What Is Pachyonychia Congenita?

• Pachyonychia congenita (or PC) is a rare hereditary disorder
• This causes an excessive buildup of keratin to be formed on the skin, nails, and mucosal surfaces
• Mutations affect one of 5 keratin genes
• Clinical features depend on which gene is affected

Overview

Pachyonychia congenita (PC) is a rare autosomal dominant disorder causing abnormal growth of the protein keratin. As keratin is found on the outermost layer of the skin and nails, these areas are greatly affected, causing a multitude of clinical features. These features can depend on which keratin gene is affected by the mutation, however, symptoms can often be very painful and can manifest as early as 1 month after birth.

Whilst there is currently no cure for PC, ongoing clinical trials and existing treatment and management options are available. 

Causes of pachyonychia congenita

The causes of PC are genetic mutations affecting 1 of 5 keratin (KRT) genes. KRT genes encode for keratin cytoskeletal proteins which are responsible for the structure of keratin proteins. When the KRT genes are mutated, this prevents the proteins from becoming strong and fibrous. This causes the epithelial tissue (primarily of the palms and soles) to become fragile and in some cases, structural abnormalities of the nails.⁵

This disorder is termed an autosomal dominant disorder, meaning that there is a 50% chance of passing down the disorder during pregnancy if only one parent is affected. If both parents are affected, there is a 100% chance of it being passed down. However, cases of sporadic mutation, (mutations which occur with no known cause), have been identified in families with no family history of the disorder. 

Types of pachyonychia congenita

Historically, PC fell within two subgroups depending on their clinical features. This includes PC type 1 or PC type 2. However, data collected via the International PC Research Registry (IPCRR) has shown considerable clinical feature overlaps between PC subtypes. As such, we now divide PC into five subtypes, depending on which gene is affected by the mutation. 

These include: 

• PC-K6A: This affects the KRT6A gene. Patients with this genetic mutation have an early onset of symptoms compared to other mutations. They may also have more extensive nail disease and worsened disease outside of the soles and palms. According to the IPCRR, there is a higher reported prevalence of oral leukokeratosis (white/grey patches which develop in the mouth) compared to other mutations¹
• PC-K6B: Clinical differences occurring in the PC-K6B subtype include the late onset of symptoms, with less frequent occurrence of keratoderma (skin thickening) and fingernail dystrophy
• PC-K6C: This mutation exhibits mild clinical features when compared to other PC mutations²
• PC-K16: This mutation is commonly associated with severe pain in the sole of the foot, with 94% of patients describing this as very painful or requiring pain relief medication³
• PC-K17: This mutation is commonly associated with the formation of natal teeth (teeth already present at birth) (75% of K17 patients) and cysts (90% of patients) according to IPCRR data⁴

Signs and symptoms of pachyonychia congenita

There are a multitude of clinical features which may be present depending on the gene affected. 

Symptoms affecting the nails: 

• Hypertrophic nail dystrophy (hard, thickened nail plate)
• Brownish colouration of the nails
• Affects all fingernails and can affect toenails to a lesser extent

Symptoms affecting the palms and soles:

• Palmoplantar keratoderma or hyperkeratosis (thickening or calloused palm and soles)
• Palmoplantar hyperhidrosis (excessive sweating from the palm and soles)
• Blistering on palms and soles caused by a warm environment and friction
• Plantar (sole) pain 

Symptoms affecting the skin:

• Follicular keratosis (painless dry, rough patches of skin with tiny bumps) located on the extremities and trunk. This symptom is less noticeable during adulthood
• Pilosebaceous cysts (at the hair follicle)
• Steatocystoma cysts
• Cysts can be painful or non-painful 

Symptoms affecting the mouth and larynx (voice box):

• Oral leukokeratosis (white patched lesions located on the tongue or cheek)
• Angular cheilitis (red swollen patches on the corner of the mouth) 
• Natal or prenatal teeth (teeth present when the baby is born). This is mainly associated with patients with the K17 mutation
• First bite syndrome (mouth pain when taking the first bite of food or salivating)
• Hoarseness of voice or airway obstruction

Management and treatment for pachyonychia congenita

Podiatry treatment and management 

Podiatry treatment aims to reduce the risk of secondary complications associated with PC. This includes bacterial or fungal infection to the skin or nails after grooming or trauma. This can be avoided by:

• Maintaining nail length through regular trimming or surgical removal in some cases
• Using antibiotics or anti-fungal creams if infection occurs 
• Utilising a ‘bleach bath’ regime to prevent infection
• Avoiding high-temperature or high-humidity environments

Secondly, reducing pain from palmoplantar keratoderma can include:

• Use of cushioned and comfortable footwear
• Use of ventilated footwear
• Maintaining ideal body weight
• Minimising walking or standing
• Using wicking socks

Maintaining good oral hygiene

The use of a soft toothbrush and gentle brushing on mucosal surfaces within the mouth can improve white oral lesions. 

Cyst drainage

Cysts can be drained if they are painful or causing aesthetic concerns. This may require an incision across the cyst or full removal. 

Pain relief medications

Use of ointments including:

• Emollient ointments
• Urea cream
• Balms for dry skin
• Salicylic ointment 

Oral retinoids

Research conducted using oral retinoids has observed thinning of hyperkeratosis, however, this treatment did not affect underlying blistering or skin fragility.⁶ Overall, a majority of patients discontinued medication use due to adverse side effects associated with the inefficacy of treatment, and some patients reported increased pain. 

Clinical trials

Whilst PC is rare, multiple ongoing clinical trials are exploring effective treatment methods for patients. This includes research involving: 

• Short interfering RNA (siRNA) in blocking disease-causing gene variant expression. siRNA-based therapeutics such as rapamycin injected into calluses of the skin have been shown to reduce pain, skin fragility, keratoderma, and ambulatory impairment⁷
• Botulinum toxin for the treatment of pain and blistering has also shown promising results in treating hyperkeratosis/keratoderma. Research has noted no side effects and an improvement in patients' quality of life^8,9

FAQs

How is pachyonychia congenita diagnosed?

PC is diagnosed following the identification of clinical features alongside genetic testing for gene variants associated with the disorder (KRT6A, KRT6B, KRT6C, KRT16, and KRT17). 

Symptoms are similar to that of Clouston syndrome. This syndrome has a variable clinical presentation which seemingly mimics nail/hair dysplasia and is seen in PC. Research has shown some patients are misdiagnosed with PC when they may be suffering from Clouston syndrome.¹¹ 

Genetic testing is recommended to provide a correct molecular diagnosis to improve patient care. 

Can pachyonychia congenita be prevented?

There are currently no known methods to prevent PC.  

Who is at risk of pachyonychia congenita?

• PC is an autosomal dominant disorder. Therefore, there is a 50% chance of PC being passed on to their offspring if only one parent is affected and a 100% chance of PC being passed on if both parents are affected¹⁰
• According to data collected by the IPCRR, 70% of PC patients inherited the disorder from a parent¹⁰
• Around 30% of cases are due to a de novo mutation (a pathogenic genetic variant noted in one family member for the first time)

How common is pachyonychia congenita?

PC is estimated to affect between 1,000 to 10,000 patients worldwide.  

When should I see a doctor?

PC should be examined by a medical professional to discuss options to improve quality of life and reduce the chance of secondary infection. Understanding clinical features is vital, and whilst the disorder is not fatal, laryngeal symptoms (affecting the voice box) can be life-threatening as the airway can become obstructed.     

Summary

• PC mainly affects an individual's skin and nails due to abnormal keratin production 
• PC is not generally life-threatening (except for laryngeal symptoms). However, this disorder causes significant pain and can reduce a person's quality of life
• Whilst it is a rare disorder, dedicated research and clinical trials are being conducted to aim to provide effective treatment options