TRPV3-pEDD (palmoplantar Epidermal Differentiation Disorder)

Also referred to as Olmsted Syndrome

Facts

• What does TRPV3 stand for? Transient receptor potential vanilloid-3.¹
• What does the TRPV3 gene do? Encodes a channel protein mainly expressed in keratinocytes.¹
• What happens when TRPV3 becomes mutated? It is hypothesized that gain of function mutation leads to apoptosis of keratinocytes causing hyperkeratosis.¹
• Clinical significance of mutation? Palmoplantar keratoderma and periorificial keratoderma.¹

About Olmsted Syndrome

Skin disease caused by TRPV3 mutations is known as Olmsted syndrome. However, not all cases of Olmsted syndrome are caused by TRPV3 mutations. Two other separate genes have been identified to cause the disease.¹ Olmsted syndrome is very rare. As of 2021, there were only 38 reported cases of TRPV3-related cases.¹ The disease is passed down from a parent to their offspring in an autosomal dominant inheritance pattern.² This means that it only takes one copy of the mutated TRPV3 gene from one parent to cause Olmsted syndrome. The disease has also been shown to be passed down in an autosomal recessive manner as well as X-linked in some cases. An autosomal recessive pattern describes a disease that is passed to the offspring when two mutated copies of a gene are present, while an X-linked mutation is carried on the “X” chromosome of either parent. Genetic testing is necessary to determine whether or not an individual with symptoms of Olmsted syndrome is caused by a mutation in the TRPV3 gene.²

Symptoms of TRPV3

Signs of Olmsted syndrome typically appear at birth or early childhood. As the child begins to walk and grasp, symptoms may start. The disease slowly worsens over the lifetime of the affected individual.² The onset of symptoms usually begins with bilateral palmoplantar keratoderma in addition to hyperkeratotic plaques affecting the skin around the mouth, eyes, ears, nose, navel, and genitals.² The keratoderma starts on the pressure points of the affected area and then extends to most of the surface where it becomes more thickened with painful, deep fissures.² Keratotic lesions can be painful with pressure, present with an itch sensation, and can appear to be focal or punctate. Most individuals with Olmsted syndrome have a form of hair abnormality ranging from sparse to coarse, easily broken hair, or alopecia. Many individuals also have nail involvement. Nails may be rough, rigid, and display hyperkeratosis or irregular curvatures. In some cases, individuals may even have an absence of nails. It is common for individuals diagnosed with Olmsted syndrome to present with a variety of eye lesions and inflamed lacrimal glands.² Olmsted syndrome can present with mild to severe symptoms and every individual is different.² Genetic testing is strongly advised to determine if phenotypic changes are due to this disease.

IPCRR Data for TRPV3

Twenty-nine (29) individuals fully enrolled in the International Pachyonychia Congenita Research Registry (IPCRR) were found not to have PC but instead carry a mutation in TRPV3 gene. Below is select data from the registry.

Palmar Keratoderma	57%
Always (never goes away)	36%
Sometimes (clears up at times)	7%
Seldom (hands usually clear)	14%

Data from 2022 Sample Size N=14

References

1. Zhong W, Hu L, Cao X, et al. Genotype‒Phenotype Correlation of TRPV3-Related Olmsted Syndrome. J Invest Dermatol. 2021;141(3):545-554. doi:10.1016/j.jid.2020.06.035
2. Duchatelet S, Hovnanian A. Olmsted syndrome: clinical, molecular and therapeutic aspects. Orphanet J Rare Dis. 2015;10:33. Published 2015 Mar 17. doi:10.1186/s13023-015-0246-5

Above photos are from individuals in the IPCRR with confirmed TRPV3 mutations.