Classification, inheritance, and clinical manifestations of epidermolysis bullosa simplex^[1,2]

Localized EBS
(previously Weber-Cockayne)

AD

KRT5, KRT 14

Keratin 5, keratin 14

• Most common EBS subtype, with majority of mild cases underdiagnosed
• Clinical onset usually during infancy or early adulthood, with blistering mainly restricted to hands and feet
• Plantar keratoderma gradually developing (painful, reduced mobility)
• EB nevi common, with variable pigmentation and irregular borders, triggered by activation of melanocytes due to tissue damage

• Clinically insignificant blisters within oral cavity during early childhood

• Nails may be thick and dystrophic
• Hair not affected

Intermediate EBS
(previously EBS generalized intermediate, EBS Köbner)

AD

KRT5, KRT14
(monoallelic missense, nonsense, frameshift, or splice-site pathogenic variants)

Keratin 5, keratin 14

• Generalized blistering, erosions, crusts presenting at birth, enhanced by heat, humidity, and sweating; tendency to diminish in adolescence, when blistering may become localized to hands and feet; blisters heal with hyperpigmentation
• Plantar keratoderma
• EB nevi common

• Rarely eye involvement

• Nails may be thick and dystrophic
• Hair not affected

Severe EBS
(previously EBS generalized severe, EBS Dowling-Meara)

AD

KRT5, KRT14, PLEC

Keratin 5, keratin 14, plectin

Characteristic clumping of keratin intermediate filaments shown by transmission electron microscopy

• Generalized, extensive (also spontaneous) blistering from birth; congenital, ulcerated areas on hands and feet; common, herpetiform (arciform) pattern of blisters; atrophic scarring, milia formation; crusting/necrotic aspect of lesions often associated or preceded by inflammatory plaques
• Plantar keratoderma (confluent)
• EB nevi common
• Clumping of keratin intermediate filaments in transmission electron microscopy

• Involvement of oral mucosa

• Nails prominently involved (thick and dystrophic)
• Hair not affected

• Life-threatening condition in the first year of life due to infection, malnutrition, and respiratory failure
• Gastro-esophageal reflux
• Growth retardation

EBS, with mottled pigmentation

AD

KRT5, KRT14, EXPH5

keratin 5, keratin 14, exophilin 5

• Generalized skin blistering of intermediate severity starting at birth, may improve throughout childhood
• Gradual development of mottled or reticulate pigmentation unrelated to previous sites of blistering in early childhood
• Focal keratoses of palms and soles over time

• Dystrophic, thickened nails occur over time

EBS, migratory circinate erythema

AD

KRT5

Keratin 5 (frameshift with elongated keratin 5 polypeptide)

• Multiple vesicles (hands, legs, feet) from birth onwards, with typical, circinate, migratory pattern (with vesicles and crusts at the advancing edge) on erythematous background later on; postinflammatory (mottled) hyperpigmentation

• Nails may be dystrophic

EBS, intermediate with cardiomyopathy

AD

KLHL24
(50% de novo mutations)

Kelch-like member 24

• Extensive skin defects on extremities at birth, heal with hypo- and hyperpigmentation and skin atrophy (burn scar-like); blistering diminishes in adulthood, but fragility persists with erosions following mechanical trauma
• Diffuse or focal plantar keratoderma

• Nail thickening and onychogryphosis (markedly curved and deformed nails resembling ram's horns)
• Diffuse alopecia in some patients

• Dilated cardiomyopathy reported in young adulthood (annual cardiologic screening recommended)

Recessive EBS, intermediate or severe with keratin 14 or 5 pathogenic variants

AR

KRT14
(biallelic nonsense, missense, or frameshift pathogenic variants)

KRT5
(biallelic loss-of-function or missense mutations)

Keratin 14, keratin 5

• Severe, generalized skin blistering at birth; absence of keratin 5 leads to widespread blisters and erosions and early lethality
• Postinflammatory hyperpigmentation

EBS, localized or intermediate with BP230 deficiency

AR

DST
(biallelic loss-of-function pathogenic variants with absence of BP230)

Bullous pemphigoid antigen 230

• Skin blistering from birth or childhood, mostly localized to acral extremities
• Plantar keratoderma

• Nail dystrophy

EBS, localized or intermediate with exophilin 5 deficiency

AR

EXPH5
(biallelic loss-of-function pathogenic variants)

Exophilin 5

• Generalized skin blistering at birth or in infancy; blistering tendency to diminish with age, ongoing crusting and scabs
• Mild, mottled pigmentary changes

EBS, intermediate with PLEC pathogenic variants

AD
PLEC
Plectin

AR
PLEC1a
Plectin isoform (expressed in skin but not in muscles)

• Skin blistering at birth (mainly acral but may be widespread)
• Autosomal dominant subtype (formerly type Ogna): mild course; mainly acral erosions; postlesional, violaceous, and hypopigmented macules
• Autosomal recessive subtype: intermediate severity
• Plantar keratoderma

• Dystrophic, thickened nails, sometimes onychogryphosis (markedly curved and deformed nails resembling ram's horns)

• No muscular dystrophy

EBS, intermediate with muscular dystrophy

AR

PLEC
(biallelic loss-of-function variants)

Plectin

Lack of immunoreactivity for plectin, cleavage deep within the basal pole of basal keratinocytes

• Generalized skin blistering from birth, intermediate severity with tendency to diminish with age; atrophic scarring, milia formation
• Focal plantar keratoderma

• Involvement of oral, ocular, and urethral mucosae
• Granulation tissue and stenosis of upper respiratory tract and hoarseness may occur
• Pyloric atresia may be associated

• Nail dystrophy and loss

• Dental anomalies
• Muscular dystrophy starts at a variable age, ranging from infancy to adulthood, usually life limiting
• Cardiomyopathy may be associated

EBS, severe with pyloric atresia

AR

PLEC
(biallelic loss-of-function variants)

Plectin

• Generalized blistering of variable severity from birth, atrophic scarring
• Widespread, full-thickness, congenital absence of skin

• Involvement of oral mucosa

• Gestational hydramnios
• Pyloric atresia
• Anemia and growth retardation
• Neonatal lethal course