Page 190 - The Vasculitides, Volume 1: General Considerations and Systemic Vasculitis

166 Lindsay Lally and Stephen A. Paget

Genetic Disorders

Certain hereditary disorders and genetic syndromes that can affect the vasculature
resembling vasculitides are further separable by a detailed history, pedigree, and targeted
genetic testing. At least three congenital disorders, Ehlers-Danlos syndrome (EDS), Marfan
syndrome (MFS), and type-4 Loeys-Dietz syndrome, all enter in to the differential diagnosis
of LVV and idiopathic aortitis, also a component of the IgG4-related disorders (IgG4-RD);
and a fourth disorder termed Grange syndrome that resembles PAN.

Autosomal dominant (AD) EDS caused by heterozygous mutation in the gene for type III
collagen (COL3A1) at the q32.2 chromosomal locus [18] leads to thoracic and abdominal
aortic aneurysm. Kontusaari and colleagues [19] described a 37-year-old woman with a
family history of sudden death due to rupture of thoracic and abdominal aortic aneurysms
with joint hyperextensibility, arachnodactyly, easy bruising. A missense mutation of the
COL31A gene was found that was identical to that noted in pathological specimens from her
mother and maternal aunt who died age 34 years and 55 years respectively of aortic
aneurysmal rupture.

AD MFS is a genetic disorder of fibrous connective tissue caused by heterozygous
mutation in the fibrillin-1 (FBN1) gene located on chromosome 15q21.1, characterized by
skeletal, ocular and cardiovascular features [20]. The latter includes congenital aortic root
dilatation and fatal aortic aneurysmal dissection and rupture, reported in single index patients
[21, 22]. Although the cause of aortic vasculopathy in MFS is not well understood, Abraham
and colleagues [23] described abnormal aortic elastin typified by reduced desmosine and
isodesmosine, and an overall reduction of elastin in three typical patients.

A third genetic disorder, AD, type-4 Loeys-Dietz syndrome caused by heterozygous
mutation in the transforming growth factor, beta-2 (TGFB2) gene at chromosome 1q41 is
associated with familial thoracic aortic aneurysm and dissection, and mild systemic features
of MFS [24]. The TGFB2 gene is associated with tissue signature for high transforming
growth factor (TGF)-??signaling. Experimental mice rendered haploinsufficient for Tgfb2
develop dilation of the aortic annulus and root by 8 months of age despite normal distal
ascending aortic dimensions suggesting that TGF-?-mediated vasculopathy results at least in
part from the causative mutation with resultant loss-of-function [25].

The congenital disorder of Grange syndrome [26] presents with stenosis of the renal
arteries and chronic hypertension, with variable stenoses or occlusion of cerebral, abdominal
and coronary arteries in association with cardiac defects, bone fragility, brachysyndactyly,
and learning disability. Four of nine sibs so studied, manifested stenotic and occlusive disease
of medium-sized arteries [26]. The explanation for this familial disorder includes autosomal
recessive (AR), AD inheritance with reduced penetrance, and parental gonadal mosaicsism
for a mutation involving a single gene or several contiguous genes. One affected 15-year-old
boy [27] demonstrated stenoses and occlusion of multiple cranial, renal and celiac arteries,
aneurysm of the basilar artery indistinguishable from PAN.

Reversible Cerebral Vasoconstriction Syndrome

Although diverse CNS infections, neoplasms, atherosclerotic disease and
thromboembolic disorders can mimic primary CNS vasculitis (PCNSV) [28], one particular

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