Marfan syndrome: clinical consequences resulting from a medicolegal autopsy of a case of sudden death due to aortic rupture

A traumatic aortic rupture in young years and without atherosclerotic changes is always suspicious for genetic disorders. Examples would be Ehlers-Danlos disease type IV or the Loeys-Dietz syndrome [6, 7], but the most common of these disorders is MFS [3].

About 85% of all cases of MFS are caused by one of more than 600 known different mutations in FBN1, whereas mutations in the transforming growth factor-β receptor 2 (TGF-βR2) gene are rarely observed [5‐9]. As this protein is of importance in the formation of elastic fibers, the general pathogenetic principle of this disease is the diminished resistance of all tissues and organs to traction and pressure [10].The spectrum of symptoms varies broadly: The major findings that can (but not necessarily must) be observed in this disease and that can also be identified during an autopsy are elongated bones, especially fingers and metacarpals, but also deformations of the thorax or the palate, mandible, and maxilla. These skeletal findings are explained by a decreased resistance of the periosteum to stretching that results in accelerated length growth of the bones [3]. Other findings, explained by a similar mechanism, are emphysema, hyperflexibility of the joints, and luxations of the lens. Crucial for the life expectancy, however, is the enlargement of large arteries, most notably the aortic root that in most cases leads to death from aortic rupture, typically in aortic roots of more than 6 cm in diameter. Prophylactic therapy with beta-blockers (as early as possible) and aortic root graft surgery in patients with aortic root diameters of more than 6 cm can double the life expectancy [3].

Unfortunately, phenotypic variation appears to be largely independent of the type of mutation. Thus, in some cases, persons with mutations will have a normal life expectancy, while in other cases persons with marfanoid habitus will have a normal FBN1 gene and sometimes even a normal TGF-βR2 gene [11]. Moreover, the rate of sporadic cases (de novo mutations) is estimated at 25%. Another problem is that the diagnosis of MFS is tedious: As there is such a diversity of mutations, on top of sequencing 65 exons of the FBN1, gene analysis of the TGF-βR2 gene may be required. These pitfalls make the MFS a diagnostic challenge both for the pathologist and the human geneticist [2].

In our case, the deceased showed typical arachnodactyly and tall build (“marfanoid habitus”), pectus excavatus, and a longitudinal rupture of the extended aortic root. These findings and the fact that the father of the deceased had also died from aortic root rupture at a similar age made the presence of MFS probable, but it must be borne in mind that a substantial proportion of patients with this syndrome can present with aortic rupture but only slight extra-arterial symptoms [2, 3].

Thus, MFS has to be distinguished from idiopathic cystic medial necrosis (Erdheim-Gsell syndrome, Erdheim disease) [12‐14], a poorly delimited syndrome that shows the same histologic findings as in MFS but lacks extravascular findings. Both for Erdheim-Gsell syndrome and for MFS, only a small number of reports of sudden deaths exists in the forensic literature [15‐18]. There is some argument whether Erdheim-Gsell syndrome exists as such [19]. It is discussed to be only an exaggerated age-related change or a manifestation of several diseases that cannot be distinguished by a routine autopsy, the most important most probably MFS [20]. This discussion is further nurtured by the recently found high incidence of atypical Marfan syndromes without the “typical marfanoid habitus,” but with mutations of FBN1 [21]. Thus, we feel that the experience from our case should prompt pathologists to use the diagnosis “Erdheim-Gsell Syndrome” as rarely as possible and take advantage of genetic testing for MFS in all cases with juvenile cystic medionecrosis, even without the presence of a “marfanoid habitus.” The goal of this procedure should be not only to establish the correct diagnosis but also to give relatives, as in our case, the opportunity of early prophylactic treatment. But not only we forensic pathologists are challenged, also the attorneys that (in the eyes of the authors) should have an autopsy ordered in every case of sudden death without prior known diseases up to the third decade, as both death from heritable diseases often occurs suddenly and unexpected in young years without prior diagnosis [22‐24], and the chance of a neglected unnatural death is much higher in sudden deaths in younger years than afterwards [25].