Multiple unilateral skin tumors suggest type 1 segmental manifestation of familial syringoma

ARTICLE

Auteur(s) : Roeland PM Ceulen¹, Ariënne MW Van Marion², Peter M Steijlen^1,3, Jorge Frank^1,3, Pamela Poblete-Gutiérrez^1,3

¹Department of Dermatology, University Hospital Maastricht, P. Debyelaan 25; PO box 5800, 6202 AZ Maastricht, The Netherlands
²Department of Pathology, University Hospital Maastricht, Maastricht, The Netherlands
³Department of Maastricht University Center for Molecular Dermatology (MUCMD), University Hospital Maastricht, Maastricht, The Netherlands

accepté le 18 Janvier 2008

Syringoma are benign adnexal tumors derived from eccrine sweat ducts. With female preponderance, the tumors either develop during puberty or in the third to fourth decade of life. Clinically, syringoma are characterized by grouped asymptomatic skin-colored, yellowish, or reddish-brown papules, varying in size from 2 to 5 mm. They are usually distributed in a bilateral and symmetric pattern, only rarely involving the entire body surface in a generalized fashion [1].

Sometimes, syringoma can be associated with additional clinical findings in the context of genetic syndromes as, e.g. the syndrome of Nicolau and Balus (syringoma, milia, and atrophodermia vermiculata) or Down syndrome [2]. In patients with Down syndrome, syringoma mostly manifests on or around the eyelids (18-64%) as is the case for syringoma observed in patients with Marfan and Ehlers-Danlos syndromes [3].

In 1950, Woringer and Eichler described for the first time the familial occurrence of disseminated syringoma inherited as an autosomal dominant trait, under the term ‘asymptomatic eruptive hidradenoma’ [4]. Since then, autosomal dominantly inherited familial syringoma has been repeatedly described, indicating that this disorder most likely represents a monogenetic entity (OMIM 186600) [5-9].

Based on these observations, we describe a patient who developed disseminated tumors in a rather unusual unilateral fashion on his trunk, suggesting a type 1 segmental manifestation of familial syringoma.

Case report

Upon clinical examination, we saw multiple skin-colored to reddish-brown papules of 1 to 4 mm that were localized in a unilateral, segmental fashion on the left side of the thorax and abdomen (figures 1A and B). In some areas, neighboring papules showed confluence. No epidermal changes were noted and Darier’s sign was negative. The lower eyelids, the cheeks, and the rest of the body were unaffected.

Histopathological examination of a biopsy obtained from the thorax revealed numerous small ducts, lined with a typical double row of cuboid epithelium. The ductal lumina contained eosinophilic debris. Some epithelial cells showed small, comma-like tails of epithelial cells, giving them the appearance of tadpoles (figures 2A and B).

Taking the clinical and histopathologic findings into consideration we made the diagnosis of type 1 segmental syringoma. Subsequently, the tumors were successfully treated with an Erbium/Yag and a CO₂ laser.

Discussion

In the localized form, syringoma are mostly confined to the lower eyelid region in a bilateral fashion. Multiple and eruptive syringoma, in contrast, are mainly observed in association with Down syndrome [1, 3, 11-13]. The differential diagnoses include acne vulgaris, milia, sebaceous hyperplasia, lichen planus, eruptive xanthoma, urticaria pigmentosa, cutaneous leiomyoma, and hidrocystoma [1, 14]. Thus, a tentative diagnosis of syringoma should always be confirmed by histological examination.

Histopathologically, syringoma are benign tumors with eccrine ductal differentiation that reveals distinctive features. In the dermis, numerous small ducts lined with a typical double row of flattened epithelial cells are seen. The outer layer often extends into the surrounding stroma, forming a comma-like or tadpole projection. Ductal lumina are filled with an amorphous, periodic eosinophilic positive material [14].

A broad range of treatment regimens with variable success has been reported, including dermabrasion, electrodessication with curettage, excision, and different laser sources, such as, e.g. CO₂, argon, and erbium-YAG laser [15-17]. In our patient, a very good therapeutic result was achieved with a combination treatment using both the Erbium/Yag and CO₂ laser.

Syringoma belong to the group of cutaneous adnexal tumors, which usually tend to follow a benign clinical course, although rare exceptions have been described [14]. These tumors can either be acquired or occur in association with inherited cutaneous tumor syndromes [18].

Interestingly, the familial occurrence of syringoma, although apparently rare, is well documented in several families of different ethnic origin [1, 5-9]. In all instances the mode of inheritance was autosomal dominant, comparable with other inherited adnexal tumor syndromes as, e.g. Brooke-Spiegler syndrome or Birt-Hogg-Dubé syndrome [18]. Careful retrospective revision of these families revealed variable localization and distribution patterns of syringoma (table 1), including tumors confined to the peri-ocular region and the cheeks [5, 7, 8], the chest and neck [5, 8, 9], and diffuse syringoma located on almost the entire body surface [1, 8].

In contrast, the patient described herein showed localized, partially confluent syringoma that were confined to the left trunk in a segmental fashion. There were no associated anomalies and his family history was negative.

According to a new genetic concept postulated by Happle, two different types of segmental manifestation can be distinguished in autosomal dominant skin disorders beside the ordinary diffuse phenotype. Type 1 reflects heterozygosity for a de novo postzygotic mutation occurring at an early stage of embryogenesis. Within the affected segments, the cutaneous lesions show a degree of severity similar to that of the non-segmental phenotype caused by a germline mutation. Outside the segmental areas, the skin is both clinically and genetically normal. By contrast, the type 2 manifestation occurs in heterozygous embryos that later develop a diffuse distribution of skin lesions. In such embryos, a postzygotic mutation occurring at an early developmental stage results in loss of heterozygosity (LOH) and gives rise, in a segmental area, to a homozygous or hemizygous state of the underlying mutation. Clinically, this would be reflected by rather pronounced segmental lesions being superimposed on the ordinary non-segmental phenotype [19]. Recently, the concept of both type 1 and type 2 segmental involvement has been genetically proven in distinct inherited skin diseases, including, e.g. Darier’s disease and Hailey-Hailey disease [20, 21]. Based on the aforesaid, the phenotype observed in the individual described here could reflect two possible forms of cutaneous mosaicism.

In some patients, generalized syringoma do not manifest before the third or fourth decade of life [1]. Therefore, we cannot entirely exclude that in the future our patient might additionally develop a diffuse, milder, and symmetrical manifestation of the phenotype, because at the time of diagnosis he was only 18-years-old. The latter would then reflect a type 2 segmental manifestation of familial syringoma since the rather severe segmental phenotype already developed early in life due to the homozygous or hemizygous state of the underlying mutation in the segmentally affected skin areas, whereas the diffuse and symmetric phenotype, which is caused by a heterozygous germline mutation, would occur later in life. If a type 2 manifestation is indeed present, the risk of disease transmission to the next generation would be 50% and thus high, because a germline mutation must be postulated. This aspect is of particular relevance for genetic counseling.

On the other hand, it is also possible that the segmental phenotype arose due to a novel heterozygous somatic mutation that occurred in an early stage of embryogenesis, particularly considering the fact that no other family member was affected and that diffuse syringoma can already manifest during puberty [1]. This would then reflect a type 1 segmental manifestation of familial syringoma. Also in this case, the trait might be transmitted to the next generation due to, e.g. a gonadal mosaicism. However, the risk of transmission would be rather low.

Conclusively, we believe that the segmental phenotype observed in our patient reflects a somatic mosaicism as the result of an early postzygotic mutation and, thus, a type 1 segmental manifestation of autosomal dominant familial syringoma. We further suggest that somatic mosaicism is also the underlying pathomechanism in patients with “nevoid” or “plaque”-like syringoma previously reported by other groups [22-24]. In support of this notion, both Happle and we have made similar observations not only in syringoma but also in various other autosomal dominantly inherited cutaneous disorders [25, 26]. Elucidation of the genetic basis of familial syringoma will eventually allow for testing of our hypothesis on the cellular and molecular level.
Table 1 Chronologic overview on familial syringoma reported to date

Acknowledgements

References

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