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Calciphylaxis: No therapeutic concepts for a poorly understood syndrome?

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DOI: 10.1111/j.1610-0387.2006.06127.x · Source: PubMed

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DOI: 10.1111/j.1610-0387.2006.06127.x Review Article 1037

Calciphylaxis: no therapeutic concepts for a poorly

understood syndrome?
Kalziphylaxie: keine therapeutischen Konzepte für ein wenig
verstandenes Syndrom?
Markus Meissner, Jens Gille, Roland Kaufmann
Dept. of Dermatology, Johann Wolfgang Goethe University, Frankfurt am Main

JDDG; 2006 • 4:1037–1044 Submitted: 30.5.2006 | Accepted: 14.7.2006

Keywords Summary
• calciphylaxis Calciphylaxis is a very uncommon and severe disease which mainly appears in
• ulcers patients with chronic renal insufficiency. It presents with ischemia and necrosis
• necrosis of the skin, subcutaneous adipose tissue, muscles and rarely viscera.The patho-
• calcium genetic mechanisms inducing calciphylaxis are for the most part unknown.The
• phosphate mortality rate of 80 % in the first year is very high. Patients experience marked
• sodium thiosulfate pain, recurrent infections and the constant risk of secondary sepsis. Even multi-
disciplinary therapeutic strategies are limited, although there are recent case
reports providing promising new therapeutic options including sodium thio-
sulfate and cinacalcet. This review summarizes the important aspects of diag-
nosis, pathogenesis, prevention and the possible therapeutic strategies of this
intriguing, rare and often fatal disease.

Schlüsselwörter Zusammenfassung
• Kalziphylaxie Die Kalziphylaxie ist eine sehr seltene und schwerwiegende Erkrankung, die
• Ulzera vorwiegend bei Patienten mit terminaler Niereninsuffizienz auftritt und mit
• Nekrose Ischämien und Nekrosen der Haut, des subkutanen Fettgewebes, der Muskula-
• Kalzium tur und in seltenen Fällen auch der inneren Organe einhergeht.Der pathogene-
• Phosphat tische Mechanismus der Erkrankung ist bis zum heutigen Tage noch zu großen
• Natriumthiosulfat Teilen ungeklärt. Die Mortalität der Patienten ist mit fast 80 % innerhalb des
ersten Jahres sehr hoch. Die Betroffenen leiden unter stärksten Schmerzen,
rezidivierenden Infektionen und dem ständigen Risiko einer Sepsis. Bis zum
heutigen Tage sind die multidisziplinären therapeutischen Strategien limitiert,
auch wenn neuere Fallberichte der effektiven Behandlung mittels Natriumthiosul-
fat oder Cinacalcet vielversprechende Therapieoptionen zu eröffnen scheinen.
Dieser Übersichtsartikel fasst die wichtigen Aspekte der Diagnose, Pathoge-
nese, Prävention und der möglichen Therapiestrategien dieser seltenen, aber
für die betroffenen Patienten fatalen Erkrankung zusammen.

Introduction
The first case of calciphylaxis was de-
scribed by Bryant and White in 1898
[1]. They described vascular calcification
and cutaneous necrosis in association
with renal insufficiency in a six-month-
old child. Not until 1976 did Gipstein et
al. highlight the clinical importance of
this syndrome in association with termi-
nal renal insufficiency [2].
The term calciphylaxis was originally
coined in 1962 by Selye et al. to describe
a purely experimental phenomenon ob-
served in animal models, including
nephrectomized rats. “Sensitization” was
induced using various agents such as
parathyroid hormone and cholecalciferol
and followed by exposure to agents such
as iron, albumin, glucocorticoids, or
mild physical trauma after an interval of
several days. The result was severe

© The Authors • Journal compilation © Blackwell Verlag, Berlin • JDDG • 1610-0379/2006/0412-1037 JDDG | 12˙2006 (Band 4)
1038 Review Article
inflammatory reactions, calcinosis, and
in some instances sclerosis and necrosis
involving nearly all organs including the
skin. At the time it was suggested that
the induced “anaphylactic” inflamma-
tion and subsequent calcium salt deposi-
tion were comparable to symptoms
observed in patients with terminal renal
insufficiency, giving rise to the name
“calciphylaxis” from “calcium” and “ana-
phylaxis” [3, 4]. Current understanding
of the pathogenesis of calciphylaxis has
departed from Selye's model because the
disease is primarily caused by calcifica-
tion, fibrosis, and sometimes thrombosis
of cutaneous arterioles, which only oc-
curred under certain conditions in the
rat model. The preferred term is “calcific
uremic arteriolopathy (CUA)", despite
continued widespread use of the patho-
genetically incorrect term “calciphylaxis”
in clinical practice.
Incidence and clinical manifestation
Calciphylaxis occurs in an estimated 1–4 %
of patients with terminal renal insuffi-
ciency; it is extremely uncommon in
patients with normal kidney function [5].
There are isolated reports of calciphylaxis
in patients with cancer, e.g., metastatic
breast carcinoma [6], as well as Crohn dis-
ease [7], liver cirrhosis [8] and primary hy-
perparathyroidism [9]. Despite such iso-
lated findings, calciphylaxis remains a
disorder that primarily occurs in associa-
tion with renal dysfunction and hemodial-
ysis treatment; about 35 % of patients
Figure 1: Clinical images of calciphylaxis in the region of the (a) breast, (b) interior part of the thigh,
(c) lower legs, (d) buttocks.
JDDG | 12˙2006 (Band 4)
have undergone renal transplant [10]. Ac-
cording to a study by Wilmer et al., signs
of the disorder first appear on average 19
months after starting dialysis [11]. Calci-
phylaxis affects women far more fre-
quently than men with a ratio of 3:1 (o+ :o )
median patient age is 48 years [10].
Most patients with calciphylaxis are
diagnosed on the basis of skin manifesta-
tions, involving a single or numerous
widespread lesions. The initial skin le-
sions are painful, livid erythematous
eruptions, sometimes resembling livedo
reticularis, and palpable subcutaneous
nodules (Figure 1a, b). Early, discrete
erythema can explode into severe
necrotic foci and deep, excruciatingly
painful ulcers (Figure 1 c, d). In the
course of disease gangrenous infections
frequently occur with life-threatening
agents. Sepsis can develop from infected
lesions, and despite maximum interdisci-
plinary therapy, often leads to death.
Predilection sites for calciphylaxis are the
proximal extremities, especially the
thighs, abdomen, buttocks, and breasts.
There are also reports of fatal pulmonary,
visceral, or muscular involvement in
association with calciphylaxis [12–13].
A particularly agonizing aspect of the
disorder is the excruciating pain, elicited
by the slightest touch, which cannot al-
ways be suppressed by standard anal-
gesics. In a large number of patients, suc-
cessful control was only possible with the
assistance of a competent, well-trained
pain management team.
Calciphylaxis
Histology
Histology reveals three important patho-
logical findings involving venules, arteri-
oles, and small cutaneous arteries with
an average vessel diameter of 100 µm
(30–600 µm) (Figure 2 a–c) [14].
Findings frequently include:
1. extensive intimal hyperplasia, fibro-
sis, and some vascular thrombosis
2. calcification within the media of
vessels
3. necrosis of the overlying epidermis
and sometimes surrounding dermis
and subcutaneous adipose tissue
Some histological analyses report giant
cells, especially in areas affected by calci-
fication [15]. Von Kossa staining is par-
ticularly well-suited for identification of
calcium salts and can accurately show
calcification of vessel walls.
Pathogenesis
The pathogenesis of calciphylaxis re-
mains rather unclear. Pathological calci-
fication of vessels is seen in a number of
disorders, including cardiovascular dis-
eases and terminal renal insufficiency.
The latter, in particular, appears to in-
volve both intimal and medial calcifica-
tion with subsequent intimal prolifera-
tion and fibrosis, distinguishing it from
Mönckeberg disease which involves
purely sclerotic medial changes. Never-
theless, all of these forms appear to be
caused by a variety of not necessarily
related mechanisms (Figure 3).
Mineralization inhibitors such as fetuin
[16], pyrophosphate, or matrix gla pro-
tein are normally expressed in blood ves-
sels [17]. Vascular calcification evidently
involves increased loss of these inhibitors,
resulting in increased mineralization. At
the same time, especially in calciphylaxis,
there is increased expression of bone
phosphoproteins such as osteopontin, os-
teonectin, and bone sialo protein, which
produce increased osteogenesis, i.e., vas-
cular deposition of calcium phosphate
[18, 19], which apparently is related to
the transformation of vascular smooth
muscle cells (VSMC) into osteoblast-like
cells. This process is mediated by in-
creased expression of the transcription
factor “core-binding factor -1 (Cbfa1)”
in VSMC, which is essential for osteoblast
differentiation. This mechanism appears
to be induced by increased serum levels of
phosphate and calcium (a frequent find-
ing in calciphylaxis), uremic toxins, or ox-
idized LDL [20–23].
Calciphylaxis Review Article 1039

In association with terminal renal insuf-
ficiency, and particularly with secondary
hyperparathyroidism, there is increased
bone metabolism and thus release of
bone nucleation complexes which can
form an important site of calcium crystal
formation [24].
In addition, recent findings show that
increased cell death, especially of VSMC,
contributes to increased crystallization of
calcium phosphates due to release of
apoptotic bodies or membrane debris
[25]. All of these mechanisms involve
potential processes which, although not
yet proven in detail, can occur with vas-
cular calcification as observed in calci-
phylaxis.
Hayden et al. recently proposed a further
hypothetical mechanism for the patho-
genesis of calciphylaxis. The authors sug-
gest endothelial dysfunction in conjunc-
tion with terminal renal insufficiency,
involving the uncoupling of endothelial
nitrogen monoxide synthetase (eNOS),
which has a protective function for the
endothelial cell. Endothelial dysfunction
results in increased formation of reactive
oxygen free radicals, fibrosis, thrombosis,
and possibly increased calcification [26].
The extent to which this hypothesis can
help explain the etiology of calciphylaxis
must be explored in further studies, espe-
cially using animal models.
Risk factors
A number of risk factors contributing
to the development of calciphylaxis
have been described in the literature.
Table 1 presents a summary of risk
factors. The most important of these will
be discussed in more detail in the following
sections.
Elevated serum concentrations of calcium
and phosphate
A large number of studies on calciphy-
laxis address the role of markedly ele-
vated serum levels of calcium and phos-
phate ions as well as dramatically
elevated Ca2PO43– product. Hyper-
phosphatemia is nearly universally
viewed as an important risk factor associ-
ated with calciphylaxis. In particular, its
influence on dedifferentiation into os-
teoblast-like cells and thus increased vas-
cular calcification appears to play a not
insignificant role [19, 27].
Data on calcium ion concentration are
less uniform. While some studies have
found an association, others have not.
Figure 2: Histology of calciphylaxis (a) HE
Expert opinion nonetheless tends to staining, (b) von Kossa staining, (c) von Kossa
hold that calcium ion concentration is a staining magnification 200.

Loss of inhibition of
bone formation

Dedifferentiation of
VSMC into
osteoblast-like cells

Elevated concentrations
of calcium and phosphate

Calciphylaxis

Cell death

Bone nucleation
complexes

Abnormal endothelial
nitrogen monoxide
synthetase

Figure 3: Overview of pathogenesis of calciphylaxis.

JDDG | 12˙2006 (Band 4)

1040 Review Article
contributing factor in the development
of calciphylaxis that should not be un-
derestimated. The use of calcium-con-
taining phosphate binders by patients
with terminal renal insufficiency, in par-
ticular, appears to have a considerable in-
fluence on onset and course of disease
[27, 28].
Ca2PO43–product has also been given
closer attention in conjunction with ter-
minal renal insufficiency. Block et al.
clearly demonstrated that a significant
increase in Ca2PO43–product is asso-
ciated with increased mortality from
vascular disease [29]. In calciphylaxis as
well, an association between Ca2PO43–
product and severity of disease has been
observed in a large number of cases. It
should be noted that none of the factors
mentioned above is by definition neces-
sarily associated with the onset of calci-
phylaxis, as elevated serum levels can also
be seen in the absence of calciphylaxis.
Nonetheless, these three factors should
be considered important risk factors and
treatment parameters.
Obesity and type 2 diabetes mellitus
Obesity and diabetes mellitus, especially
type 2 diabetes mellitus, which is often
associated with obesity, clearly put pa-
tients at risk for calciphylaxis; numerous
Table 1: Risk factors for calci-
phylaxis.
Main risk factors
Elevated serum calcium and
phosphate concentrations
Hyperparathyroidism
Hypoalbuminemia
Obesity
Vitamin D3 analogs
Possible risk factors
Protein C and protein S
deficiency
Phenprocoumon (coumarin)
Type 2 diabetes mellitus
Vitamin K deficiency
Hypoparathyroidism
Hypertension
Dyslipidemia
JDDG | 12˙2006 (Band 4)
authors have also shown that a high body
mass index is related to increased risk of
developing the disease [27, 30].
Summers et al. have shown that in over-
weight patients, blood flow in adipose
tissue is much poorer due to obesity than
in slender patients [31]. Because calci-
phylaxis has a predilection for sites with
more abundant subcutaneous fatty tis-
sue, obesity and related insufficient
blood supply could significantly con-
tribute to development of the disease.
Further studies must explore this seem-
ingly plausible hypothesis put forth by
Janigan et al. and others [32].
Hyperparathyroidism
Most patients with calciphylaxis have se-
vere secondary hyperparathyroidism,
typically in conjunction with existing
terminal renal insufficiency. In a study of
21 patients with calciphylaxis, Wilmer et
al. reported an average parathyroid hor-
mone (PTH) level of 440535 pg/dl
[33]. In 1976 Gipstein et al. showed for
the first time that patients with calciphy-
laxis and significantly elevated parathy-
roid hormone levels who underwent
parathyroidectomy experienced im-
proved ulcer healing [2]. In a recent
study of 15 patients, Duffy et al. showed
a significantly longer life expectancy
among patients who underwent parathy-
roidectomy [34]. Unfortunately, as is the
case with most calciphylaxis studies, this
was a retrospective analysis with a low
evidence grade. The role of hyper-
parathyroidism in developing the disease
remains controversial, although it should
not be considered alone, but in combi-
nation with other risk factors. Various
authors have also shown that hy-
poparathyroidism, involving reactive hy-
perphosphatemia, can lead to calciphy-
laxis and increased vascular damage [35].
The significance for treatment is ad-
dressed below.
Protein C and protein S deficiency
Chavel et al. recently reported that about
36 % of patients with calciphylaxis
demonstrate a protein S deficiency and
50 % a protein C deficiency. Both pro-
teins are involved in fibrinolysis and
inhibition of clotting factors V and VIII.
Thus their deficiency is related to a sig-
nificantly elevated risk of thrombosis. It
is likely that an elevated risk of thrombo-
sis presents an additional risk factor for
the development of calciphylaxis, but
Calciphylaxis
this possibility has not yet been com-
pletely elucidated [36].
Vitamin K antagonists
Studies by Price et al. have shown that the
vitamin K antagonist warfarin causes in-
creased accumulation of calcium salts in
heart valves and vessels with apparent dis-
ruption of the equilibrium between calcifi-
cation promoters and inhibitors in favor of
the promoters [37]. The underlying mech-
anism seems to involve inhibition of
-carboxylation of the calcification
inhibitor matrix gla protein (MGP), elim-
inating its effect [38]. Although still only
hypothetical, Coates et al. showed that
substituting low molecular weight heparin
for phenprocoumon therapy can lead to
significant clinical improvement [39].
Hypoalbuminemia
In patients with terminal renal insuffi-
ciency, there is convincing evidence that
atherosclerosis, similar to calcification of
heart valves, is inversely proportional to
serum albumin concentration [40].
Bleyer et al. and Mazahr et al. achieved
similar results in independent studies on
calciphylaxis. In these studies, the sever-
ity of hypoalbuminemia was signifi-
cantly correlated with the risk of devel-
oping calciphylaxis [27, 30].
Vitamin D3 analogues,
calcium-containing phosphate binders
A large number of patients with terminal
renal insufficiency take vitamin D3 ana-
logues or calcium-containing phosphate
binders to treat secondary hyperparathy-
roidism. Each of these therapies is consid-
ered a risk factor for increased vascular
calcification. On the basis of experimental
research as well as clinical observations,
Jono et al. and Goldsmith et al. both
showed increased vascular calcification in
patients with terminal renal insufficiency
who were on Vitamin D3 analogues [22,
41].
Diagnosis
There is no uniform diagnostic scheme
for calciphylaxis. The most important
criteria are clinical appearance, location,
and terminal renal insufficiency, the lat-
ter of which is nearly always present.
There are a number of crucial differential
diagnostic considerations (Table 2). The
need for a skin biopsy is controversial be-
cause of the risk of a new and extremely
painful, nonhealing ulcer at the biopsy
Calciphylaxis
site. In some cases a biopsy is neverthe-
less needed to insure a correct diagnosis
and then optimal therapy.
Laboratory tests to ascertain calcium and
phosphate concentrations, Ca2PO43–
product, or parathyroid hormone levels,
can aid in diagnosis, but are not always
abnormal. Some authors have described
the use of diagnostic measures such as
bone scans using Tc99 as a tracer; this
approach may aid in the differential di-
agnosis, but does not help specifically
confirm calciphylaxis [42].
Therapy options
Treatment options for calciphylaxis are
limited, as reflected by its mortality rate
of nearly 80 %. Clear, generally accepted
guidelines are lacking, particularly due to
the small number of cases. Treatment
requires the involvement of physicians
from multiple disciplines, including
nephrologists, pain specialists, dermatol-
ogists, surgeons, and infectious disease
specialists. The goal of treatment is to
reduce or eliminate risk factors, control
pain and prevent often fatal sepsis. Com-
monly employed treatment options are
summarized in Table 3 and the most im-
portant principles are described in more
detail.
Reducing calcium and phosphate levels as
well as Ca2PO43– product
Given the strong association between
terminal renal insufficiency and calci-
phylaxis, it is generally recommended
that the frequency of dialysis sessions be
increased. Dialysate solutions with a low
calcium content have been recom-
mended by some authors [43] with the
aim of lowering the calcium ion concen-
tration and thus Ca2PO43–product.
The target level of Ca2PO43–product
is below 55 mg2/dl2. Calcium-containing
phosphate binders should be avoided.
Non-calcium phosphate binders (e.g.,
sevelamer) should be used instead, as
long as they effectively reduce phosphate
levels. Use of vitamin D3 analog therapy
and calcium salts to treat secondary hy-
perparathyroidism should be discontin-
ued; if the patient has excessively high
parathyroid hormone levels, parathy-
roidectomy should be considered [44].
Parathyroidectomy
There are a number of reports in which
calciphylaxis with hyperparathyroidism
Review Article 1041
was treated with parathyroidectomy with
a resulting significant improvement of Table 2: Differential diagno-
symptoms and in some cases, complete sis for calciphylaxis.
healing of ulcers. Especially in patients
with extremely high levels of parathyroid
hormone, surgical management is Differential diagnoses
strongly recommended, because it can Peripheral arterial occlusive
considerably increase the long-term sur- disease
vival of the patient [34]. Velasco et al. re- Chronic venous insufficiency
cently showed that use of the calcimimetic
Coumarin necrosis
cinacalcet, which greatly increases sensi-
tivity of the calcium receptor, achieved Vasculitides of various causes
an effective decrease in parathyroid hor- Neoplastic causes
mone, calcium, and phosphate levels,
Hyperoxaluria
leading to ulcer healing in one patient
Erysipelas
with calciphylaxis [45]. Additional stud-
ies are needed to support this surprising Necrotizing Fasciitis
effect, which under some circumstances Collagenoses
may render parathyroidectomy unneces-
sary.
Wound management
Pain therapy
Wound care should be atraumatic. Ex-
Patients with calciphylaxis have intense
tensive wound debridement is strongly
pain which cannot always be controlled
discouraged, as even the slightest trauma,
with analgesics. Even the slightest touch
such as taking a biopsy can lead to mas-
elicits excruciating pain, which often
sive, new ulcerations leading to new sep-
causes considerable psychological strain.
tic foci. Careful wound cleansing is
Given the severity of pain, treatment by
preferably with enzymatic agents or hy-
an experienced pain management team is
drocolloid dressings as well as a local
advisable. As a last resort Green et al. de-
antiseptic. Trauma should especially be
scribe the use of a lumbar sympathetic
avoided in areas of the body at particular
risk for development of calciphylaxis,
such as the abdomen, thighs, and but-
tocks. This includes subcutaneous injec-
Table 3: Therapeutic options
tion of heparin or insulin, for which
for calciphylaxis.
other sites should be chosen.
Therapy options
Substituting alternative anticoagulants for
vitamin K antagonists Reduce serum concentrations
The studies by Price and Coates clearly of calcium and phosphate
show that oral anticoagulants have an Parathyroidectomy
added calcification effect on vessel walls
Increased dialysis
and that substitution of low molecular
weight heparin for other drugs leads to Avoid oral anticoagulants
significant improvement of symptoms Atraumatic wound manage-
[37, 39]. If at all possible, another anti- ment
coagulant should be substituted for Sufficient pain therapy
phenprocoumon in order to eliminate it
as a risk factor. Hyperbaric oxygen therapy
Sodium thiosulfate
Sepsis prevention Cinacalcet
The most dreaded complication of calci- Biphosphonate
phylaxis and the main cause of death is
Substitution of vitamin D3
fulminant sepsis. Close monitoring of
analogs
inflammatory parameters, vital signs,
and clinical picture are essential for early Sepsis prevention and therapy
initiation of targeted antibiotic therapy
and other intensive care measures.
JDDG | 12˙2006 (Band 4)
1042 Review Article
block to treat associated with calciphy-
laxis [46].
Prevention
Given the knowledge that a certain pa-
tient collective, i.e., overweight patients
with chronic renal insufficiency, is at risk
for developing calciphylaxis, it is key for
prevention that the physician pay special
attention to monitoring the risk factors
mentioned above. In addition to using
dialysis to control serum concentrations
of calcium and phosphate, treatment of
secondary hyperparathyroidism, and
optimal correction of diabetes mellitus, a
diet low in calcium and phosphate, as
well as weight loss are recommended.
Hyperbaric oxygen therapy (HBOT)
Nonhealing wounds have reduced oxy-
gen supply, which impairs normal heal-
ing. Cutaneous thrombosis in calciphy-
laxis leads to extensive hypoxia and
necrosis. A few case reports and smaller
case studies suggest that the use of hyper-
baric oxygen therapy in a pressure cham-
ber can lead to ulcer healing. Worsening
of patient condition and intensification
of pain have also been reported. A signif-
icant limitation of this treatment option
is the limited availability of such pressure
chambers, restricting its use to a small
number of patients [47].
Sodium thiosulfate
In the past two years a well-known agent
has found its way into calciphylaxis ther-
apy – sodium thiosulfate. Sodium thiosul-
fate has been in use for more than 70 years
as an antidote to poisoning from cyanide
and nitrogen mustard compounds. No
significant side effects have been reported
from its use as a parenteral agent. Sodium
thiosulfate has already been successfully
used to treat other diseases caused by cal-
cium salts such as urolithiasis [48] and
nephrocalcinosis [49].
Four independent case reports have been
published to date regarding successful
treatment of severe calciphylaxis with
sodium thiosulfate. After only a few
weeks all patients experienced dramatic
improvement of pain symptoms as well
as healing of large ulcers [50, 51]. The
underlying mechanisms remain uncer-
tain. It may be that the significantly
higher solubility of calcium thiosulfate
plays a role. It is also possible that
JDDG | 12˙2006 (Band 4)
sodium thiosulfate dissolves already pre-
cipitated calcium salts in the vessels.
Hayden et al. have postulated an antiox-
idative effect of sodium thiosulfate,
which potentially leads to reversal of the
endothelial dysfunction associated with
calciphylaxis. Further studies are needed
to determine the extent to which sodium
thiosulfate presents a new and successful
treatment option for calciphylaxis [26].
Future directions
In recent years, calciphylaxis has evolved
from a rather unknown and often misdi-
agnosed disorder (even today) to one of
increasing importance, especially for der-
matologists and nephrologists. Despite
advancements in the treatment of calci-
phylaxis, the disease is still associated
with a mortality rate of about 80 %. Its
rarity poses a challenge for developing
new treatment strategies, although drugs
such as cinacalcet or sodium thiosulfate
have certainly already expanded the arse-
nal of treatment options. The future will
tell whether these new drugs, in combi-
nation with current treatment strategies
and preventive measures, can effectively
reduce patient mortality. <<<
Correspondence to
Dr. M. Meissner
Dept. of Dermatology, Johann Wolfgang
Goethe University
Theodor-Stern-Kai 7
D-60590 Frankfurt am Main, Germany
Tel.: +49-69-63 01-53 43
Fax: +49-69-63 01-64 66
E-mail: meissner.markus@gmx.de
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