Kindler epidermolysis bullosa (ORPHA:2908)
A rare inherited epidermolysis bullosa (EB) characterized by skin fragility and blistering at birth followed by development of photosensitivity and progressive poikilodermatous skin changes.
Epidemiology
Kindler epidermolysis bullosa (KEB) is the fourth major type of EB, after EB simplex, junctional EB and dystrophic EB. The exact prevalence is unknown. More than 250 cases have been reported to date.
Clinical description
The disease usually manifests at birth with trauma-induced skin blistering that is more prominent on extremities and tends to regress with age, becoming rare in adulthood. Healing of blisters occurs with minimal scarring. With age, additional skin findings are observed: (i) in most patients, photosensitivity with erythema and photo-induced blisters is obvious since early childhood and often diminishes after adolescence, (ii) progressive skin poikiloderma (atrophy, telangiectases, and reticular pigmentation) manifests from childhood and is predominantly localized to the face and neck, and (iii) skin atrophy is localized to hands and feet in the first years of life but becomes generalized by adolescence. Blisters also affect the mucosae. In the oral cavity, chronic gingivitis and periodontitis are frequent and prominent features in adulthood. Esophageal strictures, causing dysphagia and requiring repeated dilatations, frequently develop in adulthood. Anal (bleeding, stenosis), urogenital (urethral bleeding, meatal stenosis), and ocular (ectropion) involvement has also been described. The frequency of these manifestations increases with age. An additional frequent feature is digit webbing/partial pseudosyndactyly. Laryngeal and intestinal involvement, the latter manifesting with severe colitis, are rare. Other features may include: skin xerosis and fine scaling, palmoplantar hyperkeratosis, milia formation, nail dystrophy, constricting bands of pseudoainhum type, and orogenital leukokeratosis. Finally, KEB patients present an increased susceptibility to the development of squamous cell carcinomas (SCC).
Etiology
Kindler epidermolysis bullosa is caused by loss-of-function mutations in the kindlin-1 gene (FERMT1; 20p12.3) causing the defective expression of the fermitin family homologue 1 (kindlin-1), a component of cell adhesive focal contacts.
Diagnostic methods
Diagnosis is based on clinical examination and determination by biopsy of the level within which blisters develop following minor traction. Immunofluorescence antigen mapping and transmission electron microscopy of blistered skin samples show single or multiple cleavage planes at the level of the cutaneous basement membrane zone as well as an extensive reduplication of the lamina densa. Blister formation can occur below the lamina densa, within the lamina lucida or within basal keratinocytes. The diagnosis is confirmed by molecular genetic testing, particularly during the first years of life.
Differential diagnosis
The differential diagnosis includes all forms of inherited EB, in particular dystrophic EB and EB simplex with mottled pigmentation, as well as congenital diseases with photosensitivity and poikiloderma, such as Rothmund-Thomson syndrome, Bloom syndrome, dyskeratosis congenita, poikiloderma with neutropenia or xeroderma pigmentosum.
Antenatal diagnosis
Antenatal diagnosis can be performed in families at risk of having a child with KEB where the disease-causing genetic variant has been previously identified in an affected family member.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
Management is based on the avoidance of blistering by protective padding of the skin. Skin moisturizers should be applied to reduce xerosis and skin fissures. Preventive measures should also be adopted for photosensitivity. Careful and early care of the oral mucosa is mandatory to preserve dentition. Esophageal strictures can be treated by balloon dilatation with fluoroscopic guidance. Early diagnosis of SCC (skin and mucosal membranes) requires a rigorous and regular follow-up from young adulthood onwards.
Prognosis
In the majority of cases, life expectancy is normal. However, there are reports of patients with fatal aggressive SCC and, in a case series, skin cancer affected 70% of the patients older than 45 years.

                            Last update: 
                            May 2021


                            - Expert reviewer(s): 
                            Pr Cristina HAS | ERN-Skin*


                                * European Reference Network