Pachyonychia congenita

Pachyonychia congenita (often abbreviated as "PC") is a rare group of autosomal dominant skin disorders that are caused by a mutation in one of five different keratin genes. Pachyonychia congenita is often associated with thickened toenails, plantar keratoderma, and plantar pain.
Signs and symptoms.
Pachyonychia congenita is characterized by a clinical triad present in 97% of people with PC by the time they turn 10 years old:
Other signs and symptoms found in PC include:
Cause.
The condition is caused by genetic mutations in one of five genes that encode keratin proteins. Three keratin genes were identified to have a role PC in 1995 with a fourth keratin gene's role in PC identified in 1998.
Inheritance.
Pachyonychia congenita follows an autosomal dominant pattern of inheritance, which means the defective gene is located on an autosome, and only one copy of the gene is required to inherit the disorder from a parent who has the disorder. On average, 50% of the offspring of an affected person will inherit the disorder, regardless of sex.
Occasionally, however, a solitary case can emerge in a family with no prior history of the disorder due to the occurrence of a new mutation (often referred to as a sporadic, spontaneous or de novo mutation).
Diagnosis.
Classification.
ILDS: Q84.520 
ICD-10: Q84.5
Pachyonychia congenita consists of five sub-types, each named after its corresponding genetic mutation and each associated with distinguishing clinical features:
Before the genetic basis of Pachyonychia congenita was identified and described, the disease was historically divided into the following sub-types:
Clinical Diagnosis.
In order to clinically diagnose pachyonychia congenita, the clinical triad of toenail thickening, plantar keratoderma, and plantar pain must be present. This triad is present in 97% of individuals with PC by the age of 10 years old.
Pachyonychia congenita can be suspected in patients who do not have the complete clinical triad but who exhibit other symptoms such as cysts, oral leukokeratosis, follicular hyperkeratosis, palmoplantar hyperhidrosis, or natal teeth. Since PC is inherited in an autosomal dominant fashion in 70% of individuals, it should especially be suspected in patients with symptoms who also have a parent with similar symptoms. Histopathological analysis of skin or nail tissue is not helpful in diagnosis of PC, but can be used to rule out some related diseases. If there is a clinical suspicion for PC, genetic testing can confirm the diagnosis.
Genetic Diagnosis.
The diagnosis of PC can be confirmed by the identification of a mutation in one of the five genes responsible for the condition: "KRT6A, KRT6B, KRT6C, KRT16, KRT17." Pachyonychia Congenita Project is a non-profit dedicated to finding a cure for PC. The organization houses a genetic registry (the International PC Research Registry) and offers free genetic testing for individuals suspected to have PC.
Treatment.
There is currently no cure for pachyonychia congenita. Treatment focuses on symptom relief for any plantar pain, hyperkeratoses, cysts, leukokeratosis, hyperhidrosis, or secondary infections.
Palmoplantar keratoderma can be treated with consistent grooming, including trimming back the callus, applying emollients, and draining blisters. Plantar pain is often treated by reducing pressure on the feet by minimizing walking, wearing cushioned footwear, or using wheelchairs or crutches. Hyperkeratosis can be treated with keratolytic emollients while cysts may be treated with incision and drainage. Patients with hyperhidrosis may need to wear moisture-wicking socks and ventilated shoes. Any secondary infection may need to be treated with antibiotics, though infection can often be prevented with appropriate grooming and vinegar or bleach baths.
Epidemiology.
Pachyonychia congenita is a rare disorder with an unknown prevalence. As of 2018, the International PC Research Registry has identified approximately 774 individuals with the disease, but prevalence is estimated to be 5,000–10,000 worldwide. The disease affects both males and females.
Research.
There are several ongoing investigational therapies for pachyonychia congenita, including topical sirolimus, siRNA, botulinum toxin, statins, and anti-TNF biologics. Pachyonychia Congenita Project houses a list of clinical trials and assists with clinical trial recruitment from patients enrolled in their International PC Research Registry.