Two cases of type 2 segmental manifestation in a family with cutaneous leiomyomatosis

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

REFERENCES

1. Happle R. Segmental forms of autosomal dominant skin disorders: different types of severity reflect different states of zygosity. Am J Med Genet 1996; 66: 241-2.

2. Happle R. A rule concerning the segmental manifestation of autosomal dominant skin disorders: review of clinical examples providing evidence for dichotomous types of severity. Arch Dermatol 1997; 133: 1505-9.

3. Wosyka H. Leiomyoblastoma cutis multiplex in segmentärer Anordnung. Dermatol Wochenschr 1934; 99: 1110-2.

4. Happle R. Loss of heterozygosity in human skin. J Am Acad Dermatol 1999; 41: 143-64.

5. Fearfield LA, Smith JR, Bunker CB, D. SRC. Association of multiple familial cutaneous leiomyoma with uterine symplastic leiomyoma. Clin Exp Dermatol 2000; 25: 44-7.

6. Torlone G, Giuliani L, Flati G, De Angelis F, Donati G, Bologna G, Legge A. Leiomiomi multipli cutanei: una proposta di terapia. Chron Dermatol 1985; 16: 171-80.

7. Berendes U, Kühner A, Schnyder UW. Segmentary and disseminated lesions in multiple hereditary cutaneous leiomyoma. Humangenetik 1971; 13: 81-2.

8. Gandola M. La porocheratosi di Mibelli: aspetti evolutivi tardivi e associazioni morbose insolite. Boll Soc Medicochir 1951; 51: 273-92.

9. Fryns JP, Haspeslagh M, de Muelenaere A, van den Berghe H. 9p trisomy/18p distal monosomy and multiple cutaneous leiomyomata: another specific chromosomal site (18pter) in dominantly inherited multiple tumors? Hum Genet 1985; 70: 284-6.

10. Matt D, Xin H, Vortmeyer AO, Zhuang Z, Burg G, Böni R. Detection of loss of heterozygosity on chromosome 9q22.3 in microdissected sporadic trichoepithelioma [abstract]. Arch Dermatol Res 1999; 403: 124.

11. Verhoef S, Schrander-Stumpel CT, Vuzevski VD, Tempelaars A, Jansen LA, Malfeyt GA, Ceelen TL, Lindhout D, Halley DJ, van den Ouweland AM. Familial cylindromatosis mimicking tuberous sclerosis complex and confirmation of the cylindromatosis locus, CYLD1, in a large family. J Med Genet 1998; 35: 841-5.

12. Colman SD, Williams CA, Wallace MR. Benign neurofibromas in type 1 neurofibromatosis (NF1) show somatic deletions of the NF1 gene. Nature Genet 1995; 11: 90-2.