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KINDLER SYNDROME

Alternative titles; symbols

POIKILODERMA, HEREDITARY ACROKERATOTIC
BULLOUS ACROKERATOTIC POIKILODERMA OF KINDLER AND WEARY
POIKILODERMA, CONGENITAL, WITH BULLAE, WEARY TYPE

Phenotype-Gene Relationships

Location Phenotype
20p12.3 Kindler syndrome

Clinical Synopsis

TEXT
A number sign (#) is used with this entry because Kindler syndrome can be caused by
homozygous mutation in the FERMT1 (KIND1) gene (607900) on chromosome 20p13.

Description
Kindler syndrome is an autosomal recessive dermatosis characterized by congenital blistering,
skin atrophy, photosensitivity, skin fragility, and scaling (summary by Jobard et al., 2003).

Clinical Features
Kindler (1954) described an English girl with unusual congenital blistering of her hands and
feet. Later in childhood, the patient developed reticulate erythema and diffuse cutaneous
atrophy, beginning in sun-exposed areas. Her gums bled easily, and the skin of the dorsal
hands and feet had a thin, wrinkled appearance. By 10 years of age, the blistering and sun
sensitivity had resolved, but the skin remained thin and fragile (Siegel et al., 2003).

Weary et al. (1971) described a disorder, which they named hereditary acrokeratotic
poikiloderma, in 10 members of a white kindred. Expression was highly variable and fell into
4 categories: (1) vesicopustule formation which remains confined to the hands and feet,
beginning from 1 to 3 months of age and resolving in late childhood; (2) widespread
eczematoid dermatitis somewhat resembling atopic eczema, starting between ages 3 and 6
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months and completely resolving by age 5 years; (3) gradual appearance of diffuse
poikiloderma with striate and reticulate atrophy which spares only the face, scalp, and ears
and persists into adulthood; and (4) development of keratotic papules on the hands, feet,
elbows, and knees, which first appear at varying times before 5 years of age and persist
indefinitely. Male-to-male transmission was observed. Larregue et al. (1981) reviewed 3
pedigrees supporting autosomal dominant inheritance. They stated that a pigmentary
anomaly is present in about 90% of cases.

Hacham-Zadeh and Garfunkel (1985) suggested autosomal recessive inheritance. They

described 2 related Kurdish Jewish sibships, each with first-cousin parents; 1 was affected in
the first sibship and 3 were affected in the second. The proposita had had bullae on pressure
areas from birth. These healed with atrophic scars. She also had severe photosensitivity on
exposed areas and developed widespread poikiloderma. Bullae did not occur after age 17
years. Oral examination showed limitation of mouth opening, ankyloglossia, dental overbite,
and atrophy of buccal mucosa with white spots.

Jobard et al. (2003) described 5 consanguineous families from North Africa with Kindler
syndrome. All affected family members exhibited congenital blistering, progressive
poikiloderma, ichthyosis, and xerosis. Variable clinical findings among the families included
photosensitivity, palmoplantar keratoderma, oral mucosal involvement, syndactyly, and
stenosis of mucosal openings.

Siegel et al. (2003) identified a group of 26 Native American patients with Kindler syndrome,
all younger than 40 years of age, who were members of a tribe in the Bocas del Toro province
on the northwestern Caribbean coast of Panama. The patients showed congenital acral blisters,
blistering after trauma or sun exposure, erythema and itching after sun exposure, and patchy
hyper- and hypopigmentation with atrophy and telangiectases (poikiloderma) developing in
early childhood in both sun-exposed and nonexposed skin. Other features included
hyperkeratosis of the palms and soles and diffuse cutaneous atrophy and wrinkling,
particularly on the dorsa of the hands and feet. Other mucocutaneous features included
periodontal disease, dental caries, and phimosis. Typically, the blistering and photosensitivity
improved markedly in adulthood, but the poikiloderma persisted. There was some variability
in phenotypic severity, particularly in the degree of photosensitivity, age at onset of
poikiloderma, and degree of hyperkeratosis. Siegel et al. (2003) noted that Kindler syndrome
clinically resembles both inherited blistering skin disorders such as dystrophic epidermolysis
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bullosa (226600) and congenital poikilodermas such as Rothmund-Thomson syndrome

(268400).

Mapping
Jobard et al. (2003) performed a genomewide linkage analysis in 5 North African families with
Kindler syndrome and narrowed the disease interval to an 834-kb region on chromosome
20p12.3. Siegel et al. (2003) confirmed the location of this locus in the Panamanian families and
in individuals with Kindler syndrome from diverse geographic backgrounds, some of whom
had previously been described (Wiebe et al., 1996; Shimizu et al., 1997; Suga et al., 2000;Al
Aboud et al., 2002).

Genetic Heterogeneity
Siegel et al. (2003) studied 2 families with Kindler syndrome, 1 from Canada, previously
reported by Haber and Hanna (1996), and the other from the United States, with 1 parent of
European descent and the other of African descent, who did not show linkage to
20p12.3. Siegel et al. (2003) noted, however, that both of these families showed clinical
differences from the Panamanian kindred, suggesting that they may have a disorder that is
clinically similar to, but genetically distinct from, Kindler syndrome.

Molecular Genetics
In affected members of 4 consanguineous Kindler kindreds from North Africa, Jobard et al.
(2003) characterized 4 homozygous mutations in the kindlerin (FERMT1) gene (607900.0001-
607900.0004). Three of the 4 mutations were predicted to result in truncation of the protein,
with loss of FERM and pleckstrin homology (PH) domains. The authors determined that
kindlerin is expressed in multiple tissues, including skin, and proposed that it may play a role
in cell adhesion processes via integrin signaling.

In patients with Kindler syndrome from various ethnic backgrounds, Siegel et al.
(2003) identified loss-of-function mutations in the KIND1 gene (607900.0005-607900.0006).
Because KIND1 is a human homolog of the C. elegans protein Unc112, a membrane-associated
structural/signaling protein that had been implicated in linking the actin cytoskeleton to the
extracellular matrix (ECM), Siegel et al. (2003) suggested that Kindler syndrome is the first
skin fragility disorder shown to be caused by a defect in actin-ECM linkage rather than
keratin-ECM linkage.
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Pathogenesis
Heinemann et al. (2011) demonstrated that kindlin-1-deficient keratinocytes respond to cell
stress by upregulating the expression of several cytokines, which, via paracrine
communication, launch an inflammatory response in the dermis, with subsequent activation
of fibroblasts and their differentiation to myofibroblasts, which secrete and deposit increased
amounts of extracellular matrix proteins. The data were consistent with a model in which
repeated cycles of epidermal cell stress, cytokine secretion, dermal inflammation, and
profibrotic processes underlie the mucocutaneous fibrosis in Kindler syndrome.

See Also:
Aguade et al. (1972); Wallach et al. (1981)

REFERENCES
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Aguade, J. P., Herrero, C., Castello, C. A., Grimalt, F., Rueda Plata, L. A. Congenital
poikiloderma with vesicobullous lesions: problems in classification of hereditary
1. poikilodermas. Med. Cutanea 6: 417-435, 1972.

Al Aboud, K., Al Hawsawi, K., Al Aboud, D., Al Githami, A. Kindler syndrome in a

Saudi kindred. Clin. Exp. Derm. 27: 673-676, 2002. [PubMed: 12472544, related citations]
2. [Full Text]

Haber, R. M., Hanna, W. M. Kindler syndrome: clinical and ultrastructural

findings. Arch. Derm. 132: 1487-1490, 1996. [PubMed: 8961879, related citations] [Full
3. Text]

Hacham-Zadeh, S., Garfunkel, A. A. Kindler syndrome in two related Kurdish

4. families. Am. J. Med. Genet. 20: 43-48, 1985. [PubMed: 3970073, related citations]

Heinemann, A., He, Y., Zimina, E., Boerries, M., Busch, H., Chmel, N., Kurz, T., Bruckner-
Tuderman, L., Has, C.Induction of phenotype modifying cytokines by FERMT1
mutations. Hum. Mutat. 32: 397-406, 2011. [PubMed:21309038, related citations] [Full
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Jobard, F., Bouadjar, B., Caux, F., Hadj-Rabia, S., Has, C., Matsuda, F., Weissenbach, J.,
Lathrop, M., Prud'homme, J.-F., Fischer, J. Identification of mutations in a new gene
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syndrome. Hum. Molec. Genet. 12: 925-935, 2003. [PubMed: 12668616, related citations]
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Kindler, T. Congenital poikiloderma with traumatic bulla formation and progressive

7. cutaneous atrophy. Brit. J. Derm. 66: 104-111, 1954. [PubMed: 13149722, related citations]

Larregue, M., Prigent, F., Lorette, G., Canuel, C., Ramdenee, P. Acrokeratose
poikilodermique bulleuse et hereditaire de Weary-Kindler. Ann. Derm. Venerol. 108:
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Shimizu, H., Sato, M., Ban, M., Kitajima, Y., Ishizaki, S., Harada, T., Bruckner-Tuderman,
L., Fine, J.-D., Burgeson, R., Kon, A., McGrath, J. A., Christiano, A. M., Uitto, J.,
Nishikawa, T. Immunohistochemical, ultrastructural, and molecular features of Kindler
syndrome distinguish it from dystrophic epidermolysis bullosa. Arch. Derm. 133: 1111-
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Siegel, D. H., Ashton, G. H. S., Penagos, H. G., Lee, J. V., Feiler, H. S., Wilhelmsen, K. C.,
South, A. P., Smith, F. J. D., Prescott, A. R., Wessagowit, V., Oyama, N., Akiyama, M., and
30 others. Loss of kindlin-1, a human homolog of the Caenorhabditis elegans actin-
extracellular-matrix linker protein UNC-112, causes Kindler syndrome.Am. J. Hum.
10. Genet. 73: 174-187, 2003. [PubMed: 12789646, images, related citations] [Full Text]

Suga, Y., Tsuboi, R., Hashimoto, Y., Yaguchi, H., Ogawa, H. A Japanese case of Kindler
11. syndrome. Int. J. Derm. 39: 284-286, 2000. [PubMed: 10809978, related citations] [Full Text]

Wallach, D., Vignon-Pennamen, M.-D., Cottenot, F. Poikilodermie congenitale avec

12. bulles, type Weary. Ann. Derm. Venerol. 108: 79-83, 1981.

Weary, P. E., Manley, W. F., Jr., Graham, G. F. Hereditary acrokeratotic

poikiloderma. Arch. Derm. 103: 409-422, 1971. [PubMed: 4253719, related citations] [Full
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Wiebe, C. B., Silver, J. G., Larjava, H. S. Early-onset periodontitis associated with Weary-
Kindler syndrome: a case report. J. Periodont. 67: 1004-1010,
14. 1996. [PubMed: 8910840, related citations]

Contributors: Marla J. F. O'Neill - updated : 9/14/2011

Creation Date: Victor A. McKusick : 6/2/1986

Edit History: carol : 09/14/2011