Cardiovascular Pathology

Loeys-Dietz Syndrome

Marc K. Halushka
John's Hopkins Medical Institute
Baltimore, MD


Clinical History
A 5-year-old girl was found to have an aortic root aneurysm and underwent replacement of the ascending aorta with a hemashield graft.


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Figure 1
Movat Pentachrome
Figure 2
Movat Pentachrome
Figure 3
Movat Pentachrome


Histologic Diagnosis
Loeys-Dietz Syndrome

Discussion
Ascending aortic disease in the pediatric and young adult setting is generally rare in the population, but is a significant cause of mortality in affected individuals. Most cases of ascending aortic aneurysm are the result of a genetic predisposition. Some are well known and fairly common such as Marfan Syndrome. Others are rare and less well understood. There are at least 18 causes of aortic disease in this age group and this discussion will highlight a subset of these entities [1]. From a histologic perspective, it is generally not possible to make a definitive diagnosis of a particular entity without knowledge from the clinician regarding pathognomonic features or genetic test results. It is important, though, to accurately describe the aortic wall histology to aid the clinician in making a diagnosis.

Definition of terms:
The nomenclature used to describe aortic histopathology has never been adequately standardized. Thus, a wide variety of terms are used that are both historical and regional in their meaning. The terms and definitions described have been chosen to highlight the differences and similarities between aortic disease entities.

Cystic medial degeneration: Fragmentation and/or loss of elastic fibers with glycosaminoglycan deposition creating interlamellar "cyst-like" spaces within the media.

Diffuse medial degeneration: Fragmentation and/or loss of intralamellar elastic fibers with extracellular matrix deposition.

Elastic fiber fragmentation: Fragmentation of elastin lamellae as assessed by an elastic stain.

Laminar medial necrosis: Coagulative necrosis of the media with loss of smooth muscle cell nuclei.

Inflammation: Adventitial and/or medial infiltrate by lymphocytes, macrophages, eosinophils, plasma cells, neutrophils and/or giant cells. Adventitial thickening may be present.



Disease Entities

Marfan Syndrome: Marfan syndrome (MFS), first described in 1896, is a genetic disorder caused by mutations in the fibrillin-1 (FBN1) gene [2]. The syndrome's key phenotypic features are arachnodactyly, pectus excavatum, scoliosis, and lens disclocation. Both mitral valve regurgitation and aortic root dilatation/aneurysm are frequent. Aortic root dilatation is present in 35% of individuals by the age of 5 years and 68%-80% by 19 years [3]. The most common histopathology of the aorta is elastic fiber fragmentation and cystic medial degeneration. These histopathologic findings are highly variable, with some individuals (particularly those undergoing prophylactic resection) exhibiting no histologic abnormalities.

Loeys-Dietz Syndrome: Loeys-Dietz syndrome (LDS) is a recently described disorder caused by mutations in the TGFBR1 and TGFBR2 genes [4]. LDS is characterized by craniofacial features including biphid uvula/cleft palate, hypertelorism, retrognathia, and craniosynostosis. It also shares some overlapping features with Marfan syndrome and the vascular type of Ehlers-Danlos syndrome (EDS-IV). It has a more aggressive vascular pathology than MFS with an aortic dissection rate approaching 70% of patients and a median survival of only 37 years [4]. Cardiovascular lesions in LDS include aortic valvular regurgitation and aortic root dilation, aneurysm and dissection. In contrast to cystic medial degeneration which is usually focally present in MFS, aortas from LDS patients have a more diffuse medial degeneration [5].

Arterial Tortuosity Syndrome: Arterial tortuosity syndrome (ATS) is a disorder caused by mutations in the solute carrier family 2 member 10 (SLC2A10) gene that encodes for the glucose transporter GLUT10 [6, 7]. Patients have characteristic dysmorphic features including hyperextensible skin and joints. Clinically, the disease overlaps with EDS-IV. Tortuosity of the aorta and large arteries is invariably present in ATS and often has a striking appearance on radiographic imaging. Nineteen to 31% of patients develop aortic aneurysms. Grossly, major vessels including the aorta appear thickened, elongated and tortuous. Histopathology of affected vessel walls demonstrates fragmentation of the inner elastic membrane and fragmentation and loss of elastic fibers of the tunica media and external elastic membrane. The intima is often markedly thickened due to fibrosis [8].

Bicuspid Aortic Valve: Bicuspid aortic valve (BAV) is the most common congenital heart abnormality, affecting up to 2% of the population [9]. Although mutations in NOTCH1 are associated with a subset of cases of BAV with characteristic aortic calcifications and variable aneurysm formation, the genetic basis of BAV is largely unknown [10]. Roughly 50% of young men with BAV have abnormal aortic dimensions consistent with aneurysms and ~5% of patients with BAV will develop an aortic dissection. In contrast to MFS, patients with BAV do not have dilatation of the aortic sinuses. Histopathologically, there is cystic medial degeneration and thinner elastic lamellae [11].

Ehlers-Danlos Type IV: Ehlers-Danlos syndrome (EDS) is connective tissue disease with 6 main subtypes. Significant vascular manifestations are found in EDS, type IV (EDS-IV) or 'vascular' EDS, the result of mutations in the collagen, type III, alpha-1 (COL3A1) gene. The key phenotypic features of EDS-IV are thin, elastic skin, and rupture of vessels or viscera [12]. Arterial tears of the aorta and its branches are considered hallmarks of this disease and, in general, rupture and dissection outweigh aneurysm. Patients have a 25% risk of experiencing a major vascular complication by the age of 20 years and life expectancy is around 48 years [12, 13]. EDS-IV patients have low tolerance to surgery owing to the extreme fragility of their vascular wall. Histologic findings may be relatively subtle and nonspecific despite transmural tears in the aorta. In EDS-IV, transmission electron microscopy is diagnostically valuable. These aortae have irregularities in the diameter of collagen fibers and an unidentified fibrino-granular substance within the extracellular matrix. However, due to the high number of false negatives, the absence of these features should not exclude the diagnosis EDS-IV [14].

Turner Syndrome: Turner syndrome (TS) is a sex aneuploidy syndrome in which a single X chromosome is present (45,XO). The primary manifestations of TS are short stature, webbed-neck and infertility. Cardiovascular diseases are common and include congenital heart defects such as bicuspid aortic valves and a distinctive form of coarctation of the aorta, sometimes referred to as pseudocoarctation [15]. Aortic dilation (or dissection) has been reported in conjunction with other cardiac anomalies (bicuspid aortic valves and coarctation) in ~1.5% of TS subjects [16]. The aortic dilation typically involves the root of the ascending aorta, occasionally extending through the aortic arch to the descending aorta. Aortic dilations and dissections occur in young individuals with over 65% of subjects being less than 21 years of age [16]. Histologically, cystic medial degeneration has been reported [16].

Familial thoracic aortic aneurysms and dissections (FTAAD): Up to 20% of patients referred for repair of thoracic aneurysm or dissection have familial clustering of the disease yet they fall outside of the clinical criteria for any of the above mentioned hereditary disorders. In most of these families, the inheritance is autosomal dominant with decreased penetrance and variable age-related onset of symptoms [17]. Mutations in a number of different genes (TAAD1, FAA1, TGFBR2, MYH11, ACTA2) confer a variable constellation of additional phenotypes [18]. Histologically, in aortae from subjects with MYH11 and ACTA2 mutations, there is focal medial degeneration with disorganization of smooth muscle cells, elastic fiber loss, and increased penetrance of vaso vasorum into the medial layer [19, 20].

Aortitis: Ascending aortitis is characterized by the presence of inflammation of the adventitia and media, often with giant cells. It includes the diseases Takayasu arteritis (TA), giant cell arteritis (GCA) and isolated aortitis [21]. GCA is generally described in patients older than 50 years of age. The term isolated aortitis is used when patients have no clinical symptoms other than those related to aortic root disease [22]. TA is an inflammatory disease of unknown etiology predominantly affecting the aorta and its main branches [23]. It generally presents between the ages of 10 and 30 years, most commonly in Southeast Asian countries and has a female to male ratio of 8.5 to 1 [24]. Grossly the aorta is thick and often rigid secondary to transmural fibrosis. Often a thick intima may reveal wrinkling and ridges and give rise to a "tree bark" appearance [25]. Histologically, inflammation extends to the outer layer of the media and adjacent adventitia with a mixture of inflammatory cells including lymphocytes, plasma cells and macrophages [26]. In the media there is a patchy heavy inflammatory infiltrate with giant cells that causes elastic fiber and smooth muscle cell loss and ultimate replacement by collagen. Aneurysms occur in up to 45% of patients. Burke et al [27] proposed a histologic classification of noninfectious aortitis with two categories: necrotizing and non-necrotizing aortitis. They proposed that the necrotizing form is an autoimmune condition that may be localized (isolated necrotizing aortitis) or part of a systemic autoimmune process. Infrequently, it may be a manifestation of Takayasu arteritis, suggesting there are other diseases that cause this histologic appearance.

Weightlifting: Weightlifting and severe physical exertion have been described as causes of aortic dissections. Recently, 31 patients who developed acute aortic dissection in the context of severe physical exertion were described [28]. Affected subjects ranged in age from 19 to 76 years of age with a strong male predominance (30:1). Most of these subjects had moderately enlarged aortas (4-5cm diameter). The etiology of this dissection appeared to be a rapid and dramatic elevation of blood pressure against a mildly dilated aorta. Histologically, cystic medial degeneration was described in 3 cases suggesting the possibility of an underlying condition predisposing to the dissection [29].

Take Home Messages:

  • For surgical pathology cases of the ascending aorta it is not necessary (or possible) to make a diagnosis of a particular disease entity by histology alone. One should differentiate between inflammatory disease and non-inflammatory disease and describe key features that suggest possible syndromes and diseases.

  • Always get an elastic stain (VVG, Movat) on an aortic case.

  • If you are thinking of EDS-IV - think to get EM.

  • If encountering an aneurysm/dissection at autopsy - do a thorough "genetic" physical exam. [30]

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