Naegeli-Franceschetti-Jadassohn syndrome/dermatopathia pigmentosa reticularis (NFJS/DPR) represents a rare type of ectodermal dysplasia, a group of about 150 conditions characterized by abnormal development of ectodermal tissues including the skin, hair, nails, teeth, and sweat glands. NFJS and DPR were originally described as separate conditions; however, because they have similar features and are caused by mutations in the same gene, they are now often considered forms of the same disorder.

Among the most common signs of NFJS/DPR is a net-like pattern of dark brown or gray skin coloring, known as reticulate hyperpigmentation. This darker pigmentation is seen most often on the neck, chest, and abdomen, although it can also occur in and around the eyes and mouth. Reticulate hyperpigmentation appears in infancy or early childhood. It may fade with age or persist throughout life.

NFJS/DPR also affects the skin on the hands and feet. The skin on the palms of the hands and soles of the feet often becomes thick, hard, and callused, a condition known as palmoplantar keratoderma. Some affected individuals also have blistering on their palms and soles. Their fingernails and toenails may be malformed, brittle, and either thicker or thinner than usual. Most affected individuals are missing the patterned ridges on the skin of the hands and feet, called dermatoglyphs, that are the basis for each person's unique fingerprints.

Additional features of NFJS/DPR can include a reduced ability to sweat (hypohidrosis) or excess sweating (hyperhidrosis) and dental abnormalities. Some affected individuals also have hair loss (alopecia) on the scalp, eyebrows, and underarms. The alopecia is described as noncicatricial because it does not leave scars (cicatrices).

NFJS/DPR results from mutations in the KRT14 gene. This gene provides instructions for making a protein called keratin 14. Keratins are tough, fibrous proteins that provide strength and resiliency to the outer layer of the skin (the epidermis). Researchers believe that keratin 14 may also play a role in the formation of sweat glands and the development of dermatoglyphs.

The KRT14 gene mutations that cause NFJS/DPR most likely reduce the amount of functional keratin 14 that is produced in cells. A shortage of this protein makes cells in the epidermis more likely to self-destruct (undergo apoptosis). The resulting loss of these cells alters the normal development and structure of ectodermal tissues, which likely underlies most of the skin and nail problems characteristic of NFJS/DPR. However, it is unclear how a shortage of keratin 14 is related to changes in skin pigmentation.

Normal Function

The KRT14 gene provides instructions for making a protein called keratin 14. 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 14 is specifically produced in cells called keratinocytes in the outer layer of the skin (the epidermis).

Keratin 14 partners with a similar protein, keratin 5 (produced from the KRT5 gene), to form molecules called keratin intermediate filaments. These filaments assemble into strong networks that help attach keratinocytes together and anchor the epidermis to underlying layers of skin. The network of keratin intermediate filaments provides strength and resiliency to the skin and protects it from being damaged by friction and other everyday physical stresses.

Researchers believe that keratin 14 may also play a role in the formation of sweat glands and the development of patterned ridges on the skin of the hands and feet. These ridges, called dermatoglyphs, are the basis for each person's unique fingerprints.

Health Conditions Related to Genetic Changes

Epidermolysis bullosa simplex

More than 60 mutations in the KRT14 gene have been identified in people with epidermolysis bullosa simplex, a condition that causes the skin to be very fragile and to blister easily. Most of these genetic changes alter single protein building blocks (amino acids) used to make keratin 14. The most severe form of epidermolysis bullosa simplex, the Dowling-Meara type, usually results from changes in regions of keratin 14 that are essential for the normal assembly of keratin intermediate filaments. Milder forms of the disorder, including the localized type (formerly called the Weber-Cockayne type) and a form known as the other generalized type (formerly called the Koebner type), are often caused by changes affecting less critical regions of the protein.

KRT14 gene mutations change the structure and function of keratin 14, preventing it from working effectively with keratin 5 and interfering with the assembly of the keratin intermediate filament network. Mutations that cause severe forms of the disorder severely disrupt the assembly of keratin intermediate filaments, while mutations that result in milder forms impair keratin filament assembly to a lesser degree. A disruption in this network makes keratinocytes fragile and prone to rupture. Minor trauma to the skin, such as rubbing or scratching, can cause these cells to break down, resulting in the formation of painful, fluid-filled blisters.

Naegeli-Franceschetti-Jadassohn syndrome/dermatopathia pigmentosa reticularis

Several mutations in the KRT14 gene have been found to cause Naegeli-Franceschetti-Jadassohn syndrome/dermatopathia pigmentosa reticularis (NFJS/DPR). This disorder is a rare form of ectodermal dysplasia, a group of about 150 conditions characterized by abnormal development of ectodermal tissues including the skin, hair, nails, teeth, and sweat glands. NFJS and DPR were originally described as separate conditions; however, they are now often considered forms of the same disorder.

The KRT14 gene mutations that cause NFJS/DPR most likely reduce the amount of functional keratin 14 in keratinocytes. A shortage of this protein makes these cells more likely to self-destruct (undergo apoptosis). The resulting loss of keratinocytes alters the normal development and structure of ectodermal tissues, which likely underlies most of the skin and nail problems characteristic of NFJS/DPR. However, it is unclear how a shortage of keratin 14 is related to the net-like pattern of dark skin coloring (reticulate hyperpigmentation) that is also a hallmark of this condition.

Other Names for This Gene

• CK14
• cytokeratin 14
• EBS3
• EBS4
• K14
• K1C14_HUMAN
• keratin 14 (epidermolysis bullosa simplex, Dowling-Meara, Koebner)
• keratin 14, type I
• Keratin, type I cytoskeletal 14
• Keratin-14

Genomic Location

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases of Naegeli-Franceschetti-Jadassohn syndrome, a diagnosis is made based on the typical clinical features of this condition. The diagnosis may be confirmed by genetic testing of the KRT14 gene.

Treatment for Naegeli-Franceschetti-Jadassohn syndrome is based on an individual's symptoms. Dry skin can be moisturized with creams. Exposure to heat should be limited. To avoid overheating, affected individuals should stay hydrated, wear appropriate clothing, and use wet dressings. Dental care is needed to treat cavities and tooth loss.

NFJS/DPR is a rare condition; its prevalence is unknown. Only a few affected families have been reported in the medical literature.