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Olmsted syndrome: clinical, molecular and therapeutic aspects.

Duchatelet S, Hovnanian A - Orphanet J Rare Dis (2015)

Bottom Line: Specific management of pain and itching is important to reduce the morbidity of the disease.New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms.The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR 1163, Laboratory of Genetic skin diseases, Imagine Institute, 2nd floor, 24 bld du Montparnasse, 75015, Paris, France. sabine.duchatelet@inserm.fr.

ABSTRACT
Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. The disease starts usually at birth or in early childhood. About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe. Most of reported OS cases are sporadic, although familial cases with different mode of inheritance were also described. Mutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features. OS has to be differentiated from other severe forms of PPK including Vohwinkel, Clouston, Papillon-Lefèvre or Haim-Munk syndromes, Mal de Meleda, pachyonychia congenita, Tyrosinemia type II and acrodermatitis enteropathica. When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation. However, additional genes remain to be identified. No specific and satisfactory therapy is currently available for OS. Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief. Specific management of pain and itching is important to reduce the morbidity of the disease. The disease is debilitating and progressive keratoderma and auto-amputation of digits can prevent patients from grasping and walking, and confine them to a wheelchair. New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms. The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy.

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Schematic structure of TRPV3 and localization of reported OS mutations. Dominant mutations are indicated in red and recessive mutations in green. Amino acids localized in the ARD (ankyrin repeats domain) and TRP (transient receptor potential) domains are indicated in pink and purple, respectively.
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Fig2: Schematic structure of TRPV3 and localization of reported OS mutations. Dominant mutations are indicated in red and recessive mutations in green. Amino acids localized in the ARD (ankyrin repeats domain) and TRP (transient receptor potential) domains are indicated in pink and purple, respectively.

Mentions: 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].Figure 2


Olmsted syndrome: clinical, molecular and therapeutic aspects.

Duchatelet S, Hovnanian A - Orphanet J Rare Dis (2015)

Schematic structure of TRPV3 and localization of reported OS mutations. Dominant mutations are indicated in red and recessive mutations in green. Amino acids localized in the ARD (ankyrin repeats domain) and TRP (transient receptor potential) domains are indicated in pink and purple, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4373112&req=5

Fig2: Schematic structure of TRPV3 and localization of reported OS mutations. Dominant mutations are indicated in red and recessive mutations in green. Amino acids localized in the ARD (ankyrin repeats domain) and TRP (transient receptor potential) domains are indicated in pink and purple, respectively.
Mentions: 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].Figure 2

Bottom Line: Specific management of pain and itching is important to reduce the morbidity of the disease.New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms.The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMR 1163, Laboratory of Genetic skin diseases, Imagine Institute, 2nd floor, 24 bld du Montparnasse, 75015, Paris, France. sabine.duchatelet@inserm.fr.

ABSTRACT
Olmsted syndrome (OS) is a rare genodermatosis classically characterized by the combination of bilateral mutilating transgredient palmoplantar keratoderma (PPK) and periorificial keratotic plaques, but which shows considerable clinical heterogeneity. The disease starts usually at birth or in early childhood. About 73 cases have been reported worldwide. OS is observed in both sexes, although male cases are more frequent. The most suggestive symptoms associate PPK with pseudoainhum and periorificial keratotic plaques. Frequently associated features include hair and nail abnormalities, leukokeratosis, corneal default and recurrent infections. Pain and itching are variable but can be severe. Most of reported OS cases are sporadic, although familial cases with different mode of inheritance were also described. Mutations in TRPV3 (Transient receptor potential vanilloid-3) gene have recently been identified as a cause of autosomal dominant (gain-of-function mutations) or recessive OS. Mutations in MBTPS2 (membrane-bound transcription factor protease, site 2) gene were identified in a recessive X-linked form. The diagnosis relies mainly on clinical features associating severe PPK and periorificial keratotic plaques, but can be challenging in patients with incomplete phenotype or atypical features. OS has to be differentiated from other severe forms of PPK including Vohwinkel, Clouston, Papillon-Lefèvre or Haim-Munk syndromes, Mal de Meleda, pachyonychia congenita, Tyrosinemia type II and acrodermatitis enteropathica. When differential diagnoses are difficult to exclude, genetic studies are essential to search for a TRPV3 or MBTPS2 mutation. However, additional genes remain to be identified. No specific and satisfactory therapy is currently available for OS. Current treatments of hyperkeratosis (mainly emollients, keratolytics, retinoids or corticosteroids), either topical or systemic, are symptomatic and offer only temporary partial relief. Specific management of pain and itching is important to reduce the morbidity of the disease. The disease is debilitating and progressive keratoderma and auto-amputation of digits can prevent patients from grasping and walking, and confine them to a wheelchair. New therapeutic options are therefore crucial and are expected from a better understanding of the disease mechanisms. The use of TRPV3 antagonists would represent such a targeted and potentially powerful strategy.

Show MeSH
Related in: MedlinePlus