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Linear Cowden nevus: a new distinct epidermal nevus

European Journal of Dermatology. Volume 17, Number 2, 133-6, March-April 2007, Genes and skin

DOI : 10.1684/ejd.2007.0125

Summary

Author(s) : Rudolf Happle , Department of Dermatology, Philipp University of Marburg, Deutschhaus-Str. 9, 35033 Marburg, Germany.

Summary : Within the group of epidermal nevi, a so far nameless disorder is described under the term “linear Cowden nevus”. This non-organoid epidermal nevus is caused by loss of heterozygosity, occurring at an early developmental stage in an embryo with a germline PTEN mutation, giving rise to Cowden disease. Hence, linear Cowden nevus can be categorized as a characteristic feature of type 2 segmental Cowden disease. Until now, several authors had mistaken this epidermal nevus as a manifestation of Proteus syndrome. The concept of linear Cowden nevus implies that Proteus syndrome is by no means caused by PTEN mutations. As a clinical difference, linear Cowden nevus is markedly papillomatous and thick, whereas linear Proteus nevus tends to be rather flat. Moreover, the spectrum of possibly associated cutaneous or extracutaneous anomalies differs in the two types of nevi. In conclusion, linear Cowden nevus, that may also be called “linear PTEN nevus”, represents a distinct clinicogenetic entity.

Keywords : epidermal nevi, linear Cowden nevus, linear PTEN nevus, Proteus syndrome, PTEN mutations, type 2 segmental Cowden disease

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ARTICLE

Auteur(s) : Rudolf Happle

Department of Dermatology, Philipp University of Marburg, Deutschhaus-Str. 9, 35033 Marburg, Germany

accepté le 18 Octobre 2006

Current molecular research has an important impact on our understanding of the various types of nevi and their classification. Here, as a consequence, a new type of non-organoid epidermal nevus is delineated, for which the name linear Cowden nevus is proposed.

PTEN mutations cause Cowden disease

PTEN mutations are known to cause Cowden disease which is inherited as an autosomal dominant trait [1, 2]. There is both clinical overlap and allelic coincidence of Cowden disease with other subtypes of PTEN hamartoma syndromes such as Bannayan-Riley-Ruvalcaba syndrome (macrocephaly, lipomas and pigmented macules of the glans penis) [3] and Lhermitte-Duclos disease (dysplastic cerebellar gangliocytoma) [4].

Linear Cowden nevus is a feature of type 2 segmental Cowden disease

In autosomal dominant skin disorders, a type 2 segmental manifestation results from loss of the corresponding wild-type allele at an early developmental stage [5]. The segmental involvement appears at a rather young age and tends to be very pronounced, thus being superimposed on the non-segmental lesions of the ordinary trait developing later in life [6]. This concept has been proven at the molecular level in Hailey-Hailey disease [7]. Recently, an unusual case of reputed “Proteus syndrome” occurring in a family affected with Cowden syndrome and showing loss of heterozygosity for an inherited PTEN mutation was reported by Loffeld et al. [8]. In fact, this case can be taken as a classical example of type 2 segmental Cowden disease [9]. Hence, the associated epidermal nevus should be categorized as linear Cowden nevus.

Absence of PTEN mutations in Proteus syndrome

During the past years several investigators have reported the presence of germline PTEN mutations in patients with anomalies reminiscent of Proteus syndrome, such as macrocephaly, asymmetry of limbs, lipomas, and a linear epidermal nevus [10-12]. They believed, therefore, that Proteus syndrome can be caused by germline mutations of the PTEN gene [13, 14]. Other authors, however, fervently argued against this view [15-18]. Today it is clear that the grumbling critics were right. In fact, all of the reports of “Proteus syndrome” or “Proteus-like syndrome” caused by a PTEN mutation can now be categorized as a type 2 segmental manifestation of Cowden disease [9, 19]. Conversely, in typical cases of Proteus syndrome, a search for PTEN mutations always gave negative results [15, 17, 20].

Hence, from a molecular point of view we can discriminate linear Cowden nevus, representing a cutaneous feature of type 2 segmental Cowden disease, from linear Proteus nevus which is of unknown cause, since Proteus syndrome has not so far been elucidated at the molecular level.

Clinical differences between linear Cowden nevus and linear Proteus nevus

So far, linear Cowden nevus has had no name and so did not exist in our mind as a nosological entity, which is why its clinical features remained undefined. For example, Loffeld et al. [8] stated that the clinical and histological features of this nevus were “identical to simple verrucous epidermal nevi”. Smith et al. [12] categorized the epidermal nevus of their patient as “classical features of Proteus syndrome”. Today, however, a careful comparison of linear Cowden nevus and linear Proteus nevus suggests that the two types of nevi can be distinguished by characteristic clinical attributes.

Firstly, linear Cowden nevus is rather thick and has a surface reminiscent of the papillomatous structure of common warts (figure 1) [12, 21]. By contrast, linear Proteus nevus is rather flat and its surface resembles that of a plane wart (figure 2) [23-27]. A histopathological comparison of the two types of epidermal nevi has so far not been performed but would be interesting.

Secondly, the spectrum of associated anomalies appears to be different. Linear Cowden nevus is associated with features peculiar to type 2 segmental Cowden disease, such as polyps of the jejunum or colon [12], lipoblastomatosis (to be distinguished from ordinary lipomas) [12], cutis marmorata-like skin lesions [8], and focal segmental glomerulosclerosis [21]. Moreover, according to the concept of loss of heterozygosity occurring at an early developmental stage one would expect that elder patients with linear Cowden nevus should develop, in addition, the typical disseminated hamartomas of ordinary Cowden disease. So far, however, I could not find any report in the literature of an adult patient with linear Cowden nevus.

By contrast, anomalies peculiar to Proteus syndrome include cerebriform hyperplasia of plantar connective tissue, lymphatic malformations in the form of large cystic lymphangiomas (‘cystic hygromas’), and rather pronounced, disproportionate overgrowth of fingers or toes or entire limbs [25].

It should be emphasized, however, that we are just beginning to become aware of such clinical differences, which is why we cannot exclude the possibility of being led astray with regard to some details when exploring this new field of clinical research.

On the other hand, it should be borne in mind that most of the non-organoid epidermal nevi, regardless whether they are flat and velvety or thick and wart-like, are non-syndromic and, therefore, have nothing to do with linear Proteus nevus or linear Cowden nevus.

The term ‘non-organoid’ means that these epidermal nevi are purely keratinocytic and do not show any change in adnexal structures such as sebaceous glands or hair follicles, as is found in the organoid nevi [28].

“Linear PTEN nevus” as a possible synonym

Because linear Cowden nevus reflects loss of heterozygosity for a PTEN mutation, it could also be called “linear PTEN nevus”. In this context, the meaning of PTEN would be twofold. Firstly, the term stands for phosphatase and tensin homolog, the tumor suppressor gene that harbors the mutations causing this particular type of epidermal nevus. On the other hand, PTEN would stand for “papillomatous, thick, epidermal, non-organoid”, thus describing the clinical and histopathological features of this nevus.

Type 2 segmental Cowden disease represents a new epidermal nevus syndrome

Linear Cowden nevus tends to be associated with other anomalies of type 2 segmental Cowden disease such as cutaneous or extracutaneous lipomas [8, 10, 12, 21], connective tissue nevi [8], vascular nevi including cutis marmorata-like lesions [8, 12], extracutaneous vascular malformations [8, 10], hemihypertrophy including asymmetrical growth of limbs [8, 10-12], macrocephaly [10-12, 21], hydrocephalus [8], epileptic seizures [21], multiple polyps of the jejunum or colon [12, 21], or focal segmental glomerulosclerosis [21].

Hence, within the group of epidermal nevus syndromes, this phenotype can be categorized as an additional distinct entity.

Conclusion

In a comment on Proteus syndrome published in 2004, I said that “the PTEN story now comes to an end” [18]. With respect to Proteus syndrome I was right. On the other hand, with respect to linear Cowden nevus a new and thrilling PTEN story is just beginning.

The concept of linear Cowden nevus can explain and wipe out several contradictions and inconsistencies inherent in previous articles on Proteus syndrome. For example, Loffeld et al. [8] stated that “there is to date no clear phenotypic distinction beween Proteus syndrome with and without PTEN mutations, and both may fulfil the diagnostic criteria”. Such phenotypic distinction is now feasible. For clinical practice, the diagnostic criteria as outlined by Biesecker et al. [25] should now be reconsidered and updated with the particular differential diagnosis of type 2 segmental Cowden disease in mind. In 2000, Zhou et al. [10] wrote that “overgrowth with asymmetry has never been described in true Cowden syndrome and Bannayan-Riley-Ruvalcaba cases”. Today it is clear that this statement was wrong because type 2 segmental Cowden disease can undoubtedly be taken as a particular form of “true Cowden syndrome” [9].

Because Proteus syndrome tends to occur sporadically, it was difficult to understand why it should be caused by germline mutations of PTEN, as proposed by some authors [8, 11, 12]. The concept of linear Cowden nevus implies that such mutations are not involved in the origin of Proteus syndrome.

Other authors have argued that the name “Proteus-like syndrome” [10, 11, 13] is unhelpful and misleading [16, 17, 29]. I fully agree with this critical view. The concept of linear Cowden nevus renders this misleading term superfluous, and it should now be jettisoned.

Finally, it should be borne in mind that the term “genetic heterogeneity”, when applied to non-organoid epidermal nevi, should be used with great caution. By a careful genotype-phenotype correlation we are now able to discriminate morphologically distinct types within this group of disorders, such as the CHILD nevus reflecting NSDHL mutations [30, 31]; linear Cowden nevus resulting from PTEN mutations; linear Proteus nevus that originates from mutations at another, so far unknown gene locus; and an apparently non-syndromic epidermal nevus caused by FGFR3 mutations [32]. On the other hand, non-syndromic epidermal nevi of the non-organoid category will certainly turn out to be genetically heterogeneous. For the time being, it remains a heuristic challenge to delineate within this class of skin disorders as many distinct clinicogenetic entities as possible.

Acknowledgements

Financial support: none

Conflict of interest: none

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