Inherited and Acquired Blistering Diseases

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.

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.

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.

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.

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.

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.