Olmsted syndrome: clinical, molecular and therapeutic aspects

Most reported OS cases are sporadic, although familial cases with different modes of inheritance (dominant or recessive autosomal or X-linked inheritance) were also reported.

Recently, the genetic basis has been partially elucidated by the identification of mutations in TRPV3 (Transient receptor potential vanilloid-3) in 14 OS patients with different genetic background (Chinese, Indian, Iranian, Arabic, Caucasian) [37,49,50,53,55‐58]. TRPV3 has been reported as a thermosensible cation non selective channel, activated by temperature and several chemical ligands, predominately expressed in keratinocytes, and in sensory neurons [63,64]. TRPV3 is a transmembrane channel belonging to the family of TRP (Transient receptor potential) [63,64] and consists of 6 transmembrane domains with cytoplasmic N and C-termini, assembling as tetramers. TRPV3 mutations are responsible for autosomal dominant but also recessive OS (Figure 2). To date, 7 dominant mutations (p.Gly573Ser in 5 unrelated patients, p.Gly573Cys, p.Gly573Ala, p.Gln580Pro, p.Leu673Phe, p.Trp692Gly and p.Trp692Cys each in an unique case) have been reported (Figure 2). Several dominant mutations were demonstrated to be gain-of-function mutations leading to an increased intracellular Ca²⁺ [50,57]. Three recessive mutations (p.Trp521Ser in a homozygous state in one patient, and p.Gly568Cys and p.Gln216-Gly262del in a compound heterozygote state in two brothers) were also reported (Figure 2) [37,49,50,53,55‐58]. Thus, the Gly573 residue, and Trp692 to a lesser extent, are recurrently mutated. In addition, all mutations, except for two recessive mutations, are located in the S4-5 linker or in the C-terminal part of the protein (Figure 2). The recessive p.Trp521Ser and p.Gln216-Gly262del (resulting from the splicing site mutation c.784 + 1G > A) mutations are located in the S2-3 linker and in the N-terminal part of the protein respectively (Figure 2). OS caused by TRPV3 mutations shows clinical heterogeneity. Indeed, OS patients with TRPV3 mutations present either with typical OS hallmarks or incomplete phenotype with atypical features. Genotype-phenotype correlations are difficult to establish at present because of the few reported cases. However, the 5 patients with the same p.Gly573Ser mutation present with a similar phenotype including mutilating PPK with variable severity, hair abnormalities (from dry hair to alopecia) and keratotic plaques (periorificial or only in the natal cleft). In the other hand, other mutations, located in the same part or in different domains of the protein, are associated with atypical features (Figure 2). The p.Leu673Phe (dominant), p.Gly568Cys (recessive) and p.Gln216-Gly526del (recessive) mutations lead to atypical OS, with nonmutilating PPK and no periorificial keratotic plaques, associated with erythromelalgia [55,56]. The patient with the p.Gly573Ala presents with immune dysregulation [53]. The 2 related patients with the p.Gln580Pro mutation have a very mild phenotype with only focal PPK even at 37-year-old for the father [57].

Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene (p.Phe464Ser and c.671-9 T > G), encoding a zinc metalloprotease essential for cholesterol homeostasis and endoplasmic reticulum stress response, have also been reported in recessive X-linked OS [41,59]. Mutations in MBTPS2 also lead to IFAP (Ichthyosis follicularis - atrichia - photophobia) syndrome with or without BRESHECK syndrome (MIM #308205, ORPHA2273) [65]. BRESHECK syndrome is a multiple congenital malformation characterized by intellectual disability, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, particularly of the vertebrae. The OS patient with the c.671-9 T > G mutation also presents with classic IFAP syndrome [59], whereas previously reported patients with the same mutation in MBTPS2 has no OS features. The mechanism by which MBTPS2 mutations lead to IFAP or OS is currently unclear.

There is no obvious clinical difference between OS caused by TRPV3 and MBTPS2 mutations despite the mode of inheritance. In addition, clinical variability is observed even in patients from the same family or unrelated patients harbouring the same mutation, suggesting the implication of modifier genes, epigenetics and/or environmental factors.

Finally, some patients do not carry detectable mutations in either gene, indicating further genetic heterogeneity.

The pathogenesis of OS is poorly understood. However, a defect in the expression of mature epidermal keratins (1 and 10) and persistence of basal keratins (5 and 14) was reported [20,21,27,45], as well as increased expression of Ki-67, a mitotic activity marker in basal and suprabasal layers [29,44,48]. Thus, involved areas remain in an immature state and continue to proliferate in an improper fashion. This excessive epithelial proliferation may result in hyperkeratosis. The mechanism by which TRPV3 mutations lead to OS pathogenesis is unknown. Functional studies of four TRPV3 mutations (p.Gly573Ser, p.Gly573Cys, p.Trp692Gly and p.Gln580Pro) using patch clamp analysis on transfected HEK293 cells expressing TRPV3 mutants were performed [50,57]. These studies have shown that these mutations lead to much larger inward currents probably because of the constitutive opening of the mutants [50]. Thus, these mutations are gain-of-function mutations and result in elevated intracellular Ca²⁺ inducing increased apoptosis, suggesting that enhanced cell-death could drive OS [50]. In addition, murine models have shown that TRPV3 is also associated with TGF-α/EGFR signaling, which plays a role in keratinocyte differentiation control [66]. Reported immune dysregulation in OS suggests a primary (as TRPV3 is expressed by Langerhans cells) or secondary role of immunological processes in OS pathogenesis [53]. Transcriptomic and proteomic investigation in patients with the p.Gln580Pro mutation, leading only to focal PPK, showed decreased expression of proteins involved in keratinocyte differentiation, in gap junction, tight junction and desmosome formation, but increased expression of proteins involved in keratinocyte proliferation and cell death [57]. Thus, the TRPV3 p.Gln580Pro gain-of-function mutation disrupts the balance between keratinocyte proliferation and differentiation, and compromises cell adhesion. In addition, previous studies on murine models have also demonstrated that TRPV3 mediates release of pro-inflammatory cytokines including interleukin IL-1α [67], an important mediator of cutaneous inflammation, but also prostaglandin E2 [68]. Of note, TRPV3 is expressed in nociceptive neurons. Thus, it is also likely that TRPV3 over-activation leads to local overproduction of inflammatory cytokines which could affect the somatosensory system, leading to a peripheral neuropathic pain.