Alternative titles; symbols
SNOMEDCT: 238836000; ORPHA: 2908; DO: 0060472;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p12.3 | Kindler syndrome | 173650 | Autosomal recessive | 3 | FERMT1 | 607900 |
A number sign (#) is used with this entry because of evidence that Kindler syndrome (KNDLRS) is caused by homozygous mutation in the FERMT1 gene (607900) on chromosome 20p12.
Kindler syndrome (KNDLRS) is an autosomal recessive dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling (summary by Jobard et al., 2003).
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 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 bullosa (226600) and congenital poikilodermas such as Rothmund-Thomson syndrome (268400).
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, one 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.
The transmission pattern of Kindler syndrome in the families reported by Jobard et al. (2003) was consistent with autosomal recessive inheritance.
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 (FERMT1) gene (607900.0005-607900.0006). Because kindlerin 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.
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.
Aguade, J. P., Herrero, C., Castello, C. A., Grimalt, F., Rueda Plata, L. A. Congenital poikiloderma with vesicobullous lesions: problems in classification of hereditary 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] [Full Text: https://doi.org/10.1046/j.1365-2230.2002.01127.x]
Haber, R. M., Hanna, W. M. Kindler syndrome: clinical and ultrastructural findings. Arch. Derm. 132: 1487-1490, 1996. [PubMed: 8961879] [Full Text: https://doi.org/10.1001/archderm.132.12.1487]
Hacham-Zadeh, S., Garfunkel, A. A. Kindler syndrome in two related Kurdish families. Am. J. Med. Genet. 20: 43-48, 1985. [PubMed: 3970073] [Full Text: https://doi.org/10.1002/ajmg.1320200107]
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] [Full Text: https://doi.org/10.1002/humu.21449]
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 encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome. Hum. Molec. Genet. 12: 925-935, 2003. [PubMed: 12668616] [Full Text: https://doi.org/10.1093/hmg/ddg097]
Kindler, T. Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy. Brit. J. Derm. 66: 104-111, 1954. [PubMed: 13149722] [Full Text: https://doi.org/10.1111/j.1365-2133.1954.tb12598.x]
Larregue, M., Prigent, F., Lorette, G., Canuel, C., Ramdenee, P. Acrokeratose poikilodermique bulleuse et hereditaire de Weary-Kindler. Ann. Derm. Venereol. 108: 69-76, 1981. [PubMed: 7015974]
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: 1111-1117, 1997. [PubMed: 9301588]
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. Genet. 73: 174-187, 2003. [PubMed: 12789646] [Full Text: https://doi.org/10.1086/376609]
Suga, Y., Tsuboi, R., Hashimoto, Y., Yaguchi, H., Ogawa, H. A Japanese case of Kindler syndrome. Int. J. Derm. 39: 284-286, 2000. [PubMed: 10809978] [Full Text: https://doi.org/10.1046/j.1365-4362.2000.00962.x]
Wallach, D., Vignon-Pennamen, M.-D., Cottenot, F. Poikilodermie congenitale avec bulles, type Weary. Ann. Derm. Venereol. 108: 79-83, 1981. [PubMed: 7015975]
Weary, P. E., Manley, W. F., Jr., Graham, G. F. Hereditary acrokeratotic poikiloderma. Arch. Derm. 103: 409-422, 1971. [PubMed: 4253719]
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, 1996. [PubMed: 8910840] [Full Text: https://doi.org/10.1902/jop.1996.67.10.1004]