This thesis is dedicated to my grandparents

d/ clinical signs and symptoms
The five major components of the PXE retinopathy are (Figure 12):
1/ Ocular peau d’orange (Pd’O), a diffuse mottled hyperpigmentation of the fundus which
is probably the first ocular sign of PXE [22, 23, 114, 115]. It consists of fine, relatively
symmetrical flat lesions in the RPE. As it does not give rise to any symptoms, its exact
time of origin is unknown and discovery is often postponed to a later age. Located in the
retinal periphery, most prominent temporal to the fovea, approximately 28 to 73% of
patients are presumed to have this aberration [116, 117]. The peau d’orange is however
known to regress with age, significantly reducing the prevalence in elder PXE patients.
When readily identifiable in one individual, siblings should be investigated for the
presence of Pd’O, even in the absence of angioid streaks.
2/ Angioid streaks (AS) represent the breaks in Bruch membrane due to elastorrhexis.
In fundo, they are seen as irregular, often jagged pigmented red-brown lines, radiating
out from the optic disk, resembling normal retinal or choroidal vasculature at first glance,
hence their name [25]. Sometimes, connecting streaks encircling the optic disk can be
observed. AS are typically bilateral and variable in their number and extent. While in
many patients there is a slow increase in number and length/width of streaks, they are
asymptomatic and, although their mean age of onset is in the second decade, detection
often only occurs when they are complicated by retinal haemorrhages. It is considered
that all PXE patients will develop AS sooner or later and, if taken together with the other
characteristics of the retinopathy, they have a high specificity for PXE [24, 25].
Occasionally, AS are found in isolation, but they have also been seen in younger
individuals with PXE who had no cutaneous manifestations of the disease but developed
them later. Therefore, when AS are identified in a patient, a systemic disorder as PXE
must always be suspected and the patient should remain under surveillance.
3/ Peripapillary atrophy, can be observed in different forms (varying from helicoid to
cuboid) and can be so extensive around the disk and in the macula that AS are no longer
visible [24]. Generalized atrophy of the RPE and choroid, as well as reactive hyperplasia
of the RPE with less marked AS have been described [23, 118].
4/ Subretinal neovascularisation, haemorrhages and macular degeneration, are
regarded as complications of AS and were, in the past, often the first sign leading to the
diagnosis of PXE. Neovascularisation engages from the choroid through the breaks in
BrM, possibly triggered by Vascular Endothelial Growth Factor (VEGF). The novel vessel
will push against the outer retinal layers, deforming the otherwise tightly stretched retina.
Due to a lack of tight junctions in the neovessels, an exsudative reaction – leakage
through the vessel wall – occurs. As a result, patients can experience metamorphopsia, a
distortion of their vision, with straight lines becoming curved. As these neovessels also
have brittle walls, rupture – either spontaneous or traumatic – can occur easily, resulting
in a haemorrhage and subsequent (partial) vision loss (scotoma), depending on the size
and location of the haemorrhage in fundo. When the macula is affected, patients lose
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