ARTICLE
Auteur(s) :, Benedikt J Folz1,*,
Burkard M Lippert1, Ana Cerra Wollstein1,
Julia Tennie1, Rudolf Happle2, Jochen A
Werner1
1Department of Otolaryngology, Head and Neck Surgery,
Philipp University of Marburg, Deutschhausstr. 3, 35037 Marburg,
Germany
2Department of Dermatology, Philipp University of
Marburg, Deutschhausstr. 9, 35037 Marburg, Germany
accepté le 17 Août 2004
Rendu-Osler-Weber syndrome or hereditary hemorrhagic telangiectasia
(HHT) is a disease of the entire vascular system. Two gene loci
have so far been identified. They are situated at 9q34.1 (HHT-1,
Endoglin ) [1] and at 12q11-q14 (HHT-2, ACVRL-1) [2]. Recently
one further locus has been recognized on 18q21.1, harbouring
mutations that cause a combined form of juvenile colonic polyposis
and HHT, the so-called JPHT syndrome [3]. Vascular lesions in HHT
may present as telangiectases, arteriovenous malformations (AVM)
and aneurysms [4]. The disorder is inherited as an autosomal
dominant trait, but about 20% of cases appear to be sporadic [5],
which either indicate incomplete pedigrees or new mutations. The
incidence of HHT varies from 1:5000 to 1:8000 [6]. Epistaxis is the
most common symptom, with 80-96% of all HHT individuals affected
[7]. Aneurysms and AVMs in parenchymatous organs may put HHT
subjects at risk for severe complications through hemorrhage,
embolism or cardiovascular failure [8]. The most obvious sign of
the disorder is telangiectases of the skin, but telangiectases are
not specific to HHT and may also be found in a variety of other
conditions. Plauchu and coworkers [7] found that 74% of their HHT
patients had developed telangiectases and about 50% of these had
appeared by the age of 30 years. Telangiectases are an
important diagnostic sign of HHT [9]. It is not entirely clear
whether telangiectases outside the nasal and gastrointestinal
mucosa harbor any clinical risk. The present study was initiated to
analyse the characteristics of telangiectases in individuals with
HHT and to evaluate their significance for the diagnosis and the
course of the disease.
Patients and methods
The study included 70 individuals with HHT. The cases were
ascertained according to at least two positive clinical diagnostic
criteria of the Scientific Advisory Board of the HHT Foundation
International. The files of these patients were reviewed for the
results of a general physical examination with regard to
telangiectases of the skin. Additionally, results of
otolaryngologic examination of the upper aerodigestive mucous
membranes were reviewed for mucosal telangiectases. All
photographic material obtained during routine photodocumentation of
the respective individuals at initial and follow-up presentations
was reviewed, including video recordings of endoscopic operations
for control of hemorrhages in the upper aerodigestive tract, mostly
for control of epistaxis. Video documentation was recorded on
digital videotape (Panasonic® DVC Pro AJ-D450,
Matsushita Electric Industrial Co., Ltd., Osaka, Japan) and was
analysed in the media laboratory with the commercial computer
software Media 100i (Media 100 Inc., Marlboro, USA). The
videotapes were evaluated by analysing stills and frames of the
video tapes with regard to location, distribution and shape of the
telangiectases. The patient group comprised 44 females and
26 males. The ages ranged from 6-91 years (mean value:
52.7 years, median: 58, standard deviation: 19.53).
Results
Sixty-eight patients (97%) had spontaneous and recurrent epistaxis,
which was the most common cause for initial presentation in the
Department of Otolaryngology. Further causes of presentation were
positive family history (5 p.), hemorrhages from the oral
cavity (2 p.) and vertigo (2 p.), caused by cerebral
arteriovenous malformations (AVMs). Sixty-three people (90%)
exhibited telangiectases of the skin and the upper mucous
membranes. The earliest onset of cutaneous telangiectases was at
the age of 6 years; four individuals stated that they had
developed telangiectases before puberty, and 30 persons
estimated that telangiectases erupted between the ages of
15 and 30. Nine people estimated that telangiectases first
appeared between 30 and 50 years of age; six people had
noted telangiectases first appearing after their 50th birthday.
Nineteen people could not indicate at which age the telangiectases
had appeared. No correlation between an early onset of
telangiectases and a more severe course of the disease with regard
to visceral vascular malformations could be found, but screening
for occult visceral vascular lesions was only performed in a small
fraction of the individuals. The majority of the people
investigated (38/70) stated that telangiectases increased in size
and number with age no change was reported by twenty-one of the
individuals and four persons had noticed a decrease of
telangiectases with advancing age. An objective assessment clearly
showed that the number of body sites involved increased with age
(Table I( Table I )). Concerning
the question whether epistaxis or telangiectases first appeared,
almost half of the patients said that telangiectases appeared the
onset of epistaxis, one third of the subjects stated that
telangiectases started before the onset of epistaxis; one fifth of
the individuals reported that telangiectases occurred
simultaneously with epistaxis. Within the nose, the distribution of
telangiectases was most pronounced in the anterior third of the
nasal cavity. Cutaneous telangiectases could be found most commonly
on the facial skin, especially the forehead, the cheeks and the
chin. The involvement on the cheeks was reminiscent of a triangle,
with the base in the infraorbital region and the acute angle in the
perioral region (( Figure 1 )).
Table II( Table II ) shows the
distribution of telangiectases in correlation to hemorrhagic
events. Telangiectases were most commonly hemorrhagic in the nose.
Treatment of the nosebleeds consisted of regular application of
lubricating ointments, Nd:YAG laser therapy, septodermoplasty,
arterial embolization or a combination of these modalities. Apart
from epistaxis, 19 patients complained about hemorrhages at
other sites than the nose (Table II). Most of these
hemorrhages were self-limiting and could be stopped by the patients
themselves. Therapeutic interventions were necessary in three
patients with hemorrhages from the tongue, four patients with
hemorrhages from the fingers or toes (( Figure 2 )) and in one
patient with prolonged episodes of bleeding from a telangiectasia
in the supraclavicular fossa.
The morphologic aspects of telangiectases showed some
variations. Scattered, pin-sizedvessels as well as elongated
vessels in a brushwood pattern were found. Large, elevated angiomas
were evident as well as confluent lakes of dysplastic vessels.
Telangiectases were either macular or papular. In most mucosal
lesions the basic component was a superficially situated vascular
loop (( Figure 3 )), and these
loops typically formed clusters.
Table I Table I shows the age-related
distribution of telangiectases with regard to involved body sites
(face, oral cavity, hands, fingers, etc.). Most individuals (almost
75%) were older than 40 years of age. The number of sites
involved increases with age
|
Age range in years
|
Number of cases
|
Average number of sites involved
|
|
0-20
|
7
|
1.4
|
|
20-40
|
11
|
2.1
|
|
40-60
|
25
|
3.5
|
|
> 60
|
27
|
4.7
|
Table II Predilection sites of telangiectases in
the investigated group. Most common areas were the nose, the oral
cavity, the face and the fingers. Telangiectases were most
frequently hemorrhagic in the nose and the oral cavity as well as
on the fingers
|
Rank
|
Site involved
|
Hemorrhagic events
|
|
1
|
Nose (endonasal mucosa), 63/70 (88%)
|
+, 63/70
|
|
2
|
Body of tongue (except base of tongue), 55/70 (77%)
|
+, 3/55
|
|
3
|
Facial skin, 53/70 (74%)
|
-
|
|
4
|
Cheeks, 42/70 (59%)
|
-
|
|
5
|
Lips, 40/70 (56%)
|
+, 5/40
|
|
6
|
Hard and soft palate, 34/70 (48%)
|
+, 1/70
|
|
7
|
Hands, 33/70 (46%)
|
+, 8/33
|
|
8
|
Nose (external skin), 27/70 (38%)
|
-
|
|
9
|
Auricle, 27/70 (38%)
|
-
|
|
10
|
Buccal mucosa, 16/70 (22%)
|
+, 1/16
|
|
11
|
Thorax, 13/70 (18%)
|
+, 1/13
|
|
12
|
Base of tongue, 8/70 (11%)
|
+, 3/8
|
|
13
|
Posterior pharyngeal wall, 7/70 (10%)
|
-
|
|
14
|
Toes, 4/70 (6%)
|
+, 1/4
|
|
15
|
Gingiva, 4/70 (6%)
|
+, 1/4
|
|
16
|
Larynx (vocal fold), 1/70 (1.4%)
|
-
|
Discussion
In the late 19th and early 20th century,
Rendu, Osler and Weber independently described a disease
characterized by recurrent nosebleeds and vascular lesions of the
skin and the mucous membranes, with a familial aggregation. This
was regarded as the classic triad of HHT for decades. Today the
spectrum of associated features has been extended by the presence
of visceral vascular malformations, especially of the lung [8, 10].
Telangiectases are multiple and found at characteristic sites like
the lips, the oral cavity, the fingers and the nose. No minimal
number of telangiectases has been indicated [9]. Haitjema and
coworkers stated that telangiectases are the hallmark of the
disease, but they are thought to appear in the third decade of life
and may be subtle and sometimes difficult to distinguish from
cherry angiomas or venectasia [11]. In recent years little has been
published on the clinical characteristics of telangiectases in HHT
patients, which is why we analysed the natural history of
telangiectases in our series of 70 cases of HHT.
Mutations in the endoglin and ALK-1 gene [1-2] have been
identified as the primary cause of HHT, but so far no
genotype-phenotype correlation can be assigned to the various
allelic mutations. It has therefore been postulated that additional
factors contribute to the development of vascular defects in HHT.
Jacobson used the term “second hit”, which is supposed to set off
the derangement of the vessels [12]. Immunologic events, clonal
variation or lineage diversity either in the endothelial cells or
in the smooth muscle cells have been postulated as explanations for
the “second hit” theory [12]. From a clinical perspective the
“second hit” theory is appealing, but other “second hits” should
likewise be considered. In the following we would like to replace
the term “second hit” by “second step”, because the term “second
hit” is generally used to describe a second mutation occurring in
somatic cells in autosomal dominant diseases, whereas the following
aspects describe epigenetic phenomena. Expression of telangiectases
tends to increase with age, although reduction of telangiectases
with advancing age has also been noted, but only in few cases.
Telangiectases were found most frequently in the nose and the oral
cavity. The fact that telangiectases in the nose become hemorrhagic
more frequently than those in the oral cavity can be explained by
differences in the density of the vasculature and in the epithelial
lining. Telangiectases are found more frequently in acral areas of
the body than on the trunk [13]. The fingers are frequently
involved and the toes to a lesser extent. In the face
telangiectases preponderantly involve the sun-exposed areas. In
other words, age and environmental factors such as mechanical
stress and exposure to sunlight should be considered as “second
steps » triggering the development of telangiectases in
HHT.
The highest prevalence of telangiectases is found in the nasal
mucosa. Haitjema and coworkers found that 68-100% of their patients
exhibited telangiectases on the mucous membranes of the nose. The
second most common location was the oral mucosa with 58-79%, and
the third place was the facial skin where 30-63% of the patients
had visible telangiectases [11]. Our findings were similar to those
of other authors. Ninety percent of our subjects had
macroscopically detectable telangiectases in the nose and 97% of
all individuals had epistaxis, but the intensity and frequency
varied from occasional bleeding to debilitating chronic
hemorrhages. Nd:YAG laser therapy has been shown to be an effective
treatment for mild to moderate epistaxis in HHT [14] especially
when combined with regular application of lubricating ointments
[15]. The more severe forms of epistaxis require a multimodal
approach [16]. Most authors agree that the appearance of cutaneous
telangiectases is preceded by recurrent epistaxis [7, 11] that may
already be noted in childhood [6]. The third decade of life has
frequently been described as typical for the occurrence of
telangiectases [7, 11], but this may not always be correct.
Telangiectases can be found in children, but usually they are
discrete and cause no symptoms other than minor cosmetic
impairment. Moreover, some telangiectases are not uncommon in
healthy children, and vascular spiders may occur spontaneously or
after trauma, and they frequently disappear without intervention
[17]. The natural course of telangiectases in children is not
known, but it is of significance to distinguish them from
telangiectases in other syndromes like hereditary benign
telangiectasia [18]. In the group investigated, two children, aged
6 and 7 years, both had telangiectases of the skin as
well as spontaneous epistaxis. Because of their family history, a
diagnosis of HHT was fairly certain. Hence, telangiectases and
epistaxis may be present, albeit in a mild form, at a rather early
age. The distribution of telangiectases among various body sites
seems to be quite stable, but it is difficult to determine a
uniform pattern. Some consistent patterns could be found, e.g., the
triangular distribution of telangiectases on the cheeks, but a
uniform type and distribution of telangiectases could not be
delineated. Recently Poblete-Gutiérrez and coworkers described a
case of unilateral facial telangiectases in an 11-year-old boy
[19]. The authors interpreted the findings as a mosaic originating
from a postzygotic mutation, thus being a type 1 segmental
manifestation of HHT. The skin has proved to be particularly
suitable for the study of mosaicism [20] that may include vascular
lesions.
Our observations concerning hemorrhages from telangiectases
outside the nose are in contrast to most of the other authors who
usually state that cutaneous telangiectases are merely a cosmetic
problem [6, 21]. Obviously such statements should be reconsidered,
because telangiectases at mucocutaneous sites other than the nose
were hemorrhagic in 27% of the present cases, although only 13%
required treatment, mostly for hemorrhages from the tongue and the
fingers. However, even if telangiectases of the skin are regarded
as a mere cosmetic problem, one should not underestimate the
influence that telangiectases may have on the quality of life of
the affected individuals, because of the stigmatisation.
Individuals with HHT should therefore be offered laser treatment
when they perceive telangiectases as undesirable [22-23].
Telangiectases of the gastrointestinal-tract become hemorrhagic
in 10-40% of the cases with a peak incidence in the 5th decade of
life [7]. This is a crucial point. Visceral AVMs can put patients
at serious risk through hemorrhages, embolism, organ failure or
secondary heart failure. There is no way to predict the behavior of
these occult lesions, which emphasizes the importance of screening
asymptomatic relatives of HHT patients. Patients with
telangiectases should be questioned in a pointed way about
epistaxis, family history and symptoms that may herald a visceral
involvement. This would allow the recognition of HHT and the
initiation of screening as well as eventual preventive therapy at
an early stage.
In conclusion telangiectases are a hallmark of HHT, although
they are not specific of this disorder. The present study shows
that telangiectases occur at an earlier age than previously
assumed, and that extranasal telangiectases may cause morbidity
rather than mere cosmetic stigmatization.
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