Skill Checkup: A Student With an Inherited Blistering Condition and Painful Bullae on His Feet

William D. James, MD

Disclosures

April 12, 2021

DEB is characterized by cleavage of the skin in the region of the sublamina densa, in the upper portion of the dermis. DEB can be inherited in an autosomal dominant pattern (DDEB), autosomal recessive (RDEB), or a compound heterozygous dominant and recessive pattern. DEB is associated with mutations in the COL7A1 gene that encodes type VII collagen, which is a main component of anchoring fibrils in the dermoepidermal layers. It is associated with a wide phenotypic and severity spectrum ranging from the isolated occurrence of mild nail dystrophy to the generalized formation of blisters with mutilating scarring of the hands and feet, severe extracutaneous involvement, and premature death. Mutations that cause premature termination codons in RDEB result in absence of type VII collagen expression and severe subtypes of disease. COL7A1 mutations that do not cause premature termination codons usually produce less severe disease. Heterozygous mutations often manifest in intermediate RDEB where variants in premature stop codon variant and an amino acid substitution result in this subtype of disease. Mutations that produce glycine substitutions of the triple helical region can interfere with triple helical assembly of the type VII collagen molecule. These types of mutations, which exert a dominant-negative type of effect, are present in many patients with milder dominant forms of DEB.

Junctional epidermolysis bullosa (JEB) is characterized by cleavage and blistering within the lamina lucida of the skin. All JEB subtypes are inherited in an autosomal recessive pattern. LAMA3, LAMB3, and LAMC2 genes code for the trimeric laminin 332 (formally laminin 5) which consists of α3, β3, and γ2 chains. Most JEB subtypes are caused by laminin 322 mutations leading to loss of function in its protein and the cleavage of the dermis at the lamina lucida. Other genes associated with JEB are COL17A1, which codes for collagen XVII, and the ITGA6 and ITGB4, which code for α6β4 integrin in hemidesmosomes. JEB with respiratory and renal involvement is associated with mutations in the α3 subunit of the α6β4 integrin gene. The severity of disease is determined by mutation variation and the amount of protein expression. The most severe subtype is severe JEB (previously known as Herlitz JEB or generalized severe JEB), associated with complete absence or profound reduction of laminin 332. It is manifested as mucocutaneous blistering and erosions from birth, which result in loss of proteins, fluids, and iron, and increased susceptibility to infections. Other clinical findings include the formation of granulation tissue around the mouth, nose, and on the nails and buttocks; developmental delay; wound healing delay; and respiratory complications. Mortality in infancy and early childhood occurs because of infections.

In intermediate JEB (formerly generalized intermediate JEB or generalized non-Herlitz JEB), the expression of laminin 332 or type XVII collagen is reduced but not entirely absent. Clinically, intermediate JEB manifests with generalized blistering, absence or atrophy of nails, alopecia, enamel defects, granulation tissue formation, corneal ulceration, and laryngeal and urinary tract involvement. Similar to intermediate JEB, localized JEB is associated with nail absence or atrophy, tooth enamel hypoplasia or cavities, and alopecia. Extracutaneous manifestations include anemia, developmental delay, ocular alterations, or respiratory and genitourinary change. JEB inversa is a rare subtype in which blistering occurs predominantly in intertriginous areas. It is present at birth and manifests as severe blisters usually localized to folds (eg, axillae, groin, and perineum), atrophic scarring, nail dystrophy, and milia formation. Extracutaneous findings include enamel hypoplasia and dental caries, as well as oral, esophageal, and vaginal blisters and erosions.

Kindler epidermolysis bullosa (KEB) was formerly known as Kindler syndrome. In addition to blistering and skin atrophy, it is characterized by poikiloderma (hypopigmentation, hyperpigmentation, telangiectasias) and photosensitivity. Extracutaneous manifestations in KEB include gum erosions and ocular, esophageal, gastrointestinal, and genitourinary involvement. Mutations of the KIND1 gene that code for kindlin-1 have been associated with KEB.

Three main subtypes of EBS (localized, severe, intermediate) are caused by pathogenic variants in the KRT5 or KRT14 genes, which encode keratins 5 and 14. Severe EBS, formerly known as severe generalized or Dowling-Meara EBS, has a unique clinical phenotype, with large generalized blisters that can occur in a group (herpetiform blisters) and can be hemorrhagic. During childhood, blisters develop throughout the body, most often on the hands and feet, around the mouth, and on the trunk and neck. In severe EBS the involvement of the oral mucosa, the occurrence of progressive palmoplantar keratosis, and nail dystrophy are common. Lesions commonly heal without scarring, but inflammation can occur, especially in hemorrhagic blisters, followed by milia and hypo- and hyperpigmentation of the skin. As in the other EBS subtypes, the blisters tend to improve with age; however, palmoplantar keratoderma is more severe in most cases.

Localized EBS, formerly known as Weber-Cockayne EBS, is characterized by blisters limited to the regions of the palms and soles of the feet. Intermediate EBS, formerly known as intermediate generalized EBS or Koebner EBS, often manifests at birth, with the generalized distribution of blisters but without the formation of herpetiform clusters. Clinically, findings are milder in comparison with severe EBS, and there are no extracutaneous involvements. Blisters predominantly affect the hands and feet; focal palmoplantar keratoderma may occur, and lesions tend to get worse with heat.

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