Case 1 -
Marc K. Halushka
John's Hopkins Medical Institute
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A 5-year-old girl was found to have an aortic root aneurysm and underwent replacement of the
ascending aorta with a hemashield graft.
Case 1 - Slide 1
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 . 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
Marfan Syndrome: Marfan syndrome (MFS), first described in 1896, is a
genetic disorder caused by mutations in the fibrillin-1 (FBN1) gene . 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 . 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
Loeys-Dietz Syndrome: Loeys-Dietz syndrome (LDS) is a recently described
disorder caused by mutations in the TGFBR1 and TGFBR2 genes . 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 . 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 .
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
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 .
Bicuspid Aortic Valve: Bicuspid aortic valve (BAV) is the most common
congenital heart abnormality, affecting up to 2% of the population . 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 .
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 .
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 . 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
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 .
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 . Aortic dilation (or dissection) has been reported in conjunction with other
cardiac anomalies (bicuspid aortic valves and coarctation) in ~1.5% of TS subjects . 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 . Histologically, cystic medial degeneration has been
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 . Mutations in a number of different genes (TAAD1, FAA1, TGFBR2, MYH11, ACTA2) confer a variable constellation of additional
phenotypes . 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
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 . 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 . TA is an inflammatory disease of unknown
etiology predominantly affecting the aorta and its main branches . 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 . 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 . 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 . 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  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 . 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
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
- If you are thinking of EDS-IV - think to get EM.
- If encountering an aneurysm/dissection at autopsy -
do a thorough "genetic" physical exam. 
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