ARTICLE
Auteur(s) : Thomas Hofer1, Jorge
Frank2, Peter H Itin3
1Winkelriedstrasse 10, Dermatology FMH, CH-5430
Wettingen SwitzerlandFax: (+41) 56 427 00 12.
2Department of Dermatology, University Hospital
Maastricht, P. Debyelaan 25, PO Box 5800, 6202 AZ Maastricht, The
Netherlands
3Department of Dermatology, University of Basel,
Department of Dermatology, Kantonsspital Aarau, Petersgraben 4,
CH-4031 Basel Switzerland
accepté le 1 Juin 2005
Klippel-Trenaunay syndrome (KTS) is a vascular malformation that
becomes manifest at birth and is characterized by the combination
of a nevus flammeus, varicose veins, and soft tissue swelling with
or without bone hypertrophy. The disease always presents in a
mosaic pattern with skin lesions usually being confined to one limb
and only rarely manifesting on multiple limbs. Its prevalence is
about 1 per 100,000 live births [1]. Although KTS commonly occurs
sporadically, a few cases of familial occurrence of hemangiomas
and/or vascular malformations have been reported [2-5]. Since
inheritance in all these families did not reveal a mendelian
pattern, the genetic basis of KTS still is the topic of continuous
discussion.While some authors tried to explain these observations
by a multifactorial [2] or an autosomal dominant mode of
inheritance with variable expression [4, 5], it was Happle who
proposed for the first time in 1993 the concept of paradominant
inheritance for KTS [6]. According to his theory, KTS is produced
by a single gene defect that must be lethal if present in a zygote
in the homozygous state. By contrast, individuals who are
heterozygous for the underlying genetic defect would not express
the clinical phenotype. Hence, the mutated allele would be
transmitted in an autosomal dominant fashion over generations
without overt phenotypic manifestation. Clinical symptoms of the
disease would only manifest on the basis of an additional somatic
mutation occurring in early embryogenesis leading to loss of
heterozygosity (LOH).Consequently, in affected skin regions a cell
population harbouring the mutation in the homozygous state would be
expected. According to Happle’s postulation a lethal homozygous
mutation would only be able to survive if localized in close
proximity to phenotypically normal heterozygous cells. Therefore,
involvement of the entire body with KTS would not be compatible
with life and has not been described to date.Here, we describe
monozygotic male twins discordant for KTS which thereby strongly
supports the concept of paradominant inheritance for this disease.
Case report
In November 2003, an otherwise healthy and athletic 24-year-old
monozygotic male twin presented with a vascular malformation that
was present since birth and consisted of a nevus flammeus combined
with varicose veins and a persistent embryonic lateral marginal
vein on his right leg (figures 1 and 2). Five years earlier, a
duplex-ultrasound examination1 had
revealed an aplasia of the popliteal vein and the lateral marginal
vein was assessed to be the main collecting vein of the right leg.
The patient only sought information about the vascular
malformation and declined further examination. Examination of his
identical twin brother did not reveal pathological findings.
Further, the family history (father, mother, and an older brother)
was negative for hemangiomas, vascular malformations or other
diseases. The twins were born after an uneventful pregnancy at 37
weeks of gestation and their mother denied the ingestion of
hormones or other drugs prior to or during pregnancy.
Method
For determination of zygosity and to prove monozygosity, haplotype
analysis was performed using 20 autosomal polymorphic
microsatellite markers, in detail: D1S196, D1S1677, D1S104, D1S398,
D1S1653, D1S303, D1S2140, D2S436, D8S298, D8S1786, D9S925, D9S169,
D13S141, D16S769, D16S753, D16S771, D18S69, D18S1152, D18S1144, and
D18S1155 (( figure
3 )). Fluorescently labelled forward primers were used for
PCR amplification according to conditions outlined elsewhere
(http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?db=unists). As
previously reported in detail [7], fragment length analysis was
performed on an ABI PRISM 310 Genetic Analyzer using GeneScan
software (Applied Biosystems, Foster City, CA) according to the
manufacturer’s guidelines. In brief, at each marker typed the
signal intensity of the respective haplotype-defining PCR product
was determined and the signal of all other PCR products (i.e.
stutter bands) was excluded from further analysis.
Haplotype-defining PCR products were analyzed for their length (bp)
and relative signal intensity compared to the total intensity of
haplotype-defining PCR products (excluding stutter bands), as
determined by the GeneScan software, thereby normalizing for
different total fluorescence of individual PCR reactions. The
smallest PCR product detected was designated as haplotype 1, and
all other haplotypes were designated according to the number of
additional repeats.
Discussion
It is widely accepted now that KTS is a genetic disease. Recently,
Tian et al. for the first time reported a mutation, designated
E133K, in the VG5Q gene encoding an angiogenetic factor underlying
KTS [8]. It is, however, noteworthy that in the large cohort
studied by them, only 5 out of -130 patients revealed this
mutation, indicating that the genetic basis of KTS might be more
complex and that other genes and different genetic mechanisms could
contribute to this disease.
Although a few reports on familial cases of KTS support the
assumption of heritability [2-5], the proposed inheritance patterns
such as multifactorial inheritance or autosomal dominant
inheritance with variable expression or penetrance are not
convincing explanations for the usually sporadic occurrence of KTS.
In addition, the skin lesions encountered in KTS always manifest in
a mosaic pattern, suggesting postzygotic somatic mutational events
being involved in disease pathogenesis rather than classical
Mendelian inheritance or a polygenic origin.
In support of this notion, Huq et al in 2002 [9] found evidence
for somatic mosaicism in Sturge-Weber syndrome (SWS), a vascular
malformation characterized by a facial port wine stain with
ipsilateral leptomeningeal angiomatosis. Further, Vissers et al.
[10] recently presented a case of coexisting KTS and SWS. Reviewing
the literature for this rare combination, the authors concluded
that KTS and SWS most likely represent two manifestations of one
single entity.
In an effort to explain the rare familial occurrence of sporadic
syndromes like KTS, Happle proposed the genetic concept of
paradominant inheritance [6, 11]. As a rule, individuals who are
heterozygous for a paradominantly inherited trait would be
phenotypically normal and the gene could therefore be transmitted
unperceived through many generations. The disease would only become
manifest when a somatic mutation in the corresponding wild-type
allele occurs in the developing embryo, subsequently giving rise to
LOH and a cell population being homozygous for the mutated allele.
As a consequence, the embryo would be mosaic for two genetically
and phenotypically different cell populations [12]. In support of
this theory, LOH underlying the type 2 segmental variant of
Hailey-Hailey disease has recently been demonstrated on the
cellular and molecular level [7].
Today, the concept of paradominant inheritance [13] helps to
retrospectively explain reports of a giant pigmented nevus
occurring only in one of two identical twins [14, 15] and of SWS
manifesting in one of two monozygotic female twins [16]. These
previous observations are in accordance with the case presented
herein in which a monozygotic male twin developed the full clinical
picture of KTS on his right leg while his identical twin brother
shows no signs of hemangioma or vascular malformation.
To ascertain that the two brothers are indeed identical
monozygotic twins we performed zygosity studies by haplotyping at
20 autosomal polymorphic loci and, thereby, established genotypes
for different microsatellite markers as previously described in
detail [7, 17, 18]. Based on the identical segregation of
haplotypes for all microsatellite markers examined (( figure 3 )) we assumed a
probability of monozygosity > 99:1 in the male twins studied
here [19].
Due to the fact that at the moment of initial fusion between the
paternal and maternal gametes both monozygotic twins harboured the
same genetic information, we propose that the somatic mutation,
which led to the mosaic pattern of KTS in one of them, must have
occurred after the separation into two independent embryos took
place. If, by contrast, the postzygotic somatic mutation had
occurred prior to the division of the zygote into two embryos, KTS
would have been expected to manifest in both twins, an observation
that has already been reported by Teller et al. in 1953 [20].
In conclusion, the case presented herein can hardly be explained
as the result of autosomal dominant inheritance with variable
expression or multifactorial inheritance, whereas the newly
proposed concept of paradominant inheritance delivers an excellent
model to explain uncommon patterns of inheritance in mostly
sporadically occurring human genetic disorders as KTS.
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1 Department of Angiology, University
Hospital of Zurich (Switzerland).
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