Kindler Syndrome

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Background

Kindler syndrome (KS) was first described in 1954 by Theresa Kindler. Kindler syndrome is a rare subtype of epidermolysis bullosa (EB), along with EB simplex, junctional EB, and dystrophic EB. Kindler syndrome is an autosomal recessive genodermatosis characterized by congenital acral skin blistering, photosensitivity, progressive poikiloderma, and diffuse cutaneous atrophy. Mucosal manifestations are common, with frequent involvement of the oral mucosa, gingiva, and gastrointestinal tract. Various complications and associated features have been identified. See the image below.



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Images show the progression of lesions. A and B: At birth, acral blisters and erosions are present. C and D: At age 5 years, atrophy and reticulated e....

Pathophysiology

Kindler syndrome is the result of loss-of-function mutations of the FERMT1 gene (also known as KIND1).This gene has been mapped to band 20p12.3 by using linkage and homozygosity analysis in an isolated cohort of patients with Kindler syndrome.[1] FERMT1 encodes a 677–amino acid protein, kindlin-1, which binds β1 (as well as β3 and β6) integrin cytoplasmic domains. The integrin family mediates cell adhesion to the basement membrane, and absence of kindlin-1 results in poor anchoring of the basal layer of the epidermis to the underlying basement membrane.[2, 3, 4] Kindlin-1 is a human homolog of the Caenorhabditis elegans protein UNC-112, a membrane-associated structural/signaling protein that had been implicated in linking the actin cytoskeleton to the extracellular matrix (ECM). Kindler syndrome is the first genodermatosis caused by a defect in actin-ECM linkage rather than keratin-ECM linkage, underlying the pathology of other inherited skin fragility disorders (eg, other subtypes of EB).[5] Nonsense, deletion/insertion frameshift, and single-nucleotide mutations have all been described in the mutated FERMT1 gene in both introns and exons,[6, 7, 8] resulting in a truncated kindlin-1 protein. Additionally, a promoter region deletion in the FERMT1 gene has been described in a patient with Kindler syndrome.[9, 10]

Kindler syndrome keratinocytes show an up-regulation of basal level proinflammatory cytokines interleukin (IL)–1β, IL-6, and tumor necrosis factor-α (TNF-α). Ultraviolet (UV)–B irradiation to cells lacking kindlin-1 induces a greater degree of proinflammatory cytokine and p38 induction compared with control cells. UV-B–induced apoptosis has been found to be rescued by expression of kindlin-1, TNF-α blockers, a p38 inhibitor, or antioxidant plant flavonoids.[11] Oxidative stress may also result in mitochondrial dysfunction in kindlin-1–deficient keratinocytes.[12, 13] Kindlin-1 expression has also been shown to prevent premature senescence in keratinocytes,[14] as well as regulate microtuble function in mitosis.[15] Up-regulation of numerous other cytokines has been described, resulting in the activation of fibroblasts to secrete ECM proteins and differentiate into myofibroblasts.[16]

See the infographic below.



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Kindlin proteins anchor intracellular actin filaments to the basement membrane via integrins. Deconstructing the skin: Cytoarchitectural determinants ....

Epidemiology

Frequency

Since the first description in 1954, more than 250 cases of Kindler syndrome have been reported worldwide. A cluster of 26 patients with the syndrome has been identified within a tribe in the Bocas del Toro province on the northwestern Caribbean coast of Panama.[17] Owing to the rarity and autosomal recessive nature of the condition, many cases have been seen in consanguineous families, although sporadic cases are common.

Race

Persons of any race can be affected.

Sex

No sex predilection has been documented.

Age

Patients usually present with the initial skin manifestations during the first year of life. Many patients, however, may not be diagnosed until late in life.

Prognosis

Patients usually have normal intelligence and a normal life span. Blistering improves with age, but poikiloderma and atrophy are progressive. Morbidity and mortality are primarily related to secondary infections arising from cutaneous bullae and to cosmetic disfigurement.

Patient Education

Patients should be advised to avoid trauma, which helps prevent blister formation. The use of broad-spectrum photoprotection should be emphasized. Frequent consultation with a dermatologist is essential.

History

The hallmark of Kindler syndrome (KS) is congenital blistering and photosensitivity, combined with progressive poikiloderma and diffuse cutaneous atrophy. Both blistering and photosensitivity begin in infancy or early childhood and improve significantly with age. Photosensitivity can manifest as increased susceptibility to sunburn. The poikiloderma appears gradually and becomes more prominent later in life. Some patients develop sclerodermoid changes of the fingers and nails. Recurrent trauma-induced blister formation occurs primarily on hands and feet, which may prompt an incorrect diagnosis of epidermolysis bullosa (EB). Although the condition presents early in life, numerous patients have been diagnosed late in life.

Physical Examination

Highly suggestive findings of Kindler syndrome include the following:

Other prominent features may include the following:

Rarely described features are as follows:

Complications

Complications of blistering can result in secondary bacterial infection. The blisters usually heal without residual scarring, but they can result in hypopigmentation and transient milia. Accelerated periodontal disease is common. Ophthalmic complications, such as conjunctival scarring, may occur. Mucosal involvement is frequent and may lead to urethral, ileal,[24] anal, vaginal,[27] and esophageal[25] stenosis; esophageal webs[26] ; and labial agglutination[28] and phimosis. Early development of actinic keratoses may occur. Kindler syndrome increases the risk of nonmelanoma skin cancer. Squamous cell carcinoma of the lower lip and transitional cell carcinoma of the bladder, as well as invasive squamous cell carcinoma of the hand[32] and laryngeal squamous cell carcinoma,[33] have been reported. Cutaneous precancerous lesions and epithelial skin cancer have been seen in individuals with Kinder syndrome.[34] Synchronous bilateral breast cancer in a postmenopausal woman affected with Kindler syndrome has also been reported.[35]

Laboratory Studies

The diagnosis of Kindler syndrome (KS) is established in a proband with characteristic clinical findings and identification of either of the following[37] :

Histologic Findings

Light microscopy

Histopathologic examination of atrophic skin lesions in patients with Kindler syndrome reveals nonspecific features of poikiloderma. The epidermis is flattened and atrophic, edema is present at the dermoepidermal junction, and the basal layer shows focal vacuolization with basal cell degeneration. Other histologic features include a prominence of dermal capillaries, pigmentary incontinence, and, possibly, perivascular lymphocytic infiltrate. The most common cleavage plane is through the lowermost portion of the basal layer of the epidermis.

Electron microscopy

Electron microscopy shows reduplication and disruption of the lamina densa with attached anchoring fibrils along the dermoepidermal junction and cleft formation in the lamina lucida, suggestive of continual remodeling of the basement membrane zone. Ultrastructural studies of bullae in the skin of affected persons have demonstrated a coexistence of three levels of abnormal cleavage: (1) within or just above the basal layer of epidermis (intraepidermal), (2) within the lamina lucida (junctional), and (3) below the lamina densa (dermal).

Immunohistochemistry

In Kindler syndrome, normal staining of epidermal structure proteins (plakophilin, pan-keratin, cytokeratin 5, and cytokeratin 14) is observed. Proteins of the hemidesmosome (α6β4 integrin and collagen XVII) is strongly reduced. Staining for the underlying extracellular matrix (laminin 332, collagen VII, and collagen IV) showed doubling of the basal membrane and overexpression of laminin 332. Wada et al have noted that expression of type VII collagen via immunofluorescence shows a broad, reticulate pattern.[38] However, mesenchymal markers such as vimentin and fibronectin are overexpressed.

Immunostaining with antikindlin-1 antibody is a useful diagnostic test in the assessment of suspected cases of Kindler syndrome; decreased/absent staining of the epidermis of patients with Kindler syndrome is observed compared with controls.[39] Control samples display linear and cell-surface staining in the basal keratinocytes.[40, 41] Immunofluorescence on a freshly induced blister is a primary method of diagnosis. 

Medical Care

Treatment is mainly symptomatic and preventative in nature. The cornerstones of care in Kindler syndrome (KS) include the following[42] :

Antioxidants and the plant flavonoid luteolin have been shown to reduce UV-B–induced apoptosis in Kindler syndrome–affected keratinocytes in vitro. These substances may play a role in the future as a topical therapy for the management of Kindler syndrome.[11]

Surgical Care

Telangiectasias can be treated with pulsed-dye laser therapy. Surgical correction of urethral, anal, or esophageal stenosis may be needed.

Consultations

Consultation with the following specialists may be necessary:

Medication Summary

The role of pharmacotherapy is supportive in nature. Emollients and good blister care reduce morbidity and help prevent complications. Sunscreen should be used daily. Topical antimicrobials may be used for secondary bacterial infections.

Author

Anthony W Linfante, Jr, MD, Resident Physician, Department of Dermatology, University of Texas Medical Branch School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Amanda T Moon, MD, Clinical Assistant Professor of Dermatology, Children's Hospital of Philadelphia

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Former Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH, Professor and Head of Dermatology, Professor of Pathology, Professor of Pediatrics, Professor of Medicine, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Anatoli Freiman, MD, FRCPC, DABD, Consulting Staff, Division of Dermatology, Women's College Hospital, University of Toronto Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

Franklin Flowers, MD, Department of Dermatology, Professor Emeritus Affiliate Associate Professor of Pathology, University of Florida College of Medicine

Disclosure: Nothing to disclose.

Acknowledgements

The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author, Laura Russell, MD, to the development and writing of this article.

References

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Images show the progression of lesions. A and B: At birth, acral blisters and erosions are present. C and D: At age 5 years, atrophy and reticulated erythema with dyschromic patches are noted. E and F: At age 7 years, progressive poikilodermatous changes with reticulated erythema and telangiectasia occur. G and H: At age 10 and 15 years, poikiloderma with telangiectasia and depigmentation are observed. Excoriations are due to pruritus. Reprinted from Yasukawa K, Sato-Matsumura KC, McMillan J, et al: Exclusion of COL7A1 mutation in Kindler syndrome. J Am Acad Dermatol 2002 Mar; 46(3): 447-50. Courtesy of the American Academy of Dermatology.

Kindlin proteins anchor intracellular actin filaments to the basement membrane via integrins. Deconstructing the skin: Cytoarchitectural determinants of epidermal morphogenesis. Reprinted with permission from Nature Reviews Molecular Cell Biology (Nature Publishing Group).

Images show the progression of lesions. A and B: At birth, acral blisters and erosions are present. C and D: At age 5 years, atrophy and reticulated erythema with dyschromic patches are noted. E and F: At age 7 years, progressive poikilodermatous changes with reticulated erythema and telangiectasia occur. G and H: At age 10 and 15 years, poikiloderma with telangiectasia and depigmentation are observed. Excoriations are due to pruritus. Reprinted from Yasukawa K, Sato-Matsumura KC, McMillan J, et al: Exclusion of COL7A1 mutation in Kindler syndrome. J Am Acad Dermatol 2002 Mar; 46(3): 447-50. Courtesy of the American Academy of Dermatology.

Kindlin proteins anchor intracellular actin filaments to the basement membrane via integrins. Deconstructing the skin: Cytoarchitectural determinants of epidermal morphogenesis. Reprinted with permission from Nature Reviews Molecular Cell Biology (Nature Publishing Group).