Pseudoxanthoma elasticum: a clinical, pathophysiological
and genetic update including 11 novel ABCC6
N Chassaing*, L Martin*, P Calvas, M Le Bert, A Hovnanian
J Med Genet 2005;42:881–892. doi: 10.1136/jmg.2004.030171
Pseudoxanthoma elasticum (PXE) is an inherited systemic
disease of connective tissue primarily affecting the skin,
retina, and cardiovascular system. It is characterised
pathologically by elastic fibre mineralisation and
fragmentation (so called ‘‘elastorrhexia’’), and clinically by
high heterogeneity in age of onset and the extent and
severity of organ system involvement. PXE was recently
associated with mutations in the ABCC6 (ATP binding
cassette subtype C number 6) gene. At least one ABCC6
mutation is found in about 80% of patients. These mutations
are identifiable in most of the 31 ABCC6 exons and consist
of missense, nonsense, frameshift mutations, or large
deletions. No correlation between the nature or location of
the mutations and phenotype severity has yet been
established. Recent findings support exclusive recessive
inheritance. The proposed prevalence of PXE is 1/25 000,
but this is probably an underestimate. ABCC6 encodes the
protein ABCC6 (also known as MRP6), a member of the
large ATP dependent transmembrane transporter family
that is expressed predominantly in the liver and kidneys,
and only to a lesser extent in tissues affected by PXE. The
physiological substrates of ABCC6 remain to be
determined, but the current hypothesis is that PXE should be
considered to be a metabolic disease with undetermined
circulating molecules interacting with the synthesis,
turnover, or maintenance of elastic fibres.
skin, retina, and cardiovascular system.1–5PXE
is characterised by elastic fibre mineralisation
and fragmentation, resulting in a diagnostic
pathology picture called ‘‘elastorrhexia’’.1To a
lesser extent, milder ultrastructural alterations of
other extracellular matrix (ECM) components
(collagen fibrils and glycosaminoglycans) have
been demonstrated.1 6–8Cutaneous PXE was first
delineated in 1896 by Darier,9who coined the
term ‘‘pseudoxanthoma elasticum’’, stating that
the yellowish papules of PXE differed from
authentic xanthomas and were related to elastic
tissue fragmentation. Angioid streaks—the car-
dinal ophthalmological sign of PXE—were also
described in the 19th century. They were
See end of article for
Dr Alain Hovnanian,
Department of Medical
Genetics and INSERM
U563, Pavillon Lefebvre,
Purpan Hospital, Place du
Dr Baylac, 31059 Toulouse
Cedex 09, FRANCE; Email:
22 December 2004
Revised version received
9 April 2005
Accepted for publication
12 April 2005
Published Online First
13 May 2005
264800) is an inherited systemic disease of
connective tissue primarily affecting the
independently related to PXE skin changes by
Gro ¨nblad and Strandberg in 1929.10 11Precocious
atheromatosis was the last sign to be related to
the condition. Carlborg reported cardiovascular
elastic calcification in 29 Swedish patients with
PXE in 1944.12
PXE was thought for a long time to be a
primary disorder of the elastic fibre system, with
candidate genes encoding structural components
of the fibres (elastin, fibrillins, or other micro-
Surprisingly, it was eventually
linked to mutations in the ABCC6 (ATP binding
cassette subtype C number 6) gene.15–18ABCC6
encodes ABCC6, a member of the large ATP
dependent transmembrane transporter family.
ABCC6 is abundantly expressed in liver and
kidney cell membranes, and to a lesser extent in
other tissues affected or not by PXE (skin, vessel
walls, and retina).15 19–23Even though the sub-
strates transported by ABCC6 remain to be
determined, the association of PXE with ABCC6
efflux transport alterations raises new and
Among these, a current theory is that PXE is a
systemic metabolic disease resulting from a lack
or accumulation in the blood stream over time of
molecules interacting with ECM synthesis, turn-
over, or maintenance.26
hypotheses.22 24 25
We searched Medline in November 2004 using
the key words ‘‘pseudoxanthoma elasticum’’,
‘‘PXE’’, ‘‘ABCC6’’, and ‘‘MRP6’’ and considered
original papers and progress reports published
after 1988. Characteristic clinical events and
pathological findings in PXE have been described
and reviewed in previous large series and these
will be referred to as appropriate.1–5Papers
updating recent progress will be commented on
in more detail.
Clinical features and management
PXE is found in all populations studied so far. Its
prevalence seems higher in Afrikaners from
South Africa, mainly because of a founder
effect.27 28A ubiquitous female to male ratio of
around 2:1 is usually reported, but there is no
satisfactory explanation for this. PXE is char-
acterised by marked clinical heterogeneity, even
Abbreviations: ABCC6, ATP binding cassette, subfamily
C, member 6; ECM, extracellular matrix; MRP6, multidrug
resistance associated protein 6; NBF, nucleotide binding
fold; PXE, pseudoxanthoma elasticum
between siblings, in relation to age of onset and the extent
and severity of organ system involvement. Most patients have
a normal life span.
The primary skin lesion is a yellowish papule of 1 to 5 mm in
diameter. Such papular lesions tend gradually to coalesce to
form plaques with a cobblestone appearance (fig 1). Typical
skin lesions of PXE are located on the neck and in flexural
areas. Cervical lesions often develop first, appearing on the
lateral aspects and commonly sparing, at least initially, the
medial part of the nape. They often rise between the ages of 8
and 12 years, but may be more precocious. Flexural
involvement tends to start in the teenage years. The most
commonly affected sites are the axillae, but involvement of
the antecubital and popliteal fossae and groins is also
generally noted. Involvement of anterior aspects of the
wrists, umbilicus, or lumbar skin area is less common. At
the point of maximum papular coalescence, skin loses its
elasticity (rather than becoming hyperelastic) and typical
redundant skin folds develop (fig 2). Most patients have
limited skin surface involvement, but generalised ‘‘cutis laxa-
like’’ PXE can occur and is of considerable aesthetic
concern.29Recently, Lebwohl et al emphasised the clinical
value of face involvement.30These investigators showed that
horizontal and oblique mental creases are a valuable sign of
PXE (fig 3). These creases have a high specificity for the
diagnosis of PXE before the age of 30. Less common
cutaneous manifestations have been described occasionally:
acne-like lesions on the neck or the trunk, featuring
comedones or inflammatory papules,31elastosis perforans
serpiginosa, and reticulate pigmented rash.32In very rare
instances, spontaneous resolution of PXE skin changes has
been reported.1Calcinosis cutis is rarely associated with PXE,
and when it occurs it is usually in association with disorders
of calcium and phosphate metabolism.33–35These conditions
could be particular subgroups of PXE. Mucosal lesions
identical to their cutaneous counterparts may be found on
the inner aspect of the lower lip (fig 4), on the cheeks or the
palate, or on the genitalia, but also all along the digestive
tract mucous membrane.36
A skin biopsy specimen is mandatory for the diagnosis of
PXE, in order to show the cardinal histological features.
Aberrant clumped and fragmented elastic fibres are demon-
strated in the mid-dermis by haematoxylin-eosin-safran
staining, or by the use of more specific elastic stains (orcein
or Verhoeff’s) which colour the fibres black (fig 5).
Deposition of calcium and phosphorus may be shown by
the von Kossa stain.1 37Characteristic pathological features
can be observed in clinically involved skin, but also in
apparently normal skin. Lebwohl et al demonstrated occult
axillary PXE in four patients who presented with premature
cardiovascular disease and angioid streaks but no skin
changes.38The same group previously found pathological
skin findings indicative of PXE in scar biopsies from six of 10
patients with angioid streaks but without clinically char-
acteristic skin lesions.39As an important consequence, the
axillary yellowish papules gradually coalescing to form plaques with
Primary skin involvement in pseudoxanthoma elasticum:
demonstrating loss of elasticity.
Redundant axillary skin folds in pseudoxanthoma elasticum,
valuable clinical sign for the diagnosis in young individuals.
Oblique mental creases in pseudoxanthoma elasticum: a
882Chassaing, Martin, Calvas, et al
diagnosis of PXE may be suspected and made in patients
without any visible skin involvement.
Ultrastructural elastic tissue alterations are seen in both
lesional and non-lesional skin, in contrast to other ECM
changes which are only seen in involved skin in the vicinity
of altered elastic fibres.6–8Prominent abnormalities affect the
elastic fibres, featuring small or large electron-dense bodies
(calcifications) and holes in the core of the fibres (fig 6).
Calcifications result in ‘‘fractures’’ of the fibres, which occur
during biopsy severing. Collagen bundles display fibrils of
irregular diameter and occasional flower-like features.
Aggregates of filamentous material composed of elastin and
proteoglycans are found close to the surface of elastic fibres.7
Electron microscopic observations are misleading unless
elastorrhexia has been demonstrated by optic microscopy.
Indeed, the ultrastructural changes described above are not
specific for PXE, and may be encountered in other inherited
diseases of the ECM, but also in skin aging.
Surgical reduction of excessive and redundant skin may be
envisaged in some instances for cosmetic improvement.40The
long term outcome has been poorly evaluated as patient
series are scarce. Viljoen et al reported favourable post-
surgical outcome in eight female patients with a mean follow
up of six years. Delayed healing and scarring occurred in two
of these because of extrusion of transepidermal calcium
particles.40 41The efficacy of collagen or autologous fat
injections in the mental creases remain to be evaluated.41
Elastic tissue is also present in the eye, in a thin layer
between the retinal pigment epithelium and the chorioca-
pillaris known as Bruch’s membrane.42The elastic fibre
content of Bruch’s membrane has a unique maze-like
structure interwoven with collagen fibres at the side and
differing from elastin structures in the skin and blood vessels.
In PXE, Bruch’s membrane becomes calcified and brittle.
Cracks in the membrane usually occur on the eye muscle/
optic nerve head track forcing lines, so they are not caused by
calcification of Bruch’s fibres alone. Elastic fibre alterations
are responsible for acquired dehiscences and subsequent
cracks in the membrane, ophthalmoscopically resulting in
‘‘angioid streaks’’ (fig 7). Angioid streaks are greyish
irregular lines radiating outward from the optic papilla and
grossly resembling vessels, hence the name.42They are
optimally visualised using fluorescein or indocyanine green
angiograms.43 44Angioid streaks are not in most cases
responsible for visual symptoms but may be complicated by
proliferation of aberrant choroidal neovessels into the
subretinal space (fig 8). Neovessels have brittle walls, and
this may result in recurrent, spontaneous, or trauma induced
retinal haemorrhages. Neovessels and retinal haemorrhages
result in macular symptoms (metamorphopsia, scotoma),
peripapillary atrophy, disciform macular/foveal scarring, and
definitive central visual loss. Eventual blindness is not
uncommon in patients with PXE. Additional ocular features
of PXE, such as the ‘‘peau d’orange’’ appearance (diffuse
aspect of the lower lip.
Mucosal lesions of pseudoxanthoma elasticum on the inner
pseudoxanthoma elasticum. Clumped and fragmented elastic fibres in
the mid dermis (arrows). By comparison, a single spared fibre is
indicated by a star in the middle of the figure.
Optic microscopy (orcein, 640) of skin biopsy in
bodies (calcifications) in the core of the elastic fibres are indicated by an
arrow. Some calcifications result in ‘‘fractures’’ of the fibres (indicated by
Electronic microscopy (62500) of skin biopsy. Electron-dense
mottling of the fundus), drusen, and comet-like streaks, are
less specific to PXE. However, they may precede angioid
streaks for years and be helpful in the diagnosis of PXE in the
presence of atypical or early skin lesions in children.1
Visual complications are very difficult to treat and have the
greatest impact on disability and quality of life in patients
suffering from PXE. Laser therapy is used when there are
submacular neovessels. This may be effective at stopping
vessel proliferation or bleeding, but it causes retinal burns
and subsequent scotomata. Because the anatomical lesions
are reminiscent of age related macular degeneration, laser
phototherapy coupled with verteporfine infusions has been
attempted.45To date, the functional results of such treatment
remain unclear in PXE and comprehensive analysis of the
results obtained in series of treated individuals is required.
Finally, surgical procedures such as macular translocation for
subfoveal choroidal neovascularisation have occasionally
been undertaken.46The use of antiangiogenic drugs in the
prevention of choroidal neovascularisation and bleeding is in
the domain of preclinical research.
Elastic fibre-rich arterial walls are also involved in the
pathology of PXE, resulting in precocious and slowly evolving
segmental arterial narrowing. This atheromatosis is histolo-
gically indistinguishable from other causes of atheroma such
as tobacco use or chronic hypertension.47The internal elastic
laminae of small and middle sized arteries are mainly
involved. The slow course of vessel narrowing is associated
with the development of arterial collaterality. Consequently,
severe vascular symptoms are infrequent in PXE. Kornet et al
found that a thicker and more elastic carotid artery was
associated with elastin fragmentation and proteoglycan
accumulation in patients with pseudoxanthoma elasticum.48
Two types of clinical manifestations may result from
Occlusive arterial disease may be responsible for limb arteritis,
coronary artery disease, digestive angina, and cerebrovascular
disease. Absence of peripheral pulses is frequent, and should
Intermittent claudication in the lower limbs and tiredness
in the upper limbs are the most common symptoms. Angina
pectoris or silent coronary insufficiency may be present.49
Myocardial infarction is rare, but has been reported in
teenagers or young individuals.50 51Thus PXE should be
considered in young patients with precocious coronary artery
disease and no cardiovascular risk factors. Apart from rare
reports to the contrary, surgical coronary revascularisation
seems valuable. However, the left internal mammary artery
may be involved in PXE and is not suitable for bypass
grafting.52 53Ischaemic brain infarction in patients with PXE
PXEin young individuals.
is caused by small vessel disease.54This is uncommon but
more prevalent than in the general population.54In the same
recent large series,54an association between intracranial
aneurysms and PXE was ruled out. Renovascular hyperten-
sion is probably also rare: we have only seen one case in our
series of more than 60 individuals with PXE (unpublished
Mucosal bleeding may also occur as the consequence of
remains to be determined. Some investigators have proposed
that bleeding may be related to defective submucosal
vasoconstriction.4The gastrointestinal tract is by far the most
common location, but case reports appear to have over-
estimated this severe complication.36 55The precise source of
bleeding may be difficult to identify, and some haemorrhages
require radical surgery. Three patients in our series have had
a gastrectomy for haemostasis. Uterine or bladder bleeding
has also occasionally been observed.1However, it is worth
noting that there is no vascular brittleness in PXE.
Spontaneous rupture of vessel walls, as seen in the vascular
type of Ehlers–Danlos syndrome, has not been reported in
PXE. Thus vascular surgery or radiological procedures can be
carried out if indicated.
Heart involvement is uncommon in PXE. Whether valvar
diseases, such as aortic or mitral stenoses56or mitral valve
prolapse, are significantly associated with PXE remains to be
determined using stringent diagnostic criteria.57Restrictive
cardiomyopathy in relation to diffuse endocardial fibroelas-
tosis seems to be specific for PXE but is very rare.58
membrane (fluorescein angiogram).
Angioid streaks featuring radiate cracks in the Bruch’s
subretinal space shading the macula and resulting in central blindness
Proliferation of aberrant choroidal neo-vessels into the
of pseudoxanthoma elasticum
Clinical differential diagnosis of the skin lesions
PapulesAcquired pseudo-PXE related to haemoglobinopathy
Skin aging (chronological and/or actinic)
Elastoma, Buschke–Ollendorff syndrome
Pseudo-PXE related to salpeter or D-penicillamine
Elastosis perforans serpiginosa
Perforating periumbilical PXE
Ehlers–Danlos syndrome (rare)
PXE, pseudoxanthoma elasticum.
884Chassaing, Martin, Calvas, et al
Gheduzzi et al recently showed that ultrastructural alterations
in the elastic fibres were present in virtually all organs and
tissues obtained postmortem from two PXE patients.59
However, clinical manifestations only occur in tissues that
are rich in elastic fibres. The lung is a remarkable exception,
for which there is no explanation. Interestingly, calcification
may also be present on mammograms. This might be of
diagnostic value in women, and breast tumour microcalcifi-
cations are usually easily ruled out.60
Most women with PXE have normal pregnancies and
deliveries. Case reports have overemphasised the risk of
gastric bleeding during pregnancy, and it is certainly
important in order to prevent retinal haemorrhages during
labour. A recent review states that there is no basis for
advising women with PXE to avoid becoming pregnant, and
that most pregnancies in PXE are uncomplicated.61
monitoring is, however,
Positive and differential diagnosis
A classification of PXE into clinical subtypes has been
proposed previously.62Its relevance should be re-evaluated
in the light of the identification of ABCC6 as the causative
gene. Up to now, the minimum criteria for the diagnosis of
PXE have been the association of dermal elastorrhexia (with
or without clinically visible changes) with angioid streaks.
While this is most always true, we have shown in rare
patients with two identified ABCC6 mutations that one or
other criterion could be absent. This observation was
confirmed by recent investigations in two Italian families in
which one patient with two identified mutations showed
only ocular symptoms, while another had only skin involve-
ment.63Neither a positive family history nor symptomatic
atheromatosis is a constant feature of PXE, so the absence of
either does not exclude the diagnosis. ABCC6 genotyping is at
present only available in specialised centres and its value for
diagnosis remains to be determined (see below).
Dermatological differential diagnosis
Clinical and pathological recognition of skin changes
suggestive of PXE is often easy. Conditions that mimic PXE
clinically are summarised in table 1.64 65In most instances,
pathological findings rule out the diagnosis by demonstrating
increased or decreased elastic tissue without elastic fibre
fragmentation or calcification. Cutaneous and articular
hyperlaxity may occur in PXE but are less severe than in
the Ehlers–Danlos syndromes.
Ophthalmological differential diagnosis
Angioid streaks are not specific for PXE and have also been
encountered in inherited haemoglobinopathies, Marfan’s
syndrome, Ehlers–Danlos syndromes, or Paget’s disease of
bone.42An additional and not yet well classified dominant
autosomal condition has recently been described in a three
generation Italian pedigree.66In this family, affected indivi-
duals had mottled fundi, angioid streaks, and drusen in
various combinations, but no skin involvement suggestive of
PXE, and linkage to ABCC6 was excluded.
Recommendations for the care of patients with PXE
At presentthereis no
Management focuses on prevention, screening, and monitor-
ing of complications. However, standards of follow up (type
and rhythm) do not exist in PXE, and the identification of
individuals who will develop serious complications related to
PXE is difficult.
The role of diet is not clear. A single study stated that early
calcium restriction could have a positive influence on the
evolution of PXE by reducing the extent of mineralisation.67
However, this work was based on a questionable (and
unvalidated) system of severity grading and retrospective
evaluation of calcium intake, which considerably reduced the
validity of the author’s conclusions.
Sports using balls and combat sports are contraindicated,
to reduce the occurrence of facial trauma and the subsequent
development of angioid streaks or retinal haemorrhages.
Reduction of atheromatosis risk factors has been proposed:
avoidance of smoking; control of diabetes, lipid disorders,
and hypertension. Aspirin, non-steroidal anti-inflammatory
drugs, or other hypocoagulant drugs should be avoided
because of the risk of mucosal bleeding. The benefit to risk
ratio of these drugs in the presence of cardiovascular
complications is unknown in PXE, and caution is advised.
Identification of the PXE gene
PXE has previously been considered as a heritable connective
tissue disease with primary involvement of elastic fibres.
Genes encoding elastin and elastin associated proteins were
therefore functional candidate genes. Subsequently, genes
encoding elastin (located on chromosome 7)68and fibrillin 1
and 2 (respectively located on chromosomes 15 and 5)13were
excluded by linkage analysis. Furthermore, other genes
encoding members of the microfibrillar protein family and
Extra- and intracellular domains
Position of the missense mutations through the ABCC6 protein.
lysyl oxidase, an enzyme participating in crosslinking of the
elastic fibres, were also excluded.14More recently, the PXE
gene was mapped to chromosome 16p13.1 using positional
cloning approaches.69 70Further studies refined this locus to a
region of about 500 kb71 72containing five genes with no
obvious relation to the extracellular matrix of connective
tissue (ABCC1, ABCC6, pM5, and two copies of an unknown
gene subsequently identified as gene encoding the Nuclear
Pore Interacting Protein (NPIP)). Direct sequencing of these
genes identified pathogenic mutations in the ABCC6 gene.15–18
No mutations were identified in the other positional
candidate genes.16 73
The PXE gene: ABCC6
ABCC6 belongs to the subfamily C of ATP binding cassette
(ABC) genes which includes 13 members (ABCC1 to ABCC13).
ABC proteins are active pumps that can transport various
substrates—including ions, phospholipids, steroids, polysac-
charides, amino acids, and peptides—against the substrate’s
concentration gradient across membranes.74They are impli-
cated in drug and antibiotic resistance, signal transduction,
protein secretion, and antigen presentation.75
ABCC6 consists of 31 exons spanning ,73 kb. The ABCC6
mRNA, ,6 kb in size, has an open reading frame of 4.5 kb
encoding ABCC6 (multidrug resistance associated protein 6),
a 1503 amino acid protein. ABCC6 is predominantly expressed
in human liver and kidneys.21 76Low expression levels of
ABCC6 were detected in tissues involved by PXE (skin, vessel
walls, and retina), and in other tissues not affected by
PXE.15 21Two ABCC6 pseudogenes homologous to the 59 part
of ABCC6 (exon 1 through intron 9, and exon 1 through
intron 4) were recently identified and are closely mapped to
The PXE protein: ABCC6
ABCC6 is composed of three hydrophobic membrane
segments comprising five, six, and six transmembrane
spanning domains, respectively, and two evolutionarily
conserved intracellular nucleotide binding folds (NBF)
(fig 9). NBFs contain conserved Walker A and B domains,
and conserved C motif critical for ATP binding and
transmembrane transporter functions.
ABCC6 was classified as a multidrug resistance associated
protein because of its homology with MRP1. Indeed, ABCC6
and MRP1 are the most closely related members of the MRP
family, with 45% identity.21 79MRP1 is a well characterised
transmembrane efflux pump transporting amphipathic anio-
nic conjugates and glucuronidated and sulphated com-
conditions, with the MgATP dependent transport of the
glutathione S-conjugate leukotriene C(4) and S-(2, 4-
BQ123.22 24 25ABCC6 also confers low levels of resistance to
several agents, including etoposide, teniposide, doxorubicin,
and daunorubicin.24However, the role of ABCC6 in drug
resistance was questionable from the beginning.21Using
several polyclonal antibodies, ABCC6 was localised to the
basolateral side of human hepatocytes and to the basolateral
membranes of kidney proximal tubules,23 82suggesting that
ABCC6 extrudes into the blood specific substrates from liver
and kidney. However, the exact function and the physiolo-
gical metabolites actively transported by ABCC6 have not
been yet identified.
Following the recognition of ABCC6 as the defective gene in
PXE, several groups identified mutations in PXE patients. To
date 90 different disease causing mutations have been
reported (79 previously published,15 17 18 63 83–89and 11 new
ones in this study) in almost all the 31 ABCC6 exons (fig 10,
table 2). Among these, there are 49 missense mutations, 13
nonsense mutations, eight splicing mutations, three small
insertions leading to frameshift, 14 small deletions mostly
leading to a frameshift, two deletions spanning at least one
exon, and one deletion of the entire ABCC6 gene (fig 10,
table 2). Although the consequences of splicing mutations
have not been investigated, at least one third of the
mutations introduce stop codons or frameshift that lead to
premature termination of the traduction. Interestingly,
among the 49 different missense mutations in ABCC6 (42
previously published and seven new ones in the present
study), the majority (43) replace critical amino acids in
intracellular domains (seven and 19 mutations are located in
Position of the mutations in the ABCC6 gene.
886Chassaing, Martin, Calvas, et al
63, 86, 88, 90
63, 87, 88
17, 63, 88, 90
18, 63, 90
63, 78, 83
63, 84, 88
15, 17, 18, 63, 78,
85, 87, 88, 90
84, 85, 88
17, 63, 90
Small deletion 179_187del Frameshift
Pseudoxanthoma elasticum 887
NBF1 and NBF2, respectively), four are located in transmem-
brane domains, and only two mutations have been identified
in extracellular domains. Distribution of the missense
mutations through ABCC6 is indicated in fig 9. This
distribution of mutations is consistent with the role of
NBFs in ATP driven transport. Functional studies have
already shown that ABCC6 transport is abolished by missense
mutations located in the NBF2.25This distribution suggests
that intracellular domains different from NBFs are also
functionally important, possibly through recognition of the
Although most of the 90 pathogenic mutations have been
identified in one or a limited number of families, two variants
(Ex23_29del and R1141X) are recurrent mutations. The
frequency of these two recurrent mutations differs according
to the population studied: mutation Ex23_29del represents
,28% of the detected mutations in the US population and
,4% in the European population, whereas mutation R1141X
represents ,4% of the detected mutations in the US
Furthermore, frequency of the R1141X differs between
European countries (for example, 30% in the Dutch popula-
tion,91 9226% in Italian patients,63and 13% in the French
population88). A common founder effect was identified for
mutation R1141X in French and Italian populations.63 88We
found that arginine codon 518 was a recurrently mutated
amino acid in a cohort of 19 French families with PXE (11.5%
of the detected mutations for each variant R518Q and
These two mutations represent 19% of the
mutations detected in the Italian population.63In Japanese
patients, neither R1141X nor Ex23_29del mutations were
identified, whereas mutations 2542delG and Q378X account
for 53% and 25%, respectively.93In South African families of
Afrikaaners, mutation R1339C represents more than half the
mutations detected,28with a common haplotype indicating a
founder effect.27 28These mutations are rarely identified in
American or European populations.90
The detection rate in different studies varies from 0.55 to
0.83.63 87 88 90Lack of mutation detection in some patients
could reflect exonic deletions (for example, deletion of exon
15), splice site mutations distant from the coding sequence,
mutations in the gene regulatory sequences, or investigation
of patients with acquired PXE-like syndrome not related to
ABCC6 mutations, such as seen in b thalassaemia and sickling
syndromes (see below).94 95Locus heterogeneity of PXE is
unlikely, but cannot currently be ruled out.
Mode of inheritance
PXE was first described as a sporadic disorder, but both
autosomal recessive and autosomal dominant inheritances
have been reported.3In fact, no molecular evidence for
autosomal dominant inheritance has been established to
date, and a body of evidence supports a common (probably
exclusive) autosomal recessive inheritance of PXE. First, no
family with PXE transmitted through three generations has
been published. Second, both dominant and recessive forms
of PXE have been linked to the same chromosomal region
16p13.1,69and ABCC6 mutations were identified in families
described with autosomal recessive or dominant inheritance.
Moreover, no specific dominant mutation has been described,
and the same mutations have been identified in recessive and
dominant families.15Third, identification of ABCC6 mutations
established pseudodominant inheritance in two families.17 88
Finally, clinical delineation of the disease may be confusing
because limited manifestations can be detected in some
heterozygous carriers,96and because cutaneous findings
mimicking PXE, or cardiovascular manifestations, can be
found in the general population, although at an older age.97A
recent review questioning autosomal dominant PXE con-
cluded that this mode of inheritance might exist, but it would
then be marginal.98
To date, no correlation has been established between the
phenotype and the nature or the position of the muta-
tions.63 88 90A high degree of allelic heterogeneity makes such
an approach difficult. Nevertheless, homozygosity or com-
pound heterozygosity for mutations leading to a premature
stop codon is not significantly associated with a more severe
phenotype.88High intrafamilial phenotypic variation1 63 88is
suggestive of the contribution of factors other than ABCC6
genetic background to phenotype severity, such as nutrition,
hormones, lifestyle, environmental factors, or medical his-
tory.1 67 99ABCC6 independent modifying genetic factors may
also contribute to the phenotype severity.
Epidemiology and allelic frequencies
The prevalence of PXE in the general population is still
uncertain, but estimates have increased dramatically over
recent decades. A few years ago an estimated prevalence of 1
in 105births or less could be found in textbooks. This was
undoubtedly an underestimate, probably reflecting in part a
15, 87, 90
84, 85, 88, 90
Nucleotide numbers are derived from cDNA ABCC6 sequences (GenBank accession no. NM_00171.2).
CL X, cytoplasmic loop number X; COOH, C terminal portion; ECL X, extracellular loop number X; NBF X,
nucleotide binding fold number X; TS X, transmembrane segment number X.
888Chassaing, Martin, Calvas, et al
lack of knowledge of PXE by physicians. In 2000, the
American patients support group PXE International proposed
a prevalence of PXE of ,1/25 000 in New England. According
to this prevalence, the calculated frequency of heterozygosity
using the Hardy–Weinberg law is 1.25% (1/80).*
In 2002, Trip et al reported that the prevalence of the sole
R1141X mutation was significantly increased in young
individuals with coronary artery disease (3.2%), but was also
frequent in the general Dutch population.100They identified
eight heterozygous carriers for mutation R1141X among 1057
controls (0.76%). This mutation represents about one quarter
of the mutant alleles in this population.101
prevalence of heterozygous carriers in the population could
be estimated to be approximately 3% (0.76%64). This high
rate of heterozygous carriers was unexpected. This result
should be confirmed by other studies in other countries (even
if PXE is a ubiquitous condition), but it suggests that the
prevalence of PXE individuals (temporarily defined as
individuals carrying two ABCC6 mutations) is around 1/
4450, assuming this population is in Hardy–Weinberg
One critical issue is to determine whether all individuals
carrying two ABCC6 mutations have a PXE phenotype. In
France (750 000 lifeborn infants/year), with a disease
prevalence of 1 in 4450, 169 individuals carrying two ABCC6
mutations should be born each year (or 30 with a prevalence
of 1 in 25 000). However, far fewer than 1000 patients are
recognised as having PXE in France. Do the remaining
individuals have a mildly symptomatic form of PXE that does
not prompt them to seek medical advice? Do they have a total
absence of symptoms? The consequence of this observation is
that the classical PXE phenotype may only represent a small
proportion of the ABCC6 mutation carriers.
Sherer et al have reported on mild ophthalmological or
cutaneous involvement in heterozygous carriers96but they
did not indicate the frequency of this phenomenon in their
cohort of patients. A few reports have emphasised the
carriage of a sole ABCC6 mutation as a cardiovascular risk
factor.70 100 102In the study by Trip et al, mutation R1141X in
ABCC6 appeared to be an independent risk factor for coronary
heart disease in young people.100
confirmed in other similar cohorts, could be of course of
considerable concern for public health.
Because some PXE patients sometimes have only moderate
symptoms, it can be very difficult to distinguish patients with
mild PXE from heterozygous carriers with mild expression.
The course and prognosis are probably not the same for these
two categories, and this should prompt clinicians to consider
molecular diagnosis in members of pedigrees with a patient
suffering from PXE.
This observation, if
PXE mode of inheritance is probably exclusively autosomal
recessive. Risk for parents of an affected child is therefore one
in four for another pregnancy, without the possibility of
evaluating the phenotype severity. For a PXE patient the risk
of having affected children varies, in the absence of
consanguinity, with the rate of heterozygous carriage in their
population. In the light of the recent data, that risk could lie
somewhere between 1/66 (for a rate of 1/33 heterozygous
carriers (3%)) to 1/160 (for a rate of 1/80 heterozygous
carriers). This risk is significant and could explain pseudo-
dominant inheritance in some families.
Novel issues in pathophysiology and perspectives
Both elastin synthesis and degradation are accelerated in the
dermis of PXE patients compared with controls, and this
seems to correlate with age and with the extent of the
disease.8 103 104The time dependent mineralisation of elastic
fibres has been recurrently studied by several groups over the
past 20 years.6–8A critical step in the pathogenesis of PXE was
achieved when Baccarani-Contri et al revealed the mechan-
isms whereby PXE elastic fibres become calcified and
secondarily fragmented. Using immuno-electron microscopy
these investigators showed that elastic fibres had enhanced
expression of normal constitutive proteins (for example,
vitronectin), but also accumulated aberrant matrix proteins
known for their high affinity for calcium and normally
involved in mineralisation processes (such as alkaline
phosphatase, bone sialoprotein, and osteonectin).105 106The
investigators therefore stated that PXE was primarily a
disorder of the fibroblast, in accordance with their previous
results showing arguments for aberrant fibroblast behaviour.
The study by Quaglino et al showed that PXE skin fibroblasts
had altered cell–cell and cell–matrix interactions and
enhanced proliferation, with synthesis capabilities in vitro.107
Other biochemical reports are also in favour of a role of the
fibroblast in PXE, as other matrix structural alterations have
been demonstrated in addition to elastorrhexia. Aggregates
of thread material containing glycosaminoglycans, as well as
structural collagen fibril alterations, are seen in the vicinity of
elastic fibres. Abnormalities in the metabolism of glycosami-
noglycans have been found.7 108
Most of these observations were made before the identi-
fication of ABCC6 as the PXE gene, and the outstanding
question now is to find the link between the absence or the
functional insufficiency of a membrane transporter in liver
and kidney and the mineralisation of elastic fibres in distant
organs. The hypothesis that PXE is a metabolic condition
with impaired and circulating factors responsible for elastic
tissue changes has been proposed.26The metabolic hypothesis
does not exclude the possibility of local changes in clinically
involved tissues and cells.
b Globin diseases: another pathway to the
One of the most puzzling findings in the field of clinical and
basic PXE research is that patients with inherited haemoglo-
binopathies, most often b thalassaemia, but also sickling
syndromes, may have elastic tissue changes closely resem-
Indeed, the so called ‘‘PXE-like’’ clinical
syndrome consists in skin, eye, and cardiovascular symptoms
indistinguishable from those of ‘‘classic PXE’’. Notably, these
manifestations occur later in life than in patients with PXE,
and their prevalence increases with advancing age. Their
frequency is significant in patients with major or intermedi-
ate b thalassaemia: in a cohort of 100 consecutive patients, 16
had skin changes, 20 had angioid streaks, and 26 at least one
of both symptoms.109The causative defect is believed to be
acquired and related to the primary haemoglobinopathy.95
Baccarani-Contri et al showed, however, that structural
elastic changes were strictly identical to those they had
described in ‘‘classic’’ PXE.110Hence, the ‘‘PXE-like’’ pheno-
type identified in a number of cases of thalassaemia is
indistinguishable from ‘‘classic PXE’’, but with no defect in
*Hardy–Weinberg law: p2+2pq+q2=1, with p and q being the
frequency of the wild type and the mutated alleles respectively, p2the
frequency of homozygosity for the wild type allele, 2pq the frequency of
heterozygosity, and q2the frequency of the disease. Here, q2=1/
25 000, q=!(1/25 000)=0.0063; p=12q=120.0063=0.9937
Thus the frequency of heterozygous carriers (2pq) can be calculated
as 260.993760.0063 , 0.0125 (1.25%).
?Here the frequency of heterozygous carriers (2pq)=0.03 (3%). Thus,
considering p , 1, q=0.03/2=0.015, and the frequency of the disease
(q2)=0.0152, 2.2561024, 1/4450.
Pseudoxanthoma elasticum 889
the ABCC6 gene.94This raises the possibility that there is an
changes, leading to the PXE phenotype.
We thank our colleagues Drs P Bonicel, F Maı ˆtre, and B Arbeille for
ocular, optical, and electronic microscopy pictures, respectively, and
Dr O Le Saux for critically reading the manuscript.
N Chassaing*, P Calvas, A Hovnanian, Department of Medical
Genetics, INSERM U563, Purpan Hospital, Toulouse, France
L Martin*, Department of Dermatology, Porte-Madeleine Hospital,
Orle ´ans, France
M Le Bert, Team elastogenesis and metabolism, FRE 2815, CNRS
Orle ´ans, France
*NC and LM contributed equally to this paper
Competing interests: none declared
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Clinical Evidence—Call for contributors
Clinical Evidence is a regularly updated evidence-based journal available worldwide both as
a paper version and on the internet. Clinical Evidence needs to recruit a number of new
contributors. Contributors are healthcare professionals or epidemiologists with experience in
evidence-based medicine and the ability to write in a concise and structured way.
Areas for which we are currently seeking contributors:
N Pregnancy and childbirth
N Endocrine disorders
N Palliative care
N Tropical diseases
We are also looking for contributors for existing topics. For full details on what these topics
are please visit www.clinicalevidence.com/ceweb/contribute/index.jsp
However, we are always looking for others, so do not let this list discourage you.
Being a contributor involves:
N Selecting from a validated, screened search (performed by in-house Information
Specialists) epidemiologically sound studies for inclusion.
N Documenting your decisions about which studies to include on an inclusion and exclusion
form, which we keep on file.
N Writing the text to a highly structured template (about 1500-3000 words), using evidence
from the final studies chosen, within 8-10 weeks of receiving the literature search.
N Working with Clinical Evidence editors to ensure that the final text meets epidemiological
and style standards.
N Updating the text every 12 months using any new, sound evidence that becomes available.
The Clinical Evidence in-house team will conduct the searches for contributors; your task is
simply to filter out high quality studies and incorporate them in the existing text.
If you would like to become a contributor for Clinical Evidence or require more information
about what this involves please send your contact details and a copy of your CV, clearly
stating the clinical area you are interested in, to CECommissioning@bmjgroup.com.
Call for peer reviewers
Clinical Evidence also needs to recruit a number of new peer reviewers specifically with an
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reviewers are healthcare professionals or epidemiologists with experience in evidence-based
medicine. As a peer reviewer you would be asked for your views on the clinical relevance,
validity, and accessibility of specific topics within the journal, and their usefulness to the
intended audience (international generalists and healthcare professionals, possibly with
limited statistical knowledge). Topics are usually 1500-3000 words in length and we would
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throughout the year, and out turnaround time for each review is ideally 10-14 days.
If you are interested in becoming a peer reviewer for Clinical Evidence, please complete the
peer review questionnaire at www.clinicalevidence.com/ceweb/contribute/peerreviewer.jsp
892 Chassaing, Martin, Calvas, et al