Type 2 segmental cutaneous leiomyomatosis: an example of mosaicism

ARTICLE

Auteur(s) : Beatriz Fleta Asín, Margarita Berzal Rosende, Rosario Carrillo Gijón, Montse Fernández-Guarino, Pedro Jaén Olásolo

Dept of Dermatology, Ramón y Cajal Hospital, Carretera de Colmenar, km. 9.100, 28034 Madrid, Spain

A 66-year-old woman presented to the Dermatology Department for evaluation of cutaneous lesions which had appeared progressively over the past four years. They consisted of firm, pale red, oval shaped papules. Individual lesions measured 5 to 10 mm and some of them were confluent; they were distributed in a segment involving the lower right side of the trunk. A few similar isolated lesions were scattered over both arms and upper part of the trunk (figure 1). The lesions were symptomless. Family history was unremarkable: there were no known family members with cutaneous leiomyomas. She had undergone a hysterectomy because of uterine leiomyomatosis 26 years before. Clinically the diagnosis of cutaneous leiomyomatosis was assumed. Histological examination of hematoxylin-eosin-stained sections showed a well demarcated lobulated tumour located in the dermis. It consisted of fascicles of muscle cells with eosinophilic cytoplasm and elongated nuclei. These findings confirmed the diagnosis of cutaneous leiomyoma. An abdominal ultrasound revealed no abnormalities.

Cutaneous leiomyomas are uncommon neoplasms, but their exact incidence is not known. Both solitary and multiple forms exist (leiomyomatosis); the latter are transmitted as an autosomal dominant trait and may be associated with uterine leiomyomas (Multiple cutaneous and uterine leiomyomatosis, also known as Reed’s syndrome or MCUL). A disease variant involving aggressive renal cancer can occur (hereditary leiomyomatosis and renal cell carcinoma or HLRCC) [1]. Cutaneous leiomyomatosis predominantly manifests in a symmetrical and diffuse fashion or in a segmental pattern, usually following the lines of Blaschko. It is believed the latter most likely reflects mosaicism. There have been two segmental patterns reported in dominantly inherited skin disorders; a type 1 segmental involvement is present when segmental skin lesions share the same degree of severity as the corresponding non-mosaic trait, a germline mutation is absent; in type 2 segmental pattern, a more severe involvement is observed, and in some occasions, it is superimposed on the ordinary diffuse phenotype; genetic and molecular mechanisms involved in type 2 segmental manifestation are unknown, but might reflect a heterozygous germline mutation associated to a postzygotic loss of heterozygosity [2-4].

Patients with MCUL or HLRCC have a germline mutation in a single copy of the fumarate hydratase (FH) gene, located on chromosome 1q42.3-43. The mechanism by which it may cause predisposition to cutaneous leiomyomas is unknown; although different mutation mechanisms have been described (missense, nonsense and whole gene deletions), no definite association has been found. Failure to detect a germline FH mutation in affected patients might suggest underlying cryptic FH mutation or mosaic cases. Somatic FH mutations in sporadic leiomyomas have been reported, but are rarely encountered [1, 3, 5].

Considering association between multiple cutaneous leiomyomas and renal cell carcinoma, screening protocols for early identification of tumors should be considered. Difficulties arise in deciding which patients to screen, when, by what means and how frequently. Different strategies have been advocated: screening all individuals with the FH mutation from their early teens, only those FH mutation carriers whose families have a history of renal cancer or no screening at all. Some renal cancers require computed tomography or magnetic resonance imaging and it has to be determined whether earlier detection provides an improved outcome [1, 6].

In conclusion, we describe a woman affected by type 2 segmental leiomyomatosis based on clinical appearance. According to the data available, a postzygotic loss of heterozygosity associated to a germline mutation should be expected, although her family history was not contributory. Screening for FH mutation would be relevant in this case: renal cell carcinoma associated to leiomyomatosis results from a germline mutation, and previous data suggest that FH mutations associated with HLRCC are not preferentially clustered in the amino terminal half of the protein; it would have implications for screening the patient and family members and for genetic counselling [3].

Acknowledgements

References

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3 Badeloe S, van Geel M, van Steensel MA, et al. Diffuse and segmental variants of cutaneous leiomyomatosis: novel mutations in the fumarate hydratase gene and review of the literature. Exp Dermatol 2006; 15: 735-41.

4 König A, Happle R. Two cases of type 2 segmental manifestation in a family with cutaneous leiomyomatosis. Eur J Dermatol 2000; 10: 590-2.

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6 Hayedeh G, Fatemeh M, Ahmadreza R, Masoud A, Ahmad S. Hereditary leiomyomatosis and renal cell carcinoma syndrome: a case report. Dermatol Online J 2008; 14: 16.