ARTICLE
Introduction
Mosaic manifestations are sometimes observed in autosomal dominant skin
disorders. Such segmental involvement may show an asymmetrical, patchy,
band-like or otherwise confined arrangement, often following the lines
of Blaschko. Two different types of segmental manifestation have been
delineated, both of which derive from an early postzygotic mutation. Type
1 involvement reflects heterozygosity for the underlying mutation. In
an otherwise healthy individual the segmental lesions show the same degree
of severity as observed in the ordinary nonmosaic trait. By contrast,
type 2 manifestation reflects loss of heterozygosity (LOH) and shows a
far more pronounced involvement which is superimposed on the ordinary
nonsegmental phenotype. This phenomenon can be best explained by early
postzygotic loss of the wild-type allele in a heterozygous embryo [1,
2].
A first report of what today can be categorized
as a type 2 segmental manifestation of cutaneous leiomyomatosis (hereditary
multiple leiomyoma of skin, MIM 150800) was published by Wosyka in 1934
[3]. In fact, in this autosomal dominant trait a type 2 segmental involvement
appears to occur rather often: there are at least 7 such cases to be found
in the world literature [4-6]. The lesions distributed in a segmental
pattern are more numerous and prominent than the ordinary nonsegmental
tumors present in the same patient or his affected first-degree relatives
[2, 7].
However, a familial occurrence of type 2 segmental cutaneous leiomyomatosis
has not so far been reported. Here we provide evidence that early postzygotic
allelic loss giving rise to this type of segmental involvement may occur,
by way of exception, in several heterozygous members of one family.
Clinical report
A 37-year-old woman presented with agminated nodular lesions present
since adolescence in a circumscribed area above the right breast. Some
years later similar but disseminated skin lesions developed in other parts
of her body. She reported that these nodules were sometimes painful, especially
when exposed to cold water. Moreover, she had a history of multiple uterine
myoma.
On physical examination, we saw an agglomeration of approximately 20
papulonodular lesions arranged in an
8 x 20 cm triangular area on her right anterior chest wall. These lesions
did not cross the midline (Fig.
1). The nodules were firm and pale-red. Their diameter varied
between 0.5 and 1.2 cm. Five smaller isolated lesions were found in a
scattered, nonsegmental distribution on her back and her neck.
The patient's 70-year-old mother had likewise had uterine myomata and
reported that since the age of 18 years she noted the development of multiple
tumors on the anterior aspect of her left shoulder and her left arm. When
she was 30 years old, one of these slightly painful lesions had been excised.
Histopathological examination showed features of cutaneous leiomyoma.
On physical examination more than 50 reddish skin tumors were found in
a band-like distribution involving the anterior aspect of her left shoulder
as well as the extensor surface of her left upper arm (Fig.
2). Many of these lesions were larger than 1.5 cm in diameter.
Approximately 15 solitary and slightly smaller lesions were found to be
disseminated bilaterally on her neck and her trunk.
According to the family history, the proposita's grandmother as well
as one aunt had likewise uterine myomas and multiple nonsegmental cutaneous
tumors. The family did not give permission to obtain an additional skin
biopsy.
Discussion
Cutaneous leiomyomatosis is an autosomal dominant trait characterized
by multiple disseminated leiomyomas that are associated, in female patients,
with multiple uterine leiomyomas [5]. Sporadic cases suggesting a type
2 segmental involvement have been described in several families affected
with cutaneous leiomyomatosis [4], but the present observation of a segmental
type 2 manifestation in a mother and her daughter is unusual. A familial
occurrence of type 2 segmental involvement had only once been observed
previously in another autosomal dominant skin disorder, disseminated superficial
actinic porokeratosis (DSAP). Gandola [8] described two brothers with
severe systematized linear porokeratosis of early onset. Their mother
had the ordinary diffuse phenotype in the form of DSAP.
Segmental manifestations of autosomal skin disorders
result from early postzygotic mutational events giving rise to genetically
different cell clones and thus to cutaneous mosaicism. A segmental type
2 manifestation can be explained by postzygotic loss of the wild-type
allele in an otherwise heterozygous embryo. Various genetic mechanisms
of LOH may give rise to either homozygosity or hemizygosity for a mutant
allele [4]. Because a type 2 segmental manifestation of cutaneous leiomyomatosis
appears to occur quite frequently [4-6], one might hypothesize that the
underlying gene locus is particularly prone to mitotic recombination or
other postzygotic mutational events resulting in loss of the corresponding
wild-type allele.
The gene locus of cutaneous leiomyomatosis is so far unknown. Remarkably,
Fryns et al. [9] described a case of 9p trisomy/18pter monosomy.
The patient showed the well-known clinical signs of 9p trisomy and, in
addition, severe diffuse cutaneous leiomyomatosis. Provided that the underlying
gene would map to 18pter, LOH involving this region might be responsible
for the development of cutaneous leiomyoma, in analogy to LOH documented
in other benign skin tumors such as trichoepithelioma [10], cylindroma
[11] or neurofibroma of neurofibromatosis type 1 [12]. Future research
may show whether the concept of dichotomous types of segmental cutaneous
leiomyomatosis can be confirmed at the molecular level.
Article accepted on 2/10/00
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