Epidermolysis bullosa

Epidermolysis bullosa (EB) is a family of rare, inherited disorders characterized by fragility of the skin and sometimes the mucosa in response to minor mechanical trauma. EB is caused by mutations in at least 14 genes that encode proteins of the basement membrane zone (BMZ) of the skin ( Fig. 11.1 ). BMZ proteins are structural molecules involved in the adhesion of the epidermis and dermis. When an affected protein is absent or abnormal, adhesion strength is diminished and blistering occurs as a response to frictional stress. Data from the National Epidermolysis Bullosa Registry (NEBR) estimates the incidence of all forms of EB in the USA to be 20 cases/million live births.

Many proteins interact to form the basement membrane zone, the junction of the epidermis and dermis.

(Courtesy of Dr M. Peter Marinkovich.)

The classification of EB was revised in 2008 and utilizes the level of ultrastructural blistering as the primary categorical designation. The four major types of EB are: EB simplex (EBS) where cleavage occurs in the epidermis; junctional EB (JEB) with blistering through the BMZ; dystrophic EB (DEB) with cleavage arising in the superficial dermis, and Kindler syndrome where multiple splits can be seen. Each type is further divided into major and minor subtypes based on inheritance pattern, clinical findings, and the implicated molecular and genetic defects ( Table 11.1 ).

Neonatal features

Neonates with EB may present at birth with large ulcers, usually on the lower extremities, called congenital localized absence of skin (CLAS) ( Fig. 11.2 ). The edges of such ulcers are well-demarcated and the base is red and shiny. Bart and colleagues originally described the association of CLAS, mucosal blistering, and nail dystrophy and proposed that this triad represented a distinct syndrome, later termed Bart syndrome. Since that description, however, CLAS has been reported as a presenting sign in all types of EB, and Bart’s original kindred was further examined and found to have DDEB. CLAS likely results from intrauterine friction, such as the leg rubbing against the uterine wall, and is not specific for any one type of EB. The use of the term Bart syndrome is now discouraged.

Congenital localized absence of skin can be seen in all types of EB.

With or without CLAS, neonates with EB develop friction-induced blistering and erosions after birth. Skin changes may initially correlate with areas traumatized during birthing, such as the scalp and face in cases of vaginal birth. In many instances, blistering may be generalized. After birth, areas that are most subject to friction, such as the hands, diaper area, extensor extremities, and back, are most likely to blister ( Fig. 11.3 ). Intact blisters are filled with serous or hemorrhagic fluid. In JEB and RDEB, the bullae can be quite large, and the pressure of fluid within the blister cavity can cause the lesion to extend ( Fig. 11.4 ). More superficial blisters may rupture easily, leaving open erosions.

Blistering caused by the edge of a diaper in an infant with a milder form of EB.

Tense, fluid-filled blisters rapidly enlarge in patients with severe EB phenotypes.

The blisters in EBS and JEB often heal without scarring, but macular hypo- or hyperpigmentation may be a transient change after blisters heal. DEB blisters heal with scarring that is often atrophic. Milia are most suggestive of DEB but can be seen in all forms of EB ( Fig. 11.5 ). Granulation tissue, which is often described as ‘exuberant’ or ‘hyper-’ in JEB, can be seen in any EB erosion that has been slow to heal but is not often seen in the neonatal period.

Healing with milia most often occurs in DEB.

Oral involvement is most often seen in neonates with JEB or DEB but can be seen in EBS as well. Open erosions or intact vesicles can occur on the lips, gums, and palate. These lesions probably result from the trauma of sucking and may result in pain with feeding. In any form of EB, trauma to the periungual skin can result in nails that are absent, dystrophic, or may be shed.

Blisters and erosions are at risk of becoming infected, signaled by the formation of crusts and foul-smelling or purulent drainage. Neonates with EB and extensive erosions are at risk for developing fluid and electrolyte abnormalities as well as sepsis. Neonates with EB and pyloric atresia may present with gastrointestinal obstruction at birth. In these cases, polyhydramnios and gastric distension may have been noted on prenatal ultrasound, and genitourinary strictures and obstruction may be present as well. Airway involvement is uncommon in neonates with EB, but can occur. Although it is most often associated with JEB-Herlitz (JEB-H), laryngeal involvement can occur in infants with certain forms of EBS and with RDEB. An early sign of blisters and erosions of the larynx is hoarseness, which can progress to stridor as airway obstruction worsens.

Suprabasal epidermolysis bullosa simplex

Lethal acantholytic EB (LAEB) is an extremely rare subtype of EB. Affected infants present at birth with rapidly progressive erosions with a positive Nikolsky’s sign. Intact vesicles and erosions are not seen. Other common features are complete alopecia, anonychia, and oral erosions. All reported cases have been fatal in the neonatal period. Histology shows suprabasal acantholysis, but immunofluorescence studies will be negative for pemphigus and the typical causes of EB (see below). Ultrastructural studies show that keratin filaments fail to connect properly to desmosomes. Loss of function mutations in DSP that lead to truncation of the desmoplakin protein are causative.

Plakophilin deficiency was initially described in 1997 as ectodermal dysplasia/skin fragility syndrome, by McGrath and colleagues. Children with this disorder develop spontaneous erosions and fissures, and the perioral area is commonly affected. Painful, fissured keratoderma, absent, sparse or wooly hair, nail dystrophy, and growth failure are other universal features. Biopsies of affected skin show acanthosis and hyperkeratosis and widened spaces between keratinocytes in the spinous layer. Desmosomes are small and poorly formed on electron microscopy. This is an autosomal recessive disorder caused by mutations in the PKP1 gene that encodes plakophilin.

Basal epidermolysis bullosa simplex

Basal EBS is the most common and often mildest form of EB. Most forms are transmitted in an autosomal dominant manner. Individuals with localized forms of EBS may not present for medical evaluation, thus precise estimates of the true prevalence of EBS are lacking. For example, the NEBR calculated the prevalence of EBS to be 4.60 cases/million, but also estimated that the registry probably captured only 10% of all individuals affected with EBS. Population-based data from Scotland show a prevalence of 28.6 cases/million in 1992.

EBS, localized (EBS-loc, formerly Weber–Cockayne) is characterized by blisters of the hands and feet. Other than mild oral disease, extracutaneous involvement does not occur. Patients may first develop blisters at any age, including birth, but it is common for the first signs to present in the toddler years, or sometimes as late as adolescence, after a period of marked frictional stress.

EBS, other generalized (EBS, gen-nonDM, formerly Koebner) presents at birth and is characterized by intraepidermal blistering in a generalized distribution. Oral involvement can be seen in infancy but improves with age. Atrophic scarring, dyspigmentation, and nail dystrophy may be seen. Extracutaneous involvement in this type of EB is uncommon. For both EBS-loc and EBS, gen-nonDM, life expectancy is normal and the overall prognosis is good. However, affected adults report that acral blistering can be painful and limits daily activities such as walking, thereby affecting quality of life.

EBS Dowling–Meara (EBS-DM), on the other hand, is more severe and can even be fatal in the newborn period. Blistering presents at birth or within the first days of life. Skin involvement ranges from generalized to localization of blisters and erosions to areas of friction. A clinical clue to the diagnosis of EBS-DM is the occurrence of blisters in grouped or annular configurations ( Fig. 11.6 ). This feature, however, is not always reliable and may not be present until after 1 year of age. Milia and atrophic scarring may occur, and nail dystrophy in which nails may be thickened, ridged, or shed, is fairly common. In childhood, a confluent palmoplantar keratoderma develops and becomes more prominent with age, persisting into adulthood. This hyperkeratosis can interfere with ambulation, and joint contractures may be a subsequent complication. Oral blistering is often present and varies in severity. Laryngeal involvement, presenting as hoarseness, has been reported, but unlike in JEB, does not signal a poor prognosis. Gastroesophageal reflux and constipation may also be seen as complications. The severity of EBS-DM generally improves over time, with less blistering in adolescence, and rare blistering in adulthood in many cases. Patients may also report reduced blistering during febrile illnesses.

Annular blistering is characteristic of EBS-DM.

EBS with mottled pigmentation (EBS-MP) is a rare subtype. It is characterized by acral, nonscarring blistering that presents in infancy. In addition, 2–5 mm hypo- and hyperpigmented macules occur in a reticulate pattern around the neck, axillary, and groin areas. This mottled pigmentation may be congenital or can develop later in infancy.

EBS with muscular dystrophy (EBS-MD), EBS with pyloric atresia (EBS-PA), and EBS, Ogna (EBS-Og) are all due to mutations in PLEC1 , encoding plectin, although EBS-MD and EBS-PA are inherited recessively and EBS-Og is autosomal dominant. EBS-MD is a rare disorder that begins at or shortly after birth with mild generalized blistering and mucous membrane involvement. Other cutaneous findings include milia, atrophic scarring, and nail dystrophy. Nonmucosal findings can include respiratory involvement and dental enamel hypoplasia, leading to prominent caries. In most cases, progressive muscle weakness begins in adolescence or adulthood, although onset in infancy has been reported. The presentation of neonates with EB with pyloric atresia is discussed below.

Junctional epidermolysis bullosa

Junctional epidermolysis bullosa (JEB) is the least common type of EB. Data from the NEBR suggests an incidence of two cases/million live births. Inheritance of all forms of JEB is autosomal recessive, and a spectrum of clinical phenotypes can be seen. The JEB–Herlitz (JEB-H) and JEB with pyloric atresia (JEB-PA) subtypes, however, are often incompatible with survival beyond infancy.

JEB-H is characterized by generalized skin and mucosal erosions with a propensity for wounds to form exuberant granulation tissue. Other associated findings include nail dystrophy ( Fig. 11.7 ), dental enamel hypoplasia, and involvement of the respiratory epithelium. Blistering and erosions are seen at, or shortly after, birth ( Fig. 11.8A ), although the amount of blistering is not predictive of outcome, as infants with little skin involvement can do poorly. Severe involvement of the back and buttocks is common but not pathognomonic ( Fig. 11.8B ). In neonates who survive into infancy, the development of exuberant or hypergranulation tissue within erosions is a finding with high specificity for JEB-H. The central face, especially the periorificial areas ( Fig. 11.9 ), periungual skin (paronychial inflammation), and nape of the neck are commonly affected. Absent or dystrophic nails or nail shedding are often present. Ocular erosions can also occur. Oral blistering and erosions are often present in the neonatal period and can make feeding difficult. The laryngeal and respiratory epithelia may also be affected, typically first presenting as a weak or hoarse cry. Stridor suggests worsening airway obstruction, which can be fatal. Involvement of the gastrointestinal and urinary epithelia can also occur. Anemia, probably due to a combination of iron deficiency and chronic inflammation, is common. Patients with JEB-H typically die in the first few years of life due to failure to thrive, sepsis, pneumonia or respiratory failure. Data from the NEBR reported a cumulative risk of death of ~45% in the first year of life, while the Dutch EB registry found that over 23 years, all 22 subjects with JEB-H passed away in the first 3 years, with the average age of death being 5.8 months.

Junctional EB.

Nail dystrophy at birth.

(Courtesy of Dr Julie S. Prendiville.)

(A) Junctional EB infant at 2 h of age; localized erythema and erosions. (B) Same infant 1 week later with diffuse erosions.

Exuberant granulation tissue in a nonhealing facial erosion in a toddler with JEB-H. A tracheostomy tube is also in place.

JEB-non-Herlitz, generalized (JEB-nH gen) has features similar to JEB-H, although it is generally less severe and its overall prognosis tends to be better. In the neonatal period, however, clinical signs and pathologic analysis may not fully distinguish between JEB-H and JEB-nH gen, and a final diagnosis may be based on long-term outcome and/or results of genetic mutation analysis. Generalized blistering and mucous membrane involvement are seen in the neonatal period, and both improve as the child ages. Healing with granulation tissue is less common and less pronounced than in JEB-H, but can occur. Cutaneous lesions may heal with atrophy and pigmentary alterations. In hair-bearing areas, progressive alopecia may result, although this finding is most pronounced in adulthood. Likewise, nail dystrophy can begin in infancy and is progressive and marked with increasing age. Laryngeal involvement may occur, sometimes resulting in respiratory failure. Although the overall prognosis for JEB-nH gen is generally better than for JEB-H, the fatalities in the neonatal period and infancy are not uncommon. Data from the NEBR reported a cumulative risk of death of 40% and 49% in the first year and 2 years of life, respectively.

EB with pyloric atresia (EBS-PA or JEB-PA) presents at birth with upper gastrointestinal obstruction, most often affecting the pylorus. The degree of skin involvement is variable and ranges from extensive CLAS to normal skin, with the onset of blistering at several months of age. Prenatal signs of an affected fetus include polyhydramnios and abdominal masses appreciated on ultrasound. The ocular, respiratory, and urogenital epithelia are often affected. The prognosis for neonates with EB with pyloric atresia is generally poor, but nonlethal cases are reported. Infants with extensive erosions often expire quickly due to fluid and electrolyte imbalances as well as sepsis. If surgical correction of the pyloric atresia is successful, infants may still succumb to sepsis, feeding intolerance, failure to thrive, and respiratory or renal disease before 1 year of age.

Dystrophic epidermolysis bullosa

DDEB may be more common than reported, as individuals with mild phenotypes may not seek medical attention. The NEBR estimated the prevalence of DDEB to be approximately 1/million, while Scottish data suggests a point prevalence of 1/14.6 per million. Infants with DDEB may present with CLAS and/or with blistering in the newborn period. As the child ages, the tendency for blistering decreases. Blistering most commonly affects areas predisposed to trauma, such as the hands, feet, elbows, and knees, and heals with atrophy and milia. Oral erosions occur but are often mild. Nail dystrophy is common and may be the only clinical sign of disease. Extracutaneous complications such as esophageal strictures are uncommon. Transient bullous dermolysis of the newborn is a distinctive variant of DEB that is benign and self-limited. Blistering begins at birth or in the newborn period and dramatically improves or even remits completely, usually within the first year of life. Most reported cases are sporadic, but familial cases are described.

The incidence of RDEB is approximately 1–2/million live births. The current classification includes RDEB, severe generalized (RDEB-sev gen, formerly Hallopeau–Siemens), RDEB, generalized other (RDEB-O, formerly non-Hallopeau–Siemens), and several rare subtypes with more limited involvement ( Table 11.1 ).

In RDEB, blistering and erosions begin at birth and can be extensive. The compromised skin barrier is a risk for infection, and during the neonatal period sepsis is the most worrisome complication. Although death can occur, infants with RDEB generally do fairly well, especially compared with infants with JEB. Affected areas heal with scarring that can lead to the development of joint contractures over time. Recurrent scarring of the hands and feet leads to loss of the interdigital spaces and eventual contracture of the digits, called pseudosyndactyly or ‘mitten’ deformities ( Fig. 11.10 ). Joint contractures and pseudosyndactyly may begin in the first year of life. Nail involvement is common with anonychia due to nail shedding and scarring of the nail bed at an early age.

The foot of a young child with RDEB.

Note the erosions, chronic erythematous scarring, loss of nails, and webbing of the toes.

Extracutaneous involvement is common in RDEB, and generalized RDEB (and JEB) are effectively multisystem disorders. Mucosal involvement includes the gastrointestinal tract, ocular, and genitourinary system. Oral ulcers are painful and make eating difficult, limiting the ability of the child to take in adequate calories. Oral scarring leads to microstomia, ankyloglossia, and loss of the vestibule. Esophageal involvement is extremely common; erosions lead to progressive strictures that produce dysphagia and limit adequate caloric intake. Malabsorption is another gastrointestinal complication that is poorly understood. Anal erosions make defecation painful, exacerbating constipation. The cornea and conjunctiva are frequent sites of ocular injury. Recurrent abrasions and ulcers lead to scarring that can affect visual acuity. Urinary tract involvement may present with dysuria, hematuria, meatal stenosis, or even sepsis. Ureterovesical obstruction and hydronephrosis can occur.

Failure to thrive is a common complication of generalized RDEB and results from unmet nutritional needs. Affected neonates and infants demonstrate failure to gain weight adequately before height velocity drops off. Chronic wound healing, blood and protein losses from erosions, and infection increase the body’s need for calories. Oral, esophageal and intestinal involvement hinders adequate intake and absorption of nutrients. In addition to causing growth failure, chronic malnutrition contributes to poor wound healing, the development of anemia, deficiencies of essential minerals and trace elements, and increased susceptibility to infection. Anemia likely results from both iron deficiency and poor iron utilization due to chronic inflammation. Additional long-term complications of RDEB that are most often seen in older children, adolescents or adults include renal failure, osteopenia and osteoporosis, cardiomyopathy, and aggressive squamous cell carcinomas.

Kindler syndrome

Kindler syndrome (KS) is a rare, autosomal recessive disorder in which trauma-induced blistering begins at birth or early in infancy. Based on clinical and laboratory features, it is often diagnosed as a form of EB in the neonate. However, patients with KS develop progressive poikiloderma and cutaneous atrophy in childhood. Photosensitivity is variable. Gingivitis and periodontitis are common mucosal findings. In addition, esophageal and urogenital stenosis can occur. KS is caused by mutations in FERMT1 which encodes fermitin family homolog 1 (kindlin-1), involved in cell–matrix interactions.