Download Progeroid Syndromes

MEDICINE
REVIEW ARTICLE
Progeroid Syndromes
Clinical Symptoms and Molecular Causes of Premature Aging
Gregor Hirschfeld, Mark Berneburg, Christine von Arnim,
Sebastian Iben, Albert C. Ludolph, Karin Scharffetter-Kochanek
SUMMARY
Introduction: Progeroid syndromes are caused by single gene mutations and comprise a group
of diseases characterized by signs of premature aging. Clinical symptoms of premature aging
are skin atrophy with loss of cutaneous elasticity, mottled pigmentation, dysfunction of cutaneous
appendices and of the central nervous system, degeneration, and an increased susceptibility for
malignant tumors. Methods: Selective literature review. Results: At a molecular level, there are
clear correlations between premature aging and impaired function of proteins involved in DNA
repair, cell cycle control, apoptosis, and gene expression. The numerous premature aging
syndromes include Xeroderma pigmentosum, Werner syndrome, ataxia telangiectasia, Cockayne
syndrome, Hutchinson Gilford syndrome, Fanconi syndrome and Bloom and Rothmund Thomson
syndrome. The understanding of these syndromes has improved significantly. They are characterized
by genomic instabilities of varying aetiologies in various different genes, and result in accelerated
aging, tumors of the skin and other organs, severe neurodegenerative symptoms, arteriosclerosis,
cachexia and impaired tumor defense by the immune system. Research on progeroid syndromes
supports the importance of the maintenance of genomic stability as an important antidote to
aging and tumor formation.
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Key words: progeria, molecular medicine, gene mutation, aging process, Hutchinson Gilford
syndrome
I
t was in 1886 that a clinical aging syndrome was first described, which began in early
childhood and ended in death at age 13–17. This illness was called progeria or Hutchinson
Gilford Syndrome. More than 75 syndromes involving symptoms of premature aging are
now recognized, known as progeroid syndromes, by analogy with progeria. Unimodal
progeroid syndromes affect a single organ, and segmental progeroid syndromes affect several
organs. The segmental progeroid syndromes have in common the simultaneous onset of
premature aging in several organs, such as skin, the skeletal system with osteoporosis and
degenerative joint disease, of the vascular system, of the metabolic system with diabetes
mellitus, noticeable atrophy of subcutaneous fat, neurodegenerative diseases, increased
incidence of various tumors, immunological senescence, increased incidence of autoimmune
diseases, and increased susceptibility to infection (1, 2).
Progeroid syndromes are characterized by mutations in the germ cell line, which affect
all organs. A given mutation has a different effect in a postmitotic organ such as the nervous
system than in mitotic tissue such as connective tissue, epithelially based organs, or the
blood. The effect depends on which DNA repair mechanism is predominant in the affected
organ. The clinical criteria for premature aging in progeroid syndromes are summarized
generally in box 1. Most recent data are available on internet databases (3–6).
In recent years, the molecular and genetic understanding of aging syndromes has
improved markedly. Cells from progeroid patients react to the slightest of DNA damaging
stimuli such as ultraviolet or ionizing radiation or high concentrations of reactive oxygen
species with cell cycle arrest, apoptosis or genomic instability. Underlying this pattern of
reactions are among other things qualitative and quantitative defects in DNA repair and
genomic stability. Research into progeroid syndromes aids the understanding of the close
interplay between DNA repair, transcription and translation processes, cell cycle control,
apoptosis and key factors in physiological aging and tumorigenesis (7–9).
Universitätsklinik für Dermatologie und Allergologie, Universitätsklinikum Ulm (Dr. med. Hirschfeld, Dr. med. Iben, Prof. Dr. med. ScharffetterKochanek); Universitäts-Hautklinik der Eberhard-Karls-Universität Tübingen (PD Dr. med. Berneburg); Universitätsklinik für Neurologie,
Rehabilitationskrankenhaus Ulm (PD Dr. med. von Armin, Prof. Dr. med. Ludolph)
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Although progeroid syndromes depart from physiological aging processes in their detail,
these disease models nevertheless provide usefully generalizable insight into aging processes.
This article offers an overview of differing aging phenotypes in progeroid syndromes.
Xeroderma pigmentosum
Xeroderma pigmentosum patients show premature aging of the skin with fibrosis, atrophy,
inhomogeneous pigmentation and increased numbers of solar lentigines (figure 1). Patients
develop spinocellular carcinomas, basal cell carcinomas, Merkel cell carcinomas, and
melanomas, in response to sun exposure, during childhood. The disease has a prevalence of
1 : 40 000 to 1 : 100 000 and is inherited in an autosomal recessive pattern. The gene loci of
the complementation groups XPA–XPG are located on chromosomes 3, 9, 11, 16, and 19.
The defects affect genes which code for nucleotide excision repair (NER) proteins (10).
Because of their UV sensitivity, these patients require thoroughgoing sun protection with
the highest protection factor. Smoking leads to bronchial carcinoma at a young age. This
disease serves as a model for disordered DNA repair, which leads both to skin aging and
mutation in genes controlling the cell cycle, and in tumor suppressor genes, and in turn to
skin cancers. This disease entity has already contributed to the better understanding of the
role of senescent or prematurely aged connective tissue in tumor progression and metastasis.
The principles of damaged nucleotide excision repair in xeroderma pigmentosum (XP) are
shown in diagram 1 (11). The complementation groups in xeroderma pigmentosum are
marked XPA to XPG, and represent mutated nucleotide excision repair proteins. In defects
of XPC, XPA or XPE, the recognition of UV damaged DNA is disrupted (diagram 1). In
defects of the helicases XPB and XPD, the DNA can no longer be separated, and the access
of endonucleases is disrupted. The smallest UV radiation doses can trigger programmed
cell death of keratinocytes and other skin cells, in xeroderma pigmentosum. This correlates
with the clinical finding of marked photosensitivity. The increase in apoptosis induction is
protective against tumors, albeit without eliminating every single malignant transformed
BOX 1
Criteria of premature aging in progeroid syndromes
> Clinical criteria
– One or more tumors which are typical in an older agegroup
– Premature greying of the hair and/or hair loss
– Dementia and/or marked neurodegenerative symptoms
– Increased susceptibility to slow virus diseases
– Pigment disorders in the skin
– Regional fibrosis in the skin
– Diabetes mellitus
– Disorders of lipid metabolism
– Changes in the volume and distribution of adipose tissue
– Hypogonadism
– Autoimmune phenomena
– Degenerative vascular disease and arterial hypertension
– Osteoporosis
– Degenerative joint changes
– Cataracts
> Genetic Criteria
– Genomic instability with increased intrinsic mutagenesis and clustering of non-constitutional
chromosomal aberrations
– The demonstration of a defect in a stem cell population or in the proliferation of stem cells
– Mitochondrial changes in one or more tissues
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Figure 1:
Clinial picture in xeroderma pigmentosum.
Solar lentigines appear in sun-exposed
areas from early childhood. Later hypo and
hyperpigmentation and the development
of skin neoplasia.
cell. DNA repair defects and immunosuppression are responsible for the 1 000 fold mortality
due to UV B dependent skin carcinomas seen in xeroderma pigmentosum, such as spinocellular carcinoma, melanoma and basal cell carcinoma, before the end of the third decade
of life.
Cockayne syndrome
Cockayne syndrome patients show progressive neurodegeneration, psychomotoric developmental
delay, failure to thrive, and increasing cachexia with dry, wrinkled and photosensitive skin.
Patients die of the sequelae of neurodegeneration with widespread demyelinization and
calcification in the cerebrum, brain stem and cerebellum during the first two decades of life.
The disease has an incidence of 1 : 250 000 and is inherited in an autosomal recessive
pattern. The disease may be based on mutations in one of two genes, which lie on chromosomes
5 and 10 respectively. The underlying cause are mutations in the multifunctional proteins
CSA and CSB, which are key components of the RNA polymerase complexes I to II.
Defects in CSA and CSB inhibit transcription-coupled repair and transcription (12). The
presence of neurodegenerative changes supports the hypothesis that metabolically active
cerebral cells accumulate DNA damage through reactive oxygen species of mitochondrial
origin, because they are inadequately repaired. DNA lesions block transcription and reduced
transcription-coupled DNA repair leads to disordered neuronal differentiation. A further
cause of neurodegeneration is the increased apoptosis of neurons through irreparable DNA
damage. The removal of genetically unstable cells prevents the development of malignant
tumors, but leads to neurodegeneration, because the level of cellular regeneration in an
actively dividing pool of cells is inadequate in the largely postmitotic neural tissue.
Around 20% of all XP patients suffer neurodegenerative change. XP patients have a ten
fold risk of neural tumors, predominantly astrocytomas, medulloblastomas and schwannomas.
Trichothiodystrophy
The clinical phenotype of this disease is variable, and the full syndrome is described with
the acronym (P)IBIDS: photosensitivity (in 50% of cases), intellectual impairment, brittle
hair (cysteine deficient, brittle, hair with longitudinal splits), decreased fertility, and short
stature. The disease is autosomal recessively inherited. The mutations, as in xeroderma
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DIAGRAM 1
Mechanism of nucleotide excision repair (NER). The first step is damage recognition, which occurs as part of transcription coupled repair (TCR).
The transcribing polymerase (RNA Pol.) stops at the site of damage and activates further repair proteins. This process takes place very quickly,
because it only takes in actively transcribing genes. The recognition of damage in the remainder of the genome (GGR, "global genome repair") is
a slower process. Here, the damage is picked up by a protein complex with the XPC protein. Both recognition mechanisms recruit the xeroderma
pigmentosum complementation group A (XPA) protein in order to verify the damage and the replication protein A (RPA) which marks the undamaged
DNA strand. It is well known that Cockayne syndrome A and B proteins are involved in TCR. The precise interaction with other proteins has not
yet been fully elucidated. During strand separation, both helicases XPB and XPD open the DNA for binding with other proteins. XPB and XPD are
components of the basal transcription factor TFIIH, which is involved in DNA repair and in basal transcription of genes. At the point of incision,
two endonucleases bind to the damaged DNA strand. The protein complex made up of excision repair complement complex (ERCC) 1 and XPF
attaches at the 5´ end and XPG at the 3´ end. This allows the damaged strand to be removed and broken down. During neosynthesis of the
missing DNA segment, the DNA is copied by a protein complex consisting of replication factors C (RFC), proliferating cell nuclear antigen (PCNA)
and polymerase delta (Pol d) by reading the complementary and non-damaged strand.
pigmentosum, are in XPB und XPD. The helicases XPB and XPD are multifunctional proteins
of nucleotide excision repair and transcription initiation: XPB und XPD are components of
the basal transcription factor IIH, which interacts with RNA polymerase II (13). XPD
mutations with disturbed and reduced transcription lead to trichothiodystrophy. An overview
of the deficiency syndromes of nucleotide excision repair can be seen in the table.
Werner syndrome
Werner syndrome is characterized by partially fibrosed, partially atrophic skin with
hyperkeratoses, changes of pigmentation, and atrophy of subcutaneous fat tissue with
traceries of veins visible through the skin. Patients have short stature and a characteristic
facial appearance with a prominent forehead (bird-like face), premature greying and hair
loss. Atherosclerosis, diabetes mellitus and osteoporosis occur early. The disease manifests
in adolescence. The diagnosis is made using primary and secondary criteria (box 2). Most
patients die in their fifth decade of cardiovascular causes or malignant tumors. Of the
malignancies, which occur in about 10% of patients, 50% are made up of bone and soft
tissue sarcomas. Werner syndrome has a worldwide prevalence of 1 : 1 000 000. Its
inheritance is autosomal recessive, and affects the Werner gene on chromosome 8. The
underlying causes are defects in the gene of the helicase WRN, a DNA separation protein
with exonuclease activity.
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TABLE
Overview of deficiency syndromes of nucleotide excision repair
Key clinical symptoms
Xeroderma
pigmentosum
Cockayne
Syndrome
Trichothiodystrophy
UV sensitivity
++
+/–
+/–
Irregular skin pigmentation
and aged skin
++
–
–
Sulphur deficient, brittle hair
and nails
–
–
+
Ichthyosis
–
–
+
Skin cancer
++
–
–
Neurodegeneration
–
++
+
Facial dysmorphia
–
+
+
Short stature
+/–
++
+
Hypogonadism
–
+
+
Gene defects
XPA bis XPG*1
CSA, CSB*2
XPB, XPD*3
*1 Complementation groups in xeroderma pigmentosum which are responsible for repair proteins with
DNA damage recognition function
*2 Cockayne syndrome A and B proteins
*3 Complementation groups in xeroderma pigmentosum which are responsible for repair proteins with
DNA helicase function
++, marked; +, significant; +/–, moderate; –, not observed
Around 90% of Werner syndrome patients have mutations in the Werner gene. The
helicase WRN is involved in various DNA repair pathways and in the stabilization of
telomeres (14). Werner syndrome has contributed importantly to the understanding of
aging processes.
In the first place, Werner syndrome points to the important role of genomic instability in
many aging symptoms. Secondly, the inability of cells to replicate (replicative senescence)
seems to have a role in observed wound healing disorders, atherosclerosis, and possibly
other symptoms too. Thirdly, connective tissue seems to be particularly vulnerable, because
it is particularly in organs rich in connective tissue that aging and the development of
malignancy is most pronounced
Bloom syndrome and Rothmund Thomson syndrome
Bloom syndrome and Rothmund Thomson syndrome are characterized by diffuse skin atrophy
with loss of elasticity and poikiloderma (mottling) with an increase in small vessels in sunexposed skin. Erythema arises from birth, at first on the face. By contrast with Werner's
syndrome, marked UV sensitivity is characteristic. Spinocellular carcinomas and basal cell
carcinomas can also occur. Some patients develop alopecia of the scalp, eyebrows and eyelids.
In Bloom syndrome leukemias, lymphomas and common gastrointestinal tumors predominate.
In Rothmund Thomson syndrome livedo reticularis-like erythematous lesions appear first
on the face, then the extremities and buttocks, with sparing of the back. Patients are UV
sensitive and develop poikiloderma, skeletal anomalies and bone tumors. The disease is rare,
with only 300 cases described in the literature. Its inheritance pattern is autosomal
recessive. The cause of Bloom syndrome lies in a defect of BLM helicase, and the cause of
Rothmund Thomson syndrome (figure 2) lies in defects in RecQL4 helicase. These defects
lead to chromosomal brittleness, the discovery of which was a breakthrough in the understanding of this disease. These diseases, too, are characterized by genomic instability and an
increased tumor risk. The variable clinical course, of the helicase defects WRN, BLM and
RTS is probably attributable to differences in tissue expression, substrate specificity, and
interaction partners.
Ataxia teleangiectasia
This disease presents between the first and third year of life, and is characterized by
cerebellar ataxia, oculocutaneous telangectasias, atrophic facial skin, sensitivity to ionizing
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BOX 2
Clinical characteristics of Werner syndrome
> Primary criteria (onset from age 10)
– Bilateral cataracts
– Dermatological manifestations:
partly fibrosed skin of skin atrophy, changes of pigmentation, ulceration, hyperkeratoses,
subcutaneous atrophy of fat tissue and characteristic facies "bird-like face"
– Short stature
– Consanguinity with parents or relatives with similar symptoms
– Premature greying and/or thinning of the hair
> Secondary criteria
– Diabetes mellitus
– Hypogonadism
(reduced fertility, testicular or ovarian atrophy)
– Osteoporosis
– Osteosclerosis of the distal phalanges of the fingers or toes on X-ray
– Calcification of soft tissue
– Indicators of premature atherosclerosis (e.g. history of myocardial infarction)
– Mesenchymal, rare or multiple tumors
– Unusual vocal range (shrill or sharp)
– Pes planus
> Reliable diagnosis
– Requires one primary and two secondary criteria to be fulfilled
> Probable diagnosis
– The first three primary criteria and two other criteria are fulfilled
> Possible diagnosis
– Either cataracts or skin signs and four other criteria
> Exclusion of diagnosis
– Onset of symptoms before age 10 (with the exception of short stature)
radiation, progressive humoral and cell-mediated immunodeficiency, hypogonadism and
an 100 fold risk of lymphoma and leukemia. Patients die at the age of around 20. Ataxia
teleangiectasia is an autosomal recessively inherited multi system disease with a prevalence of
between 1 : 40 000 and 1 : 300 000. In this disease, there is a defect of the ATM gene
(Ataxia teleangiectasia mutated) on chromosome 11. The protein kinase ATM acts as a signal
transmitter, which activates repair proteins such as p53 following DNA double strand breaks.
The molecular bases for this are summarized in an excellent review (15).
Following ionizing radiation, cells arrest the cell cycle to repair DNA. Where ATM kinase
is defective, the cell cycle continues despite the need for considerable repair. The missing
activation of the DNA repair apparatus at least partially explains the genomic instability.
Signalling by ATM kinase also appears to be important in the repair of telomeres. With the loss
of ATM function, stem cells move into replicative senescence with shortened telomeres. This
observation was important in explaining progressive neurodegenerative symptoms which
characterize ataxia teleangiectasia, as part of a generalized stem cell proliferation defect.
Hutchinson Gilford syndrome (progeria infantum)
Affected children show signs of premature and accelerated aging from their first year of life
in the form of failure to thrive with delayed dentition, diffuse alopecia, nail dystrophy,
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Figure 2: Clinical picture in Rothmund Thomson syndrome: the hand of a 19 year old patient
is shown. Only the skin in light-esposed areas appear prematurely aged, with hyper and
hypopigmentation and loss of elasticity.
scleroderma-like skin changes, loss of subcutaneous fat tissue, atherosclerosis and an
atrophic skin appearance consistent with old age. The life expectancy of progeria patients
is around 13 years, with coronary and cerebral atherosclerosis the commonest cause of
death. Hutchinson Gilford syndrome (HSG) is extremely rare, with an incidence of 1 : 4 to
1 : 8 Million. The disease arises for the most part in an autosomal dominant new mutation.
Because the patients die before reaching reproductive age, the mutation disappears from
the gene pool.
The causes of HGS are mutations in the lamin gene on chromosome 1, which leads to wrong
splicing of the RNA copy. The Lamin gene codes for four similar proteins, which arise via
differential splicing of the RNA copy. Lamin proteins, as key components of the nuclear lamina,
interact with the nuclear membrane and chromatin, and are responsible for the nuclear shape,
the nuclear pore complex and organization of chromatin, regulation of DNA replication and
Figure 3:
Patient with the
clinical phenotype of
Werner syndrome,
but without a
demonstrable WRN
helicase defect.
This combination of
findings is present in
around 10% of these
patients and
suggests that gene
products of other
mutations can interact with the WRN
protein or that other
similar DNA repair
pathways are
involved.
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Figure 4:
Young adult with Fanconi anemia and
typical clinical symptoms such as short
stature and microcephaly with normal
intelligence and poikiloderma. The
appearance of multiple invasive
spinocellular carcinomas on the lower
lip are possible effects of DNA damage
on the cell.
transcription (16, 17). In those 10% of Werner syndrome patients without a mutation of the
Werner gene, mutations in the lamin gene are common (figure 3). Phenotypic similarities
between patients with defective Werner helicase and the lamin gene raise the possibility that
the gene products interact or are involved in the regulation of the same processes.
Fanconi anemia
Signs of Fanconi anemia are short stature, skeletal anomalies and pancytopenia with
progressive aplastic anemia from the sixth to eighth year of life, and increased risk of
malignancy, often acute myeloid leukemia. The haematological symptoms are curable with
bone marrow transplantation, but the genomic instability of other cells along with
hypersensitivity to DNA attacking agents and increased risk of solid tumors, in particular
spinocellular skin cancers, remains (figure 4). Fanconi anemia has a prevalence of 1 : 300 000
and its inheritance pattern is autosomal recessive or X-linked. Twelve complementation
groups have been described on the X chromosome. These proteins form the FA protein
complex, which has an important role in DNA damage recognition and repair. The molecular
functions of the proteins of the FA complex have not been elucidated in detail. Fanconi
proteins are probably involved in the repair of DNA double strand breaks and strand cross
linkings via cisplatin and other cell cycle modulating agents (18).
The basis of genomic instability
The genomic stability of DNA is a prerequisite for the functioning of organs and the body
as a whole. In evolutionary terms, various pathways have developed for the repair of DNA
damage. Even in physiological aging, DNA damage accumulates and as yet poorly
understood aging-related signalling pathways are activated. With the help of the progeroid
syndromes, the central role of intact DNA repair in genomic stability has been clarified,
even for physiological aging. The progeroid syndromes have made evident the connection
between increased concentrations of toxic reactive oxygen species and overwhelming of
the DNA repair system, as well as with shortened telomeres and replicative senescence.
There are numerous examples which suggest that a similar connection applies in physiological
aging and in age-related diseases such as osteoporosis, arthritis, atherosclerosis, and
neurodegenerative diseases. The following explains the molecular background in brief.
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DIAGRAM 2
Possible effects of DNA damage on the cell
Disturbances of nucleotide excision repair
Genetic defects of nucleotide excision repair leads to xeroderma pigmentosum, Cockayne
syndrome or Trichothiodystrophy. The partially overlapping symptoms in these syndromes
are at least partially attributable to similar defects in the proteins involved in the multiprotein
complex of nucleotide excision repair. Nevertheless, progeroid syndromes are still
distinguishable from one another (table). In order to understand their molecular basis, the
following principles of nucleotide excision repair are under discussion .
The replication and transcription of DNA can be damaged by ultraviolet light and other
genotoxic agents. Even individual lesions in the actively transcribed DNA strand of a gene
can block transcription and in the extreme case, lead to cell apoptosis. DNA damage outside
an actively transcribing gene seldom poses an acute threat to the cell, but can in the longer
term lead to malignant transformation. The most important repair system for DNA damage
arising through ultraviolet of oxidative stress is nucleotide excision repair. The two subtypes
of the nucleotide excision repair system ensure the repair of DNA damage which leads to
disordered helix formation. Transcription-coupled repair mends DNA damage solely in
actively transcribing genes. RNA polymerase II, which attaches to the point of damage, and
which transcribes DNA into RNA recruits a repair complex involving multiple proteins at
the site of the lesion. Damage in the area of the genome which is not actively transcribing
is corrected via the global genomic repair. In this system the damage is recognized by the
XPC protein complex. Further steps of the repair process are identical between the two
subtypes of nucleotide excision repair (diagram 1).
The process of transcription-coupled repair and global genomic repair can for the sake of
simplicity be reduced to four stages:
> Damage recognition and binding of the repair complex
> DNA strand separation
> Excision of the damage over a length of around 30 molecules using endonucleases
> Replacement reaction via DNA polymerases delta and epsilon and DNA reconnection.
The process of nucleotide excision is shown graphically in diagram 1.
Activation of signalling pathways
Non-repaired or incorrectly repaired DNA double strand breaks are, e.g., the cause of
ataxia teleangiectasia.
The underlying molecular mechanisms and malfunctioning signalling pathways are
summarized in a review (19). The effects of non-repaired DNA damage are depicted in
diagram 2.
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Future perspectives
The elucidation of the progeroid syndromes and the characterization of the molecular
signalling pathways aids to the understanding of both the illnesses themselves, and the
processes of physiological aging. The recognition of the underlying mechanisms has already
been used as part of the development of experimental treatment methods. Endogenous
DNA repair after UV exposure has been supported by the use of liposomally encapsulated
DNA repair enzymes from bacteriophages or cyanobacteria, used topically. These enzymes
were able to repair DNA damage independently of nucleotide excision repair. In a multi
centre study of xeroderma pigmentosum patients, the application of these enzymes reduced
the incidence of spinocellular carcinomas. In Hutchinson Gilford syndrome, the splicing
defect of the lamin gene was able to be repaired, at least in cell culture. These initial results
suggest that treatment is possible in principle, and may lead the way to new therapeutic
interventions for progeroid syndromes.
Acknowledgment
We would like to thank our colleagues Dr. hum. biol. Matthias Kohn, Dr. med. Nicolai Treiber und Dr. rer. nat. Meinhard Wlaschek
for advice and discussion during the writing of this paper.
Conflict of Interest Statement
The authors declare no conflicts of interest in the terms of the guidance of the
International Committee of Medical Journal Editors.
Manuscript dates
Manuscript received on 7 September 2004, final version accepted on 24 August 2006.
Translated from the original German by Dr. Sandra Goldbeck-Wood.
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Corresponding author
Prof. Dr. med. Karin Scharffetter-Kochanek
Universitätsklinik für Dermatologie und Allergologie
Universitätsklinikum Ulm
Maienweg 12, 89081 Ulm, Germany
[email protected]
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