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Olmsted syndrome: clinical, molecular and therapeutic aspects.

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.

SUBMITTER: Duchatelet S

PROVIDER: S-EPMC4373112 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Olmsted syndrome: clinical, molecular and therapeutic aspects.

Duchatelet Sabine S Hovnanian Alain A

Orphanet journal of rare diseases 20150317

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 periorifici ...[more]

PMID: 25886873

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Project description:BackgroundKabuki syndrome type 1 (KS1), a rare multisystem congenital disorder, presents with characteristic facial features, intellectual disability, persistent fetal fingertip pads, skeletal abnormalities, and postnatal growth delays. KS1 results from pathogenic variants in the KMT2D gene, which encodes a histone methyltransferase protein involved in chromatin remodeling, promoter and enhancer regulation, and scaffold formation during early development. KMT2D also mediates cell signaling pathways, responding to external stimuli and organizing effector protein assembly. Research on KMT2D's molecular mechanisms in KS1 has primarily focused on its histone methyltransferase activity, leaving a gap in understanding the methyltransferase-independent roles in KS1 clinical manifestations.MethodsThis scoping review examines KMT2D's role in gene expression regulation across various species, cell types, and contexts. We analyzed human pathogenic KMT2D variants using publicly available databases and compared them to research organism models of KS1. We also conducted a systematic search of healthcare and governmental databases for clinical trials, studies, and therapeutic approaches.ResultsOur review highlights KMT2D's critical roles beyond methyltransferase activity in diverse cellular contexts and conditions. We identified six distinct groups of KMT2D as a cell signaling mediator, including evidence of methyltransferase-dependent and -independent activity. A comprehensive search of the literature, clinical databases, and public registries emphasizes the need for basic research on KMT2D's functional complexity and longitudinal studies of KS1 patients to establish objective outcome measurements for therapeutic development.ConclusionWe discuss how KMT2D's role in translating external cellular communication can partly explain the clinical heterogeneity observed in KS1 patients. Additionally, we summarize the current molecular diagnostic approaches and clinical trials targeting KS1. This review is a resource for patient advocacy groups, researchers, and physicians to support KS1 diagnosis and therapeutic development.

Dataset Information

Olmsted syndrome: clinical, molecular and therapeutic aspects.

Publications

Olmsted syndrome: clinical, molecular and therapeutic aspects.

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