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Pachyonychia congenita
This genetic disorder affects the skin, nails, and sometimes the mucous membranes, leading to symptoms like dystrophic (malformed) nails, painful skin lesions, and oral leukokeratosis. It is present from birth or early childhood.
Overview
Pachyonychia congenita (PC) is a rare genetic skin disorder that primarily affects the nails, skin, and sometimes the mucous membranes (the moist inner linings of certain organs and body cavities). The most prominent feature is usually thickened, discoloured, and abnormally shaped nails on both the hands and feet, often present from birth or early infancy [PMID:17961208]. However, the condition can also cause a range of other symptoms, including painful calluses and blisters on the soles of the feet, and white patches in the mouth. PC is a chronic condition, meaning it is long-lasting, and its severity can vary significantly among affected individuals.
While PC is present from an early age, some symptoms may develop or worsen over time. The impact on daily life can range from cosmetic concerns to significant discomfort and functional limitations, especially due to foot pain. PC is classified as a keratinopathy, a group of genetic conditions caused by defects in keratin proteins, which are essential for the structural integrity of skin, hair, and nails.
Symptoms & clinical features
The hallmark symptom of Pachyonychia congenita is thickened, discoloured nails (pachyonychia), which can appear from birth or soon after [PMID:17961208]. These nails may also be brittle, curved, and may lift from the nail bed. Other common skin symptoms include focal plantar keratoderma, which means thickened skin and painful calluses on the soles of the feet, particularly on pressure-bearing areas. These can lead to blistering and significant pain, making walking difficult for some individuals. Similar calluses may also occur on the palms of the hands.
Beyond the nails and feet, other symptoms can include follicular keratosis, which are small, rough bumps that often appear on the elbows, knees, and torso, resembling goosebumps. Some individuals also develop oral leukokeratosis, which are white patches on the tongue and inner cheeks, and these can sometimes be painful or interfere with eating [PMID:17961208]. Less commonly, cysts, particularly steatocystomas (benign cysts arising from sebaceous glands), may occur. Hoarseness and excessive sweating (hyperhidrosis) are also reported in some individuals with PC.
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Affected organs
Pachyonychia congenita predominantly affects organs and tissues that rely heavily on keratin proteins for their structure and function. The primary affected systems are the skin, including the nails, and the mucous membranes. The nails on both hands and feet are typically involved, showing significant thickening and other abnormalities. The skin of the palms and soles is commonly affected, leading to painful calluses and blisters due to abnormal keratinisation.
Other skin areas can also be involved, presenting with follicular keratosis. The mucous membranes, particularly those lining the mouth, may develop white patches. In some cases, the larynx (voice box) can be affected, leading to hoarseness, and there may also be involvement of the sweat glands, causing increased sweating.
Risks & severity
Pachyonychia congenita is a rare condition with a wide spectrum of severity; some individuals experience mild symptoms, while others face significant discomfort and functional limitations. The most impactful symptoms are often the painful calluses and blisters on the feet, which can severely affect mobility and quality of life. The severity of symptoms can also vary even within the same family.
Symptoms typically begin at birth or during early childhood, with nail changes often being the first sign. The pain associated with plantar keratoderma tends to worsen over time, especially with increased activity or weight-bearing. The condition is chronic, and its manifestations can change throughout an individual's life. Exact prevalence is not well established due to its rarity.
Genetic causes
Pachyonychia congenita is caused by pathogenic variants in genes that produce keratin proteins. Keratins are a family of tough, fibrous proteins that are fundamental structural components of skin, hair, and nails, providing strength and flexibility. When these proteins are abnormal, the affected tissues cannot form correctly, leading to the symptoms observed in PC.
Specifically, PC can be caused by variants in KRT6A, KRT16, and KRT17 [PMID:23522108]. These genes encode different types of keratin proteins that are crucial for the integrity of cells in the epidermis (the outermost layer of skin), nails, and mucous membranes. A pathogenic variant in one of these genes means that the keratin protein produced is faulty, which disrupts the normal structure and function of the cells, resulting in the characteristic features of PC. Different variants within these genes may lead to variations in the specific symptoms and their severity.
- KRT16 keratin 16
- KRT17 keratin 17
- KRT6A keratin 6A
Inheritance pattern
Pachyonychia congenita is inherited in an autosomal dominant pattern. This means that a person only needs to inherit one copy of the altered gene from a parent to develop the condition. If one parent has PC, there is a 50% chance that each child they have will also inherit the condition, regardless of the child's sex.
In many cases, an affected individual has inherited the pathogenic variant from a parent who also has the condition. However, PC can also occur as a result of a new (de novo) pathogenic variant in a person with no family history of the disorder. In such cases, the variant arises spontaneously in the affected individual and was not present in either parent's germ cells.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
Diagnosis & testing
Diagnosis of Pachyonychia congenita is typically made based on a thorough clinical examination of characteristic symptoms, including the nail dystrophy, plantar keratoderma, and other skin findings. However, a definitive diagnosis requires genetic testing to identify a pathogenic variant in one of the associated genes (KRT6A, KRT16, or KRT17).
Genetic testing for PC is available through the NHS Genomic Medicine Service (GMS) via an appropriate referral. A clinical geneticist or dermatologist can refer individuals for testing if PC is suspected. The relevant NHS National Genomic Test Directory R-code for Pachyonychia congenita is R157. Genetic counselling is often offered before and after testing to discuss the implications of the diagnosis for the individual and their family.
Management & lifestyle
Management of Pachyonychia congenita focuses on alleviating symptoms and improving quality of life, as there is currently no cure. Treatment strategies are highly individualised and managed by a multidisciplinary team, which may include dermatologists, pain specialists, and podiatrists. For the painful calluses on the feet, regular debridement (careful removal of thickened skin) by a podiatrist can help reduce pain and improve mobility.
Topical treatments, such as emollients and keratolytics (creams that soften and shed the outer layer of skin), may be used to manage thickened skin and follicular keratosis. Pain management is crucial, and strategies may include special footwear, orthotic inserts, and sometimes systemic medications. Research continues into targeted therapies, but current management is primarily supportive and symptomatic. Individuals with PC should remain under regular medical review within the NHS care pathway, and genetic counsellors can provide ongoing support and information.
UK care pathway
In the UK, individuals suspected of having Pachyonychia congenita are typically referred to a clinical geneticist or dermatologist through their GP. These specialists can assess the clinical features and, if appropriate, initiate genetic testing through the NHS Genomic Medicine Service (GMS) using the National Genomic Test Directory R-code R157. Following a confirmed diagnosis, ongoing care is coordinated by specialists within the NHS, often involving a multidisciplinary team to manage various symptoms. Genetic counsellors are available to provide support, information, and discuss inheritance patterns and family planning options.
Frequently asked questions
Can Pachyonychia congenita be cured?
Currently, there is no cure for Pachyonychia congenita. Management focuses on treating the symptoms and improving comfort and quality of life. Research is ongoing into new therapies.
Is Pachyonychia congenita painful?
Many individuals with Pachyonychia congenita experience pain, particularly from the thickened skin and calluses on the soles of their feet, which can make walking difficult. Pain management is a key part of treatment.
How does Pachyonychia congenita affect daily life?
The impact on daily life varies. While some individuals have mild symptoms, others may experience significant discomfort from foot pain, limiting mobility. Nail changes can also cause difficulties with fine motor tasks, and oral lesions can affect eating or speaking. Support and appropriate management can help.
If I have Pachyonychia congenita, will my children get it?
Pachyonychia congenita is inherited in an autosomal dominant pattern. If you have the condition, each of your children has a 50% chance of inheriting the pathogenic variant and developing PC. Genetic counselling can provide more specific information and support.
Where can I find support for Pachyonychia congenita in the UK?
Your clinical genetics team and genetic counsellor can provide support and signpost you to patient organisations or charities. Within the NHS, dermatologists and podiatrists will help manage your care. National organisations may also offer community support.
References
- Nahmani L, Fitoussi F. Congenital nail abnormalities. Hand surgery & rehabilitation. 2024. PMID: 38879228
- Weinberg RL, Kim S, Pang Z. Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2024. PMID: 38866482
- Knöbel M, O'Toole EA, Smith FJ. Keratins and skin disease. Cell and tissue research. 2015. PMID: 25620412