KINDLER'S SYNDROME: A CASE SERIES OF THREE INDIAN CHILDREN

Abstract

Kindler's syndrome is a very rare genodermatosis characterized by acral blistering starting in infancy, photosensitivity, progressive poikiloderma, cutaneous atrophy, and various forms of mucosal involvement. A large number of other cutaneous and extracutaneous features have also been described. We report here three cases of Kindler's syndrome from eastern India for the rarity of the syndrome and to emphasize the importance of considering this condition in the differential diagnosis of disorders that can cause blistering, cutaneous atrophy, and/or poikilodermatous skin changes.

Introduction

Kindler syndrome's (KS) is a very rare, autosomal recessive disorder characterized by acral blistering in infancy, followed by photosensitivity, progressive poikiloderma, cutaneous atrophy, and various forms of mucosal involvement.[1] Theresa Kindler originally described the syndrome in 1954[2] and about a hundred cases have been reported in the literature since then; the largest series being a cluster of 26 patients identified within a tribe in the Bocas del Toro province on the northwestern Caribbean coast of Panama.[3] We report here three cases of typical Kindler's syndrome from eastern India to emphasize the rarity and the importance of differentiating this syndrome from similar bullous and poikilodermatous disorders.

Case Reports

Case 1

A 13-year-old boy, born of consanguineous parentage (first cousins), presented with a history of severe oral ulceration, halitosis, and a history of intolerance to sunlight. According to the parents, there was a history of repeated blistering, mainly involving the dorsum of the hands almost since his birth; the blistering tendency gradually subsiding with age. He also had a history of occasional gum bleeding. His younger brother was also affected by the same illness [Figure 1], but their only sister had been spared. There was no history of any similar illness, icthyotic, or blistering disorders in the family. Cutaneous examination revealed multiple hyper- and hypopigmented macules distributed all over the body, prominent poikilodermatous changes, and xerosis and atrophy of the skin. The dorsum of the hands and feet had marked cigarette paper-like wrinkling. The patient had palmoplantar keratoderma, a few palmer pits, and markedly reduced dermatoglyphics. There was also large perioral erosions, crusting, and severe gingivitis [Figure 2]. In addition, he had phimosis and borderline mental retardation. The patient had received repeated courses of zinc and multivitamins without any clinical benefit before presenting to us.

Figure 1.

Two brothers of Kindler's syndrome having xerotic atrophic skin, hyper- and hypopigmented macules, and perioral erosion in the older brother

Figure 2.

Atrophic skin with cigarette paper-like wrinkles on dorsum of the hands and perioral ulceration

Case 2

Our second case was the nine-year-old younger brother of our first patient. He also had a history of acral blisters since infancy and intolerance to sunlight. However, his mental and motor development was normal for his age and sex. Examination revealed multiple xerotic, atrophic, hyper- and hypopigmented macules all over the body. There were multiple large ulcerations over the photo-exposed areas of the hands, legs, and forearms. He also had periodontitis, gingivitis, palmoplantar keratoderma, diminution of palmer creases [Figure 3], and cigarette paper-like wrinkling of the dorsum of hands and feet.

Figure 3.

Thick and glazed appearance of palmer skin with decreased palmar creases

Case 3

The third patient was a 12-year-old boy presenting with a history of discoloration of the skin and inability to tolerate sunlight since childhood. There was no history of consanguinity in the family. According to his parents, there was a history of acral blistering, which started as early as the 7th day of the neonatal period, but the tendency to blistering had decreased gradually over time. In addition, the patient had a history of recurrent conjunctivitis. The only other female sibling was unaffected and there was no history of any similar illness in the family. The patient had a history of oral ulceration and foul-smelling breath.

Clinical examination revealed normal motor and mental development. Cutaneous examination revealed multiple hypopigmented and a few hyperpigmented macules of variable sizes, distributed over his face, neck, trunk, and limbs [Figure 4]; poikilodermatous skin changes was present [Figure 5]. The overall texture of the skin was xerotic with marked cutaneous atrophy. The palms showed hyperkeratosis with diminution of palmar creases. The dorsal aspect of the hands and feet showed atrophic scarring with shiny, cigarette paper-like wrinkling and a few small ulcerations [Figure 6]; freckling was noted over the axillary region. Oral mucosa revealed gingivitis, periodontitis, and a few erosive lesions.

Figure 4.

Multiple hypo- and hyperpigmented macules of variable sizes, wrinkling, and erosions from ruptured blisters

Figure 5.

Poikilodermatous skin changes on neck and a few hypo- and hyperpigmented macules on face

Figure 6.

Atrophic scarring with shiny cigarette paper-like wrinkling and small ulcerations on dorsum of the hands

The scalp hairs and nails were normal in all of our patients. None of the patients had any ophthalmological abnormalities at the time of examination. Laboratory examinations were noncontributory in all of them, apart from the presence of microcytic, hypochromic anemia in the first case. Ultrasonography of the abdomen and imaging of the bones did not reveal any abnormalities in any of the cases.

Histopathological examination showed nonspecific findings of epidermal atrophy, orthokeratotic hyperkeratosis, and numerous melanophages with melanin incontinence in the upper dermis with sparse lymphocytic infiltrates. Genetic analysis and electron microscopy could not be done due to local unavailability and financial constraints.

Discussion

The molecular basis underlying KS has recently been demonstrated to involve loss-of-function mutations in a novel gene, kind0 , encoding kindlin-1, an actin-extracellular matrix linker protein, and the gene was mapped to chromosome 20p12.3.[4] An autosomal recessive pattern of transmission is usual, but sporadic cases are not uncommon. Variable expression has also been recognized within families; similar to our observations in the cases 1 and 2.

The dominant cutaneous findings in KS are increased skin fragility, acral blistering, photosensitivity, atrophy, and poikiloderma.[1] Although increased skin fragility may be explained by the weakening of basal keratinocyte-extracellular matrix adhesion, the pathomechanisms of other features like photosensitivity and skin atrophy remain unclear. The photosensitivity usually decreases over time, coinciding with decreased blister formation by 10–12 years of age, although some degree of photosensitivity usually persists even after that age. On the other hand, poikiloderma and atrophy are often progressive;[3] the development of poikiloderma in non-photoexposed areas indicates that it is not exclusively caused by photodamage. Nail plate thinning and onycholysis have been documented in some patients but none of our patients had any nail abnormality. Palmar hyperkeratosis often had a glassy appearance, obscuring the dermatoglyphics.

Mucosal involvement is quite common and may lead to urethral, anal, and esophageal stenosis.[5] Apart from ectropion, other ophthalmic abnormalities like keratoconjunctivitis and conjunctival scarring have also been described.[1] Early development of actinic keratoses, squamous cell carcinoma of the lower lip and transitional cell carcinoma of the bladder, xerostomia, hypohidrosis, corneal opacities, and thickened corneal nerves have also been reported.[1] Squamous cell carcinoma of the leg has also been reported in an Indian patient.[6] Associated joint hyper mobility,[3] syndactyly, a dome-shaped skull, bifid or missing ribs are other documented features of this syndrome.[7] There are no diagnostic histopathological features of KS. Atrophic skin lesions usually demonstrate nonspecific features of poikiloderma. The epidermis is flattened and atrophic, dermoepidermal junction is usually edematous; vacuolar degeneration of basal cells can occur. Additional histological features include prominent dermal capillaries, pigmentary incontinence, and sparse perivascular lymphocytic infiltrate.[1]

Several conditions that can cause blistering, cutaneous atrophy, and/or poikilodermatous skin changes must be differentiated from KS.[1,5] KS might be difficult to differentiate from variants of epidermolysis bullosa in newborns. Progressive improvement of blistering, photosensitivity, poikilodermatous changes, and cutaneous atrophy with age help to differentiate Kindler's syndrome from epidermolysis bullosa. In dystrophic epidermolysis bullosa, there is a mutation in the gene encoding type vii0 collagen ( COLA7A ) distinguishing it from KS.[8] Rothmund-Thomson syndrome shows poikiloderma and photosensitivity like KS, but additional features like sparse hair, hypogonadism, and cataracts in the former condition distinguish it from KS.

Several photosensitivity disorders related to impaired DNA repair may simulate cutaneous findings of KS. These include xeroderma pigmentosum, an autosomal recessive genodermatosis characterized by photosensitivity and poikilodermatous changes on photo-exposed skin, but without skin fragility seen in KS. Moreover, patients with xeroderma pigmentosum usually have early-onset skin cancers and might have multiple neurological abnormalities.

Bloom's syndrome is characterized by telangiectasia and photosensitivity with the presence of erythema on the face and other sun-exposed areas without showing true poikiloderma. Short stature, recurrent infections, and increased frequency of hematological malignancies are also features of this disease.

Patients with Cockayne's syndrome develop erythema in photo-distributed areas, atrophy, and hyperpigmentation. The associated features of dwarfism, cachexia, progressive pigmentary retinopathy, deafness, and birdlike faces differentiate Cockayne's syndrome from KS.

Reticulated hyperpigmentation, nail dystrophy, and leukoplakia are characteristic features of dyskeratosis congenita. Unlike KS, the pigmentary changes are not truly poikilodermatous and bullae are not an important feature of this rare genodermatosis.

Weary et al. described an analogous syndrome with an autosomal dominant pattern of inheritance named “hereditary acrokeratotic poikiloderma.” A subsequent report by Larregue et al. proposed the name, “Weary-Kindler syndrome” to describe patients with this constellation of features. The blisters in Weary-Kindler syndrome are not usually congenital, photosensitivity is generally absent, keratotic papules develop on the dorsal hands, elbows, and knees, and there is no mucosal involvement.[3] Elucidation of the genetic location in KS has successfully established it as a distinct entity unrelated to Weary-Kindler syndrome.[9] A set of clinical diagnostic criteria has recently been proposed for this condition to facilitate clinical diagnosis.[9] The major criteria are acral blistering in infancy and childhood, progressive poikiloderma, skin atrophy, photosensitivity, and gingival fragility, and/or swelling. The minor criteria proposed were syndactyly and involvement of other mucosal sites. The additional features of these criteria are nail dystrophy, ectropion, palmoplantar keratoderma, pseudoainhum, leukokeratosis of lips, squamous cell carcinoma, anhidrosis, skeletal abnormalities, and dental problems. According to the proposed criteria, the presence of four major criteria makes the diagnosis certain, the presence of three major and two minor criteria makes the diagnosis probable, and diagnosis is considered to be likely if two major and two minor / additional features are present. According to these criteria, all of our patients had definitive diagnosis of KS. Genetic mapping could not be done in our patients due to financial constraints and local nonavailability.

As there is no definitive treatment of the condition, management is essentially preventive. Avoidance of the sun and protecting the skin from light exposure may prevent or even slow the progression of poikiloderma; a broad-spectrum sunscreen would be of help. Good wound care including the use of topical and systemic antibiotics for infected bullous lesions and ulcerations might reduce the morbidity.[1] Patients suffering from this disorder usually have a normal life span but significant morbidity may be caused by secondary infections of congenital blisters, mucosal involvement leading to urethral, anal, and esophageal stenosis, accelerated periodontal disease, and ocular complications.