Kindler syndrome

Authors: Vikram K Mahajan, M.D., Nand Lal Sharma1, M.D.and Ramesh Chander Sharma, M.D. Creation date: March 2005

Scientific editor: Jemima Mellerio, MD

1Department of , Venereology & Leprosy, Indira Gandhi Medical College, Shimla, India. [email protected]

Abstract Keywords Disease name/synonyms Definition/diagnostic criteria Differential Diagnosis Etiology Clinical description Diagnostic methods Management including treatment Kindler syndrome and Kindler syndrome and Weary’s hereditary acrokeratotic References

Abstract Kindler syndrome (KS) is a rare autosomal recessive genophotodermatosis. It combines features of acral blistering and photosensitivity from infancy, which tend to improve through childhood, with progressive poikiloderma and cutaneous developing later. Phenotypic heterogeneity and variable expression of the condition is known and additional features have been described. It shares some clinicopathologic similarities with dystrophic epidermolysis bullosa and Weary’s hereditary acrokeratotic poikiloderma. However, characteristic immunohistochemical, ultrastructural and molecular features have been demonstrated which distinguish KS as a separate entity. Specifically, this condition has recently been shown to result from loss of function mutations in KIND1, the gene encoding kindlin-1, a novel protein involved in attachment of the to the via focal contacts.

Keywords , poikiloderma, skin blistering, periodontitis

Disease name/synonyms are seen at the dermal-epidermal junction Kindler syndrome along with reduplication of the basement Poikiloderma of Kindler membrane. The locus of the disease has been mapped to 20p12.3 (Jobard et al., Definition/diagnostic criteria 2003) and, subsequently, the causative KS is a rare genophotodermatosis described gene identified as KIND1, which encodes first in 1954 by Theresa Kindler (Kindler, kindlin-1, a protein involved in attaching the 1954). Its salient features include trauma- actin cytoskeleton to the extracellular matrix induced blistering and photosensitivity at focal contacts (Jobard et al., 2003; Siegel usually starting in early infancy. With et al., 2003; Ashton et al., 2004). advancing age, improvement in blistering and photosensitivity usually occurs; a Differential Diagnosis progressive and more persistent A number of other conditions can cause poikiloderma and cutaneous atrophy arise. blistering, cutaneous atrophy and / or Ultrastructurally, variable planes of cleavage poikiloderma. Notably, dystrophic

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 1 epidermolysis bullosa (DEB) and Weary's wane in intensity (Penagos et al., 2004). hereditary acrokeratotic poikiloderma (HAP) Subsequently a more persistent reticular may cause confusion with KS (see below). A poikilodermatous pigmentation and set of clinical criteria (Table 1) may assist in cutaneous atrophy ensue. making a bedside diagnosis until new Poikiloderma, first noticed between 2-3 molecular diagnostic techniques are widely years of age, becomes persistent for life available. (Penagos et al., 2004). Although It may also be difficult to differentiate and photosensitivity diminishes, the poikiloderma individually define different congenital becomes more pronounced and generalized poikiloderma syndromes as these rare eventually involving both sun exposed and conditions may have overlapping clinical non-sun exposed areas (Fig. 2 & 3). features (Table 2). Again, delineation of the Evidently, photodamage is not the sole molecular pathology underlying KS will help cause for poikiloderma. confirm this as a distinct entity. A characteristic diffuse cutaneous atrophy that involves abdomen, thighs, knees and Etiology elbows occurs in all patients. Dry, atrophic, KS has been recently mapped to a locus on cigarette-paper-thin skin atrophy is more chromosome 20p12.3 and pathogenic marked over dorsa of hands (Fig. 4) and mutations have been detected in a new feet. Webbing of the digits is also a feature gene KIND1, encoding a 677 amino acid as is dystrophy of finger- and toenails. protein, kindlin-1 (Jobard et al., 2003; Siegel Mild to moderately severe diffuse, et al., 2003; Ashton et al., 2004). Kindlin-1 sometimes punctate, of is expressed mainly in basal keratinocytes palms (Fig. 5) and soles with a characteristic and plays a role in the attachment of the waxy feel is usual. Associated fissuring, actin cytoskeleton via focal contacts to the wrinkling and scaling may occur. Acral extracellular matrix (Ashton et al., 2004). sclerosis, pseudoainhum and loss of Loss of function mutations in KIND1 appear dermatoglyphics may accompany to be responsible for the mucocutaneous sometimes (Krunic et al., 1997; Binder et al., fragility observed in KS, therefore. However, 2002). the precise mechanisms whereby mutations Mucosal involvement is frequent in KS. in this gene lead to photosensitivity and Leukokeratosis of oral mucous membranes poikiloderma are not yet clear. (Fig. 6), seen as adherent white patches, is the most frequent finding but may Clinical description occasionally involve the anal mucosa as well KS usually becomes clinically evident by the (Fig.7) (Sharma et al., 2003). Restricted age of 2-3 years when photosensitivity, acral mouth opening has been attributed to blistering and poikiloderma are established repeated erosions and scarring of oral (Hovnanian et al., 1989). Hair, teeth and commissures (Fig. 6). In addition, atrophy of nails have no or only mild abnormalities. buccal mucosa and gums, erosions of lips Endocrine or hematologic abnormalities are and hard palate and geographic tongue not seen, and physical and intellectual have also been observed (Wiebe et al., development remains unimpaired throughout 2003). Severe phimosis to the extent that life (Thappa et al., 2000). prepucial skin may appear adherant to the Skin fragility and blistering, mostly over the glans is another frequent feature (Fig.8) dorsa of hands and feet, are the most (Thappa et al., 2000). Stenosis of the anal consistent clinical features in KS. Bullae may canal, esophagus and urethral meatus may be present at birth or appear during first few be encountered occasionally (Hovnanian et days of life. Blistering follows cutaneous al., 1989). trauma (Fig. 1) or occasionally exposure to Dental abnormalities (Wiebe et al., 2003) sunlight, and may get secondarily infected. include severe periodontal bone loss and Blistering continues to occur in all age periodontitis, swollen, fragile bleeding gums groups albeit in a diminished frequency after and early exfoliation of deciduous as well as 10 – 12 years of age (Penagos et al., 2004). permanent dentition (Fig. 9). Periodontal Photosensitivity of variable severity is disease in most cases begins in early observed by 1 month to 2 years of life. adolescence coinciding with eruption of Erythema associated with a burning permanent teeth. Patients presenting before sensation followed by blister formation is the age of 10 years, therefore, may exhibit usual after sun exposure. With advancing little or no periodontal disease. The age and coinciding with diminished blister pathomechanism of these defects is not well formation, the photosensitivity, too, tends to understood. The inherited defect of

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 2 cutaneous fragility is perhaps also and reduplication of the lamina densa which expressed in gums and mucous may reflect continuous remodeling of the membranes. Spontaneous bleeding from basement membrane zone (Shimizu et al., gums suggests it to be due to microblistering 1997; Yasukawa et al., 2002). and breakdown of periodontal tissues due to Immunohistochemically, a broad reticular minor trauma of normal occlusal function. labeling pattern of types IV and VII collagen Occasional stenosis of esophagus/anus also streaking deep into the connective tissue points towards mucosal fragility and beneath the basement membrane is seen, subsequent fibrosis (Forman et al., 1989). reflecting the basement membrane Many uncommon and less consistent reduplication seen ultrastructurally (Shimizu features of this syndrome have also been et al., 1997; Wiebe et al., 1999). described (Person et al., 1979; Forman et With the identification of kindlin-1 pathology al., 1989; Hovnanian et al., 1989; Binder et in KS, it is now possible to use al., 2002; Sharma et al., 2003 and Penagos immunohistochemistry to assist diagnosis et al., 2004). Ophthalmic involvement may (Siegel et al., 2003). Using a polyclonal occur in the form of pigment on lens surface, antibody against kindlin-1, the skin from KS corneal opacities, thickened corneal nerves, patients shows very reduced or absent keratoconjunctivitis, bacterial blephritis and staining compared to bright staining in basal ectropion. Isolated abnormalities such as keratinocytes and along the dermal- laryngeal webs, imperforate anus, synechia epidermal junction in normal controls. of labia, anhidrosis / hypohidrosis and Mutation analysis of KIND1 in affected abnormalities of skeletal maturation families can further confirm diagnosis and manifesting as turricephaly, malformation of also provides the potential for first trimester ribs, mandible and metacarpals have also DNA-based prenatal testing in at risk been observed. pregnancies. Development of actinic keratoses and squamous cell carcinoma involving the lower Management including treatment lip and leg in KS (Alper et al., 1978; The treatment of KS is mainly symptomatic. Karthikaeyan et al., 2003) suggests some Avoidance of trauma, photoprotection and predilection for malignant change. Recurrent use of emollients helps prevent blistering. erosion and regeneration of mucosal Antibiotics may be needed for bacterial surfaces has also been postulated to be infections and physiotherapy is responsible for transitional cell carcinoma of recommended to prevent contractures. bladder in an isolated case (Alper et al., Gingival problems improve with conservative 1978). periodontal therapy and by maintaining good oral hygiene (Wiebe et al., 1996). Diagnostic methods Psychological counseling is important in The histopathology of KS is not diagnostic view of cosmetic disability. and varies with the type of lesion biopsied. Moreover, due to the sequential appearance Kindler syndrome and epidermolysis of blistering, photosensitivity and bullosa poikiloderma, the age at which the patient As the characteristic poikilodermatous has been assessed is also important. cutaneous changes appear in later life, the On light microscopy, blister formation may bullous component of KS in infancy may be evident within or just beneath basal often be misdiagnosed as epidermolysis keratinocytes (Hovnanian et al., 1989). bullosa. Indeed, Kindler’s original case was Features of poikiloderma with epidermal considered to have incidental co-occurrence atrophy, hyperkeratosis, hyper- or of DEB and congenital poikiloderma. Clinical hypopigmentation and telangiectatic vessels absence of photosensitivity and may be present. Additionally, there may be poikiloderma in DEB, helps differentiate it disrupted collagen and elastic fibres in the from KS, but these features may not be papillary dermis and increased numbers of apparent for a number of months or years. In melanophages (Hovnanian et al., 1989; contrast, bullae in DEB heal with extensive Patrizi et al., 1996). scarring, milia formation, nail loss, flexural With electron microscopy, variable levels of contractures and often marked digital cleavage through basal keratinocytes, the webbing. Although blistering at the dermal- lamina lucida and sub-lamina densa have epidermal junction may occur in both KS and been observed (Hovnanian et al., 1989; different forms of EB, multiple planes of Shimizu et al., 1997; Şenturk et al., 1999). cleavage in an individual patient are more Also, there is a characteristic interruption consistent with KS. Also, the extensive

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 3 reduplication of the lamina densa seen Jobard F, Bouadjar B, Caux F, et al. ultrastructurally is not a feature of EB. Identification of mutations in a new gene Finally, the molecular mechanisms encoding a FERM family protein with a underlying KS and DEB are now understood pleckstrin homology domain in Kindler and separate (Yasukawa et al., 2002): whilst syndrome. Hum Mol Genet 2003 ; 12 : 925 – DEB is caused by mutations in the type VII 935. collagen gene, COL7A1, KS is caused by Kapasi AY, Khopkar U, Raj S, Wadhwa SI. mutations in the kindlin-1 gene, KIND1 Weary-Kindler syndrome with multiple (Jobard et al., 2003; Siegel et al., 2003). seborrhoeic . Int J Dermatol 1993 ; 32 : 444 – 445. Kindler syndrome and Weary’s hereditary Karthikeyan K, Thappa DM, Jeevankumar acrokeratotic poikiloderma B. Kindler syndrome with squamous cell In 1971, an autosomal dominant condition carcinoma of the leg. Indian J Dermatol named hereditary acrokerototic poikiloderma 2003 ; 48 : 231 – 233. (HAP) with clinical features similar to those Kindler T. Congenital poikiloderma with of KS was described (Weary et al., 1971). traumatic bulla formation and progressive Subsequent reports also revealed significant cutaneous atrophy. Br J Dermatol 1954 ; 66 overlapping clinical findings in KS and : 104 – 111. Weary’s HAP. Some workers even adopted Krunic ALJ, Ljiljana M, Novak A, et al. the term “Weary-Kindler syndrome” to Hereditary bullous acrokeratotic describe similar cases (Krunic et al.,1997; poikiloderma of Weary-Kindler associated Kapasi et al., 1993). Weary’s HAP is the with pseudoanihum and sclerotic bands. Int main differential diagnosis when J Dermatol 1997; 36: 529 – 533 poikiloderma appears in KS. However, the Patrizi A, Pauluzzi P, Neri I, et al. Kindler hallmark photosensitivity, cutaneous atrophy syndrome : report of a case with and mucosal lesions of KS are not seen in ultrastructrual study and review of the Weary’s HAP and poikiloderma appears literature. Ped Dermatol 1996 ; 13 : 397 – before the first year of life in most cases of 402. KS. Palmoplantar when Penagos H, Jaen M, Sancho MT, et al. present in Weary’s HAP is usually of Kindler syndrome in native Americans from punctuate variety. Keratotic papules over Panama. Arch Dermatol 2004 ; 140 : 939 – knees, elbows, dorsa of hands and feet and 944. eczematous dermatitis are strikingly Person JR, Perry HO. Congenital exclusive to Weary’s HAP. Histologically, poikiloderma with traumatic bulla formation, also, cleft formation is epidermal in Weary’s anhidrosis and keratoderma. Acta Dermatol HAP. Venereol 1979 ; 59 : 347 –351. Şentürk N, Usubütün A, Şahin S, et al. References Kindler syndrome : absence of definite Alper JC, Baden HP, Goldsmith LA. ultrastructural features. J Am Acad Dermatol Kindler syndrome. Arch Dermatol 1978 ; 1999 ; 40 : 335 – 337. 114 : 457 Sharma RC, Mahajan V, Sharma NL, Ashton GH, McLean WH, South AP, et al. Sharma AK. Kindler syndrome. Int J Recurrent mutations in Kindlin-1, a novel Dermatol 2003 ; 42 : 727 – 732. keratinocyte focal contact protein in the Shimizu H, Sato M, Ban M, et al. autosomal recessive skin fragility and Immunohistochemical , ultrastructrual and photosensitivity disorder, Kindler syndrome. molecular features of kindler syndrome J Invest Dermatol 2004 ; 122 : 78 – 83. distinguish it from dystrophic epidermolysis Binder B, Metze D, Smolle J. Congenital bullosa. Arch Dermatol 1997; 133 : 1111 – bullous poikiloderma (Kindler syndrome) 1117. Hautarzt 2002 ; 53 : 546 – 549. Siegel DH, Ashton GH, Penagos HG, et al. Forman AB, Prendiville JS, Esterly NB, et Loss of kindlin-1, a human homolog of the al. Kindler syndrome : report of two cases Caenorhabditis elegans actin-extracellular- and review of the literature. Ped Dermatol matrix linker protein UNC-112, causes 1989 ; 6 : 91 – 101. Kindler syndrome. Am J Hum Genet 2003; Hovnanian A, Blanchet-Bardon C, de Prost 73: 174-87. Y. Poikiloderma of Theresa Kindler : report Thappa DM, Jeevankumar B, Karthikeyan of a case with ultrastructural study and K, Sethuraman G. Kindler syndrome : a case review of the literature. Ped Dermatol 1989 ; report. Indian J Ped Dermatol 2000; 3 : 19 – 6: 82 – 90 22.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 4

Weary PE, Manley WF Jr, Graham GF. Wiebe CB, Silver JG, Larjava HS. Early- Hereditary acrokeratotic poikiloderma. Arch onset periodontitis associated with Weary- Dermatol 1971 ; 103 : 409 – 422. Kindler syndrome : a case report. J Wiebe CB, Larjava HS. Abnormal deposition Periodontol 1996 ; 67 : 1004 – 1010. of type-VII collagen in Kindler syndrome. Yasukawa K, Sato-Matsumura KC, Arch Dermatol Res 1999 ; 291 : 6 – 13. McMillan J, et al,. Exclusion of COL 7A1 Wiebe CB, Penagos H, Luong N, et al. mutation in Kindler syndrome. J Am Acad Clinical and micro biological study of Dermatol 2002 ; 46 : 447 – 450. periodontitis associated with Kindler syndrome. J Periodontol 2003 ; 74 : 25 – 31.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 5

Table 1 : Proposed Clinical criteria for bedside diagnosis of Poikiloderma of Kindler

Essential Criteria

1) Progressively diminishing photosensitivity since early infancy.

2) Traumatic acral bullae since birth or developing during first few days of life.

3) Characteristic cigarette-paper-thin cutaneous atrophy, more pronounced over

acral areas.

4) Diffuse, generalized poikiloderma involving sun exposed and non-sun

exposed skin with onset after 1st year of birth.

Minor Criteria

1) Early onset of severe gingivitis/periodontitis.

2) Mucosal leukokeratosis.

3) Normal physical and mental development.

4) Palmoplantar hyperkeratosis with a waxy feel.

5) Severe phimosis.

6) Webbing of fingers and toes.

7) Absence of definite histopathologic features.

Presence of all essential and four of minor criteria is diagnostic

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 6

Table 2 : Differential Diagnosis of major Hereditary Bullous Poikiloderma syndromes

S.No. SYNDROME INHERIT BULLAE PHOTO POIKILODERMA KERATOTIC ECZEMA NAIL PALMO- MUCOSAL REMARKS/ISOLATED ANCE SENSITIVITY LESIONS CHANGES PLANTAR LESIONS ADDITIONAL FEATURES KERATODERMA

1 KINDLER AR/AD Acral with onset Since infancy Widespread, Absent Absent Mild or Diffuse Leukokeratos Defective gene mapped to SYNDROME before 1yr of age Involves Sun none is cromosome 20p12.3. exposed & Non- Stenosis of Oesophagus, Anus & sun exposed body Urethra, Webbing of digits, Dental areas. Abnormalities Anhidrosis

2 WEARY’S AD Acral with onset after Absent Limited to neck & Present in Present None Punctate or absent Absent Poor dentition, Enteropathy HEREDITORY 1 yr of age upper chest. Onset Acral ACROKERATOTIC within 1st year of distribution POIKILODERMA life

3 HEREDITORY AD Absent Absent Accentuated in Absent Absent Clubbing is Sclerosis Absent Poor dentition, cutis SCLEROSING flexors with occasional POIKILODERMA sclerotic bands

4 DYSKERATOSIS XR or AD Absent (or Absent Poikiloderma is Absent Absent Present Absent Premalignant Blood dyscrasias, Growth CONGENITA occasional) more of leukokeratosi retardation, Poor dentition dyschromatic s variety

5 ROTHMUND – AD Occasional (over Present Present (in Photo Absent Absent None or Absent Absent Cataract, Dwarfism, Hypo THOMSON photo exposed skin) distribution) Occasional gonadism, Bone abnormalities SYNDROME

6 XERODERMA AR Occasional (over Present Present (in Photo Present (not Absent Absent Absent Absent Cutaneous malignancies, PIGMENTOSA photo exposed skin) distribution) limited to Neurologic changes, Photo Acral areas) phobia/Corneal opacities

7 MENDES DA COSTA XR Present (Acral bullae) Absent Present (spares the Absent Absent Occasional Absent Absent Acrocynosis, Scarring alopecia, SYNDROME trunk) Dwarfism, Micro cephaly, Mental retardation, Short conical digits, Bone abnormalities

8 DERMATOPATHIA AD Present (Acral bullae) Absent Dyschromatic Present Absent Dystrophy Hyperkeratosis Absent Corneal opacities, Alopecia, PIGMENTOSA – (Trunkal) (scattered or Axillary papillomatosis RETICULARIS Keratotic Hypoplasia Pseudoainhum, Flexon contractures, lesions) Hypertrophic

9 FRANCESCHETTI – AD Absent Absent More of Absent Absent Absent Present Absent Hypo/Anhidrosis, Poor dentition JADASSOHN Reticulated SYNDROME hyperpigmentation

10 DEGOS – TOURAINE ? Present (Acral or Absent Photo distributed Present in Absent Absent Absent Absent Enteropathy SYNDROME facial) Acral distribution (Modified after Forman et al., 1989). Few isolated reported cases of poikiloderma syndromes and reviewed by Person et al., 1979 are not included (AD = Autosomal Dominant, AR =Autosomal Recessive, XR =X-linked Recessive)

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 7

Fig. 1. Multiple infected crusted lesions of acral bullae over lower limbs. Note: Characteristic atrophic skin over dorsa of feet and dystrophic toe nails.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 8

Fig. 2. Poikiloderma of left side of neck extending over face

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 9

Fig. 3. Poikiloderma of abdominal skin.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 10

Fig. 4. Characteristic atrophic skin over dorsa of hands.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 11

Fig. 5. Mild palmar hyperkeratosis. Note: Unusual shape of fingers.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 12

Fig. 6. Leukokeratosis of oral mucosa near angle of mouth. Note: Erosions and scarring at oral commissures

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 13

Fig. 7 Leukokeratosis of anal mucosa.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 14

Fig. 8. Severe phimosis.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 15

Fig. 9. Severe periodontitis and loss of teeth

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 16 17

Fig.10.Turricephaly. Premature obliteration of transverse sutures causes upward growth via sagital sutures resulting in a dome shaped skull. Note: Loss of mandibular angle.

Mahajan VK, Sharma NL and Sharma RC, Kindler syndrome. Orphanet Encyclopedia. Mars 2005. http://www.orpha.net/data/patho/GB/uk-kindler.pdf 17