhesions in the abdominal cavity and of the small liver (1050 g) to the stomach and the intestine were found. The liver capsule was thickened and the liver tissue was of increased density, however with normal structure. The gallbladder was missing.
The cause of death was a subarachnoidal hemorrhage with invasion in the ventricular system due to a ruptured aneurysm of the terminal basilary artery. 3. Discussion AGS is the most common inherited disorder that causes liver disease in children caused by mutations of the JAG1 gene that encodes Jagged1 which is a ligand in the Notch receptor signaling pathway [9–11]. The Notch receptor is involved in the fetal development of various organs, which explains the multisystemic appearance. The receptor plays an important role in the organ and the vascular development [8–10]. Mutations are especially associated with an impaired development of the bile duct and of
Fig. 2. 2 cm saccular aneurysm of the terminal basilar artery.
E. Doberentz et al. / Legal Medicine 17 (2015) 309–312
Fig. 3. The ruptured aneurysmal dome (upper right corner of the image), coronal section (elastica van Gieson stain, 4).
Fig. 4. Fragmentation of the aneurysmal internal elastic lamina. Elastica van Gieson stain 10.
Fig. 5. Arterio-aneurysmal junction. Smooth muscle cells colored brownish, increasing disappearance of the smooth muscle cells (SMA stain, 1,25) from left to right.
311
Fig. 6. Inconspicuous liver tissue, H&E 10.
the cardiovascular system [12]. Up to 90% of the patients show pulmonary artery involvement with peripheral pulmonary artery stenosis which is the most common feature in AGS [13,14]. Other vascular abnormalities affect the renal arteries (total obstruction or stenosis with renovascular hypertension), mesenteric vessels, aorta (aortic coarctations), and intra- and extracranial carotid arteries [14–16]. In this way, AGS patients have an increased risk of intracranial hemorrhage. The incidence of intracranial hemorrhage is 14–16% of all patients with AGS [3,13,15,17,18] in comparison to the incidence of subarachnoid hemorrhage due to aneurysmal rupture in the normal population of 10/100.000 which typically occurs at an age of 50 [19]. The cause of subarachnoid hemorrhage in the normal population is usually a congenital or degenerative aneurysm of the circle of Willis. In the presented case, the aneurysm was also located in the circle of Willis – a large basilary terminus aneurysm. In adults, aneurysm are typically located in the area of the anterior communicating arteries [20]. In the recent literature about AGS, reports describe 3 cases of subarachnoidal hemorrhage (Table 1), and one patient died [6]. In these cases and in the presented case the oldest patient was 30 years. Aneurysms are divided into small (25 mm) ones [21]. In contrast to the other reported cases with aneurysms less than 1 cm [6–8], in the presented case the aneurysm was large with approx. 2 cm in diameter. This large aneurysm was apparently without significant clinical symptoms and it was not pre-diagnosed. The 25-year-old woman obviously did not show typical symptoms of subarachnoid hemorrhage with headache, nausea and vomiting. She was in a good state of health following the liver transplantations during childhood. She was integrated into normal life with obviously good life expectancy. The symptoms which have lead to hospitalization 4 weeks prior to death were not imperatively indicating a life-threatening cerebral lesion. Lethal intracranial vascular abnormalities was not expected, but most cerebral aneurysms remain asymptomatic. Since the Ferric stain of the aneurysm was negative symptoms 4 weeks prior to death are not due to rupture of the vessel. Obviously the degeneration of smooth muscle cells and focal arteriosclerotic alterations predisposed to the vessel rupture. However, the reason of the aneurysm rupture often remains unclear. The disappearance of smooth muscle cells in the aneurysm in the present case is well illustrated in Fig. 5. Obviously the missing smooth muscle cells were the morphologic equivalent of a Locus minoris resistentiae. Life expectancy in AGS patients depends primarily on the severity of the affected liver and cardiac involvement, but also on
312
E. Doberentz et al. / Legal Medicine 17 (2015) 309–312 Table 1 Reported aneurysmal subarachnoid haemorrhage in AGS patients. Authors
Age, sex
Aneurysm location
Aneurysm diameter
Outcome
Schlosser et al. [8] Cowan et al. [7] Tumialán et al. [6]
30, f 23, f 21, f
Internal carotid artery Posterior communicating artery Terminal basilar artery
0.8 cm 0.5 cm 0.9 cm
Survived Survived Died
multiple and various vascular lesions which can lead to lethal complications. The expression of the autosomal dominant disease is quite variable; probably it is never diagnosed in a mild form and in the absence of severe hepatic disease [22]. 86% of the affected infants show symptoms of cholestasis and pruritus up to progressive liver failure before the age of 6 months. 15% of these patients require liver transplantation (2% of all pediatric liver transplantations) [4]. Noncardiac vascular complications are the most common cause of death in patients with AGS in up to 34%. AGS is also limited by heart disease (21%), liver disease (10%), and septical complications (7%), [15]. In case of clinical suspicion of a cerebral aneurysm or even a ruptured aneurysm, a cranial CT scan angiography is essential for the diagnosis. Therapeutic attempts of the aneurysm surgery are vascular clips being placed on the aneurysm neck (clipping), or the aneurysm can be filled with platinum coils and closed (coiling embolization). Depending on the location of the affected vessel also a bypass can be inserted. The prognosis of aneurysms of the posterior circulation of the circle of Wills is poor, because the access is significantly worse than to the anterior circulation [23,24]. In the forensic context it is of special importance that in cases of diagnosed AGS a vascular screening is carried out. If a vascular screening is omitted medical malpractice may be claimed by relatives and a very detailed multidisciplinary expert report may be necessary. Intracranial hemorrhage is one of the leading causes of mortality in AGS. Treating physicians have to be aware of this. According to the literature aneurysmal subarachnoid hemorrhage is one major cause of intracranial hemorrhage in AGS. However, there seem to be still other causes which require further investigations [6]. References [1] Alagille D, Borde J, Habid EC, Thomassin N. L´atresie des voies biliaires intrahépatiques avec voies biliaires extrahepatiques perméable chez l‘enfant. Arch Fr Pediatr 1969;26:51–71. [2] Krantz ID, Piccoli DA, Spinner NB. Alagille syndrome. J Med Genet 1997;34:152–7. [3] Hoffenberg EJ, Narkewicz MR, Sondheimer JM, Smith DJ, Silverman A, Sokol RJ. Outcome of syndromic paucity of intralubular bile ducts (Alagille syndrome) with onset of cholestasis in infancy. J Pediatr 1995;127:220–4. [4] Tzakis AG, Reyes J, Tepetes K, Tzoracoleftherakis V, Todo S, Starzl TE. Liver transplantation for Alagille‘s syndrom. Liver Transpl 1993;128:337–9.
[5] Alagille D. Splenectomy in hereditary hemolytic disorders in children. Acquis Med Recent 1969:41–50. [6] Tumialán LM, Dhall SS, Tomak PR, Barrow DL. Alagille syndrome and aneurysmal subarachnoid hemorrhage. Pediatr Neurosurg 2006;42:57–61. [7] Cowan JA, Barkhoudarian G, Yang LJS, Thompson BG. Progression of a posterior communicating artery infundibulum into an aneurysm in a patient with Alagille syndrome. J Neurosurg 2004;101:694–6. [8] Schlosser HG, Kerner T, Woiciechowsky, Benndorf G. Multiple cerebral aneurysms and subarachnoid haemorrhage in a patient with Alagille syndrome. AJNR Am J Neuroradiol 2004;25:1366–7. [9] Ropke A, Kujat A, Garber M, Giannakudis J, Hansmann I. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 2003;21:100. [10] Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 2001;108:161–4. [11] Lindner V, Booth C, Prudovsky I, Small D, Maciag T, Liaw L. Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cel matrix and cell–cell interaction. Am J Pathol 2001;159:875–83. [12] Jacquet A, Guichon-Mantel A, Noel LH, Sqalli T, Bedossa P, Hadchouel M, et al. Alagille syndrome in adult patients: it is never too late. Am J Kidney Dis 2007;49:705–9. [13] Emerick KM, Rabd EB, Goldmuntz E, Krantz ID, Spinner NB, Piccolin DA. Features of Alagille syndrome in 92 patients: frequency and relation to prognosis. Hepatology 1999;29:822–9. [14] Moreau S, Bourdon N, Jokie M, de Rugy MG, Babin E, Valdazo A, et al. Alagille syndrome with cavernous carotid artery aneurysm. Int J Pediatr Otorhinolaryngol 1999;50:139–43. [15] Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccolin DA, et al. Vasculcar anomalies in Alagille syndrome. A significant cause of morbidity and mortality. Circulation 2004;23:1354–8. [16] Connor SEJ, Hewes D, Ball C, Jarosz JM. Alagille syndrome associated with angiographic moyamoya. Childs Nerv Syst 2002;18:186–90. [17] Bérard E, Triolo V. Intracranial haemorrhages in Alagille syndrome. J Pediatr 2000;136:708–9. [18] Lykavieris P, Crosnier C, Trichet C, Meunier-Rotival M, Hadchouel M. Bleeding tendency in children with Alagille syndrome. Pediatrics 2003;111:167–70. [19] Linn FH, Rinkel GJ, Algra A, et al. Incidence of subarachnoid hemorrhage: role of region, year, and rate of computed tomography: a meta-analysis. Stroke 1996;27:625–9. [20] Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms and arteriovenous malformations. Based on 6368 cases in the cooperative study. J Neurosurg 1966;25:219–23. [21] Malisch TW, Guglielmi G, Vinuela F, Duckwiler G, Gobin YP, Martin NA, et al. Intracranial aneurysms treated with the Guglielmi detachable coil: midterm clinical results in a consecutive series of 100 patients. J Neurosurg 1997;87:176–83. [22] Yucel H, Hoorntje SJ, Bravenboer B. Renal abnormalities in a family with Alagille syndrome. Neth J Med 2010;68:38–9. [23] Quiros-Tejeira RE, Ament ME, Heyman MB, Martin MG, Rosenthal P, Hall T, et al. Variable morbidity in Alagille syndrome: a review of 43 cases. J Pediatr Gastroenterol Nutr 1999;29:431–7. [24] Ostergaard JR, Volsdby B. Intracranial arterial aneurysms in children and adolescents. J Neurosurg 1983;58:832–7.
