INTRODUCTION — Kindler epidermolysis bullosa (KEB; MIM #173650), or Kindler syndrome, is a rare autosomal recessive type of epidermolysis bullosa characterized by skin blistering, photosensitivity, progressive poikiloderma (the combination of extensive skin atrophy, telangiectasias, and pigmentary changes), and squamous cell carcinomas of skin and mucosal membranes. It was first described in 1954 by Theresa Kindler and considered a poikilodermatous disorder until 2008, when it was classified as a distinct type of epidermolysis bullosa [1,2]. As the first genetic cutaneous disorder associated with alterations in proteins of focal adhesions (intracellular attachment points to extracellular matrix) [3], KEB and its pathogenesis became an important model for understanding the role of focal adhesions in the skin.
This topic will discuss the pathogenesis, clinical features, diagnosis, and management of KEB. Other types of inherited epidermolysis bullosa are discussed separately.
●(See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features".)
●(See "Diagnosis of epidermolysis bullosa".)
●(See "Overview of the management of epidermolysis bullosa".)
EPIDEMIOLOGY — The incidence and prevalence of KEB are unknown. The disease occurs worldwide and affects males and females of all ethnic groups. More than 250 cases have been reported in the literature so far (Leiden Open Variation Database [LOVD]) [4]. Like all autosomal recessive conditions, it is more prevalent in populations with a high degree of consanguineous marriages and in isolates, such as Iran or Panama [5,6].
PATHOGENESIS
Genetics — KEB is caused by variants in the FERMT1 gene, encoding FFH1 (also referred to as kindlin-1), a focal adhesion protein predominantly expressed in skin basal keratinocytes, periodontal tissues, and the colon [7,8]. KEB is inherited in an autosomal recessive manner. FERMT1 pathogenic variants are found in patients in a homozygous or compound heterozygous state. The molecular pathology is complex, and in addition to a few recurrent variants (eg, c.676dup), many families bear their "private" mutations [9]. FERMT1 variants are distributed over the entire gene, spanning exons, introns, and the promoter region. The variant types include nonsense variants, small deletions, and insertions leading to frameshift and premature termination codons and absence of the protein. Splice-site variants may have the same outcome or allow the expression of truncated polypeptides [10]. In addition, large deletions, promoter variants, and deep intronic variants have been described [6,11-13].
Kindlin-1 protein — Kindlin-1 is an intracellular adaptor protein of the integrin-linked adhesion sites, known as focal adhesions in cell cultures (figure 1). Functionally, focal adhesions represent supramolecular signaling and actin-anchoring platforms.
In human adult tissues, kindlin-1 is expressed in tissues of ectodermal and endodermal origin, in particular in the skin, periodontal tissues, intestinal epithelium, and kidneys [7,14,15]. In the skin and oral mucosa, kindlin-1 is localized in basal epidermal keratinocytes in a polarized manner facing the basement membrane [16]. In the colon and rectum, kindlin-1 is localized to the plasma membrane of the epithelial cells, colocalized with ezrin and beta-catenin [17]. Together with talin, kindlins directly bind the beta-subunit cytoplasmic tails of integrins and are responsible for integrin activation and trafficking [18-20].
In KEB, skin-disorganized keratinocytes lose their proper architecture, polarization, and adhesion to the dermis [16]. In vitro, loss of kindlin-1 is associated with abnormal cell shape, modification of the cortical actin network, and increased plasticity of the plasma membrane; functionally, cell adhesion, spreading, and directed motility are perturbed [16,19,21]. In immortalized human keratinocytes, kindlin-1 was necessary for mediating epidermal growth factor (EGF)-induced activation signals, including integrin beta-1 activation, focal adhesion kinase (FAK) phosphorylation, and actin reorganization, which resulted in enhanced cell proliferation and migration [22]. These results indicate that kindlin-1 is essential in EGF-induced re-epithelialization in skin wound healing. In KEB keratinocytes, kindlin-1 has been shown to regulate the expression, subcellular distribution, and degradation of epidermal growth factor receptor (EGFR) [23].
KEB-affected cells in culture display minimal proliferation of basal keratinocytes and strongly impaired survival of keratinocytes, which explain the characteristic epidermal atrophy in patients with KEB [16]. The underlying mechanisms include involvement of kindlin-1 in mitotic spindle formation and control of stem cell proliferation [24,25].
●Photosensitivity – Several studies have shed some light on the molecular mechanisms underlying photosensitivity in KEB:
•In a mouse model study, FERMT1 knockdown impaired deoxyribonucleic acid (DNA) repair, as indicated by the increased detection of gamma-H2AX and cyclobutane pyrimidine dimers 24 hours after ultraviolet B (UVB) radiation [26]. Kindlin-1 deficiency sensitized keratinocytes to cytokine and ultraviolet (UV)-induced nuclear factor (NF)-kappa-B and c-Jun N-terminal kinase activation, while genetic or pharmacologic c-Jun N-terminal kinase inhibition and NF-kappa-B inhibition markedly reduced cyclobutane pyrimidine dimers-positive cells [26].
•Proinflammatory cytokines interleukin (IL) 1-beta, IL-6, and tumor necrosis factor (TNF)-alpha are upregulated in KEB skin and in UVB-irradiated KEB keratinocytes [27]. Expression of these cytokines depends on p38 activation, which is increased in the absence of kindlin-1 and by increased levels of reactive oxygen species. Low levels of kindlin-1 are sufficient to rescue this feature, while overexpression of kindlin-2 has no compensatory effect [28].
•Kindlin-1 is required to fully activate extracellular signal-regulated kinase (ERK) signaling after oxidative damage, and ERK activation protects cells from DNA damage following oxidative stress [29].
•Keratinocytes from patients with KEB have significantly reduced expression levels of the EGFR, resulting in defective EGF-dependent signaling. Kindlin-1 can associate directly with EGFR in vitro in an EGF-dependent, integrin-independent manner, and formation of this complex is required for EGF-dependent migration. Moreover, kindlin-1 acts to protect EGFR from lysosomal-mediated degradation [23].
●Dermal fibrosis – The pathogenesis of dermal fibrosis resulting from lack of kindlin-1 has been clarified, at least in part. Kindlin-1-deficient keratinocytes respond to cell stress (eg, UV irradiation) by upregulating the expression of proinflammatory and profibrotic cytokines such as IL-20, IL-24, transforming growth factor (TGF)-beta-2, platelet-derived growth factor-beta (PDGFB), connective tissue growth factor (CTGF), and matrix metalloproteinases [21,30]. These cytokines initiate an inflammatory response in the dermis, resulting in the activation of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased amounts of extracellular matrix proteins [30]. Repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and profibrotic processes underlie the mucocutaneous fibrosis in KEB [30]. Ribonucleic acid (RNA) sequencing of fibroblasts from patients with KEB demonstrates derangement of the extracellular matrix via transforming growth factor-beta signaling activation and oxidative state imbalance [3].
CLINICAL MANIFESTATIONS AND NATURAL HISTORY — The main clinical features of KEB are skin blistering, photosensitivity, extensive skin atrophy, poikiloderma (the combination of skin atrophy, telangiectasias, and pigmentary changes), and sclerotic features. The phenotype is progressive during the patient's life. In adults, the main cutaneous findings are poikiloderma and mucocutaneous scarring, leading to stenoses of the esophagus and genitourinary tract, ectropion, and webbing of fingers.
Cutaneous findings
●Blistering – Skin blistering is usually present at birth and shows an acral distribution (picture 1). It persists during childhood, but the tendency to develop blisters decreases with age. Blisters have no characteristic features to allow the distinction from other types of epidermolysis bullosa. Initially, they heal without scarring, but skin atrophy and sclerosis develop over time.
●Photosensitivity – The severity of photosensitivity is variable and seems to be independent of the skin phototype [31]. Most patients experience mild or unnoticeable photosensitivity.
●Skin atrophy and poikiloderma – Skin atrophy beginning on the dorsal aspects of the hands and feet is recognizable as early as at the age of one to two years (picture 2) and is a valuable clue for the diagnosis of KEB. Skin atrophy extends progressively to the entire integument. Poikiloderma can be first recognized around the age of 10 years, first localized to sun-exposed areas and later disseminated on the entire body surface (picture 3).
●Loss of dermatoglyphics – Loss of dermatoglyphics mirrors skin atrophy (picture 4); patients should be aware of this feature.
●Sclerotic changes – Sclerotic features of the hands and feet such as webbing, sclerodermiform appearance of fingers, or pseudoainhum (constrictions of the fingers) (picture 5B) manifest in young adults with significant variability, probably related to the extent of exposure to environmental factors.
Many adults with KEB have dry skin and develop diffuse keratoses of the hands and feet. On this background, dermatophyte infections, such as tinea pedis, are common.
Hair and nail changes — Scalp hair is not changed, but adults with KEB have sparse body hair. Nail dystrophy is common and may accompany the sclerosis of the fingers and pseudoainhum (picture 5A-B). Onychomycosis may also be associated.
Anomalies of the teeth — The enamel structure was assessed in a series of patients, all of whom presented with enamel structure abnormalities [32]. The severity of hypoplastic pitted amelogenesis imperfecta varied from generalized to localized pitting. Hypoplastic pitted amelogenesis imperfecta is a feature of KEB.
Mucosal lesions — Mucosal fragility is very common in patients with KEB [33].
●Oral mucosa – The oral mucosa is most frequently affected, with mechanically induced bleeding and erosions (picture 6) [34,35]. Gingivitis and early and severe periodontitis that may lead to premature loss of teeth are common. (See "Periodontal disease in children: Associated systemic conditions", section on 'Kindler epidermolysis bullosa'.)
Other orofacial features include intraoral lesions, angular cheilitis, cheilitis, gingival overgrowth, microstomia, vestibular obliteration, chronic lip ulcers, and oral squamous cell carcinoma [32]. (See 'Mucocutaneous malignancies' below.)
●Esophageal involvement – Most young adults with KEB suffer from progressive dysphagia and esophageal strictures requiring repeated dilatations. Intestinal involvement (ie, colitis induced by epitheliolysis) has been reported in a few cases [17,36,37].
●Urogenital involvement – Anal, urogenital, and ocular mucosa involvement is also common [36]. Urethral stenosis can occur in male patients during childhood or later in life [33,38,39]. Vaginal stenosis and effacement of the external female genitals have been reported in female patients [38,40].
●Ocular involvement – Patients with ocular involvement may develop ectropion and recurrent keratoconjunctivitis resulting in symblepharon [33,41].
Mucocutaneous malignancies — Patients with KEB have an increased risk of developing mucocutaneous squamous cell carcinomas. In a cohort of 91 patients with KEB, the youngest patient with squamous cell carcinoma was a 29-year-old patient [42]. The risk of squamous cell carcinoma increased with age up to 67 percent in patients over 60 years of age. The most frequently involved sites were the extremities, lips, and oral mucosa. Fifty-four percent of patients with squamous cell carcinoma developed metastatic disease. Despite a well-differentiated histopathology, these tumors have an aggressive behavior, with a tendency to recur and metastasize [43].
Revertant mosaicism — Patients with KEB due to specific FERMT1 variants demonstrate a particular, disseminated pattern of revertant mosaicism (picture 7) [44,45]. Revertant mosaicism, also called "spontaneous gene repair" or "natural gene therapy," has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin and in all types of epidermolysis bullosa [46]. In patients with KEB, revertant patches can be recognized as soon as the affected skin becomes atrophic. Revertant areas are stable in time and preserve a normal skin texture, in contrast to the surrounding atrophic skin (picture 7).
PATHOLOGY — Histopathology of KEB skin shows epidermal atrophy and hyperkeratosis, microblisters at the dermal-epidermal junction, presence of sunburn cells, and pigment incontinence. In the dermis, there are dilated vessels and fragmented and sparse elastic fibers (picture 8).
DIAGNOSIS
Clinical suspicion — In neonates, the diagnosis of KEB cannot be suspected clinically, since blistering cannot be distinguished from other types of epidermolysis bullosa [1]. In older children, the coexistence of skin blistering, photosensitivity, and cigarette-paper-like atrophy on the dorsal aspects of the hands raise the suspicion of KEB. In adults, poikiloderma in conjunction with a history of blistering and photosensitivity during childhood suggests the diagnosis.
Biopsy — A 4 mm punch biopsy taken from a freshly induced blister can be performed for the diagnosis [47]. The technique for obtaining and processing an optimal specimen for immunofluorescence microscopy and/or transmission electron microscopy is discussed in detail elsewhere. (See "Diagnosis of epidermolysis bullosa", section on 'Obtaining biopsies for epidermolysis bullosa diagnosis'.)
Transmission electron microscopy — In KEB, the level of skin cleavage is variable, intraepidermal and subepidermal, and can be discriminated by transmission electron microscopy. This technique demonstrates splits within the basal keratinocytes, in the lamina lucida and/or below the lamina densa, as well as reduplications and branches of the lamina densa of the basement membrane [1]. However, transmission electron microscopy is not widely accessible, and interpretation requires special expertise.
Immunofluorescence antigen mapping — Immunofluorescence staining with antibodies to components of the dermal-epidermal junction zone (eg, bullous pemphigoid-1 antigen, laminin-332, collagen IV, keratin 14) may be employed alternatively as a first diagnostic step in patients with suspected KEB. This procedure, also known as antigen mapping or immunofluorescence mapping, is widely used for the diagnostics of other types of epidermolysis bullosa [48-50]. (See "Diagnosis of epidermolysis bullosa", section on 'Immunofluorescence mapping'.)
In KEB skin, microblisters at the dermal-epidermal junction are indicated by discontinuous staining of markers such as type IV collagen or laminin-332. An irregular, broad staining pattern of laminin-332 and type VII collagen is highly suggestive of the diagnosis (picture 9) [51].
A negative staining with antibodies to kindlin-1 would specifically indicate the absence of this protein in the patient's skin. However, the available antibodies are not suitable for diagnosis, due to a high background staining with only a faint specific signal.
Mutation analysis — Mutation analysis represents the gold standard for the diagnosis of KEB. More than 70 distinct FERMT1 variants have been reported (Human Gene Mutation Database [HGMD]; Leiden Open Variation Database [LOVD]). Mutation analysis may be performed as candidate gene testing or by using targeted gene panel or whole exome next-generation sequencing (NGS)-based analyses [47]. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)
Because of the diverse mutational mechanisms, additional tests, such as quantitative real-time polymerase chain reaction (PCR), multiplex ligation-dependent probe amplification (MLPA), or RNA sequencing, may be required to disclose mutations. Whole-exome sequencing may also be employed, but will not capture particular types of mutations for which whole-genome sequencing or RNA sequencing are required. Genetically unsolved cases may be due to particular mutations in regions of FERMT1 that are not covered by routine diagnostic procedures [12].
DIFFERENTIAL DIAGNOSIS — In children and adults, the differential diagnosis of KEB includes other types of epidermolysis bullosa and poikilodermatous and sclerotic disorders.
●Dystrophic epidermolysis bullosa – In many patients with KEB, the diagnosis of dystrophic epidermolysis bullosa is first considered, based upon the presence of blistering, scarring, esophageal stenosis, and abnormal staining of collagen type VII in the skin. The clinical assessment of skin atrophy, photosensitivity, poikiloderma, and gingivitis may help to distinguish the two disorders. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Dystrophic epidermolysis bullosa'.)
●Junctional epidermolysis bullosa – A distinct subtype of late-onset junctional epidermolysis bullosa caused by specific variants in the gene for collagen XVII may present with clinical features that resemble KEB, in particular mild blistering, progressive skin atrophy, and irregular deposition of markers of the dermal-epidermal junction zone [52]. Features that support the diagnosis of junctional epidermolysis bullosa include nail loss, lack of photosensitivity, and the demonstration of the amino-acid substitution p.R1303Q in collagen XVII [52]. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Junctional epidermolysis bullosa'.)
●Epidermolysis bullosa simplex – Patients with KEB are sometimes initially diagnosed with epidermolysis bullosa simplex, which shares some clinical features with KEB, such as mild acral blistering that improves with age. The identification of additional clinical and molecular characteristics of KEB allows the correct diagnosis. (See "Epidermolysis bullosa: Epidemiology, pathogenesis, classification, and clinical features", section on 'Epidermolysis bullosa simplex'.)
●Dyskeratosis congenita – Dyskeratosis congenita is an inherited bone marrow failure syndrome associated with poikiloderma, palmoplantar hyperkeratosis, mucosal involvement, and predisposition to cancer (picture 10 and table 1). Detailed history, careful clinical assessment, and laboratory work-up allow the discrimination of the two entities. (See "Dyskeratosis congenita and other telomere biology disorders".)
●Rothmund-Thomson syndrome – Rothmund-Thomson syndrome is characterized by poikiloderma; sparse hair, eyelashes, and/or eyebrows; small stature; skeletal and dental abnormalities; cataracts; and an increased risk for cancer, especially osteosarcoma [53]. Detailed history and careful clinical assessment allow the discrimination of the two entities.
●Poikiloderma with neutropenia, Clericuzio type – Poikiloderma with neutropenia, Clericuzio type (MIM #604173) is a rare autosomal recessive genodermatosis characterized by poikiloderma, chronic neutropenia, recurrent pulmonary infections, short stature, facial dysmorphism, pachyonychia, palmoplantar keratoderma, and skeletal defects [54-57]. The disease, initially described in the Navajo population, is caused by variants in the C16orf57 gene on 16q13 [56,58]. Patients present with a papular erythematous rash on the limbs during the first year of life that results in progressive poikiloderma. KEB may be initially suspected in patients with poikiloderma with neutropenia, but lack of blistering and the presence of neutropenia should discriminate these two entities.
●Poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (POIKTMP) – POIKTMP (MIM #615704) is characterized by poikiloderma, hypohidrosis, lymphedema of the extremities, sclerosis of the digits, mild palmoplantar keratoderma, sparse hair, and nail dystrophy. Extracutaneous features include progressive weakness of the proximal and distal muscles of the limbs, interstitial pulmonary fibrosis, exocrine pancreatic insufficiency, liver and hematologic abnormalities, short stature, and cataract. POIKTMP is caused by variants of FAM111B and is inherited in an autosomal dominant manner [4].
●Systemic sclerosis – Mild phenotypes in adults with KEB may be misdiagnosed as systemic sclerosis, based upon the presence of mucocutaneous findings such as sclerotic fingers, microstomia, and esophageal stenosis [38,59]. Detailed history, careful clinical examination, and the demonstration of a FERMT1 variant lead to the correct diagnosis. (See "Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and diagnosis" and "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)
MANAGEMENT — There is no specific treatment for KEB. There are no experimental targeted therapies such as gene, cell, or protein therapy envisioned so far to replace kindlin-1. Genotype-phenotype correlation studies suggest that increasing the expression of kindlin-1 by approximately 10 percent would significantly alleviate the phenotype [28]. Experimental evidence for potential benefit from antioxidant therapies needs to be translated into clinical trials [27,29].
The management is largely supportive and involves an interdisciplinary team for the treatment of the complications that occur progressively, such as limited mobility of fingers, esophageal and urethral stenoses, conjunctivitis, and severe periodontitis. (See "Overview of the management of epidermolysis bullosa".)
The management strategy involves the following:
●General skin care measures, including avoidance of mechanical trauma and frequent use of moisturizers; for blisters and erosions, antiseptics and nonadhesive wound dressings should be employed [60].
●Patients should be educated to adopt photoprotection measures, even if they do not manifest photosensitivity. (See "Selection of sunscreen and sun-protective measures".)
●Careful and regular dental care is mandatory to prevent the development of periodontitis [61]. Mechanical pressure and irritations of the oral mucosa should be avoided, since they may contribute to inflammation and carcinogenesis.
●Eye care and regular ophthalmologic evaluation is an important part of the management of patients with KEB, particularly for patients who develop ectropion [62].
●Esophageal and urethral stenosis may require repeated dilatations.
●Caloric supplementation and fluid diet should be considered if body mass index is reduced due to difficulties in eating and swallowing.
●Hand surgery may be required for pseudoainhum and pseudosyndactyly. Revertant skin patches can be used for grafting.
●Patients should undergo regular total-body skin examinations for early detection of skin cancer, starting at the age of 20 years [63].
PROGNOSIS AND FOLLOW-UP — Patients with KEB can have a normal life expectancy, but it can be reduced in cases of malignancies. Complications such as limited mobility of fingers, esophageal and urethral stenoses, conjunctivitis, and severe periodontitis are frequent and require ongoing care. The prognosis is usually poor for patients who develop mucocutaneous squamous cell carcinomas. Close clinical surveillance for early detection of mucocutaneous malignancies is therefore of key importance for these patients.
We examine patients with KEB once a year to adjust skin care and detect complications. A closer follow-up is indicated for patients treated for a mucocutaneous squamous cell carcinoma. The frequency of examinations may vary for the individual patient, based upon the extent of disease and the clinician's assessment of the risk for recurrence. (See "Recognition and management of high-risk (aggressive) cutaneous squamous cell carcinoma", section on 'Follow-up' and "Posttreatment surveillance of squamous cell carcinoma of the head and neck".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Epidermolysis bullosa".)
SUMMARY AND RECOMMENDATIONS
●Definition and pathogenesis – Kindler epidermolysis bullosa (KEB) is a rare autosomal recessive type of epidermolysis bullosa characterized by skin blistering, photosensitivity, progressive poikiloderma, sclerotic features, and squamous cell carcinomas of skin and mucosal membranes. KEB is caused by a broad spectrum of pathogenic variants in the FERMT1 gene, encoding kindlin-1, an epithelial-specific protein expressed in the skin, periodontal tissues, and colon. (See 'Pathogenesis' above.)
●Clinical presentation – Skin blistering is usually present at birth with acral distribution (picture 1) and tends to decrease with age. Skin atrophy beginning on the dorsal aspects of the hands and feet (picture 2) starts in infancy or early childhood. In adults, the main cutaneous findings are poikiloderma (picture 3) and mucocutaneous scarring, leading to stenoses of the esophagus and genitourinary tract, ectropion, and webbing of fingers. (See 'Clinical manifestations and natural history' above.)
●Diagnosis – The evaluation of a skin biopsy of a freshly induced blister by immunofluorescence microscopy or transmission electron microscopy is the first step in the diagnosis of KEB. The diagnosis is confirmed by the demonstration of variants in the FERMT1 gene. (See 'Diagnosis' above.)
●Management – There is no specific treatment for KEB. The management is largely supportive and involves an interdisciplinary team for the treatment of the complications that occur progressively, such as limited mobility of fingers, esophageal and urethral stenoses, conjunctivitis, and severe periodontitis. All patients should adopt strict photoprotection measures and undergo regular skin examination for early detection of skin cancer starting in early adulthood. (See 'Management' above.)
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