DISEASE CARD

Disease group Epithelial adhesion disorders
DISEASE NAME EPIDERMOLYSIS BULLOSA JUNCTIONAL
Synonymous None
Estimated prevalence 0.5 / 1.000.000
OMIM 226700, 226650, 226730, 131800, 614748, 226440, 245660, 614748
Inheritance autosomal recessive
Gene (s) COL17A1 (113811), LAMA3 (600805), LAMB3 (150310), LAMC2 (150292), ITGA6 (147556), ITGB4 (147557), PLEC (601282), ITGA3 (605025)

Introduction

Junctional epidermolysis bullosa (JEB) encompasses a group of autosomal recessive diseases that share skin fragility and trauma- or friction- induced blistering occurring within the lamina lucida (part of the skin’s basement membrane). Mutations in several genes, encoding components critical for the dermal-epidermal adhesion, are causative.

Clinical Description

JEB shows a broad phenotypic spectrum, ranging from subtle clinical signs (that resemble EB simplex) to severe generalized involvement with early lethality. (see table)

Intermediate JEB (previously Non-Herlitz JEB): This type comprises a clinically heterogenous group with generalized blistering, superficial ulcers, crusts, fissuring or deep ulcerations. Recurrent blistering leads to atrophic scarring, pigmentary abnormalities, erythema (poikilodermatous appearance) and faint stellate scars, while severe scarring and milia are rare. Infants and children often fail to demonstrate many of these clinical manifestations and their symptoms are similar to other types of EB. Nonhealing wounding areas that are already present during infancy, may remain a problem throughout life, particularly over the lower legs. Further clinical features include a progressive, typically diffuse, incomplete alopecia that - after normal scalp hair growth in childhood - becomes apparent by the end of the first or second decade. Dystrophic or absent nails (due to repeated minor trauma and blistering), dental enamel hypoplasia and caries, as well as EB nevi are additional symptoms. Involvement of mucous membranes tends to be worse in infancy and early childhood, but is usually milder than in severe JEB. However, more than 10% of intermediate JEB patients experience potentially life-threatening airway obstruction due to tracheolaryngeal stenosis or obstruction. This complication almost exclusively occurs within the first 2 years of life. Affected individuals may also suffer from esophageal webs and strictures, urogenital pathologies, resulting in renal dysfunction and ophthalmological problems. Development of squamous cell carcinoma is uncommon in intermediate JEB.1-3

Severe JEB (previously Herlitz JEB) is characterized by generalized mucocutaneous blistering at birth or within the first few days of life and early lethality (most patients do not survive past infancy) despite therapeutic interventions. Extensive skin and mucous membranes fragility may result in loss of proteins, fluids and iron that increases the susceptibility to infections. Sepsis, failure to thrive and respiratory failure are the major causes of death. 5 However, the initial presentation can be deceptively mild and indistinguishable from other types of EB. In general, scarring is not a prominent feature (as in dystrophic EB). Secondary lesions following chronic, repeated tissue damage include moderate atrophic scarring, occasionally webbing (intradermal scar formation between finger and toes) and contractures (typically in axillary vaults) as well as miliae, although not as numerous as in DEB. Mucosal and subungual blistering is frequently present, leading to onychodystrophy (thickened, yellowish, longitudinally grooved nail plates) or absence of nails. In contrast to DEB, scalp lesions are commonly present as well as anal fissuring and constipation. Pigmentary abnormalities (mainly hypo-, de-, or mottled pigmentation) rarely also comprise EB nevi.1, 2

Exuberant granulation tissue (moist, red, friable plaques with tendency to bleed) is almost pathognomonic of severe JEB and usually develops by the second year of life as healing tends to become worse. Common sites are around the mouth, central face, ears or nose in a symmetrical distribution, as well as on the upper back, in axillary vaults and periungual (drumstick appearance). Periorificial and pharyngeal granulation tissue can cause substantial pain, feeding problems and thus worsen growth faltering, a typical complication of severe JEB. Pain is usually high in severe JEB. Rather uncommon cutaneous manifestations of severe JEB comprise localized or more diffuse scarring alopecia, palmoplantar keratoderma and congenital absence of skin (aplasia cutis congenita).4, 5

Prototypical lesions of severe JEB such as blisters and erosions, followed by strictures, contractures and even stenoses, also occur in other epithelial tissues outside the skin, involving e.g. the mucous membranes of the gastrointestinal, upper respiratory and genitourinary tracts, the kidney and external eye. Anaemia, occasionally marked, is common and related to iron deficiency and inflammation. 5

Upper respiratory tract involvement is a frequent phenomenon in severe JEB. The most common symptoms, i.e. chronic hoarseness, weak cry or inspiratory stridor are seen in up to 50% of all patients. They are usually caused by laryngeal webs, stenosis and airway obstruction due to mucous blistering, diffuse edema or progressive scar formation and thus should be considered as an alarming sign. Airway injury arises spontaneously or follows episodes of coughing, crying or upper respiratory tract infection. It may occur with rapid onset and life-threatening progression and can be precipitated or exacerbated by intubation as well as unrecognized gastroesophageal reflux disease.6 Partial or complete occlusion of upper airway is the most severe otorhinolaryngeal complication in EB that is almost exclusively seen in the generalized subtypes of JEB within the first year of life. The cumulative risk decreases in later childhood, most likely due to the age-related increase in luminal diameter of airways.6

Enamel hypoplasia (pitting and furrowing of thin enamel) is a characteristic feature of intraoral disease in all JEB subtypes. It reflects a deregulated interaction of mutated adhesion proteins in the course of odontogenesis and cytodifferentiation. The spatially and temporally aberrant expression of mutated laminin-332 and type XVII collagen by enamel forming ameloblasts interferes with enamel formation and other processes during odontogenesis7, 8. Dysfunctional adhesion results in leaking of serum fluids into developing enamel, leading to the retention of albumin and decreased mineralization. Enamel defects such as excessive pitting over tooth surfaces create non-cleansable areas ideal for microbial growth and substrate retention that are known to cause dental caries. Excessive caries and premature loss of teeth is thus very common in affected individuals.9

Oral, oropharyngeal and/or gastrointestinal complications (e.g. pain, strictures, ulcerations) may further lead to impaired nutritional intake or absorption.

Urologic abnormalities in EB occur with the highest frequency in patients with severe JEB Urethral meatus stenosis is the most common complication, observed in 11.6% of severe JEB patients within the National Epidermolysis bullosa registry of the US (NEBR), followed by urinary retention, hydronephrosis and bladder hypertrophy.6, 10

Infections are common due to transcutaneous entry of Staphylococcus aureus, Streptococcus, Candida or methicillin-resistent Staphylococcus aureus via widespread skin erosions and probably an underlying immune deviation in patients with complete loss of laminin 332. Furthermore, septic embolism, pneumonia and respiratory failure other than pneumonia (e.g. tracheolaryngeal obstruction) as well as failure to thrive and renal failure are occurring.10

Anaemia is highly prevalent, especially in severe types, due to chronic inflammation, increased blood loss of wounds and malabsorption of iron.

 

JEB subtypes

Subtypes

Gene (protein)

Typical clinical features

Severe

LAMA3, LAMB3, LAMC2 (laminin 332)*

Generalized blistering, nail dystrophy, granulation tissue, atrophic scarring, anaemia, growth faltering, severe mucosal fragility, excessive caries; involvement of GI-tract, GU-tract, R-tract; delayed puberty; commonly early death in the first years of life;

Intermediate

COL17A1, LAMA3, LAMB3, LAMC2 (type XVII collagen, laminin 332)

Generalized blistering, atrophic scarring, milia, rarely granulation tissue, focal palmoplantar keratoderma, enamel hypoplasia, excessive caries, mucosal fragility; alopecia; sometimes anaemia and growth retardation, involvement of GI, GU, R-tract;

With pyloric atresia

ITGA6, ITGB4, PLEC1 (Integrin α6β4, plectin)

Pyloric atresia (vomiting, distended abdomen absence of stool, life-threatening), generalized blistering, atrophic scarring, nail dystrophy, may be associated with large areas of aplasia cutis, GU-abnormalities, mucosal fragility, enamel hypoplasia, rudimentary ears, anaemia and growth retardation can oocur; early lethality

Localized

COL17A1, ITGB4, LAMA3, LAMB3, LAMC2, ITGA3 (laminin 332, type XVII collagen, integrin α6β4, integrin α3 subunit)

Localized blistering (mainly on extremities), nail dystrophy, enamel hypoplasia; no extracutaneous involvement;

Inversa

LAMA3, LAMB3, LAMC2 (laminin 332)

Cutaneous manifestations predominantly in intertriginous areas (more extensive than in localized JEB), atrophic scarring, nail dystrophy; enamel hypoplasia, caries, GI-tract involvement,

Late onset

COL17A1 (type XVII collagen)

Onset at young adulthood or later; variable skin blistering, nail dystrophy, hypohidrosis, absent dermatoglyphs, enamel hypoplasia, variable mucosal fragility;

LOC syndrome

LAMA3A (laminin α3A)

Granulation tissue on skin/wounds, larynx (resulting in stricture/stenosis) and conjunctiva (symblepharon); hoarse cry at birth due to vocal cord thickening / laryngeal granulation tissue; generalized blistering/erosions (rather mild), nail dystrophy, atrophic scarring, enamel hypoplasia, caries

With interstitial lung disease and nephrotic syndrome

ITGA3 (Integrin α3 subunit)

Marked respiratory involvement due to interstitial lung disease, nephrotic syndrome; mild skin fragility and nail dystrophy; death in infancy or early childhood due to complications (lung, kidney)

*JEB severe is rarely caused by pathogenic variants affecting the type XVII collagen gene; GI=gastrointestinal; GU=genitourinary; R=respiratory tract

 

Pathogenesis

The split formation in JEB occurs through the lamina lucida within the basement membrane and in most cases results from absent or (in number) reduced, hypoplastic hemidesmosomes.

Intermediate JEB is predominantly caused by autosomal recessive COL17A1 gene mutations, although dominant inheritance has been reported. Despite the fact that most mutations lead to premature termination codons, their consequences and resulting phenotypes are difficult to predict. Milder phenotypes have been associated with expression of partially functional collagen 17 molecule (e.g. via alterantive splicing). 11 In particular, spontaneous revertant mosaicisms can interfere with the disease severity, presenting with an atypically mild phenotype of nonlethal JEB.12

Homozygous null mutations or frame-shift mutations (deletions and insertions) in LAMA3, LAMB3 and LAMC2 genes (encoding α, β, and γ subunits of laminin-332) are typical for severe JEB. These mutations generate premature termination codons that either lead to accelerated nonsense mediated mRNA decay or truncated, non-functional proteins sensitive to proteolytic degradation. Two recurrent mutations in LAMB3, R635X and R42X, account for almost 60% of the mutant LAMB3 alleles. Moreover, intragenic duplication by mispairing between DNA sequences in close proximity was described for LAMC2 gene.13, 14

Severe JEB is usually inherited in autosomal recessive trait from heterozygous healthy parents to 25% of their offspring. However, a higher reported incidence of uniparental isodisomy (UPD) must be considered. 15UPD refers to a recessive condition that arises from a mutation carried by a single heterozygous carrier parent that is converted to homozygosity. It results from sporadic events that operate to restore the correct chromosomal number in the embryo consequent to alterating errors during meiosis and gamete maturation. Molecular mechanisms include trisomic rescue, duplication of monosomy, gamete complementation or somatic recombination. Therefore, genetic analysis of each parent should be routinely performed in patients with severe JEB and their families in order to identify a hidden UPD. In contrast to the classic autosomal recessive pattern of inheritance in severe JEB with a 25% recurrence risk for future pregnancies, an autosomal recessive condition caused by UPD has a negligible risk of recurrence.16

 

Diagnosis

Whenever possible, laboratory diagnosis should be performed in a specialized EB centre.

To determine the level of skin cleavage, immunomapping or transmission electron microscopy of skin biopsies (4-6mm) is recommended. The immunomapping has diagnostic accuracy similar to transmission electron microscopy, with the advantage of simple and fast execution and reading. The splitting of the skin occurs within the lamina lucida of the basement membrane. Electron microscopy may identify anomalies / lack of hemidesmosomes at the lamina densa.

In parallel, blood sampling for the extraction of genomic DNA is recommended. Genetic testing is the gold standard since it provides a definite diagnosis and classification of the major EB type and in many cases the subtype. It also enables genetic counselling and DNA-based prenatal testing. Most JEB types are due to mutations in LAMB3 (70%), followed by COL17A1 (12%), LAMA3 and LAMC2 (9%) and ITGB4 (<1%). A next-generation sequencing (NGS) EB-gene panel is the method of choice as it encompasses all known pathogenic EB genes and shows good sequencing coverage. In addition, Sanger sequencing may be performed if the target gene is known and of small size, or to detect familial and recurrent genetic variants. Immunofluorescence findings and genetic analysis provide complementary information that enables precise and fast diagnosis but also prediction of consequences of novel sequence variants and genotype-phenotype correlations. The vast majority of EB cases can be genetically characterized with these methods. 2, 17

 

Treatment

There is no cure for EB. Wound care as well as early recognition and treatment of complications (e.g. skin infections) remain the mainstays of management.

General measures: Prevention of blister formation in everyday life, e.g., by choosing appropriate foot wear and wide clothing without raised seams or labels as well as padding of trauma-exposed sites, should be routinely implemented. If palmar or plantar hyperkeratosis is present, regular debridement and/or keratinolytics will help reducing walking pain and preventing fissuring and infection under the thickened skin. Occurrence of pain should be regularly assessed and adequately treated, e.g. for mild pain with non-opioid analgesics (e.g. paracetamol in conjunction with nonsteroidal anti-inflammatory drug), for moderate to severe pain with opioid analgesics (e.g. codeine, morphine) and/or tricyclic antidepressants, gabapentin, pregabalin and non-pharmacologic practices. Cannabinoids (nonaddictive) either oral or topical have also some effectiveness in many patients. Pain may be inherent (blistering, wounds, erosions) or caused by manipulation or dressing changes. Management of pruritus is also a prominent, debilitating feature of JEB and frequently challenging and includes pharmacologic interventions (e.g. antihistamines, antidepressants, gabapentin), topical emollients and psychological therapies like relaxation training, biofeedback or distraction. As oral involvement can occur, children should be referred to the dentist before the teeth erupt and preventative measures applied (e.g. oral hygiene, fluoride). Nutritional status (especially fluid and electrolyte balance in infants) should be checked regularly and special diets or vitamin supplements/micronutrients, if needed, introduced. Neonates with severe JEB may require enteral nutrition support. Many patients require iron supplementation (either orally or parenteral)Evaluation of bone mineral density should be regularly performed to screen for osteopenia and/or osteoporosis. Patients can profit from physical therapy, starting early in life. Some may require tracheostomy (especially LOC-syndrome patients). Treatment of urologic and renal disease should be initiated as required.18, 19

Wound care: Large blisters can cause pain and should be carefully opened (e.g. with a sterile needle), in order to release the pressure from surrounding tissue. The blister roof can be left in place for a better healing. However, when it has been removed, special non adhesive dressings are needed to reduce the risk of wound infections and pain. The choice of the dressing should consider the wound characteristics (site, exudate, critical colonization/infection), size, patient age, patient/parent preferences). Adhesive dressings or tapes must be avoided as they can induce blistering. Surveillance for squamous cell carcinoma is recommended in the second decade of life.18 Systemic antibiotics, that cover common pathogens, may be needed if tissue infection (especially lymphadenopathy, malaise, fever) occurs.

Ocular involvement (e.g. corneal erosions, blistering, scarring, blepharitis, symblepharon, visual impairment, refractive errors, strabismus) requires regularly monitoring and experienced ophthalmologic evaluation and therapy. Topical lubricants are frequently helpful against mild symptoms and antibiotic ointments are regularly used for corneal erosions.9

 

 

 

 

 

References

1. Fine JD. Inherited epidermolysis bullosa. Orphanet J Rare Dis. 2010;5:12 

2. Has C, Bauer JW, Bodemer C, et al. Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility. 2020;183(4):614-627.

3. Kiritsi D, Has C, Bruckner-Tuderman L. Laminin 332 in junctional epidermolysis bullosa. Cell adhesion & migration. 2013;7(1):135-141.

4. Laimer M, Lanschuetzer CM, Diem A, Bauer JW. Herlitz junctional epidermolysis bullosa. Dermatologic clinics. 2010;28(1):55-60.

5. Yuen WY, Lemmink HH, van Dijk-Bos KK, Sinke RJ, Jonkman MF. Herlitz junctional epidermolysis bullosa: diagnostic features, mutational profile, incidence and population carrier frequency in the Netherlands. Br J Dermatol. 2011;165(6):1314-1322.

6. Fine J-D, Mellerio JE. Extracutaneous manifestations and complications of inherited epidermolysis bullosa: part I. Epithelial associated tissues. Journal of the American Academy of Dermatology. 2009;61(3):367-384.

7. Aberdam D, Aguzzi A, Baudoin C, Galliano MF, Ortonne JP, Meneguzzi G. Developmental expression of nicein adhesion protein (laminin-5) subunits suggests multiple morphogenic roles. Cell Adhes Commun. 1994;2(2):115-129.

8. Asaka T, Akiyama M, Domon T, et al. Type XVII collagen is a key player in tooth enamel formation. Am J Pathol. 2009;174(1):91-100.

9. Krämer S, Lucas J, Gamboa F. Clinical practice guidelines: Oral health care for children and adults living with epidermolysis bullosa. 2020;40 Suppl 1(Suppl 1):3-81.

10. Fine J-D, Mellerio JE. Extracutaneous Manifestations and Complications of Inherited Epidermolysis Bullosa: Part II. Other Organs. Journal of the American Academy of Dermatology. 2009;61(3):387-404.

11. Hérissé AL, Charlesworth A, Bellon N, Leclerc-Mercier S, Bourrat E, Hadj-Rabia S. Genotypic and phenotypic analysis of 34 cases of inherited junctional epidermolysis bullosa caused by COL17A1 mutations. 2021;184(5):960-962.

12. Kiritsi D, Kern JS, Schumann H, Kohlhase J, Has C, Bruckner-Tuderman L. Molecular mechanisms of phenotypic variability in junctional epidermolysis bullosa. Journal of medical genetics. 2011;48(7):450-457.

13. Pulkkinen L, Meneguzzi G, McGrath JA, et al. Predominance of the recurrent mutation R635X in the LAMB3 gene in European patients with Herlitz junctional epidermolysis bullosa has implications for mutation detection strategy. J Invest Dermatol. 1997;109(2):232-237.

14. Posteraro P, De Luca N, Meneguzzi G, et al. Laminin-5 mutational analysis in an Italian cohort of patients with junctional epidermolysis bullosa. J Invest Dermatol. 2004;123(4):639-648.

15. Fassihi H, Wessagowit V, Ashton GH, et al. Complete paternal uniparental isodisomy of chromosome 1 resulting in Herlitz junctional epidermolysis bullosa. Clin Exp Dermatol. 2005;30(1):71-74.

16. Castori M, Floriddia G, Pisaneschi E, et al. Complete maternal isodisomy causing reduction to homozygosity for a novel LAMB3 mutation in Herlitz junctional epidermolysis bullosa. J Dermatol Sci. 2008;51(1):58-61.

17. Has C, Fischer J. Inherited epidermolysis bullosa: New diagnostics and new clinical phenotypes. Exp Dermatol. 2019;28(10):1146-1152.

18. Has C, El Hachem M. Practical management of epidermolysis bullosa: consensus clinical position statement from the European Reference Network for Rare Skin Diseases. 2021;35(12):2349-2360.

19. Marro M, De Smet S, Caldari D, Lambe C, Leclerc-Mercier S, Chiaverini C. Gastrostomy for infants with severe epidermolysis bullosa simplex in neonatal intensive care. 2021;16(1):271.