ARTICLE
Auteur(s) : WK
Huh1, K Fujiwara2, H
Takahashi3, J Kanitakis4
1Department of Dermatology, Kousei General Hospital,
3-3-28 Minami Mihara-city, Hiroshima 723-8686 Japan, 2
2Department of Pathology, Kousei General Hospital,
Hiroshima
3Department of Dermatology, Asahikawa Medical College,
Asahikawa, Japan
4Department of Dermatology, Ed. Herriot Hospital, Lyon,
France
accepté le 18 Octobre 2006
Epidermal nevi often show a linear, zosteriform or segmental
distribution along Blaschko’s lines. Histologically they may be of
simple type, i.e. characterized by a simple epidermal hyperplasia,
or exhibit specific pathologic features such as epidermolytic
hyperkeratosis [1] or acantholytic dyskeratosis [2]. In the latter
case they may represent segmental forms of genodermatoses, such as
epidermolytic hyperkeratosis or Darier’s disease (DD),
respectively; the limited cutaneous expression of the disease in
these cases is due to a post-zygotic mutation affecting a limited
skin zone. Indeed, several cases of unilateral, linear or
zosteriform epidermal lesions showing the clinicopathological
features of DD are known. Starink and Woerdeman [3] advocated that,
in the case of negative family history, of childhood onset and the
absence of other features of DD in a given patient, the diagnosis
of acantholytic dyskeratotic epidermal nevus (ADEN) rather than
that of mosaic/localized form of DD should be privileged. The
molecular basis of DD was unraveled in 1999: it corresponds to
mutations in the ATP2A2 gene encoding the Sarco/Endoplasmic
Reticulum Calcium pumping ATPase type 2 (SERCA) [4-7]. We present
herein a Japanese boy with clinicopathological features of ADEN
following Blaschko’s lines, for whom the diagnosis of segmental DD
disease was considered; however, search for mutations in the ATP2A2
gene proved negative. This case further raises the issue of the
relationship between segmental DD and ADEN.
Case report
A Japanese boy was born with a pigmented eruption on the left half
of his trunk and left limbs. He was the first child born to
unrelated parents following an uneventful pregnancy. At one-month
of age, physical examination showed whorled linear brownish
verrucous papules distributed along Blaschko’s lines on the left
side of the trunk and extremities. No oral, nail, or hair
abnormalities were found. There was no family history of skin
disease and growth was normal. The patient was seen again at the
age of one year; the papular lesions were slightly more raised and
mildly pruritic (figure
1). A skin biopsy taken from a lesion of the left knee
showed a highly hyperplastic epidermis, overlaid by a thick,
compact, orthokeratotic horny layer. There was hypergranulosis and
acanthosis. The upper stratum spinosum contained occasional round
dyskeratotic keratinocytes with a condensed eosinophilic cytoplasm,
resulting in the formation of acantholytic clefts (figure 2A). Some
acatholytic/dyskeratotic keratinocytes were also seen in the inner
epithelial sheath of an underlying hair follicle (figure 2B). The dermis
contained a mild lymphocytic perivascular infiltrate. On the basis
of these clinicopathologic findings the diagnosis of type 2
segmental DD was considered. Search for ATP2A2 mutations was
performed on genomic DNA extracted from both involved and
clinically normal-looking skin and from peripheral leucocytes, as
described elsewhere [5]. Sequence analysis revealed no mutation in
the ATP2A2 gene. Treatment with local applications of vitamin D3
ointment was tried for two months but proved inefficient. An
association of local emollients and steroids to relieve itch was
subsequently advised.
Discussion
Segmental DD is an unusual form of the disease characterized by a
linear distribution of the warty papules along Blaschko’s lines
[6-9]. Blaschko’s lines were defined by Dr. Alfred Blaschko, a
dermatologist from Berlin, who drew the common linear distribution
patterns of numerous nevus cases he had seen. Blaschko’s lines are
convexly arch-shaped on the chest, S-shaped on the abdomen,
V-shaped on the central back, and a slightly curved straight line
on the extremities. They are believed to represent the lines of
migration of embryonal cells proliferating from the neural crest,
and are also adopted by abnormal (mutated) cells resulting in the
linear appearance of the lesions. Several skin diseases are
distributed along Blaschko’s lines, including various forms of
epidermal and adnexal nevi, inflammatory dermatoses (such as lichen
striatus) and genodermatoses expressed in a mosaic form (such as
epidermolytic hyperkeratosis, Ito’s hypomelanosis, Incontinentia
pigmenti, Mibelli’s porokeratosis, leiomyomas). For reasons that
remain so far unclear, some of these diseases develop after birth.
Epidermal nevi with acantholytic dyskeratosis (ADEN) may be
clinically and histologically indistinguishable from segmental
(localized, linear or zosteriform) forms of DD [2]. Accordingly, it
has been suggested that ADEN represent localized, mosaic forms of
DD [10-15]. It has also been suggested that the term “ADEN” might
be replaced by the term “segmental DD induced by post-zygotic
mosaicism”. Bergua et al [16] have proposed to group these cases
with acantholytic dyskeratosis without family history or other
manifestations of DD disease as “congenital acantholytic
dyskeratotic dermatosis”. The diagnosis of DD can definitely be
confirmed if SERCA mutations are found. However, in cases showing
mosaicism, mutations are sometimes difficult to detect, probably
because of the low percentage of keratinocytes carrying mutations
[1]; hence, failure to detect SERCA mutations in a given patient
showing segmental distribution of lesions is not sufficient to
exclude the diagnosis of DD and, more importantly, the risk of
transmission of a generalized form of DD, which depends on the
presence of germinal mosaicism for SERCA mutations and the
proportion of gametes harboring the mutation.
Two types of segmental manifestation of autosomal dominant skin
disorders exist. Type 2 represents loss of heterozygosity in a
heterozygous individual [17]. In this case, post-zygotic loss of
the wild-type allele in a heterozygous embryo gives rise to an
aberrant cell clone that has become homozygous or hemizygous. This
cell clone survives and causes a mosaic phenotype with an unusually
severe manifestation. Hence, the segmental manifestation occurs
much earlier and in a more severe form as compared with the diffuse
manifestation of the underlying heterozygous genodermatosis [8,
9].
Our patient presented as ADEN with a blaschkoid distribution and
despite the lack of family history, could correspond to type 2
segmental DD. In the absence of detectable SERCA mutation, the
evolution of lesions will hopefully allow to distinguish between
ADEN and DD. In the first event, skin lesions are expected to
remain stable throughout life, whereas, in the second event, the
patient will be expected to develop the common symmetric diffuse DD
phenotype after puberty, with the congenital lesions remaining
superimposed on the heterozygous skin. Finally, although we are not
aware of cases of genuine DD not associated with SERCA mutations,
it can be speculated that cases similar to the one reported here,
presenting with clinicopathological features similar to segmental
DD but not associated with SERCA mutations, may be due to mutations
of other, probably as yet unknown, genes, controlling the
differentiation of epidermal keratinocytes.
Acknowledgments
Financial support: none.
Conflict of interest: none.
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