Extracutaneous manifestations and complications of inherited epidermolysis bullosa^[1-13]

• Periungual or subungual blistering, hemorrhages and nail bed hyperkeratosis with onycholysis, onychomadesis; periodic nail shedding and regrowth with progressive onychodystrophy (EBS, JEB, DEB) +/– onychogryphosis (EBS, JEB)
• Paronychia-like lesions and nail loss, with nail bed erosions and development of subungual and periungual granulation tissue soon after birth (severe JEB and JEB-LOC syndrome)
• Complete nail loss, nail bed and matrix scarring, mitten deformity (DEB)
• Thin, brittle, short, atrophic nails due to nail matrix damage by repetitive blistering (JEB, DEB)
• Few nails affected in localized DEB
• Autosomal dominant trait of toenail onychodystrophy in a child may be sign of DEB
• Parrot beak nail deformity from recurrent blistering in distal fingers resulting in soft tissue and bone reabsorption with nail bending around shortened fingertip (KEB)

• Increased hair and skin fragility due to deficient stabilization of the upper permanent portion of the follicle (infundibulum, isthmus, bulge region) to the surrounding connective tissues (DEB)
• Cicatricial alopecia secondary to blistering (JEB, DEB) or infection involving interfollicular epidermis and upper portion of hair follicle
• Transient, reversible telogen effluvium due to anemia or sepsis
• Sparse, short, dry, curly, woolly hair; hypotrichosis
• Absent eyebrows and eyelashes (ectodermal dysplasia-skin fragility syndrome)
• Secondary scarring alopecia (JEB with pyloric atresia)

• Red, watery eyes, photophobia, ocular pain; conjunctival injection, edema, blisters; subconjunctival hemorrhage, blepharoconjunctivitis (severe RDEB; RDEB, inversa), exposure keratopathy
• Corneal bullae, erosion, ulceration, abrasions, pitting, opacities, scars; peripheral corneal vascularization, corneal pannus formation, limbal broadening, cornea plana, sclerocornea, cataracts
• Eyelid blisters or ectropion with exuberant granulation tissue (severe JEB), eyelid scarring, pseudopterygium, symblepharon (JEB, RDEB), ankyloblepharon
• Lacrimal duct obstruction (RDEB, inversa; severe JEB)
• Refractive errors, amblyopia, strabismus, lens subluxation, posterior vitreous detachment, impaired vision (severe RDEB; RDEB, inversa), blindness (severe RDEB)

• Mucosal fragility, blistering, ulceration, mostly localized (EBS)
• Significant involvement and oral scarring (severe EBS)
• Variable blistering and ulceration; exuberant perioral granulation tissue resulting in a reduction of the oral opening (microstomia) and loss of tissue mobility in lips and perioral tissues (severe JEB)
• Involvement from mild to severe; extreme fragility evident shortly after birth with inability to suckle (severe RDEB, intermediate RDEB)
• Restricted oral aperture, ankyloglossia, obliteration of vestibules, loss of lingual papillae, ablated palatal rugae; intraoral keratocysts (milia), elevated risk for intraoral squamous cell carcinoma (severe RDEB)
• Early-onset periodontal disease, gingival inflammation and hyperplasia; sometimes severe oral blistering in neonates and infants, decreasing with age (KEB)

Hard tissues:

• Normal dentition, caries risk not increased (EBS)
• Enamel lesions including pitting, horizontal hypoplastic bands, white mottled enamel, generalized hypoplasia, abnormal tooth eruption; increased risk of dental caries (JEB)
• Normal enamel (type VII collagen not expressed by ameloblasts); excessive dental caries, extensive tooth plaque formation and bacterial inoculation (DEB)
• Normal dentition; risk of dental caries unknown (KEB)

• Painful esophageal blistering, erosions, scarring, web formation, stenosis, strictures; hiatus hernia, abnormal esophageal peristalsis, atony, spontaneous perforation (severe RDEB)
• Gastroesophageal reflux disease common in more severe forms (RDEB, severe JEB, severe EBS, intermediate JEB) and prominent in pediatric populations; peptic ulcer disease
• Malabsorption, diarrhea; protein-losing enteropathy; irritable bowel disease; inflammatory bowel disease (EBS, DEB); diverticular disease; megacolon; colon perforation and peritonitis
• Rectal tears, prolapse, strictures; perianal fistulae; hemorrhoids, intussusception; megarectum
• Constipation
• Anemia, deficiencies of specific nutrients and vitamins (iron, selenium, zinc, vitamins A, B6, B12, C, D), hypoalbuminemia, osteoporosis/osteopenia
• Hypercatabolic state with failure to thrive (severe RDEB; severe JEB; severe EBS; intermediate JEB; RDEB, inversa; intermediate RDEB)

• Dysuria
• Blistering, fibrosis and scarring of glans penis; urethral meatal stenosis (RDEB); chronic inflammation of detrusor muscles secondary to exposure of denuded tissues to urine
• Urethral diverticula, penile and bulbar urethral strictures, hypospadias, epispadias
• Erosion or ulcerations on labia (RDEB, inversa), partial fusion of labia, narrowing of vaginal vestibule; urinary reflux into vagina and filling of uterine cavity
• Macroscopic blisters within the bladder, bladder edema, bladder cystitis, reduced bladder capacity, thickened bladder wall, bladder exstrophy
• Microscopic cleft formation within bladder, renal pelvis, ureter
• Urinary retention, stenosis or obstruction of the ureterovesical junction, ureteral fibrosis and stenosis, ureteral reflux with posterior urethral valves, hydroureter, hydronephrosis, renal pelvis stenosis, pyelocaliectasis, ureterectasis
• Pyelonephritis; poststreptococcal, IgA, or mesangial glomerulonephritis (RDEB); renal amyloidosis (RDEB); recurrent urinary tract infections, recurrent urosepsis
• Renal insufficiency and failure (severe RDEB)

• Trauma-induced blistering, erosions, crusting on auricle and external auditory canal; secondary microbial colonization and infections (JEB), meatal scarring/stenosis (RDEB); auricular milia formation (DEB)
• Otitis media and externa (severe JEB; RDEB)
• Bilateral sensorineural deafness (RDEB)

Nose:

• Erosions, crusting, around nares and within nostrils; rhinitis
• Granulation tissue (severe JEB) resulting in airway narrowing and repeated bleeding
• No increased frequency of atopy among any EB subtype

Oropharynx:

• Blisters, erosions, scarring, stenosis (JEB; DEB)

Larynx, trachea:

• Blisters, erosions, inflammation and soft tissue edema, scar formation along luminal surfaces including vocal cords (hoarse cry or voice; stridor); cysts; webbing, stenosis, strictures; complete or partial luminal occlusion secondary to exuberant granulation tissue with secondary aspiration pneumonitis or acute airway occlusion (severe JEB, JEB-LOC syndrome)

• Pseudosyndactyly and total encasement of digits (severe RDEB; RDEB, inversa; infrequently in DDEB, intermediate JEB, severe EBS); contractures of hands (adduction contractures of thumb), feet, popliteal and antecubital fossae, and axillary vaults; progressive functional disability (difficulties in weight bearing, standing, walking; reduced fine manipulative skill; loss of digital prehension); muscle atrophy; bone absorption
• Osteopenia, osteoporosis (RDEB) consequent to restricted mobility and weight-bearing activity (painful skin wounds, contractures); impaired nutritional intake despite greater requirements (calcium, vitamin D, anemia); reduced sunlight exposure (restricted outdoor activities, extensive bandaging); induction of catabolic osteoclastic activity by proinflammatory cytokines in the course of chronic inflammation and chronic skin infection
• Cardiomyopathy (severe RDEB; rarely, intermediate RDEB; JEB) due to malnutrition and micronutrient (selenium and carnitine) deficiency, chronic anemia, transfusion-associated iron overload, viral myocarditis; precipitating or exacerbating cardiotoxic medications (amitriptyline, cisapride); may present in early childhood