Butterfly skin explained: understanding epidermolysis bullosa

Epidermolysis bullosa (EB), sometimes called butterfly skin, is a group of rare skin diseases with a common symptom: fragile skin that tears and blisters easily. Children with this disease are sometimes called “butterfly children” because their skin is as delicate and fragile as a butterfly’s wing. Friction from clothing, touch or knocks to the skin can all cause blisters to form, and they can occur anywhere on the body. In mild disease the blisters occur on hands, knees and elbows, while in severe disease the blisters are more widespread and can also affect the mouth and gastrointestinal tract. In some cases, blisters can leave scars when they heal. This rare, genetic disease is usually seen from birth or in infancy and affects an estimated 1 in 50,000 people [1]; however, only 250 cases of the rare subtype Kindler syndrome have been reported worldwide [2].

In this article, you can find a detailed description of the different types of EB, including symptoms and causes, as well as information about treatment and disease management.

What are the types of epidermolysis bullosa?

There are 4 main types of inherited EB [2, 3] categorized based on which layer of the skin is affected by blisters:

• Epidermolysis bullosa simplex: blisters occur in the epidermis (the top layer of skin)
• Junctional epidermolysis bullosa: blisters occur in the basement membrane, which is found between the epidermis and the lower layer of skin called the dermis.
• Dystrophic epidermolysis bullosa: blisters occur in the dermis.
• Kindler syndrome: blisters occur in all layers of the skin, including the basement membrane

Another type of EB, epidermolysis bullosa aquisita is an autoimmune disorder that is acquired not inherited [3] and typically occurs in adulthood [4].

What are the symptoms of epidermolysis bullosa?

Fragile skin that tears easily, causing blisters and sores to develop is the main symptom of all types of EB. The location and severity of the sores varies with type and between people: in general, blisters can be localized or generalized. They can develop anywhere on the body or even inside the body, including in the mouth, gastrointestinal tract, upper airway, bladder, genitals, and eyes [1, 3].

Epidermolysis bullosa simplex symptoms

Epidermolysis bullosa simplex (EBS) is the most common form of EB. It is thought that are four main types of epidermolysis bullosa simplex, which differ with regard to severity of symptoms and localization of blisters [5]. Symptoms can range in severity from mild to severe. Blisters, that do not usually scar, are localized in mild forms to the hands and feet, or found all over the body in more severe forms. Other symptoms are thickened skin on palms and soles, thickened fingernails or toenails, and oral blisters [1, 3, 6].

Junctional epidermolysis bullosa symptoms

Junctional EB (JEB)is usually a severe form of EB. Blisters affect the mouth and upper airway, as well as the gastrointestinal tract, urinary system, and genitals. In this form of EB, blisters on the face, body and legs can become infected. Other symptoms of JEB include thickened fingernails or toenails, hair loss due to blisters on the scalp, dehydration due to fluid loss from open sores, malnutrition and anemia due to blisters in the mouth and gastrointestinal tract that affect calorie and nutrient uptake, slow growth, and weak tooth enamel [1, 3].

JEB can be split into 2 subtypes: Herlitz JEB and all other forms of JEB (known as JEB generalized intermediate, including non-Herlitz JEB and JEB with pyloric atresia). Herlitz JEB is often fatal in infants with death caused by factors such as sepsis, malnutrition and dehydration [6, 7].

Dystrophic epidermolysis bullosa symptoms

There are two subtypes of dystrophic EB (DEB) with slightly different symptoms. The subtype is determined by the mode of inheritance.

The recessive subtype (recessive DEB, RDEB) is the most common form of DEB. There are also several types of RDEB with recessive dystrophic epidermolysis bullosa severe generalized the most severe form [8]. Symptoms include blisters on feet, knees and elbows in mild cases that are more widespread in severe cases and can also occur in the mouth and gastrointestinal tract, nail loss, scarring, milia (also known as milk spots, which are small white bumps on skin), itching, anemia, malnutrition, and slow growth. In more severe cases there may be tooth malformation or loss, eye damage and an increased risk of developing skin cancer as young adults [3, 6, 8].

Dominant DEB (DDEB) is usually milder than RDEB with blisters typically seen only on the hands, feet, elbows, and knees. Other symptoms include oral blisters, nail changes or nail loss, milia, and scarring [3, 6].

Sometimes, missing nails are the only sign of mild disease [8].

Kindler syndrome symptoms

In Kindler syndrome, blisters usually form on the hands and feet, although other areas, including mouth and eyes, can be affected in severe cases. Other symptoms of Kindler syndrome include thin, papery, patchy or discolored skin, changes in skin coloring, visible blood vessels under the skin, scarring, milia, and sun sensitivity with an increased risk of developing skin cancer. Sometimes the skin on the hands and feet can thicken and harden [2, 3].

In all forms of EB, the blisters can also have consequences. In some cases, they leave scars, and scaring can also lead to skin fusing especially between fingers and toes, causing deformities and impairing movement. Other consequences include difficulty swallowing or blocked airways, affecting the ability to eat, drink or breath, as well as impaired vision from blisters in the eyes. Infected blisters are another complication [1, 4].

What causes epidermolysis bullosa?

EB is an inherited disease. It is caused by a mutation (variant) in a gene that is passed from parents to their children (a child inherits one copy of each gene from each parent) and can be inherited in a dominant or a recessive manner. In the dominant disease form, the child inherits one unaffected gene copy and one with the EB causing mutation, while in the recessive form, both parents carry a recessive mutation but do not have the disease and the child inherits one affected gene from each parent. If the child inherits one recessive gene and one unaffected gene, they will be a carrier of EB [3].

Mutations in at least 18 different genes are known to cause EB. Typically, these are genes involved in the structure of collagen in the epidermis, dermis, or basement membrane [1, 3, 6].

EBS is usually dominantly inherited, caused by mutations in the KRT5 or KRT1 genes which provide instructions for making keratin 5 and 14, and PLEC, which provides instructions for making a protein called plectin that is important in attachment of the epidermis [, 6].

JEB is recessively inherited and involves genes such as LAMA3, LAMB3, LAMC2, which provide instructions for making laminin that is important for skin strength and attachment of the layers, COL17A1, which provides instructions for the assembly of type XVII collagen, and ITGB4,which provides the instructions for making integrin and is important for cell adhesion [7].

DEB is caused by mutations in COL17A1 leading to defects in type VII collagen [6, 8].

Kindler syndrome follows an autosomal recessive inheritance pattern. It is caused by variants in the FERMT1 gene which contains the instructions for making the protein kindlin-1 in the epithelial cells that are a major component of the epidermis [2].

As EB is a genetic disease, couples with a family history of the disease should consider genetic counseling to assess their risk for passing the disease to their children before having children.

How is epidermolysis bullosa diagnosed?

EB is usually diagnosed by skin biopsy. Genetic testing can detect the mutations known to associated with EB. It is also possible to detect some forms of EB via prenatal testing. VERAgene can detect the mutations in LAMC2 that cause JEB, Herlitz type using a maternal blood sample from 10 weeks of pregnancy.

How is epidermolysis bullosa treated and managed?

Although the outlook is largely dependent on the severity of the disease, treatment and management plans can improve quality of life by addressing symptoms and pain.

Treatment is not curative, but can treat symptoms, and reduce both pain and the risk of complications. It can include pain medication, draining blisters, topical treatments for blisters, antibiotics for infections, dietary changes in cases of blisters in the mouth and gastrointestinal tract (warm, soft or liquid foods), and vitamin and mineral supplements if necessary. Severe cases may require surgery to widen the esophagus or insert a feeding tube [1, 6].

Disease management includes taking steps to reduce friction on the skin, e.g., by wearing soft, lose clothing and applying non-adhesive bandages to protect the skin, keeping skin cool, wearing sun screen, and skin cancer monitoring [1, 6].

In 2023, the first gene therapy gel (Vyjuvek) for the treatment of wounds in patients with DEB who have mutations in the COL7A1 gene was approved for use by the U.S. Food and Drug Administration (FDA) [6]. Vyjuvek uses a modified herpes simplex virus to deliver two normal copies of the COL7A1 gene directly to skin cells, allowing them to produce type 7 collagen (CCOL7) and improving the skin’s ability to repair wounds and reduce blistering [9].

Conclusion

EB, or butterfly skin, is a distressing disease for patients and their care-givers, although treatment and management plans can improve quality of life by addressing symptoms and pain. Being a genetic disease, couples with a family history of EB should consider genetic counseling to assess their risk for passing the disease on before having children, and genetic testing, including prenatal genetic testing, can detect the mutations known to associated with EB.

Furthermore, parents of children with EB may feel guilty at having to hurt their child to change bandages, or overwhelmed by the nature of the disease and the child’s perceived limitations. It is important to communicate with healthcare providers and reach out to self-help groups and other hard-working patient advocacy groups for support.

References

[1] “Epidermolysis Bullosa: Signs, Symptoms, Causes, Diagnosis, Treatment.” Cleveland Clinic, 26 May 2022, https://my.clevelandclinic.org/health/diseases/17792-epidermolysis-bullosa. Accessed 27 June 2024.

[2] MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 2020 Jun 24]. Kindler epidermolysis bullosa [updated 17 Mar. 2023]. Available from: https://medlineplus.gov/genetics/condition/kindler-epidermolysis-bullosa/. Accessed 01 July 2024.

[3] “Epidermolysis Bullosa.” National Institute of Arthritis and Musculoskeletal and Skin Diseases, Last Reviewed: Sep 2023, www.niams.nih.gov/health-topics/epidermolysis-bullosa. Accessed 27 June 2024.

[4] “Butterfly Skin Disease (Epidermolysis Bullosa): A Rare Disorder.” Healthline, 23 Feb. 2022, www.healthline.com/health/butterfly-skin. Accessed 01 July 2024.

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[5] MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 2020 Jun 24]. Epidermolysis Bullosa Simplex [updated 01 May 2013]. Available from: https://medlineplus.gov/genetics/condition/epidermolysis-bullosa-simplex/. Accessed 01 July 2024.

[6] “Epidermolysis Bullosa.” NORD (National Organization for Rare Disorders), 22 Jan. 2024, www.rarediseases.org/rare-diseases/epidermolysis-bullosa/. Accessed 27 June 2024.

[7] MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 2020 Jun 24]. Junctional Epidermolysis Bullosa [updated 01 Apr. 2020]. Available from: https://medlineplus.gov/genetics/condition/junctional-epidermolysis-bullosa/. Accessed 01 July 2024.

[8] MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); [updated 2020 Jun 24]. Dystrophic Epidermolysis Bullosa [updated 01 Feb. 2020]. Available from: https://medlineplus.gov/genetics/condition/dystrophic-epidermolysis-bullosa/. Accessed 01 July 2024.

‌[9] ‌Staff, BioNews. “Vyjuvek (Beremagene Geperpavec) for Epidermolysis Bullosa.” Epidermolysisbullosanews.com, https://epidermolysisbullosanews.com/kb103/. Accessed 01 July 2024.