Background

• Pachyonychia congenita is a rare genetic disorder characterized by various abnormalities affecting the nails, skin, hair, and oral mucosa. It is primarily an autosomal dominant genetic condition, which means that a mutation in a single gene from one parent causes disorder. There are two main subtypes of pachyonychia congenita: PC-1 and PC-2.
• PC-1, caused by mutations in the KRT16 gene, is also known as Jadassohn-Lewandowsky syndrome. PC-1 is characterized by hypertrophic nail changes (pachyonychia), palmoplantar keratoderma (thickened skin on the palms and soles), cysts, and sometimes oral leukokeratosis (white patches on the oral mucosa). The severity of symptoms varies among the individuals with PC-1.
• PC-2, caused by mutations in the KRT6A, KRT6B, KRT6C, or KRT6D genes, is also known as Jackson-Lawler syndrome. It shares some clinical features with PC-1, including nail abnormalities and palmoplantar keratoderma. However, PC-2 tends to have milder nail changes and more prominent painful blisters and calluses on the hands and feet.
• Both subtypes of pachyonychia congenita are relatively rare, and their symptoms can have a significant impact on an individual’s quality of life. The disorder is diagnosed depending on the clinical presentation and confirmed through genetic testing. While there is currently no cure for pachyonychia congenita, treatment is focused on managing the specific symptoms and providing relief from discomfort and pain. This may include measures like softening the thickened skin, managing blisters and calluses, and addressing nail abnormalities. Given the complexity of the disorder, a multidisciplinary approach involving dermatologists, geneticists, and other specialists may be necessary to provide comprehensive care.

Epidemiology

Prevalence:

• PC is considered to be an extremely rare disorder, with estimated prevalence rates varying between 1 in 200,000 to 1 in 500,000 individuals worldwide.
• It affects individuals of all races and ethnic backgrounds, without a significant gender predilection.

Subtypes and Genetic Factors:

• PC is classified into two main subtypes: PC-1 and PC-2, each associated with distinct genetic mutations.
• PC-1 is caused by mutations in the KRT16 gene, while PC-2 is associated with mutations in the KRT6A, KRT6B, KRT6C, or KRT6D genes.
• The rarity of the disorder is partly attributed to the specific mutations required for its development.

Onset and Presentation:

• PC is usually present from birth or becomes evident during early childhood.
• Its clinical presentation involves a combination of nail changes, palmoplantar keratoderma (thickened skin on the palms and soles), and, in some cases, oral mucosal lesions.

Inheritance Patterns:

• PC is primarily inherited in an autosomal dominant manner, meaning that individuals with a single mutated gene from one parent can develop the disorder.
• However, de novo mutations (mutations occurring for the first time in an affected individual) can also contribute to the occurrence of PC.

Geographic Distribution:

• PC has been reported worldwide, with cases documented across different regions and populations.
• Due to its rarity, there might be geographic variations in the prevalence of PC.

Genetic Counseling and Management:

• Genetic counseling is an essential aspect of managing PC, as affected individuals and their families may have questions about inheritance patterns and the likelihood of passing on the disorder to their offspring.

Anatomy

Pathophysiology

Genetic Mutations:

• PC-1 is caused by mutations in the KRT16 gene, and PC-2 is caused by mutations in the KRT6A, KRT6B, KRT6C, or KRT6D genes. These genes encode different keratin proteins.
• Mutations in these genes disrupt the normal assembly and structure of keratin filaments, which are essential for maintaining the structural integrity of the affected tissues.

Keratin Filaments:

• Keratin filaments provide mechanical strength and resilience to various tissues, including the skin, nails, and hair.
• These filaments are composed of keratin proteins that form a network, helping cells withstand mechanical stress and maintain their shape.

Effects on Tissues:

• The mutations in PC lead to the formation of abnormal keratin filaments, which in turn cause a range of clinical manifestations.
• Thickening of skin on palms and soles (palmoplantar keratoderma) occurs due to the accumulation of keratinocytes.
• Nail abnormalities, such as hypertrophic nails (pachyonychia), are a result of disrupted keratin filament organization in the nail matrix.
• Painful blisters and calluses can form due to increased mechanical stress on the skin.

Cellular Disruption:

• The abnormal keratin filaments disrupt cellular processes within affected tissues.
• This disruption can lead to various signs and symptoms, including inflammation, hyperkeratosis (excessive thickening of the skin), and the formation of cysts.

Clinical Variability:

• The clinical presentation and severity of PC is likely due to the specific nature of the mutations and their effects on keratin filament formation.
• Different mutations can result in varying degrees of abnormal keratin assembly and cellular disruption.

Etiology

Genetic Mutations:

• PC-1 is caused by mutations in the KRT16 gene, and PC-2 is caused by mutations in the KRT6A, KRT6B, KRT6C, or KRT6D genes. These genes encode keratin proteins that are crucial for maintaining the integrity of various tissues.
• The mutations result in abnormal keratin filament assembly and disrupt cellular processes, leading to the characteristic features of PC.

Inheritance Patterns:

• Pachyonychia congenita is primarily inherited in autosomal dominant manner. This means the affected individual has a 50% chance of passing mutated gene to their offspring.
• However, not all individuals with a mutated gene develop severe symptoms, and there can be variability in clinical presentation even within affected families.

De Novo Mutations:

• In some cases, individuals can develop PC due to de novo mutations. These are mutations that occur for the first time in the affected individual and are not inherited from their parents.
• De novo mutations can explain cases where there is no family history of the disorder.

Genetic Variability:

• The specific genetic mutations in PC can vary among affected individuals, contributing to the heterogeneity in clinical presentation.
• Different mutations can result in different degrees of disruption to keratin filament formation and cellular function.

Mutation Types:

• The mutations in PC can include missense mutations (altering a single amino acid), insertions, deletions, and other structural changes in the keratin genes.

Genetics

Prognostic Factors

Genetic Mutation:

• The specific genetic mutation causing PC can influence the severity and types of clinical manifestations.
  Certain mutations may result in more severe symptoms, while others might lead to milder presentations.
  The severity and extent of symptoms, such as palmoplantar keratoderma (thickened skin on palms and soles) and nail abnormalities, can vary widely.
  Individuals with milder forms of PC may experience less impact on their daily lives compared to those with more severe manifestations.

Management and Treatment: 

• Early diagnosis & appropriate management can significantly improve prognosis and quality of life for individuals with PC.
  Regular follow-up with healthcare professionals, dermatologists, and other specialists can help address symptoms and prevent complications.

Complications: 

• Some individuals with PC may experience complications such as recurrent infections, painful calluses, and blistering.
  The presence of complications can impact the prognosis and require careful management.

Supportive Care: 

• Adequate supportive care, including proper skin and nail care, can improve comfort and function for individuals with PC.

Response to Treatment: 

• The response to various treatment strategies, such as topical therapies, surgical interventions, and other medical approaches, can influence the prognosis.

Psychosocial Well-being: 

• The psychosocial impact of PC, including self-esteem, body image, and emotional well-being, can affect an individual’s overall quality of life.

Clinical History

Age of Onset:

• Pachyonychia congenita can manifest at different ages. Some individuals may show symptoms from birth or infancy, while others may develop symptoms later in childhood or adolescence.

Physical Examination

Skin:

• The dermatologist will examine the skin on the palms, soles, and other areas for signs of palmoplantar keratoderma, a hallmark feature of PC. This may include thickened, hyperkeratotic skin with a yellowish hue.
• Blisters, calluses, and areas of friction or pressure on the skin will be assessed to understand their impact on daily functioning and discomfort.

Nails:

• The nails will be closely examined for changes such as thickening, deformities, discoloration, and subungual hyperkeratosis (thickening under the nails).
• The dermatologist may also assess any involvement of the nail beds and surrounding skin.

Mucous Membranes:

• If mucous membranes are affected, the oral cavity and throat will be examined for the presence of blisters, lesions, or any signs of discomfort.

Hair and Hair Follicles:

• Hair abnormalities, if present, will be evaluated. These may include changes in hair texture, excessive sweating, and other related features.

Mobility and Functional Impact:

• The dermatologist will assess the individual’s mobility, particularly in cases of severe palmoplantar keratoderma, to understand any challenges in walking or daily activities.

Age group

Associated comorbidity

• People with PC may experience complications such as recurrent infections due to disrupted skin barrier function and blistering.
• The impact of the disorder on mobility, especially in cases with severe palmoplantar keratoderma, can lead to challenges in daily activities and discomfort.

Associated activity

Acuity of presentation

• The acuity of presentation can vary. Some individuals may have relatively mild symptoms that do not significantly affect their daily lives, while others may experience more severe manifestations that require medical attention.
• The presence of painful symptoms, difficulty walking, or complications like infections may lead to more urgent medical evaluation.

Differential Diagnoses

Hereditary Palmoplantar Keratodermas (PPKs):

• Several other types of hereditary palmoplantar keratodermas can have overlapping features with PC.
• Examples include diffuse nonepidermolytic palmoplantar keratoderma (Vörner type) and focal palmoplantar keratoderma (tylosis).

Mal de Meleda:

• Mal de Meleda is the rare autosomal recessive disorder characterized by symmetric palmoplantar keratoderma, similar to PC.
• It can be differentiated by the specific distribution pattern and clinical features.
• Epidermolytic Hyperkeratosis (Epidermolytic Ichthyosis):
• This is a genetic disorder that causes thickened, hyperkeratotic skin similar to PC, but it is usually generalized rather than restricted to palms and soles.
• Blisters and changes in skin texture are also characteristic.

Palmoplantar Keratoderma with Deafness:

• Some syndromes involve both palmoplantar keratoderma and hearing loss, such as Vohwinkel syndrome and Bart-Pumphrey syndrome.

Palmoplantar Ectodermal Dysplasias:

• These rare genetic disorders affect the development of skin, hair, nails, and teeth.
• They can manifest with palmoplantar keratoderma and other ectodermal abnormalities.

Laboratory Studies

Imaging Studies

Procedures

Histologic Findings

Staging

Treatment Paradigm

Diagnosis and Genetic Counseling:

• Accurate diagnosis through clinical examination and genetic testing.
• Genetic counseling for individuals and their families to understand the inheritance pattern, prognosis, and potential risks.

Symptomatic Relief and Acute Management:

• Immediately focus on alleviating acute symptoms such as pain, blisters, and discomfort.
• Topical treatments to soften and thin thickened skin, and management of blisters.
• NSAIDs or other pain management strategies to address pain and inflammation.

Long-Term Management:

• Long-term management plan tailored to the individual’s symptoms and needs.
• Regular follow-up with dermatologists or specialists experienced in managing genodermatoses.

by Stage

by Modality

Chemotherapy

Radiation Therapy

Surgical Interventions

Hormone Therapy

Immunotherapy

Hyperthermia

Photodynamic Therapy

Stem Cell Transplant

Targeted Therapy

Palliative Care

non-pharmacological-treatment-of-pachyonychia-congenita

Lifestyle modifications:

Skin Care:

• Use mild, fragrance-free skincare products to avoid irritating the skin.
  Keep the affected areas moisturized to help alleviate dryness and cracking.

Footwear and Clothing:

• Choose comfortable, well-fitting shoes and socks to minimize friction and pressure on the feet.
  Opt for loose-fitting clothing that reduces friction and irritation on the skin.

Nail Care:

• Regularly trim and file nails to prevent ingrown nails and reduce the risk of infections.
  Consider seeking professional nail care to prevent nail-related complications.

Physical Activity:

• Engage in low-impact exercises that do not exacerbate skin and nail symptoms.
  Be mindful of activities that may cause friction or pressure on affected areas.

Pain Management:

• Work with your healthcare provider to manage any pain or discomfort associated with the condition.
  Over-the-counter pain relievers or prescribed medications may be recommended.

Use of Oral retinoids in the treatment of Pachyonychia congenita

Oral retinoids like acitretin and isotretinoin, are occasionally used in the treatment of certain subtypes of Pachyonychia congenita (PC) to manage its skin-related symptoms. It is important to note that the effectiveness of these medications can vary based on the subtype of PC and individual patient response. Here is how they can be used in the treatment of PC.

• Acitretin: It is a synthetic retinoid commonly used to treat various skin disorders, including some subtypes of PC.
• Mechanism of Action: Acitretin helps normalize the keratinization process of the skin, which can help reduce the thickening and scaling of the skin seen in PC.
• Administration: Acitretin is taken orally in the form of capsules.
• Use in Pachyonychia Congenita: Acitretin might be considered for individuals with PC who have severe skin involvement, thickened and hyperkeratotic palms and soles, and painful calluses.
• Isotretinoin: It is used to treat severe acne and is occasionally considered for some subtypes of PC.
• Mechanism of Action: Isotretinoin reduces sebum production and helps normalize skin cell turnover, which can benefit individuals with thickened and hyperkeratotic skin seen in PC.
• Administration: Isotretinoin is taken orally in the form of capsules.
• Use in Pachyonychia Congenita: Isotretinoin may be considered for individuals with PC who have significant skin symptoms, particularly those involving sebaceous glands.

Use of Botulinum toxin in the treatment of Pachyonychia congenita

Botulinum toxin, also known as Botox, is a neurotoxin that is used for various medical and cosmetic purposes. While it is not a standard treatment for Pachyonychia congenita (PC), there have been some reports of its use to alleviate certain symptoms associated with the condition.

Hyperhidrosis (Excessive Sweating):

Excessive sweating (hyperhidrosis) is a common symptom in some subtypes of Pachyonychia congenita, particularly in PC-1.
Mechanism of Action: Botulinum toxin injections can temporarily block the signals that cause sweat glands to produce sweat, reducing excessive sweating.

Administration: Injected directly into the affected areas where excessive sweating occurs, such as the palms, soles, or underarms.

Use in Pachyonychia Congenita: Botulinum toxin injections might be considered to manage hyperhidrosis in individuals with PC-1 subtype.

Pain Management:

Painful calluses and thickened skin can cause discomfort in some individuals with Pachyonychia congenita.
Mechanism of Action: Botulinum toxin injections can temporarily weaken specific muscles, potentially reducing pressure and friction on affected areas.

Administration: Injected into the muscles around the affected areas to relieve pressure and pain.

Use in Pachyonychia Congenita: Botulinum toxin injections might be considered as part of a comprehensive pain management strategy for individuals with painful calluses.

Use of Rapamycin (sirolimus) in the treatment of Pachyonychia congenita

Rapamycin (Sirolimus):

Rapamycin, also known as sirolimus, is an immunosuppressant medication investigated for its potential therapeutic effects in various medical conditions, including rare genetic disorders. While there is limited research on the use of rapamycin in the treatment of Pachyonychia congenita (PC), some studies and case reports suggest it may positively impact certain symptoms associated with the condition. However, it is important to note that the use of rapamycin for PC is still experimental and not considered a standard treatment. Here’s how rapamycin might be used in the Context of PC.

Mechanism of Action: Rapamycin inhibits a protein called mTOR (mammalian target of rapamycin), which plays a role in cell growth and proliferation. By inhibiting mTOR, rapamycin can impact various cellular processes, including protein synthesis and immune responses.

Use of Keratolytics in the treatment of Pachyonychia congenita

• Keratolytics are topical medications used to soften and remove the outer layer of thickened skin, often seen in conditions like Pachyonychia congenita (PC). While they do not cure the underlying genetic cause of PC, keratolytic can help manage the symptoms associated with thickened and hyperkeratotic skin.

Salicylic Acid Topical:

• Salicylic acid is a common keratolytic used to soften and exfoliate thickened skin.
• Mechanism of Action: Salicylic acid helps break down the keratin protein in the outer layer of skin, promoting gentle peeling and shedding of dead skin cells.

Application:

• Topical salicylic acid preparations are applied directly to the affected areas of thickened skin.
• Use in Pachyonychia Congenita: Salicylic acid topical can be used to soften and thin hyperkeratotic skin seen in PC.

Urea (Ureacin-40):

• Urea-containing creams, such as Ureacin-40, are also used as keratolytic.

Mechanism of Action:

• Urea has both keratolytic and moisturizing properties. It helps soften and hydrate the skin while promoting exfoliation.

Application:

• Urea creams are applied topically to the affected areas.
• Use in Pachyonychia Congenita: Urea creams can help soften and improve the texture of hyperkeratotic skin in PC.

Use of Statins in the treatment of Pachyonychia congenita

• Statins are primarily used to lower cholesterol levels and are not typically prescribed to treat the skin and nail symptoms associated with PC. PC is caused by mutations in specific genes, and its management focuses on symptomatic relief rather than targeting the underlying genetic cause.
• Statins like rosuvastatin are primarily prescribed to manage high cholesterol levels & decrease the risk of cardiovascular disease. Statins act by inhibiting an enzyme involved in cholesterol production in the liver. The use of statins for the treatment of PC is not supported by evidence or medical guidelines.

various-procedures-involved-in-pachyonychia-congenita

Callus Removal:

Painful calluses or hyperkeratotic lesions on the palms and soles.

Procedure: Callus removal involves carefully debriding and thinning the thickened skin to relieve pressure, discomfort, and pain.

Podiatrists or dermatologists skilled in treating rare skin disorders can perform this procedure.

Nail Management:

Thickened and dystrophic nails, a common symptom in PC.

Procedures: Nail reduction: Thinning and reducing the thickness of the nails to improve their appearance and prevent them from causing discomfort.

Nail avulsion: Partial or complete removal of a nail that is causing pain or recurrent infection.

Custom Orthotics or Insoles:

Hyperkeratotic lesions or painful calluses on the feet.

Procedure: Custom-made orthotics or insoles are designed to provide cushioning and redistribute pressure on the feet, reducing the risk of callus formation.

Surgical Excision:

Large, painful, or problematic hyperkeratotic lesions or cysts that do not respond to conservative treatments.

Procedure: Surgical excision involves removing the problematic lesion or cyst under local or general anesthesia.

Surgical options should be discussed with a specialist experienced in rare skin disorders.

Supportive Wound Care:

For individuals with PC who develop wounds, ulcers, or blisters that are prone to infection or slow healing.

Procedure: Application of specialized dressings, wound care techniques, and infection prevention strategies.

management-of-pachyonychia-congenita

1. Acute Phase:

Symptomatic Relief:

• Addressing immediate symptoms such as pain, discomfort, and skin irritation.
• Management of painful calluses, blisters, and thickened nails that can cause acute discomfort.

Wound Care:

• Treating and preventing infection in any open sores, ulcers, or blisters.
• Applying appropriate dressings to promote healing and reduce the risk of complications.

Pain Management:

• Addressing acute pain associated with skin lesions, calluses, and related complications.
• Providing pain relief strategies to improve the patient’s immediate comfort.

Acute Infections:

Treating any acute infections that may arise due to skin breakdown or complications.

2. Chronic Phase:

Symptom Management:

Developing a long-term plan to manage chronic symptoms such as hyperkeratosis, painful calluses, and nail abnormalities.

Skin Care:

Implementing a regular skin care regimen to moisturize and maintain the skin’s integrity.

Nail Management:

Regularly trimming and managing nails to prevent discomfort and reduce the risk of infections.

Pain Management:

Developing strategies for ongoing pain management, which might involve a combination of medications and procedures.

Preventive Measures:

Identifying and addressing triggers that exacerbate symptoms and taking steps to prevent their occurrence.

Medication

Future Trends

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References

www.Overview of Pachyonychia Congenita.ncbi.nlm.nih.gov

www.Pachyonychia Congenita.ncbi.nlm.nih.gov