Epidermolysis Bullosa Junctional, generalized severe
|Disease group||Epithelial adhesion disorders|
|DISEASE NAME||EPIDERMOLYSIS BULLOSA JUNCTIONAL, GENERALIZED SEVERE (formerly JEB-Herlitz)|
|Synonymous||None (old synonyms may be confusing and should not be used any more)|
|Estimated prevalence||0,1/1.000.000 in the United States|
|Gene (s)||LAMA3 (600805), LAMB3 (150310), LAMC2 (150292)|
Epidermolysis bullosa (EB) is the term applied to a clinically and genetically heterogeneous spectrum of rare inherited conditions that are characterized by a marked mechanical fragility of epithelial tissues with blistering and erosions following minor trauma. EB is based on mutations involving at least 14 structural genes expressed within the epidermis and mucocutaneous basement membrane zone (BMZ) . In addition to the skin involvement, many EB forms present as a multisystemic disease associated with numerous extracutaneous manifestations. The resulting morbidity and mortality makes it necessary to approach the patients by multidisciplinary management.
Molecular pathogenesis of EB
Causative mutations target intracellular, transmembrane and extracellular matrix proteins of the BMZ that is the adhesive interface between epithelial cells and the underlying matrix (Fig. 1). These components mantain the integrity of the dermal-epidermal anchoring complex and barrier function, control organization, proliferation and differentiation of epithelial cells and extracellular matrix substitutes .
The consequences of these mutations at mRNA and protein levels, epigenetically influenced by the individuals' genetic background and environmental trauma contribute to the pronounced phenotypic variability and severity within the broad spectrum of EB subtypes . The genetic heterogeneity also highlights the relevance of identification and characterization of specific mutation as a prerequisite for exact diagnosis and targeted molecular therapy.
Epidemiology of EB
Accuracy and comparability of epidemiological data regarding EB are limited by frequent misdiagnosis, misclassification and restricted access to experts . The first initiative to overcome these obstacles, the U.S. National EB registry (NEBR), was founded in 1986. It became the wolrd's largest cohort of well-characterized and systematically monitored EB patients that currently comprises more than 3200 individuals with long term follow-up and whose demographics have been shown to closely mirror that of the entire North American population, as well that of EB patient cohorts elsewhere in the world . Referring to evidence-based data on the NEBR study population, the overall prevalence and incidence rates of EB have been estimated to be 8.22 and 19.60 per million, respectively, by extrapolation (EBS: 4.60/10.75; JEB: 0.44/2.04; DDEB: 0.99/2.86; RDEB: 0.92/2.04).
Junctional EB, generalized severe (JEB- gen sev)
JEB-gen sev is characterized by generalized, extensive mucocutaneous blistering at birth and early lethality despite therapeutic interventions . Secondary lesions following chronic, repeated intrauterine tissue damage include atrophic scarring, webbing (intradermal scar formation between finger and toes), contractures (typically in axillary vaults) and miliae. Additionally, onychodystrophy with thickened, yellowish, longitudinally grooved nail plates or absence of nails due to atrophy and scarring of the nail bed are common findings in JEB-gen sev. Pigmentary abnormalities (mainly hypo-, de-, or mottled pigmentation) rarely also comprise EB nevi .
Exuberant granulation tissue (defined as moist, red, friable plaques with tendency to bleed) is almost pathognomonic of JEB-gen sev and typically arises symmetrically around the mouth, central face or nose as well as on the upper back, in axillary vaults and around nail folds. Periorificial vegetations can cause occlusion and may sometimes clinically mimick squamous cell carcinomas.
Rather uncommon cutaneous manifestations of JEB-gen sev comprise localized or more diffuse scarring alopecia, palmoplantar keratoderma and congenital absence of skin (aplasia cutis congenita) with ulcerated lesions with complete absence of all skin layers .
Prototypical lesions of JEB-gen sev such as blisters and erosions, followed by strictures, contractures and 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. These complex affections make JEB-gen sev a systemic disease and account for a considerably high morbidity and mortality.
Upper respiratory tract involvement is a frequent phenomenon in JEB-gen sev. The most common symptoms, i.e. chronic hoarseness, weak cry or inspiratory stridor are an alarming finding seen in up to 50% of all patients with JEB-gen sev . They may be caused a considerable respiratory affection with end-stage sequelae like laryngeal webs, stenosis and airway obstruction due to occlusion by blisters, diffuse edema, progressive scar formation. 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 . 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.
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 odontogenesis [11,12]. 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.
Urologic abnormalities in EB occur with the highest frequency in patients with JEB-gen sev . Urethral meatus stenosis is the most common complication, observed in 11.6% of JEB-gen sev patients within the National Epidermolysis bullosa registry of the US (NEBR), followed by urinary retention, hydronephrosis and bladder hypertrophy.
Due to extensive disease, mortality (i.e. death related to JEB-gen sev) is very high, especially in the first year of life. Causes of premature death most commonly include recurrent infections and massive sepsis. Transcutaneous entry of Staphylococcus aureus, Streptococcus, Candida or methicillin-resistent Staphylococcus aureus via widespread skin erosions and an underlying immune deviation in patients with complete loss of laminin 332 might be causative . 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 .
JEB-gen sev is caused by 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). 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 .
JEB-gen sev 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 . UPD 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 JEB-gen sev and their families in order to identify a hidden UPD. In contrast to the classic autosomal recessive pattern of inheritance in JEB-gen sev with a 25% recurrence risk for future pregnancies, an autosomal recessive condition caused by UPD has a negligible risk of recurrence.
Figure 1: Schematic of the basement membrane zone (BMZ).
© graphic design by R. Hametner
Intermediate filaments composed of keratin 5 and 14 insert on the keratin (cytoskeletal) linker proteins plectin and BPAG1 (BP230) at the superior aspect of the BMZ. Plectin and BPAG1 interact with transmembrane a6b4 integrin and type XVII collagen (BP180/BPAG2), forming hemidesmosomes that attach basal keratinocytes to the underlying basement membrane. Anchoring filaments reach out below the hemidesmosome and include laminin-332 and laminin-311 that associate with type XVII collagen and a6b4 integrin, but also laminin-511, type IV collagen and nidogen, thereby forming the lamina densa. Anchoring fibrils extend as banded projections from the lamina densa and contain type VII collagen molecules. Type VII collagen triple helices attach the lamina densa to papillary dermis and are critical for the integrity of the epidermal-dermal junction through their ability to bind laminin-332.
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