Kindler Syndrome 

Updated: Aug 17, 2015
Author: Anatoli Freiman, MD, FRCPC, DABD; Chief Editor: Dirk M Elston, MD 

Overview

Background

Kindler syndrome was first described in 1954 by Theresa Kindler. Kindler syndrome is a rare autosomal recessive genodermatosis characterized by congenital acral skin blistering, photosensitivity, progressive poikiloderma, and diffuse cutaneous atrophy. The syndrome is a combination of features of inherited blistering skin disorders (eg, dystrophic epidermolysis bullosa) and congenital poikilodermas (eg, Rothmund-Thompson syndrome). Kindler syndrome is identified as entry 173650 in the Online Mendelian Inheritance of Man database. Note the image set below.

Images show the progression of lesions. A and B: A 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.

Pathophysiology

In 2003, Siegel et al mapped the disease locus to band 20p12.3 by using linkage and homozygosity analysis in an isolated cohort of patients with Kindler syndrome.[1] Loss-of-function mutations were identified in the candidate gene FLJ20116, which was renamed KIND1. This gene encodes a 677–amino acid protein, kindlin-1, which is thought to play a regulatory role in inhibiting oversecretion of basement membrane components by basal keratinocytes at the dermoepidermal junction.[2, 3]

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 such as epidermolysis bullosa.

Epidemiology

Frequency

Since the first description in 1954 by Theresa Kindler, more than 100 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.[4]

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.

 

Presentation

History

The hallmark of Kindler syndrome 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. 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.

Photosensitivity can manifest as increased susceptibility to sunburn. Additionally, patients with Kindler syndrome frequently have poor dental hygiene and dental problems.

Physical

Diffuse poikiloderma (reticular telangiectasia, patchy hypopigmentation and hyperpigmentation, epidermal atrophy), skin fragility, and atrophic changes (cigarette paper–like wrinkled appearance of the skin) are most prominent in sun-exposed areas, most commonly on the dorsal surfaces of the hands and feet.

During the neonatal period and early childhood, acral blisters and bullae are seen in trauma-prone areas.

Dental abnormalities occur commonly in affected persons and include advanced periodontal bone loss, mild-to-severe gingivitis, dental caries, and leukokeratosis of buccal mucosa. In one study, 13 of 18 patients with the syndrome had marked periodontal disease.[5]

Less common and variable features of the syndrome include pitted or punctate palmoplantar hyperkeratosis (≤65% of individuals), webbing of fingers and toes, nail dystrophy, and, in one case report, abnormal skeletal maturation.

Mucosal involvement is frequent and leads to urethral, anal, and esophageal stenosis.

Ophthalmic abnormalities have also been described in some patients and include ectropion, keratoconjunctivitis, and conjunctival scarring.

Early development of actinic keratoses may occur. Squamous cell carcinoma of the lower lip and transitional cell carcinoma of the bladder have also been reported in one patient with Kindler syndrome.

Causes

Kindler syndrome has been shown to result from mutations in the KIND1 gene on band 20p12.3 (see Pathophysiology). An autosomal recessive pattern of transmission has been reported, but sporadic cases are common, with many originating in consanguineous families. Variable expressivity within families has also been documented. Mutations in the gene encoding type VII collagen (COLA7A1) have been excluded, distinguishing Kindler syndrome from dystrophic epidermolysis bullosa.

 

DDx

Diagnostic Considerations

Because of the overlapping clinical features, the differential diagnosis of Kindler syndrome consists primarily of inherited blistering diseases and congenital poikilodermas with photosensitivity. The lack of specific features in early childhood often leads to difficulty or delay in diagnosis.

Congenital bullous diseases

In the newborn period, Kindler syndrome may be difficult to differentiate from variants of epidermolysis bullosa. Progressive improvement of photosensitivity and blistering, followed by the appearance of poikiloderma and cutaneous atrophy with age, help confirm a diagnosis of Kindler syndrome.[6]

Congenital poikilodermas and photosensitivity disorders

Rothmund-Thompson syndrome has poikiloderma and photosensitivity similar to those observed in Kindler syndrome, but it is also accompanied by short stature, sparse hair, hypogonadism, and cataracts, which are not features of Kindler syndrome.

Photosensitivity disorders related to defective DNA repair

Several photosensitivity disorders related to defective DNA repair share cutaneous findings with Kindler syndrome.

Xeroderma pigmentosum is an autosomal recessive genodermatosis characterized by photosensitivity and poikilodermatous changes in sun-exposed areas. However, patients typically do not have acral bullae. In addition, patients with xeroderma pigmentosum experience early-onset skin cancers and multiple neurologic abnormalities.

Bloom syndrome is characterized by telangiectasia and light sensitivity with erythema on the face and other sun-exposed areas, but not true poikiloderma. Short stature, recurrent infections, and increased frequency of hematological malignancies are also present.

Patients with Cockayne syndrome develop photodistributed erythema, atrophy, and hyperpigmentation. The associated features of dwarfism, cachexia, progressive pigmentary retinopathy, deafness, and birdlike facies differentiate Cockayne syndrome from Kindler syndrome.

Dyskeratosis congenita is a rare genodermatosis characterized by the triad of reticulated hyperpigmentation, nail dystrophy, and leukoplakia. Unlike in Kindler syndrome, the pigmentary changes are not truly poikilodermatous and bullae are not a prominent feature.

Hereditary sclerosing poikiloderma described by Weary in 1969 is an autosomal dominant disease characterized by progressive poikiloderma in flexural areas, sclerotic bands, poor dentition, and, occasionally, calcinosis. Absence of bullae and photosensitivity clearly distinguish it from Kindler genodermatosis. However, in 1971, Weary et al described a large kindred of patients with widespread eczematous dermatitis, acral bullae in infancy, keratoses, and gradual appearance of diffuse poikiloderma. Several authors have noted the similarity of these patients to the original case described by Theresa Kindler, and some believe that Weary and Kindler syndromes are variants of the same disorder.

Differential Diagnoses

 

Workup

Laboratory Studies

Mutation analysis of the KIND1 gene can be performed.

Histologic Findings

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.

Immunostaining with anti–kindlin-1 antibody is a new and useful diagnostic test in the assessment of suspected cases of Kindler syndrome; decreased staining of the epidermis of patients with Kindler syndrome is observed compared with controls.[7]

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 3 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).

 

Treatment

Medical Care

Treatment is mainly symptomatic and preventative in nature. Patients should be advised to avoid trauma, which helps prevent blister formation. Sun avoidance and photoprotection may prevent or slow the progression of poikiloderma. Good wound care includes the use of topical and systemic antibiotics for infected bullous lesions, which may reduce morbidity.

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:

  • Dermatologist

  • Geneticist

  • Dentist

  • Psychological counselor

  • Ophthalmologist and/or surgeon depending on related complications

 

Medication

Medication Summary

The role of pharmacotherapy is supportive in nature. Emollients and good blister care reduce morbidity and help prevent complications.

 

Follow-up

Deterrence/Prevention

Avoiding the sun and protecting the skin from light exposure may prevent or slow the progression of poikiloderma. Good wound care includes the use of topical and systemic antibiotics for infected bullous lesions, which may reduce morbidity.

Complications

Secondary infections from congenital blisters and bullae may occur. The blisters usually heal without residual scarring, but they can result in hypopigmentation and transient milia. Mucosal involvement can lead to urethral, anal, and esophageal stenosis. Accelerated periodontal disease is common. Ophthalmic complications, such as conjunctival scarring, may occur.

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 mostly 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.

For patient education resources, see the Skin, Hair, and Nails Center.