Dermatology

Kindler Syndrome (Poikiloderma, hereditary acrokeratotic; Bullous acrokeratotic poikiloderma of Kindler and Weary; Poikiloderma, congenital with bullae Weary type)

Are You Confident of the Diagnosis?

What you should be alert for in the history

Personal history for Kindler syndrome (KS) includes congenital blistering associated with mild photosensitivity and progressive poikiloderma. Family history includes consanguinity and autosomal recessive inheritance pattern.

Characteristic findings on clinical examination

Skin blistering begins at birth and persists during childhood, but progressively decreases with age. Skin fragility is rather mild in adults, whereas atrophy and dryness become the most prominent features (Figure 1). The thin wrinkled appearance of the skin of the dorsal hands and feet is very suggestive for the diagnosis of KS, and occurs as early as the age of 2-3 years.

Figure 1.

Clinical features of KS. Note dry atrophic skin in a 27-year-old patient. Hemorrhagic crust resulted from intensive scratching.

Poikiloderma develops progressively and disseminates from the extremities and neck to the entire skin surface. Sclerosing features of hands and feet, such as webbing, sclerodermiform appearance, or pseudoainhum occur with a variable degree of severity in patients (Figure 2). Atrophy and sclerosis lead to loss of dermatoglyphics (Figure 2).

Figure 2.

Sclerosis and atrophy of the skin on hands and feet may lead to loss of dermatoglyphics and pseudoainhum.

The occurrence of squamous cell carcinoma was reported in patients as young as 16, but in most cases, nonmelanoma skin cancers develop after the age of 45 years.

Mucosal involvement is very common in KS and accounts for the main complication in adults. The oral mucosa is affected very early and frequently, manifests as easy bleeding of the gums and periodontitis. Esophageal involvement develops in adults and progresses from dysphagia to strictures requiring repeated dilatations. Anal, urogenital, and ocular mucosa involvement occur occasionally in adult patients. Intestinal involvement, such as colitis, is rather rare.

Diagnosis confirmation

In neonates and infants, KS resembles any other hereditary skin blistering disorder of the epidermolysis bullosa (EB) group. Because of skin atrophy and sclerosis, junctional or dystrophic EB may be suspected; however, in those conditions, poikiloderma is not a feature. The hypo- and hyperpigmentation may suggest EB simplex with mottled pigmentation or hereditary poikilodermas. The latter differential diagnoses may be considered if photosensitivity is prominent.

Acquired disorders may mimic KS. This is the case with systemic sclerosis, which was suspected in two of our patients because of sclerotic changes of hands and feet associated with telangiectasias and esophageal stenosis; however, no autoantibodies were present.

Expected results of diagnostic studies

Mutational analysis is the gold standard for the diagnosis of KS. Mutations in the FERMT1 gene underlie KS and are found in patients with typical clinical findings and characteristic abnormalities of the skin morphology.

Morphological analyses of a skin biopsy are usually the first diagnostic procedures performed. Routine H&E staining shows epidermal atrophy, loss of rete ridges, and focal vacuolization of the basal keratinocyte layer, consistent with poikiloderma (Figure 3 [A]). Melanophages and colloid bodies may be found in the dermis. The immunofluorescence mapping and transmission electron microscopy findings of multiple levels of skin cleavage (Figure 3 [B]), and irregular, branched, and interrupted basement membrane are characteristic and indicative for KS and justify FERMT1 mutation analysis for confirmation of the diagnosis.

Figure 3.

(A, B, C) Morphological abnormalities of the skin in KS. (A) H&E staining of KS skin demonstrates epidermal atrophy, loss of rete ridges, microblisters at the dermal-epidermal junction, and melanophages in the dermis. (B) Transmission electron microscopy shows multiple levels of skin cleavage in KS: in the basal layer, along the lamina lucida, and below the lamina densa. (Courtesy of Ivelina Yordanova, MD, PhD) (C) Indirect immunofluorescence staining of control (left) and KS (right) skin with antibodies to kindlin-1 (red). Nuclei are stained with DAPI in blue.

Immunostaining with anti-kindlin-1 antibodies shows variable results, including positive, reduced, or absent labelling, and is therefore not reliable as a diagnostic tool (Figure 3 [C]).

Who is at Risk for Developing this Disease?

KS is an autosomal recessive disorder, reported so far in all populations all over the world. As with all autosomal recessive conditions, the offspring of consanguineous relationships are at greater risk.

What is the Cause of the Disease?

Etiology

KS is caused by biallelic mutations in the FERMT1 (KIND1, MIM#607900) gene encoding the protein kindlin-1. Thus far, forty-five mutations that lead to premature termination of translation, and to loss of the kindlin-1 protein or of its function, have been reported.

Pathophysiology

The direct mechanisms by which loss of kindlin-1 leads to the clinical manifestations of KS are not clear . Kindlin-1 is expressed in epithelial cells, e.g. epidermal keratinocytes, as well as oral and intestinal epithelial cells. It is a component of integrin-associated focal adhesions, which link the actin cytoskeleton to the cell membrane and extracellular matrix.

In the skin, loss of kindlin-1 leads to blistering because of a cell-extracellular matrix adhesion defect, and to epidermal atrophy because of reduced proliferation of basal keratinocytes. The molecular mechanisms underlying photosensitivity and carcinogenesis are completely unknown. Importantly, cell stress, e.g. ultraviolet irradiation, seems to have stronger and more persistent effects on KS keratinocytes, when compared to normal keratinocytes.

Systemic Implications and Complications

  • Esophageal strictures

  • Urethral strictures

  • Vaginal stenosis

  • Ectropion and exposure keratitis

  • Webbing, contractures, and pseudoainhum of fingers

  • Nonmelanoma skin cancer

Treatment Options

As for all genetic disorders, curative treatment for KS is not available.

GENERAL RECOMMENDATIONS

  • Avoidance of mechanical trauma, tight bandages, or compression on the skin

  • Avoidance of exposure to sunlight

  • Protection of skin and mucosae from any environmental stress

MEDICAL OPTIONS

Topical

  • Management of skin dryness with emollients

  • Wound care with nonadhesive wound dressings and antiseptics

  • Photoprotection with sunscreens

Dental care

  • Dental care to prevent severe periodontitis

SURGICAL OPTIONS

  • Esophageal dilatation

  • Urethral dilation

  • Surgery for webbing of the fingers and for nonmelanoma skin cancer

Optimal Therapeutic Approach for this Disease

Since the genetic defect cannot be repaired, the optimal therapeutic approach aims to alleviate the course of the disorder and to detect and treat its complications early.

The optimal therapeutic approach includes:

  • Avoidance of mechanical trauma of the skin (lifelong)

  • Avoidance of exposure to sunlight (lifelong). Vitamin D testing and replacement in recommended.

  • Wound care: nonadhesive wound dressings, antiseptics (during childhood), if applicable

  • Management of dry skin: emolients (mainly in adults)

  • Photoprotection: sunscreens (lifelong), even if most patients do not experience any immediate symptoms after sun exposure. In vitro studies (not published) demonstrate that KS keratinocytes are more sensitive to UVB (when compared to control keratinocytes). To the best of my knowledge, no clinical study is available.

  • Dental care (lifelong)

  • Esophageal dilation (if applicable). We refer to gastroenterology when symptoms suggest the presence of oesophageal strictures. We do not recommend a baseline examination or regular check.

  • Urethral dilation (in most male patients with KS, starting in childhood or later, in the third or fourth decade of life). We refer to a urologist when symptoms develop.

  • Nonmelanoma skin cancer (if applicable). After the age of 45 years, skin checks every 6 months are recommended

  • Genetic counseling for patients and parents of affected child.

Patient Management

  • Monitoring skin care: wound management, emollients, sunscreens

  • Screening for skin cancer in adults

  • Dental care to prevent severe periodontitis

  • Mutation analysis and genetic counseling

Unusual Clinical Scenarios to Consider in Patient Management

  • Early onset and/or aggressive squamous cell carcinomas: surgical therapy

  • Severe contractures and pseudoainhum of hands and finger: surgery. Even if the course of the pseudoainhum is progressive, autoamputation of the fingers was not observed in our patients.

  • Severe periodontitis

  • Anemia, probably because of esophageal strictures: medical treatment of anemia and treatment of the strictures. The mechanism could be multifactorial, as in the case of dystrophic EB, but malnutrition was the main cause in our experience.

  • Vaginal stenosis: surgical treatment

  • Severe recurrent urethral strictures: permanent catheterization

  • Ocular complications, e.g. severe cicatricial ectropion: surgical treatment

  • Severe colitis: if associated with KS, immunotherapy and surgery are not effective, but symptoms improve with age

What is the Evidence?

Lai-Cheong, JE, McGrath, JA. "Kindler syndrome". Dermatol Clin. vol. 28. 2010. pp. 119-24.

(Update on clinical and genetic aspects of KS)

Lai-Cheong, JE, Tanaka, A, Hawche, G, Emanuel, P, Maari, C, Taskesen, M. "Kindler syndrome: a focal adhesion genodermatosis". Br J Dermatol. vol. 160. 2009. pp. 233-42.

(Review on kindlin-1 and KS)

Has, C, Burger, B, Volz, A, Kohlhase, J, Bruckner-Tuderman, L, Itin, P. "Mild clinical phenotype of Kindler syndrome associated with late diagnosis and skin cancer". Dermatology. vol. 221. 2010. pp. 309-12.

(Describes the natural history of KS)

Mansur, AT, Elcioglu, NH, Aydingoz, IE, Akkaya, AD, Serdar, ZA, Herz, C. "Novel and recurrent KIND1 mutations in two patients with Kindler syndrome and severe mucosal involvement". Acta Derm Venereol. vol. 87. 2007. pp. 563-5.

(Describes two patients with severe involvement of mucosal membranes)

Kern, JS, Herz, C, Haan, E, Moore, D, Nottelmann, S, von Lilien, T. "Chronic colitis due to an epithelial barrier defect: the role of kindlin-1 isoforms". J Pathol. vol. 213. 2007. pp. 462-70.

(Describes the KS-associated colitis and the expression of kindlin-1 in the gastrointestinal tract)

Fine, JD, Eady, RA, Bauer, EA, Bauer, JW, Bruckner-Tuderman, L, Heagerty, A. "The classification of inherited epidermolysis bullosa (EB): report of the third international consensus meeting on diagnosis and classification of EB". J Am Acad Dermatol. vol. 58. 2008. pp. 931-50.

(This is the consensus classification of epidermolysis bullosa, which includes KS as a new form of epidermolysis bullosa with mixed level of skin cleavage.)

Lai-Cheong, JE, Parsons, McGrath, JA. "The role of kindlins in cell biology and relevance to human disease". Int J Biochem Cell Biol. vol. 42. 2010. pp. 595-603.

(This is a review on kindlins, describing the associated genetic disorders and the expression in tumors.)

Techanukul, T, Sethuraman, G, Zlotogorski, A, Horev, L, Macarov, M, Trainer, A. "Novel and recurrent FERMT1 gene mutations in Kindler syndrome". Acta Derm Venereol. vol. 91. 2011. pp. 267-70.

(Describes novel mutations, including patients reported in the literature in the early 80s.)

Herz, C, Aumailley, M, Schulte, C, Schlötzer-Schrehardt, U, Bruckner-Tuderman, L, Has, C. "Kindlin-1 is a phosphoprotein involved in regulation of polarity, proliferation, and motility of epidermal keratinocytes". J Biol Chem. vol. 281. 2006. pp. 36082-90.

(Describes the molecular consequences of loss of kindlin-1 in human primary keratinocytes)

Lelli, GJ. "Kindler syndrome causing severe cicatricial ectropion". Ophtal Plast Reconstr Surg. vol. 26. 2010. pp. 368-9.

(Describes severe involvement of eyes in KS)

Has, C, Castiglia, D, del Rio, M. "Kindler syndrome: extension of FERMT1 mutational spectrum and natural history". Hum Mut. vol. 32. 2011. pp. 1204-12.

(Review of clinical and genetic findings in sixty-two patients with KS and describes the natural history of the disorder)
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