Recently, mutations in the transient receptor potential vanilloid-3 (TRPV3) gene have been linked to autosomal dominant and recessive inheritance of the condition. Additionally, mutations in the membrane-bound transcription factor protease, site 2 (MBTPS2) gene have been observed in families with X-linked recessive inheritance. Some cases of Olmsted syndrome are caused by mutations in PERP (TP53 apoptosis effector) disrupting desmosomal proteins. The clinical presentation of Olmsted syndrome does not appear to be affected by mutation type nor mode of inheritance. The pathogenesis of this disease remains poorly understood.
The hallmarks of Olmsted syndrome are mutilating bilateral palmoplantar keratoderma (PPK) and periorificial keratotic plaques. However, the condition demonstrates great clinical variability with a wide range of inconsistent features. There are also rare cases that present without periorificial plaques, which can make diagnosis challenging.
PPK is rarely present at birth but usually develops within the first year or in early childhood. The lesions are initially focal, predominantly affecting pressure points, but they eventually spread to most of the palmoplantar surface. The keratoderma subsequently becomes thicker with time, and painful fissures can develop. Severe pruritus and pain with pressure in the affected areas can be debilitating, causing individuals with the disease to avoid walking and grasping. The clinical course progressively worsens over time and can be complicated by frequent bacterial and fungal infections, flexion deformities, pseudoainhum (constriction of digital bands), spontaneous digit autoamputation, squamous cell carcinoma, and malignant melanoma.
Additionally, periorificial keratotic plaques develop, and these can affect many other areas as well, including the anus, ears, eyes, genitals, mouth, nose, and navel. Less commonly, individuals with Olmsted syndrome may have nonperiorificial keratoses involving the thighs, arms, elbows, knees, or intertriginous folds.
An atypical form of Olmsted syndrome presents with nonmutilating PPK, erythromelalgia, and no periorificial hyperkeratosis.
Other findings with more variable frequency include hair and nail abnormalities, oral lesions, abnormal dentition, eye lesions, sweating abnormalities, short stature, bone abnormalities, and high-frequency hearing loss.
Joint laxity, primary sclerosing cholangitis, intellectual disability, and hemangioma are rarely observed in individuals with Olmsted syndrome. However, these features may be incidental.
Q82.8 – Other specified congenital malformations of skin
239072003 – Congenital palmoplantar and perioral keratoderma of Olmsted
- Vohwinkel syndrome – GJB2 or LOR mutation, no periorificial involvement
- Mal de Meleda – SLURP1 mutation, no periorificial involvement
- Papillon-Lefèvre syndrome – CTSC mutation, no periorificial involvement
- Clouston syndrome – GJB6 mutation, no periorificial involvement
- Pachyonychia congenita – KRT6, KRT16, or KRT17 mutations, no periorificial involvement
- Tyrosinemia type 2 – TAT mutation, no periorificial involvement
- Haim-Munk syndrome – CTSC mutation, no periorificial involvement
- Acrodermatitis enteropathica – SLC39A4 mutation, low serum zinc levels
- Howel-Evans syndrome – most have esophageal cancer