Pachyonychia congenita (PC) is a very rare genetic disorder that affects the skin and nails. The symptoms usually begin at birth or early in life, and the condition affects people of both sexes and all racial and ethnic groups.

PC is caused by mutations affecting keratins, proteins that provide structural support to cells, and it is classified into five types based on which keratin gene harbors the mutation. Symptoms vary from person to person and depend on the type, but thickened nails and calluses on the soles of the feet occur in almost all cases. The most debilitating symptom is painful calluses on the soles that make walking difficult. Some patients rely on a cane, crutches, or a wheelchair to help manage the pain of walking.

There is no specific treatment for PC, but there are ways to manage the symptoms, including the pain.

People who have pachyonychia congenita have a mutation in one of five keratin genes. Researchers have found more than 115 mutations in these genes that are linked to the disorder. In some cases, PC is inherited from a parent, while in others, there is no family history and the cause is a spontaneous mutation. The disorder is genetically dominant, which means that a single mutated gene copy is enough to cause the condition. PC is very rare. It affects people of both sexes and all racial and ethnic groups.

There are five types of pachyonychia congenita, and they are classified based on the keratin gene that is altered. Thickened nails and painful calluses on the soles of the feet are typical of all forms of the disorder, but the presence of other features can depend on which keratin gene is affected, and possibly on the specific mutation.

The symptoms and severity of PC can vary widely, even among people with the same type or in the same family. Most symptoms typically appear within the first months or years of life.

The most common features of PC include:

• Painful calluses and blisters on the soles of the feet. In some cases, the calluses itch. Calluses and blisters may also form on the palms of the hands.
• Thickened nails. Not all nails are affected in every patient with PC, and some people do not have any thickened nails. But the vast majority of patients have some affected nails.
• Cysts of various types.
• Bumps around hairs at friction sites, such as the waist, hips, knees, and elbows. They are most common in children and lessen after the teenage years.
• White film on the tongue and inside the cheeks.

Less common features of PC include:

• Soresat the corners of the mouth.
• Teeth at or before birth.
• White film on the throat, resulting in a hoarse voice.
• Intense pain on first bite (“first bite syndrome”). The pain is near the jaw or ears and lasts 15–25 seconds when beginning to eat or swallow. This is more common in younger children and may cause feeding difficulties for some infants. It typically goes away during the teenage years.

Pachyonychia congenita is caused by mutations in genes that encode keratins, proteins that are the main structural components of skin, nails, and hair. The mutations prevent keratins from forming the strong network of filaments that normally gives skin cells strength and resilience. As a result, even normal activities like walking can cause cells to break down, ultimately leading to the painful blisters and calluses that are the most debilitating features of the disorder.

Normal Function

The KRT6A gene provides instructions for making a protein called keratin 6a or K6a. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, nails, and similar tissues. Keratin 6a is produced in the nails, the skin on the palms of the hands and soles of the feet, and the oral mucosa that lines the inside of the mouth.

Keratin 6a partners with a similar protein, keratin 16, to form molecules called keratin intermediate filaments. These filaments assemble into dense networks that provide strength and resilience to the skin, nails, and other tissues. Networks of keratin intermediate filaments protect these tissues from being damaged by friction and other everyday physical stresses. Keratin 6a is also among several keratins involved in wound healing.

Health Conditions Related to Genetic Changes

Pachyonychia congenita

About 40 mutations in the KRT6A gene have been identified in people with pachyonychia congenita, a rare condition that primarily affects the nails and skin. In most cases, this condition becomes apparent within the first few months of life. Most of these mutations change single protein building blocks (amino acids) in keratin 6a. A few mutations add or delete a small number of amino acids.

The KRT6A gene mutations responsible for pachyonychia congenita change the structure of keratin 6a, preventing it from interacting effectively with keratin 16 and interfering with the assembly of the keratin intermediate filament network. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of severe, painful blisters and calluses. Additionally, fragile skin cells may abnormally produce more keratin in response to damage, which makes the skin problems worse. Defective keratin 6a also disrupts the growth and function of other tissues, such as the hair follicles and nails, which explains why the signs and symptoms of pachyonychia congenita can also affect these other parts of the body.

Other Names for This Gene

• 56 cytoskeletal type II keratin
• CK 6A
• CK6A
• CK6C
• CK6D
• cytokeratin 6A
• cytokeratin-6A
• K2C6A_HUMAN
• K6A
• K6C
• K6D
• keratin 6A, type II
• keratin, epidermal type II, K6A

Genomic Location

Normal Function

The KRT6B gene provides instructions for making a protein called keratin 6b or K6b. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, and nails. Keratin 6b is produced in the nails, the hair follicles, and the skin on the palms of the hands and soles of the feet. It is also found in the skin's sebaceous glands, which produce an oily substance called sebum.

Keratin 6b partners with a similar protein, keratin 17, to form molecules called keratin intermediate filaments. These filaments assemble into dense networks that provide strength and resilience to the skin, nails, and other tissues. Networks of keratin intermediate filaments protect these tissues from being damaged by friction and other everyday physical stresses. Keratin 6b is also among several keratins involved in wound healing.

Health Conditions Related to Genetic Changes

Pachyonychia congenita

At least four mutations in the KRT6B gene have been identified in people with pachyonychia congenita, a rare condition that primarily affects the nails and skin. In most cases, this condition becomes apparent within the first few months of life. These mutations either change single protein building blocks (amino acids) in keratin 6b or delete a small number of amino acids from the protein.

The KRT6B gene mutations responsible for pachyonychia congenita change the structure of keratin 6b, preventing it from interacting effectively with keratin 17 and interfering with the assembly of the keratin intermediate filament network. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of painful blisters and calluses. In the sebaceous glands, abnormal keratin filaments lead to the development of sebum-filled cysts called steatocystomas. Defective keratin 6b also disrupts the growth and function of other tissues, such as the hair follicles and nails, which explains why the signs and symptoms of pachyonychia congenita can also affect these other parts of the body.

Other Names for This Gene

• CK 6B
• CK6B
• cytokeratin 6B
• cytokeratin-6B
• K2C6B_HUMAN
• K6B
• K6b keratin
• keratin 6B, type II
• keratin, epidermal, type II, K6B
• keratin, type II cytoskeletal 6B
• KRTL1

Genomic Location

Normal Function

The KRT6C gene provides instructions for making a protein called keratin 6c or K6c. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, and nails. Keratin 6c is found in the skin, although it is unknown which other tissues may produce this protein.

Keratin 6c is a component of molecules called keratin intermediate filaments. These filaments assemble into dense networks that provide strength and resilience to the skin, nails, and other tissues. Networks of keratin intermediate filaments protect these tissues from being damaged by friction and other everyday physical stresses.

Health Conditions Related to Genetic Changes

Pachyonychia congenita

At least four mutations in the KRT6C gene have been found to cause pachyonychia congenita, a rare condition that primarily affects the nails and skin. In most cases, this condition becomes apparent within the first few months of life.

One of the mutations associated with pachyonychia congenita changes a single protein building block (amino acid) in the keratin 6c protein. Specifically, this mutation replaces the amino acid glutamic acid with the amino acid lysine at protein position 472 (written as Glu472Lys or E472K). The other KRT6C gene mutations delete one or more amino acids from the keratin 6c protein.

All of the known KRT6C gene mutations alter the structure of keratin 6c and interfere with the assembly of the keratin intermediate filament network. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of severe, painful blisters and calluses. Additionally, fragile skin cells may abnormally produce more keratin in response to damage, which makes the skin problems worse. Defective keratin 6c also disrupts the growth and function of other tissues, such as the hair follicles and nails, which explains why the signs and symptoms of pachyonychia congenita can also affect these other parts of the body.

Other Names for This Gene

• CK-6C
• CK-6E
• cytokeratin-6C
• cytokeratin-6E
• K2C6C_HUMAN
• K6C
• K6E
• keratin 6C, type II
• keratin 6E
• keratin K6h
• keratin, type II cytoskeletal 6C
• keratin-6C
• KRT6E
• type-II keratin Kb12

Genomic Location

Normal Function

The KRT16 gene provides instructions for making a protein called keratin 16 or K16. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, and nails. Keratin 16 is produced in the nails, the skin on the palms of the hands and soles of the feet, and the oral mucosa that lines the inside of the mouth.

Keratin 16 partners with a similar protein, keratin 6a, to form molecules called keratin intermediate filaments. These filaments assemble into dense networks that provide strength and resilience to the skin, nails, and other tissues. Networks of keratin intermediate filaments protect these tissues from being damaged by friction and other everyday physical stresses. Keratin 16 is also among several keratins involved in wound healing.

Health Conditions Related to Genetic Changes

Pachyonychia congenita

At least 19 mutations in the KRT16 gene have been identified in people with pachyonychia congenita, a rare condition that primarily affects the nails and skin. In most cases, this condition becomes apparent within the first few months of life. Most of the KRT16 gene mutations associated with pachyonychia congenita change single protein building blocks (amino acids) in keratin 16. A few mutations delete a small number of amino acids from the protein.

The KRT16 gene mutations responsible for pachyonychia congenita change the structure of keratin 16, preventing it from interacting effectively with keratin 6a and interfering with the assembly of the keratin intermediate filament network. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of severe, painful blisters and calluses. Additionally, fragile skin cells may abnormally produce more keratin in response to damage, which makes the skin problems worse. Defective keratin 16 also disrupts the growth and function of other tissues, such as the hair follicles and nails, which explains why the signs and symptoms of pachyonychia congenita can also affect these other parts of the body.

Other Names for This Gene

• CK16
• cytokeratin 16
• cytokeratin-16
• K16
• K1C16_HUMAN
• K1CP
• keratin 16 (focal non-epidermolytic palmoplantar keratoderma)
• keratin 16, type I
• keratin, type I cytoskeletal 16
• keratin-16
• KRT16A
• NEPPK

Genomic Location

Normal Function

The KRT17 gene provides instructions for making a protein called keratin 17 or K17. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, nails, and similar tissues. Keratin 17 is produced in the nails, the hair follicles, and the skin on the palms of the hands and soles of the feet. It is also found in the skin's sebaceous glands, which produce an oily substance called sebum that normally lubricates the skin and hair.

Keratin 17 partners with a similar protein, keratin 6b, to form molecules called keratin intermediate filaments. These filaments assemble into dense networks that provide strength and resilience to the skin, nails, and other tissues. Networks of keratin intermediate filaments protect these tissues from being damaged by friction and other everyday physical stresses. Keratin 17 is also among several keratins involved in wound healing.

Health Conditions Related to Genetic Changes

Pachyonychia congenita

More than 20 mutations in the KRT17 gene have been identified in people with pachyonychia congenita, a rare condition that primarily affects the nails and skin. In most cases, this condition becomes apparent within the first few months of life. Most of the KRT17 gene mutations associated with pachyonychia congenita change single protein building blocks (amino acids) in keratin 17.

The KRT17 gene mutations responsible for pachyonychia congenita change the structure of keratin 17, preventing it from interacting effectively with keratin 6b and interfering with the assembly of the keratin intermediate filament network. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities such as walking can cause skin cells to break down, resulting in the formation of painful blisters and calluses. In the sebaceous glands, abnormal keratin filaments lead to the development of sebum-filled cysts called steatocystomas. Defective keratin 17 also disrupts the growth and function of other tissues, such as the hair follicles and nails, which explains why the signs and symptoms of pachyonychia congenita can also affect these other parts of the body.

Steatocystoma multiplex

At least four mutations in the KRT17 gene have been found to cause a skin disorder called hereditary steatocystoma multiplex. Researchers suggest that this condition may be a mild form (variant) of pachyonychia congenita (described above). Like pachyonychia congenita, hereditary steatocystoma multiplex involves the development of multiple sebaceous gland cysts called steatocystomas. Most people with hereditary steatocystoma multiplex do not have the other features of pachyonychia congenita, although mild nail and dental abnormalities are possible.

The KRT17 gene mutations that cause hereditary steatocystoma multiplex change single amino acids in the keratin 17 protein, which interferes with the assembly of the keratin intermediate filament network. In the sebaceous glands, these keratin abnormalities lead to the development of steatocystomas. It is unclear why these sebum-containing cysts are typically the only feature of this disorder.

Other Names for This Gene

• CK-17
• cytokeratin-17
• K17
• K1C17_HUMAN
• keratin 17, type I
• keratin, type I cytoskeletal 17
• keratin-17

Genomic Location

Doctors usually diagnose PC by:

• Completing a physical exam, including examination of the skin and nails.
• Asking about the family and medical history, as many cases of PC are inherited.
• Ordering a genetic test. By identifying the disease mutation, a genetic test can rule out other conditions with similar symptoms and confirm that a person has PC. A genetic test may also provide a clearer picture of what to expect, as symptoms of PC differ based on the mutation.

There is no cure and there are no specific therapies for PC. The main goal of treatment is relieving the pain by most people with the condition.

Your doctor may recommend the following treatments for calluses:

• Thinning the calluses. Regular grooming of the feet is a mainstay of treatment. It is important not to trim too aggressively, as overly thinning the calluses can increase the pain. Conversely, trimming regularly, as needed, is important because overly thick calluses can also increase the pain.
  • Physical abrasion, such as by paring or filing the callused areas, is the most common approach. Soaking the skin prior to abrading is helpful for some people. While many people pare or file their calluses themselves, others see a podiatrist, a medical professional who specializes in caring for the feet.
  • Oral retinoids, which are related to vitamin A, can thin calluses, but they may not decrease the pain, and in some cases they increase it. If a doctor prescribes these, he or she will carefully monitor the dosage and duration of treatment.
• Moisturizing creams or lotions. Moisturizers can provide relief by softening the skin and preventing cracks.
• Over-the-counter or prescribed anti-inflammatory and pain medications. These may help temporarily alleviate pain and are sometimes taken prior to engaging in physical activity to “get ahead” of the anticipated pain.
• Special orthotics or insoles. These can redistribute the weight on your feet and provide relief from pain. In severe cases, a person may need a cane, crutches, or a wheelchair.
• Nails and cysts. Your doctor may recommend the following treatments for thickened nails and cysts:
• Thickened nails.
  • Regular trimming. Nails are not usually painful, but they can become so if they become infected or broken.
  • Bleach baths. Routinely bathing your nails and feet in mild bleach solutions can help prevent infections. You should not use this treatment without first talking to your doctor.
  • Oral antibiotic or antifungal medications. These may be needed if infections develop.
  • Surgery to remove especially troublesome nails.
• Cysts. These may need to be drained or surgically removed. Your doctor may prescribe antibiotics if cysts become infected. Antiseptic cleansers may help prevent flare-ups.

Dermatologists, who specialize in skin disorders, usually treat PC. Other health care professionals who may be involved in your care include:

• Clinical geneticists, who diagnose and treat children and adults with genetic disorders.
• Mental health professionals, who can help you cope with difficulties in the home and workplace that may result from having the disorder.
• Podiatrists, medical specialists who provide care for the feet and lower legs.
• Primary care doctors, such as family physicians, internal medicine specialists, and pediatricians, who coordinate care between the different health providers and treat other problems as they arise.

Having a painful disorder like PC can be challenging, but the following may make it easier to manage:

• Maintain a healthy weight, and limit walking and standing. This may lessen the pain from the calluses on the soles of the feet.
• Wear comfortable shoes and socks that reduce moisture. This may help decrease rubbing that can worsen painful calluses.
• Wear gloves to protect the hands during activities like riding a bicycle or using hand tools.
• If you have white patches in the mouth, brush your teeth and tongue frequently and gently to reduce their appearance. Infants with this symptom may feed better if you use a bottle with a soft nipple and a wide opening.
• Use moisturizers, such as those that contain petroleum jelly or lanolin, to soothe bumps that develop near friction sites, such as the waist, elbows, and knees.
• Visit a mental health professional or join a support group. These can provide emotional support and help you cope with feelings of isolation that often come with having a rare disorder.

Remember to visit your health care providers regularly and to follow their recommendations.