ARTICLE
Multiple minute digitate hyperkeratoses (MMDH) was first described by
Goldstein [1]. Since then about forty cases of this disease have been
reported in the literature, under a variety of synonyms (Table
I).
MMDH is characterized by a disturbance of keratinization of unknown
origin. Morphologically, numerous tiny, spiked, keratotic projections
may co-exist with multiple dome-shaped, keratotic papules. Frequent sites
are the upper-back, the shoulders and the chest, but other locations such
as the arms, legs and face may be involved. A localized form of this disease,
restricted to the palms and soles, was recently reviewed by Kaddu et
al. [2] and Horton et al. [3]. Histologically, focal areas
of a compact stratum corneum are observed with orthokeratosis or parakeratosis
in a follicular or non-follicular pattern. The underlying epidermis often
shows some epidermal cell hyperplasia. The dermis is without remarkable
changes. Acquired forms of this skin disorder at older ages, whether occurring
in a dissiminated or localized form, have recently been described as a
paraneoplastic syndrome [2, 4].
Two classifications for this skin disorder have been proposed. Benoldi
et al. [5] distinguished three different types of MMDH e.g.
a familial type, a sporadic non-familial type and a post-inflammatory
type after pre-existing inflammatory skin diseases. Zarour et al.
[6] introduced a classification for the so-called filiform hyperkeratoses
merely based on distribution patterns and histopathological features.
McGovern and Gentry [7] modified this classification and separated MMDH
from porokeratosis.
We reviewed the literature, and concluded that these classifications
did not cover the whole spectrum of the clinical and pathogenetic aspects
of MMDH. We propose a new classification for this skin disorder.
Case reports
Case 1: A 54-year-old Caucasian woman presented with multiple keratotic
projections measuring 1 to 2 mm in length over the shoulders, chest, the
linea alba and behind both knees (Fig.
1). Numerous dome shaped small keratotic papules were present
on the back (Fig. 2).
The lesions were arranged in a non-follicular configuration. They had
gradually developed over the past eight years, shortly before mastectomy
followed by radiotherapy because of a ductal carcinoma of the right breast.
On regular follow-up, no signs of dissemination of the breast cancer were
observed. The general health was otherwise good. There was no history
of a long term use of medication either locally or systemically, no history
of abundant sun exposure. The family history was negative.
A biopsy of a digitate lesion showed a non-follicular filiform orthokeratotic
projection from a normal epidermis. The dermis was without remarkable
changes (Fig. 3).
Histological examination of the dome-shaped papules revealed focal areas
of a compact broadened orthokeratotic stratum corneum (Fig.
4). The epidermis was normal except for slight acanthosis. In
the upper dermis a mild perivascular lymphocytic infiltrate was observed.
The results of a hemogram, blood chemistry studies and chest X-ray were
unremarkable. Despite a complete remission of her malignancy, no remission
of her skin lesions could be observed.
Treatment of the skin disorder with keratolytica, urea and tretinoin-containing
creams was unsuccessful, so she abstained from further therapy.
Case 2: A 39-year-old Caucasian man, presented with multiple small filiform
keratotic horns in a follicular pattern over the chest, shoulders, upper
arms, back and the tip of the nose that developed shortly after some degree
of sunburn. They measured 1 to 2 mm in length (Fig.
5). The patient enjoyed a good general health. The family history
was non contributory. Histological examination revealed a dilated hair
follicle with fingerlike orthokeratotic horny plugging. The adjacent epidermis
showed focal dyskeratosis with grains and corps ronds (Fig.
6). In the upper dermis a mild perivascular lymphocytic infiltrate
was present. With direct immunofluorescence no deposits of immunoglobulins
or complement factors were observed neither within the epidermis, the
epidermal junction nor in the dermal vessel walls. The results of hemogram
and blood chemistry studies were all within normal limits. A complete
remission was achieved after a period of four months, without the need
for any topical or systemic treatment.
Discussion
In 1967 Goldstein described a peculiar disturbance of keratinization
which he entitled multiple minute digitate hyperkeratoses (MMDH) [1].
Since then this disorder has been described in the literature under
a variety of synonyms leading to confusion in separating this disorder
from other disorders of keratinization (Table
I). Typical for MMDH are multiple small keratotic spiky protuberances
of normal skin colour, 1-2 mm in length and 0.5-2 mm in diameter, which
may occur in a follicular or non follicular fashion. The favoured sites
are the chest, shoulders, upper arms, thighs and popliteal fossae. These
spiky projections were repeatedly described in the literature as like
the spines of an old fashioned music box cylinder [7-9]. They may co-exist
with flat-topped or dome-shaped keratotic papules especially situated
across the central and upper back as we observed in our female patient
[10-11]. These papules are also described as occurring in a crateriform
as well as in a linear or annular aggregated distribution pattern [10].
Besides this disseminated wide-spread form of MMDH, sparing the palms
and soles, a localized form is recognized with special preference for
the palms and soles [2, 12-15].
The co-existence of lesions in a wide spreading pattern including the
palms and soles, has been reported [16].
We noticed a slightly increased tendency for males to be affected. For
the disseminated form of MMDH a male/female ratio of 1.3:1 was calculated.
The male/female ratio for the localized form, affecting palms and soles,
was 3:2.
MMDH has been described in Caucasians and Blacks. One paper however,
reported the occurrence of lesions on the palms and soles quite similar
to MMDH in seven male patients from three generations of a Saudi family
[17].
MMDH can be divided in an early- and late onset
form. The early onset form occurs in the second and third decade, the
late onset form prefers the fourth and fifth decade. Its distribution
can be wide-spread or localized on the palms and soles. The early onset
form was described as frequently occurring in several members of one family.
An autosomal dominant trait equally affecting the male and female members
of the family, whether MMDH presented as disseminated or localized, has
been reported [10, 11, 18-21]. To our knowledge only two papers reported
a familial incidence in the late onset form of MMDH [6, 22]. Most papers
however, reported MMDH as an incidentally occurring disease without any
history of inheritance.
Typical for MMDH is a pattern of focal hyperkeratoses arising from a
finely pointed epidermal elevation or from the follicular infundiblum.
The dense compact thin spike of keratosis might be of the orthokeratotic
or parakerotic type [2, 4]. Under this horny spike the epithelium showed
mild acanthosis of the malpighian layer and some elongation of the rete
ridges. The stratum granulosum appeared normal or slightly diminished
in thickness. In the papillary dermis no significant abnormalities were
observed. A mild perivascular lymphocytic infiltrate was observed in the
upper dermis.
The morphologically more flat-topped or dome-shaped keratotic papules
revealed focal areas of a compact broadened stratum corneum extending
over the space of four to six epidermal ridges with mild acanthosis of
the malpighian layer (Fig. 4).
With electron microscopy, most obvious abnormalities were established
at the level of the stratum corneum and granular cell layers [8, 11, 18,
23]. The stratum corneum was described as thickened, compact and composed
of many layers of orthokeratotic cells. In the granular layers the keratohyalin
granules were normal or reduced in number and smaller in size. In all
papers Odland bodies were described as normally present and appeared structurally
unaltered.
The keratinocytes in the lower part of the epidermis and the cells of
the basement membrane area were normal in aspect.
The pathogenesis of MMDH is unknown. Apart from inheritance, especially
in the carly onset form, malignant and non malignant disorders are described
as associated with MMDH, especially in the late onset form. Table
II summarizes these possibly pathogenetic features in association
with MMDH. The association of MMDH with multiple myeloma is of peculiar
interest. A close relation between the activity of multiple myeloma and
the activity of MMDH has been repeatedly described [24-27]. Besides, in
the presence of cryoglobulin, MMDH was predominantly present on cold exposed
skin areas [24, 28, 29]. Monoclonal immunoglobulin could be detected in
the areas of the epidermal plug and basement membrane zone. It was hypothesized
that the presence of dysprotein modified the keratinization process [4].
Recently a patient has been described without any evidence of multiple
myeloma or dysproteinemia, identical to patients with MMDH and multiple
myeloma [30].
Other malignancies reported in association with MMDH are bronchial carcinoma
[31], carcinoma of the larynx [32], renal cancer [13], intestinal cancer
[33, 34], melanoma [2] and lymphoma [35]. Our patient (case No. 1) is
the first case described in the literature with a widespread form of MMDH
in association but not necessarely related to breast cancer.
Of the non malignant disorders, physical features like skin exposure
to radiotherapy [36-38] and actinic irradiation [39], following inflammatory
skin-diseases [40], systemic diseases [41, 42], intestinal disease [43],
genodermatoses [6, 44, 45], and the use of several drugs [3, 46, 47] are
reported as associated with MMDH. A complete remission of MMDH was observed
after zinc therapy in a patient with zinc deficiency [48].
Except for multiple myeloma, the association between MMDH and malignancy
was not always reliably decribed.
The same holds true for the non-malignant features
in association with MMDH. Of these however, the occurrence of MMDH after
radiotherapy restricted to the exposed skin areas, was rather suggestive.
Hashimoto and Toi [49] demonstrated in so-called spiny keratoderma of
the palms and soles a similarity between the keratin of the spinal column
and hair keratin by monoclonal antibody analysis. Three of the six patients
examined used simvastatine, a HMG CoA reductase inhibitor. Simvastatine
was known to induce hyperplasia of the epidermis in hairless mice and
it was suggested that spiny keratoderma represents an ectopic hair formation.
MMDH should be differentiated from other disorders of keratinization,
especially porokeratoses. Most confusion in the literature was based on
the histological similarity between the vertical ortho- or parakeratotic
column and the cornoid lamella in porokeratosis. We presume that porokeratosis
is a different entity with distinct clinical and histological features
well described in the dermatological standard text books. The keratotic
spikes described as "music box spine" [7], so typical for MMDH, are not
observed in any of the different morphological forms of porokeratosis.
Moreover, the histological features of porokeratosis with the typical
epidermal changes immediately below the porokeratotic column, such as
dyskeratosis, keratinocytes with shrunken nuclei, premature keratinization
of the malpignian cells and spongiosis are not observed in MMDH. A good
illustration of the confusion in the literature was the dermatosis described
by Osman et al. [9] under the name "spiny keratoderma of the palms
and soles". Although the clinical, histological and electron microscopical
features showed a fairly good agreement with a localized form of late
onset MMDH it was concluded that this type of dermatosis was in fact a
variant of porokeratosis.
In the classification of Zarour et al. [6] the so-called filiform
hyperkeratoses are classified in three groups on the basis of the topography
and the histology of the lesions.
Depending whether the keratotic column showed parakeratosis or orthokeratosis
they were named filiform hyperkeratoses of the porokeratotic type or orthokeratotic
type. We agree with Kaddu et al. [2], and McGovern and Gentry [7],
who reported that filiform hyperkeratosis should be differentiated from
the spectrum of porokeratosis especially based on the different histological
features between the two disorders of keratinization. Benoldi et al.
[5] subdivided MMDH into three different types, namely a familial type,
a sporadic type and a post-inflammatory type. However, this classification
did not cover the whole clinical spectrum of MMDH. Itin et al.
[16] recently reported a familial type of porokeratosis, plantaris palmaris
et dissiminata apart from MMDH in one of the family members. Apart from
porokeratosis, MMDH has to be differentiated from hystrix-like keratosis
[50], keratosis pilaris, pityriasis rubra pilaris, Kyrle's disease, lichen
spinulosis, phrynoderma and hyperkeratosis lenticularis perstans (Flegel's
disease) which, according to their clinical and histological features,
are easily distinguished.
MMDH is a chronic persisting disorder of keratinization and spontaneous
remissions are exceptional. Cox and Ince reported two patients with dissiminated
transient post-inflammatory digitate lesions resolving within one month
with no recurrence [40]. Also in our second patient, the lesions resolved
spontaneously after a transient inflammatory period due to sunburn. Wilkinson
et al. [51] described a spontaneous remission of MMDH in an otherwise
healthy person, without any preceeding illness.
Of the advocated therapeutic modalities mentioned for topical treatment,
keratolytic agents like urea, salicylic acid and vitamin A acid in fatty
emollients were in favour. Two papers reported good results after regular
applications of tretinoin 0.05% cream [52] and the topical use of 5-fluorouracil
[9]. The use of etretinate was reported in one case as successful [53],
in other cases it resulted in partial improvement [4].
In general however, the patient has to learn to live with this disorder
of keratinization.
We concluded that MMDH meets enough characteristics to designate this
disorder as a separate entity. We advocate the name multiple minute digitate
hyperkeratoses as originally proposed by Goldstein in 1967 [1]. It gives
an adequate description which covers completely the morphological hallmarks
of this peculiar disorder of keratinization. We propose that for a proper
classification of MMDH any association with porokeratosis should be avoided.
We suggest MMDH of early onset and late onset. The early onset form might
be inherited, the late onset form might act as the presenting sign of
a malignant or non-malignant concomitant disorder.
The characteristics of this classification are summarized in Table
III.
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