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Case Report/Case Series |

A New TRPV3 Missense Mutation in a Patient With Olmsted Syndrome and Erythromelalgia

Sabine Duchatelet, PhD1,2,3; Solenn Pruvost, MS2,4; Simon de Veer, BSc1,2,3; Sylvie Fraitag, MD5; Patrick Nitschké, PhD2,6; Christine Bole-Feysot, PhD2,4; Christine Bodemer, MD, PhD2,3,7,8; Alain Hovnanian, MD, PhD1,2,3,9
[+] Author Affiliations
1Institut National de la Santé et de la Recherche Médicale, U781, Paris, France
2Université Paris Descartes–Sorbonne Paris Cité, Paris, France
3Institut Imagine, Paris, France
4Genomics Platform, Institut Imagine, Paris, France
5Department of Pathology, Necker–Enfants Malades Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
6Bioinformatics Platform, Institut Imagine, Paris, France
7Department of Dermatology, Necker–Enfants Malades Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
8National Reference Centre for Genodermatoses (MAGEC), Paris, France
9Department of Genetics, Necker–Enfants Malades Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France
JAMA Dermatol. 2014;150(3):303-306. doi:10.1001/jamadermatol.2013.8709.
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Importance  Olmsted syndrome (OS) is a rare keratinizing disorder characterized by excessive epidermal thickening of the palms and soles, with clinical and genetic heterogeneity. Approximately 50 cases have been reported, with the molecular basis described in only 9. Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS. We report a new sporadic case of severe, atypical OS and its underlying genetic basis.

Observations  Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia. Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging.

Conclusions and Relevance  This case study further implicates TRPV3 in OS pathogenesis. In addition, previous reports of OS have not described erythromelalgia as a clinical feature. Its occurrence in our patient could be a chance event, but, if associated with OS, the features of erythromelalgia may expand the phenotypic spectrum of this rare syndrome.

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Figure 1.
Clinical Features

A, Plantar keratoderma initially developed in islands on pressure points of the soles and first toes, with localized redness and peeling of the skin (2 years). B, The lesions rapidly extended to the bases of all toes, to heels, and to forefeet, associated with peripheral skin inflammation (5 years). Hyperkeratosis became massive and dramatic on the right sole, with intense itching and pain causing major disability. C and D, Ears, toes, and feet became red, swollen, and extremely painful during flares of erythromelalgia. D, Hair was thin, curly, and unmanageable. E, Skin biopsy showing hyperplastic epidermis with hyperkeratosis, parakeratosis, hypergranulosis, and papillomatosis. Capillaries are dilated in the upper dermis (hematoxylin-eosin, original magnification, ×100).

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Figure 2.
Localization and Modeling of the TRPV3 Mutation

A, Alignment of TRPV3 orthologues showing part of the C-terminal domain. Transmembrane domain S6 and the TRP domain and box are indicated. Leu673 (indicated in blue) is a highly conserved residue. The mutated residue (Trp692Gly) previously identified in Olmsted syndrome is indicated in green. B, Overview of a homotetrameric TRPV3 channel (each color represents a different TRPV3 molecule). Non-S6 segments are transparent to highlight S6 helices. Leu673 is located at the S6 base (dashed black rectangle). C, Enlarged representation of the TRPV3 activation gate sealed by Met677, which is directly below Leu673.

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