Blood, 1 January 2002, Vol. 99, No. 1, pp. 30-35
REVIEW ARTICLE
Elastic tissue abnormalities resembling pseudoxanthoma
elasticum in 
thalassemia and the sickling syndromes
Athanasios Aessopos,
Dimitrios Farmakis, and
Dimitris Loukopoulos
From the First Department of Internal Medicine,
University of Athens, School of Medicine, "Laiko" General Hospital,
Athens, Greece.
 |
Abstract |
The development of clinical and histopathologic manifestations of a
diffuse elastic tissue defect, resembling inherited pseudoxanthoma elasticum (PXE), has been encountered with a notable frequency in
patients with 
thalassemia, sickle cell disease, and sickle thalassemia. The PXE-like clinical syndrome, consisting of skin, ocular, and vascular manifestations, has a variable severity in these
hemoglobinopathies and it is age-dependent, with a generally late
onset, after the second decade of life. The defect is believed to be
acquired rather than inherited and related to the consequences of the
primary disease. The high prevalence of the findings implicates the
elastic tissue injury as one of the main comorbid abnormalities encountered in thalassemia and the sickling syndromes. In these patients a number of complications, sometimes serious, has been recognized to be related to ocular and vascular elastic tissue defects.
Because several organ systems are involved, each medical specialty
should be aware of the phenomenon. This coexistence, on the other hand,
introduces a novel pathogenetic aspect of PXE and an important research challenge.
(Blood. 2002;99:30-35)
© 2002 by The American Society of Hematology.
| |
Introduction |
The clinical spectrum of a chronic disease is often
evolving continuously. The closer and more systematic follow-up of
patients, the significant improvement of available treatments, and the
resulting longer life expectancy lead to a gradual broadening of the
clinical picture with new, previously unknown manifestations. This is
the case for thalassemia and the sickling syndromes. Patients with these genetic disorders have manifested signs similar to those found in
another hereditary disease, pseudoxanthoma elasticum (PXE). The
frequency of this phenomenon, which has attracted the attention of
several groups of investigators, and the potential risk of PXE
complications prompted this review.
| |
PXE |
As conventionally described, PXE is a rare hereditary connective
tissue disorder, characterized by generalized degeneration of the
elastic fibers with a broad phenotypic expression.1,2 First described in 1881 by Rigal,3 its prevalence in the
general population ranges between 1/70 000 and
1/160 000.1 Although widely variable, the age of onset
averages 13 years.4 The clinical picture consists mainly
of cutaneous, ocular, and vascular manifestations; skin histopathology
involves swollen, irregularly clumped and multiply fragmented elastic
fibers in the middle and deep reticular dermis, with secondary calcium
deposition.1,2,5 The term "elastorrhexis" has also
been used, on the basis of the pathology findings, to describe such
abnormalities.2
The typical cutaneous lesions are small yellowish papules or larger
coalescent plaques with an appearance similar to plucked chicken
skin.1,2,5 More severely affected skin results in hanging,
redundant folds.4,5 In contrast, some patients have a more
subtle macular form that requires careful inspection to be
recognized.5 Skin lesions develop mainly at areas of flexion, such as the neck, axillae, antecubital and popliteal fossae,
inguinal areas, and periumbilical region.1,2,4,5 Mucous
membranes, mainly of the inner aspect of the lower lip, may be also
affected.4
Angioid streaks are the characteristic ocular manifestations, occurring
in 80% of patients with PXE (Figure
1)6,7; this combination has
been named the Gronblad-Stranderg syndrome.8,9 They are
funduscopic findings, caused by breaks of the elastic lamina of the
Bruch membrane, with secondary changes of the retinal pigment
epithelium and choriocapillaries.6 Not being apparent at
birth, angioid streaks are initially seen during the third or fourth
decade of life, usually later than the skin
manifestations5 and occasionally without the typical
cutaneous lesions.10 Although their presentation, color,
and distribution may be markedly variable, they typically appear as
single or multiple, asymmetrical, bilateral, dark red, brown, or gray
bands radiating from the optic disk.5-7
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| Figure 1.
Angioid streaks (arrows) in a patient with thalassemia (Dr Aessopos' collection).
Magnification, ×8.5.
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Vascular manifestations in PXE are caused by degeneration of the
elastic lamina of the arterial wall, often with calcium
deposition.11 The gastrointestinal, cerebral, coronary,
renal, and extremity arteries are usually
involved.1,2,5,10,12
| |
PXE-like manifestations in thalassemia and the
sickling syndromes |
The first manifestation of a potential elastic tissue defect
described in hemoglobinopathies were angioid streaks, the high frequency of which has led to a well-established relationship between
the 2 entities. Angioid streaks has been reported in sickle cell
disease (SCD) since the late 1950s.13,14 Since then,
several papers have been published, presenting a variable frequency of angioid streaks in SCD, ranging from 1% to 22%, depending on
patients' age.15-17 Angioid streaks were found to develop
in patients with SCD at the age of 25 years on average, although the
highest prevalence was reported in a group of 60 Jamaican patients
older than 40 years.16 In thalassemia, angioid streaks
were initially described in isolated cases18-20 and
subsequently, an occurrence of 20% was reported in a series of 100 patients (Figure 1).21 Being manifested after the age of
20 years, the findings were positively correlated with age also in this
group.21 Furthermore, angioid streaks have been
encountered in sickle thalassemia22 and a frequency of
10% was reported in a group of 58 cases.23
The etiology of angioid streaks in these hemoglobinopathies has not
been clarified. Angioid streaks are generally considered a
manifestation of an underlying systemic illness, even if such a
disorder cannot be identified at the time that the angioid changes are
first noted. PXE, Marfan syndrome, Ehlers-Danlos syndrome, and Paget
disease are the most common of these conditions.6,7 In a
large series of patients with angioid streaks, 50% had PXE on
diagnosis.24 The possibility of a high incidence of this diffuse connective tissue disorder in SCD was raised by the report of
the PXE syndrome in at least 7 adults with SCD.25 However, blind skin biopsies, performed in SCD patients with angioid streaks, failed to reveal any evidence of PXE.15,17 Accordingly,
angioid streaks were primarily thought to be related to the disease
itself and pathogenetic mechanisms, such as vascular obstruction
affecting the choriocapillary circulation or chronic hemolysis leading
to iron deposition were proposed.13,26 In contrast,
another autopsy series of 16 unselected SCD patients included 2 with
histopathologic findings identical to PXE in the dermis and the
arterial walls of multiple organs.14 A clearer
relationship was found by Lippman et al27 in 1985. Based
on histopathology and biochemical analysis of skin biopsies taken from
32 consequent SCD patients, these investigators concluded that SCD
appears to be associated with a wide spectrum of elastic tissue
disorders resembling PXE, although less severe than PXE.27
Subsequently, accumulated evidence from the literature has supported
the concept of an underlying, generalized elastic tissue defect in the
same hemoglobinopathies that were previously associated with angioid
streaks. In thalassemia, as a matter of fact, the presentation of a
PXE-like syndrome proved to be more obvious. The coexistence of PXE
skin and ocular findings was first reported in 2 cases28
and then systematically studied in 100 patients with thalassemia major
and thalassemia intermedia.29 In this study, 16% of the
patients had PXE cutaneous lesions (Figure
2), confirmed by skin histopathology,
20% had angioid streaks, and 26% at least one of the 2 findings. All
patients under the age of 19 years as well as 70 family members of
those with PXE findings did not show any skin or ocular
lesions.29 A more recent report focused on arterial
calcifications in 40 older thalassemic patients, mostly with
thalassemia intermedia, aged over 30 years (mean, 41.4 years).11 In this study, 55% of patients versus 15% of healthy controls, matched for sex and age (P < .001), had
calcification of the posterior tibial artery (Figure
3), 20% had typical skin lesions, 52%
had angioid streaks, and 85% had one or more of the 3 manifestations.
Hence, the complete clinical spectrum of PXE, with skin, ocular, and
vascular findings, has been encountered in thalassemia; however, it is
also clear that the occurrence of PXE manifestations is more frequent
with advancing age. Evidence that thalassemia-associated PXE is
structurally identical to inherited PXE was derived by a recent study
that compared dermal pathology between the 2 entities applying
sophisticated techniques including electron microscopy and
immunocytochemistry.30 Of interest is the fact that
subclinical disorders of the elastic tissue have been encountered even
in the first decade of life. In a surgical series of 45 unselected
patients with thalassemia major, aged between 6 and 25 years (mean,
16 years), spleen, liver, and lymph node biopsies revealed multiple
defects of arterial and stromal elastic tissue, characterized as
"elastorrhexis," that were present in an impressively high
percentage
96%.31 Only 4 of 45 patients had developed
typical PXE skin lesions, although none had angioid streaks at the time
of study.31 Similar histopathologic abnormalities were not
observed in corresponding specimens of control cases.31 It
seems that angioid streaks, cutaneous lesions, and arterial calcifications represent evolving changes of an underlying elastic tissue disorder that starts early in life in patients with thalassemia.
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| Figure 2.
Typical cutaneous manifestations of PXE on the dorsal
aspect of the cervical area in a thalassemic case (Dr Aessopos'
collection).
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| Figure 3.
Tibial artery calcification in a 58-year-old patient
with thalassemia (Dr Aessopos' collection).
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Besides SCD and thalassemia, the spectrum of hemoglobinopathies
with clinical PXE findings is broadened by a report of the PXE syndrome
in sickle thalassemia.23 Compound heterozygosity for thalassemia and sickle trait results in a clinical syndrome similar to
that of SCD. In this study, 5% of 58 patients had cutaneous lesions
typical of PXE, whereas 10% had angioid streaks, all lesions being
present after the age of 20 years.23 None of the 25 relatives of patients with angioid streaks, who were also examined, had any similar lesions.23
Sporadically, angioid streaks have been recorded in 
thalassemia
(hemoglobin H disease),26 AC hemoglobinopathy (hemoglobin C trait carrier),32 and thalassemia
minor.33,34 PXE lesions have also been found in a patient
with -
thalassemia.35 Such observations require
further investigation.
| |
Pathogenesis and genetics |
Classical PXE is characterized by marked genetic heterogeneity;
both autosomal dominant and autosomal recessive patterns of inheritance
have been reported, but most of the cases appear to be
sporadic.1,36,37 Recent studies have mapped the PXE locus to chromosome 16p13.1.38-41 The pathogenetic mutation is
believed to affect the MRP6 gene that encodes a cellular
transmembrane protein, associated with multidrug
resistance.42,43 MRP6 is a member of the ABC
(adenosine triphosphate-binding cassette) transporters superfamily and
its specific biologic function is currently known.
In thalassemia and the sickling syndromes, a genetic link with PXE
is unlikely. Family members who do not have a hemoglobinopathy fail to
show any PXE stigmata.23,29 The MRP6 gene and
previous PXE candidate genes, encoding elastin, fibrillins 1 and 2, elastin-related glycoproteins, and lysyl-oxidase, are located on
different chromosomes than the -globin gene defects that are
responsible for these hemoglobinopathies.42,44-48 In
addition, the genotypes of 30 homozygous -thalassemic patients of
Greek origin with PXE-like lesions did not differ from those of the
general -thalassemic population in Greece, indicating that such
manifestations develop independently of the -thalassemia
genotype.49 An interesting observation, however, is the
fact that the recently defined locus for PXE is located close to the
-globin gene, which is mapped to 16p13.350; nevertheless, there is no evidence for a genetic association between the 2 entities.
Regarding the existence of an acquired form of PXE, no clear data are
present in the literature. Posttraumatic, localized, cutaneous lesions,
lacking the retinal and vascular stigmata of the inherited type, have
been reported in a number of cases.51-53 In contrast, the
potentially acquired nature of a PXE syndrome encountered in a couple
of cases with chronic renal failure is strongly questioned by some
investigators.1,54,55 In thalassemia and SCD, it is
believed that the elastic tissue abnormalities are most likely
acquired, despite their clinical, structural, and cytochemical
resemblance to inherited PXE. In this context, the terms "PXE-like
lesions" and "PXE-like syndrome" were introduced to describe such
findings.11,29,31,49 The potential acquired form of the
syndrome renders it one of the primary complications of these
hemoglobinopathies and may introduce an important novel aspect in the
pathogenesis of PXE.
A number of acquired pathogenetic mechanisms for this phenomenon are
discussed in the literature. Taking into consideration the occurrence
of PXE manifestations in thalassemia and the sickling syndromes, a
rational approach would consider some of the common characteristics of
these hemolytic conditions. This concept is strengthened by the report
of angioid streaks in other hemolytic states, including inherited
spherocytosis and congenital dyserythropoietic anemia type
III.56,57 Many studies, however, failed to reveal a
statistical relationship between the elastic tissue defects and
patients' hematologic parameters. The hemoglobin or serum ferritin
levels, the number of blood units received, or the chelation history
have not so far been found to have a significant prognostic
value.11,20,29,31,49,58
It has been suggested that the elastic tissue injury in these patients
may be the result of an oxidative process, induced by the combined and
interactive effect of different factors.11 Plasma membrane
microparticles, derived from the oxidative damage of red cell membranes
by the effect of denatured hemoglobin products and free
iron,59-63 are considered to elicit inflammatory and
oxidative reactions.64 Moreover, the unbound fractions of
hemoglobin and haem, which exceed the binding capacity of haptoglobin
and hemopexin in the context of chronic hemolysis, also have powerful
oxidative properties.65 Particularly in sickling
syndromes, an excessive free radical production follows the
postocclusive tissue reperfusion.66 Moreover, iron
overload has a central role in multiple organ injury in these
hemoglobinopathies. Unbound iron catalyzes the formation of the most
toxic hydroxyl radical through the Fenton and Haber-Weiss reactions,
causing, in turn, peroxidation of membrane lipids and proteins.67 The accumulated and prolonged effect of the
above mechanisms may result in disturbance of elastin metabolism and structural deterioration of elastic fibers.68 Accordingly,
oxidative stress constitutes a potential acquired mechanism affecting
the same transmembrane proteins, which are implicated in the
pathogenesis of hereditary PXE. Indirect evidence of increased and
prolonged tissue injury in thalassemic and sickle patients includes
activation of polymorphonuclear neutrophils and monocytes and the
increased levels of neutrophil elastase and circulating
cytokines.49,64,69-72
It should be stated that of all hemoglobinopathies, thalassemia is
the most informative in terms of elastic tissue abnormalities. Extensive clinical and histologic findings have been presented in the
literature. However, it is a question whether this is due to the more
systematic study of this hemoglobinopathy or due to the greater iron
load and the more severe clinical condition of thalassemic patients.
| |
PXE-related complications |
The ocular and vascular complications of PXE may become quite
serious in the course of the disease. Angioid streaks, although usually
asymptomatic, may lead to macular degeneration and choroidal neovascularization that, in turn, can result in deterioration of visual
acuity, even blindness.4,6 The vascular complications include gastrointestinal or cerebrovascular bleeding, coronary artery
disease, hypertension, and intermittent
claudication.1,2,5,10,12 Such clinical manifestations of
diffuse arterial involvement often appear quite early, occurring even
in childhood. Furthermore, restrictive cardiomyopathy has also been
reported,73 and elastic tissue defects of the placenta
have been implicated in the development of obstetric complications seen
in women with PXE.74-79
The recognition of PXE manifestations and their complications in
patients with thalassemia or sickling syndromes may not be easy.
Both PXE and the hemoglobinopathies have a broad clinical spectrum with
multiorgan involvement. As a result, PXE-related signs could be
overlooked, obscured, or confused with the rest of the clinical
manifestations of the primary disease. PXE-related complications may be
misinterpreted or recognized only when they become quite severe. In
these hemoglobinopathies, such complications have only sporadically
been reported. Impaired visual acuity due to subretinal
neovascularization and hemorrhage has been described in 2 patients with
thalassemia major and another with thalassemia intermedia.18,21,80 Regarding the vascular involvement, it is a question whether it has a contributing role in the development of
leg ulcerations, tibial cramps, and easy bruising, features that are
frequent in thalassemic and SCD patients. In thalassemia, fatal
intracranial hemorrhages have been described in 2 patients with PXE
lesions.81 Concurrently, in SCD, the reported
cerebrovascular manifestations include not only vaso-occlusive events
but hemorrhages as well; subarachnoid hemorrhage due to ruptured
intracranial aneurysms is a recognized cause of morbidity and mortality
in adults with SCD.82,83 Interestingly, although
investigators did not correlate these events to a generalized elastic
tissue defect, pathology showed fragmentation of the internal elastic lamina of the arterial wall of the aneurysms, although aneurysms were
multiple and characterized by atypical localization.82,83
| |
Management and guidelines |
The surveillance for PXE-like disorders in a hemoglobinopathy
population is actually simple. A careful skin inspection, focusing mainly on the neck, axillae, antecubital and popliteal fossae, and
abdomen should be performed during the regular follow-up; biopsies of
skin lesions are usually required. An annual funduscopic examination by
an ophthalmologist beyond the second decade of life and a radiographic
examination of the limbs to detect arterial calcifications beyond the
third decade are also recommended.
Unfortunately, at present, no specific treatment for PXE exists. The
knowledge, however, of the potential complications may lead physicians
to take some necessary precautions. A primary concern should be the
reduction of the risk of bleeding. Medications such as platelet
inhibitors, which are often indicated in both thalassemia and SCD,
should be prescribed cautiously.84 Patients should also be
advised to refrain from activities that predispose to hemorrhage,
including heavy straining, head trauma, football, wrestling, and weight
lifting. In the presence of arterial calcifications, hemoglobin
concentration should be kept high to reduce the risk of myocardial and
peripheral ischemia. The need for maintaining high hemoglobin levels
has also been stressed regarding pregnancy in women with
hemoglobinopathies and has an additional importance in view of the
potential obstetric complications of PXE.74-79,85 A close
follow-up with funduscopy and fluorescein angiography is required in
patients with angioid streaks and laser photocoagulation should be
considered when choroidal neovascularization develops, to prevent
ocular hemorrhages and loss of visual acuity.87,88 The
reduction of dietary calcium intake has furthermore been proposed to
reduce organ calcium deposition.89-91 However, this
recommendation might be inappropriate given the frequent coexistence of
osteoporosis in patients with thalassemia and SCD.
| |
Conclusion |
The development of PXE-like elastic tissue disorders has been well
documented in SCD, thalassemia, and sickle thalassemia. The
abnormalities are most probably acquired and related to the consequences of the primary disease. In these hemoglobinopathies the
clinical syndrome appears to have variable severity and frequency and
seems milder, with a later onset, compared to inherited PXE.
The current therapy for hemoglobinopathies has significantly improved
survival and if it does not have an equally beneficial effect on
elastic tissue, more frequent PXE complications are likely to be seen
in the near future. Because these manifestations involve several body
systems, each medical specialty should be aware of this entity and its
coexistence with hemoglobin disorders. The presence of the entire
clinical spectrum of PXE has not so far been described in other
diseases. The hemoglobinopathy-associated PXE has, therefore, a
particular research interest and may contribute to the better
understanding of inherited PXE.
| |
Footnotes |
Submitted May 7, 2001; accepted August 23, 2001.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Athanasios Aessopos, First Department of Internal
Medicine, University of Athens, Medical School, "Laiko" General
Hospital, 17 Aghiou Thoma St, Athens 115 27, Greece; e-mail:
aaisopos{at}cc.uoa.gr.
| |
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Abstract
Introduction
...
