ARTICLE
Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized
by vesicles, erosions, hemorrhagic crusts and eczematous changes showing
an affinity for the body folds. The disorder runs a chronic course with
waxing and waning lesions. In severe cases, patients experience painful,
malodorous, and oozing lesions with secondary bacterial infection. In
advanced stages, even immobility of limbs may be caused by the axillary
or inguinal involvement [1, 2]. The phenotype usually becomes manifest
in adulthood. Overweight and sweating can be triggering factors. Histopathologically,
suprabasal clefting with marked acantholysis is noted [3]. Pronounced
acanthosis with elongation of the rete ridges is usually seen. These microscopic
changes do not affect the hair follicles and sweat glands which indicates
that these adnexal structures do not usually express the intrinsic defect
of cell adhesion [4]. Among the various proposed therapeutic approaches,
dermabrasion bears the benefit of a definite eradication with a rather
low rate of complications and convincing long-term results [5].
In 1985, one of us reported on a 5-year-old girl with unilateral manifestation
of a "relapsing linear acantholytic dermatosis" [6]. The disease exhibited
the histopathological and ultrastuctural features of severe HHD. At the
age of 24 years, the same patient presented again and asked for a therapeutic
approach.
This is a follow-up report of a case that represents a segmental manifestation
of HHD [7]. By documenting the clinical and histopathological features
of this case, we provide further evidence for the recently proposed rule
of dichotomy regarding mosaicism in autosomal dominant skin disorders
[8]. According to this hypothesis, the presented case can be characterized
as a type 2 segmental manifestation reflecting loss of heterozygosity
for the HHD mutation. We provide evidence that, unlike the heterozygous
phenotype, this mosaic type of HHD is characterized by pronounced acantholytic
involvement of adnexal structures. As a consequence, the therapeutic response
to dermabrasion was limited.
Case report
The 24-year-old woman reported a family history of ordinary Hailey-Hailey
disease involving four generations. Her mother, her grandmother and a
great-grandmother were affected. The patient's mother was examined by
us and showed typical lesions of HHD involving the axillary and submammary
regions. The proposita had shown, since the age of 3 months, relapsing
episodes of blistering and erosions arranged on the left side of her body
in a pattern following the lines of Blaschko.
On physical examination, lesions of inflammation and blistering involved
the left side of her abdomen and her back in a linear and whorled arrangement.
On the left leg and foot as well as the left palm perpendicular streaks
of involvement were present (Fig.
1). The involved areas were slightly hypopigmented and showed
multiple blisters, erosions and hemorrhagic crusts (Figs.
2, 3). In addition, the axillary regions and the groin on both
sides as well as the gluteal fold showed erythematous lesions that had
only been noted some weeks previously. Histological examination of multiple
biopsy specimens from the areas of severe involvement showed broad acanthosis
with acantholytic vesicles and bullae containing clumps of acantholytic
cells. The upper part of the dermis showed inflammatory infiltrates. The
adnexal structures were rather deeply affected by acantholysis (Fig.
4). Clinically unaffected skin from the right side of her body
showed mild acantholytic changes that spared the adnexae (Fig.
5).
As a tentative therapeutic approach, dermabrasion was performed in a
severely affected 5 x 5 cm area on the abdomen. This rectangular area
was dermabraded under local anesthesia by use of a rotating diamond fraise.
Ten weeks later, the result obtained appeared to be good, and this prompted
us to perform, under general anaesthesia, dermabrasion of all of the lesional
segmental areas.
The dermabraded areas healed within a few days. One year after the procedure,
the area appeared hypopigmented but without scarring (Fig.
6). During this follow-up period, no recurrence of blistering
was noted in these regions. The patient reported that, for the first time
in her life, she had been free of erosions and blistering for a period
longer than 6 weeks. However, another 6 months later a recurrence was
noted in the left submammary area (Fig.
7) and in the left perianal region.
Discussion
Autosomal dominant skin disorders sometimes occur in a segmental form
showing a unilateral, linear, patchy or otherwise confined involvement.
The segmental lesions often follow the lines of Blaschko and reflect cutaneous
mosaicism. On the basis of clinical evidence, two different types of mosaic
manifestation can be distinguished. In an otherwise healthy individual,
type 1 represents heterozygosity for a postzygotic mutation and the degree
of severity in the segmental area corresponds to that observed in the
nonmosaic phenotype. Type 2 reflects loss of heterozygosity and shows
a far more pronounced involvement which is superimposed on the ordinary
nonsegmental phenotype (Fig. 8).
In other words, the type 2 originates from postzygotic loss of the wild
type allele in a heterozygous embryo [8]. Genetic mechanisms that may
account for such a postzygotic mutation include mitotic recombination,
nondisjunction, deletion, or a point mutation of the corresponding wildtype
allele. A type 2 segmental involvement has been described in various genodermatoses
such as epidermolytic hyperkeratosis of Brocq, neurofibromatosis 1, Darier
disease, multiple syringomas, cutaneous leiomyomatosis, multiple glomus
tumors, and disseminated superficial actinic porokeratosis [7, 9].
So far, a type 1 segmental manifestation of Hailey-Hailey disease has
not been reported. On the other hand, a case reported in 1985 under the
title "relapsing linear acantholytic dermatosis" [6] has recently been
reclassified as a first description of type 2 segmental manifestation
of HHD [7]. The same patient is presented in this article. We emphasize
the following features that fulfill the criteria of type 2 segmental involvement.
Firstly, unilateral areas following the lines of Blaschko and showing
clinical, histopathological and ultrastructural features of HHD were noted
as early as at the age of 3 months. Secondly, this segmental involvement
is now superimposed on the ordinary phenotype that reflects heterozygosity
and is characterized by symmetrical erythema and blistering involving
the body folds, with onset in adulthood. Thirdly, several family members
are affected with the ordinary form of HHD.
Dermabrasion for the treatment of HHD, as first described by Belhaouari
et al. [10], represents an effective surgical approach. Complete
eradication has been demonstrated and excellent long-term results with
disease-free follow-up periods of more than 6 years have been documented
[5, 11]. After removal of the epidermis, regeneration occurs from the
adnexal structures that apparently do not express the intrinsic defect
of cell adhesion in the heterozygous state [4]. Our report is the first
to provide evidence that this does not hold true to the same degree for
a segmental type 2 manifestation of HHD: histopathologically, adnexal
structures are rather deeply and markedly involved by acantholysis. This
phenomenon can be taken as a hallmark reflecting the severity of involvement
caused by loss of heterozygosity. Hence it is not surprising that after
dermabrasion a recurrence may be seen especially in those areas where
a type 2 segmental manifestation reaches into the body folds. *
Article accepted on 7/2/00
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