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Legal Medicine 13 (2011) 145–147
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Case Report
Sudden death associated to vascular Ehlers–Danlos syndrome. A case report Philippe Charlier a,e,⇑, Dominique P. Germain b, Xavier Jeunemaître c, Stanislas Grassyn Delisle d, Jean-Claude Alvarez d, Geoffroy Lorin de la Grandmaison a a
Department of Forensic Medicine and Pathology, University Hospital R. Poincaré (AP-HP, UVSQ), 104 R. Poincaré Boulevard, F-92380 Garches, France University of Versailles – St. Quentin en Yvelines, France c Department of Genetics, Georges Pompidou European Hospital (AP-HP), 20 Leblanc Street, F-75015 Paris, France d Department of Toxicology, University Hospital R. Poincaré (AP-HP, UVSQ), 104 R. Poincaré Boulevard, F-92380 Garches, France e Department of Medical Ethics, Paris 5 University, France b
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Article history: Received 5 August 2010 Received in revised form 7 October 2010 Accepted 19 December 2010 Available online 26 January 2011 Keywords: Arterial dissection Hemo-pericardium Vascular disease Genetic disease Forensic pathology
a b s t r a c t This article describes the case of a sudden death in a 45-year-old female consecutive to acute and extensive arterial dissection in a context of Ehlers–Danlos syndrome type IV. The interest of this case report is that autopsy findings led to the suspicion of a clinical diagnosis prompting as carrying out a genetic testing which definitively confirms the diagnosis, opening the way to genetic council for family members. Criteria for this disease diagnosis and full methodology are described, that may help forensic practitioners. Ó 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Ehlers–Danlos syndrome (EDS) is a heterogeneous group of collagen connective tissue disorders characterized by excessive skin extensibility, joint mobility and tissue fragility [1,2]. Its prevalence varies from 1/25,000 to 1/10,000. Vascular EDS (or Sack–Barabas syndrome) corresponds to type IV representing 5% to 10% of all EDS (and the most severe form of the disease). Patients with such a type may present particular facial features with a very thin, pale and easy bruising skin. In contrast to other forms of EDS, they have an increased risk for severe arterial, digestive or uterine complications (mainly represented by tears, dissections and perforations). When present, arterial dissections involve medium and large caliber arteries, for example the proximal branches of the aortic arch and the whole aorta [3]. The underlying genetic anomaly consists in a mutation of the COL3A1 gene that encodes for the type III procollagen, resulting in a deficit of this molecule and an excessive fragility of tubular organs or vessels [4]; the identification of a mutation on this gene provides diagnosis certainty but with a sensitivity of only 60% [5]. Arterial lesions suggestive of vascular EDS are dissecting aneurysms of the internal carotid and iliac arteries, and of the anterior visceral branches of the abdominal aorta, fusiform aneurysms of ⇑ Corresponding author. Tel.: +33 147107689; fax: +33 147107683. E-mail address:
[email protected] (P. Charlier). 1344-6223/$ - see front matter Ó 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.legalmed.2010.12.004
the splenic artery, and early-onset non-traumatic direct carotidcavernous fistulae [6,7]; other non-vascular anomalies indicative of the disease consist in early-onset varicose veins, spontaneous peritonitis and unusually important perineal lesions after giving birth [5]. Even if the prognosis of vascular EDS remains poor, there is as for many autosomal dominant inherited disease some phenotypic variability [8]. The efficacy of beta-blockers associated to a close follow-up by a multidisciplinary team is currently being investigated [9]. 2. Case report 2.1. Nature of the cadaver discovery scene The dead body of a 45-year-old female was discovered in her bed, at home, 2 days after her last telephonic contact. The cadaver was found in fetal position, both hands behind the thighs. Due to the presence of slight signs of putrefaction (abdominal green patch), no reanimation was carried out. A notion of Raynaud disease existed for this subject whose brother had recently died of sudden death. No autopsy data was available for the later. A long-term treatment by calcium bromo-galactogluconate, prazepam, lormetazepam, naproxene, flavonoides, phloroglucinol, nifedipine and sulfamethizol was followed. The police investigators found no suspicious sign of violence at home.
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2.2. Autopsy findings An external examination and autopsy of the individual showed no evidence of recent or ancient trauma. Morphological aspect of the face and whole body exhibited some physical particularities evoking the diagnosis of EDS: fine and translucent skin with excessively visible subcutaneous vessels and diffuse varicosities, gingival retraction, ‘‘Madonna’’ face with ‘‘false’’ globular eyes due to orbital fat atrophy, acrogeria, bruising, and mild increase of skin elasticity (particularly on the upper limbs). The cause of death was a massive hemo-pericardium of 360 mL (Fig. 1a) complicating a complete thoracic aortic dissection (type I of De Bakey = type A of Standford) with partial thrombosis of the false canal (Fig. 1b). The origin of the dissection was present on the posterior side of the thoracic aorta, 3 cm over its cardiac insertion. A dissection of all supra-aortic arteries was present (for example a bilateral dissection of both carotid arteries, each of 3 cm-long). The distal end of the dissection was situated 4 cm after the origin of both iliac arteries. No other significant visceral or skeletal anomaly was found, with the exception of an ovarian atrophy. The case was closed as natural death. 2.3. Laboratory analyses Microscopic analysis of all the viscera was carried out. Both carotid arteries and the aorta showed a complete dissection localized in the media, the false canal being filled out by blood without any sign of organization or inflammation, testifying of a short agony (inferior to 1 h) (Fig. 2a). The disorganization of arterial collagen fibers was highlighted after a coloration by orceine, characterized Fig. 2. (a) Microscopic view of the aorta dissection without any acute inflammation (HES, 25). (b) Microscopic view of the aorta wall with complete collagen disorganization (orceine coloration, 100).
by a rarefaction, a fragmentation and a patchy architecture (Fig. 2b). Hemorrhagic foci were seen in soft tissues close to the dissection area. Other anomalies were (i) infiltration of the right heart ventricle by fat tissue without fibrosis (with nonpathological coronaries) and (ii) a diffuse nonspecific visceral congestion. A molecular analysis of peripheral blood samples showed the presence of an intronic deletion on the COL3A1 gene: IVS16 (+59) del27nt corresponding to a deletion of 27 nucleotides in intron 16 of the gene. No mutation in the coding regions was found. The identified intronic mutation has not been reported yet. In order to determine its functional consequences, a further analysis of COL3A1 messenger RNA in target organs (for example aorta wall and skin) would have been very informative. Unfortunately, mRNA are fragile and rapidly altered by RNAse liberation in the first hours following death; our forensic experience has shown that the presence of putrefactive signs (complete green abdominal spot) correlates with alteration of the mRNA preventing molecular analyzes [10]. 3. Discussion
Fig. 1. (a) Left lateral view of the opened thorax during the autopsy with the huge hemo-pericardium. (b) Macroscopic view of the false channel of the descending thoracic aorta.
Other cases of sudden death due to vascular Ehlers–Danlos have been described in the literature. Henderson and Chrostowski [11] report the case of a 12 year-old boy and underline the importance for forensic pathologists, of being aware of this type of inherited connective tissue disorder, since the autopsy findings can be easily and falsely interpreted as blunt impact trauma. In all cases, the post-mortem diagnosis of vascular (type IV) EDS remains uneasy: increasing of skin elasticity, a classic and very evocative sign of other EDS types, may be absent or mild in this form of the disease or strongly difficult to determine due to rigor mortis. If a genetic confirmation of the disease is needed, as for
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P. Charlier et al. / Legal Medicine 13 (2011) 145–147
other potential fatal genetic disorders [12,13], it has to be known that DNA analyses remain possible for a long time after death but, in contrast, mRNA will not be exploitable after a very short time due to post-mortem enzymes liberations. Moreover, the genetic and clinical heterogeneity of the disease represents a major difficulty for retrospective diagnosis. However, helped by specialized testing, the precise identification of such a disease gives the opportunity of a notification to family members of this potentially lethal inherited disease, more especially as there exists now of new therapeutic possibilities [14]. Conflict of interest We declare no conflict of interest. References [1] Barabas AP. Heterogeneity of the Ehlers–Danlos syndrome: description of three clinical types and a hypothesis to explain the basic defect. BMJ 1967;2:612–3. [2] Barabas AP. Ehlers–Danlos syndrome type IV. N Engl J Med 2000;343:366. [3] Beighton P, De Paepe A, Steinman B, Tsipouras P, Wenstrup RJ. Ehlers–Danlos syndromes: revised nosology, Villefranche 1997. Am J Med Genet 1998;77:31–7.
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[4] Pope FM, Martin GR, Lichtenstein JR, et al. Patients with Ehlers–Danlos syndrome type IV lack type III collagen. Proc Natl Acad Sci USA 1975;72:1314–6. [5] Perdu J, Boutouyrie P, Lahlou-Laforêt K, et al. Syndrome d’Ehlers–Danlos vasculaire. Presse Med 2006;35(12):1–18. [6] Boutouyrie P, Jeunemaître X, Gimenez-Roqueplo AP, Lacolley P, Germain DP, Laurent S. Phénotype artériel des maladies mendéliennes de la paroi artérielle. STV 2002;14:523–9. [7] Boutouyrie P, Germain DP, Fiessinger JN, Laloux B, Perdu J, Laurent S. Increased carotid wall stress in vascular Ehlers–Danlos syndrome. Circulation 2004;109:1530–5. [8] Lauwers G, Nevelsteen A, Dacnen G, Lacroix H, Suy R, Frijns JP. Ehlers–Danlos syndrome type IV: a heterogenous disease. Ann Vasc Surg 1997;11:178–82. [9] Germain DP. Ehlers–Danlos syndrome type IV. Orphanet J Rare Dis 2007;2:32. [10] Alaeddini R, Walsh SJ, Abbas A. Forensic implications of genetic analyses from degraded DNA. A review. Forensic Sci Int Genet 2010;4:148–57. [11] Henderson EB, Chrostowski L. Sudden death due to Ehlers–Danlos syndrome type IV in a 12 year-old child. Am J Forensic Med Pathol 2009;30(1):117 [abstract]. [12] Michaud K, Mangin P, Elger BS. Genetic analysis of sudden cardiac death victims: a survey of current forensic autopsy practices. Int J Legal Med 2010 [Epub ahead of print]. [13] Wedekind H, Schulze-Bahr E, Debus V, Breithardt G, Brinkmann B, Bajanowski T. Cardiac arrhythmias and sudden death in infancy: implication for the medicolegal investigation. Int J Legal Med 2007;121(4):245–57. [14] Ong KT, Perdu J, De Backer J, Bozec E, Collignon P, Emmerich J, et al. Effect of celiprolol on prevention of cardiovascular events in vascular Ehlers–Danlos syndrome: a prospective randomised, open, blinded-endpoints trial. Lancet 2010 [Epub ahead of print].
