7232019 Omim Entry - 173650 - Kindler Syndrome

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SNOMEDCT 238836000 ORPHA 306539173650

KINDLER SYNDROME

Alternative titles symbols

POIKILODERMA HEREDITARY ACROKERATOTIC

BULLOUS ACROKERATOTIC POIKILODERMA OF KINDLER AND WEARY

POIKILODERMA CONGENITAL WITH BULLAE WEARY TYPE

Phenotype‑Gene Relationships

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 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

Location Phenotype Phenotype

MIM number

Inheritance

(in progress)

Phenotype

mapping key

GeneLocus GeneLocus

MIM number

20p123 Kindler syndrome 173650 AR 3 KIND1 607900

7232019 Omim Entry - 173650 - Kindler Syndrome

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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)

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 20p123 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 20p123 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 (6079000001‑6079000004) 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

(6079000005‑6079000006) Because KIND1 is a human homolog of the C elegans protein Unc112 a membrane‑associated structuralsignaling

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

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 AlsoAguade et al (1972) Wallach et al (1981)

REFERENCES

1 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

2 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] [Full Text]

3 Haber R M Hanna W M Kindler syndrome clinical and ultrastructural findings Arch Derm 132 1487‑1490 1996 [PubMed 8961879

related citations] [Full Text]

4 Hacham‑Zadeh S Garfunkel A A Kindler syndrome in two related Kurdish families Am J Med Genet 20 43‑48 1985 [PubMed

3970073 related citations]

5 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 Text]

6 Jobard F Bouadjar B Caux F Hadj‑Rabia S Has C Matsuda F Weissenbach J Lathrop M Prudʹhomme 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 related citations] [Full Text]

7 Kindler T Congenital poikiloderma with traumatic bulla formation and progressive cutaneous atrophy Brit J Derm 66 104‑111 1954

7232019 Omim Entry - 173650 - Kindler Syndrome

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NOTE OMIM is intended for use primarily by physicians and other professionals concerned wit h genetic disorders by genetics researchers and by advanced students in science and medicine While tOMIM database is open to the public users seeking information about a personal medical or genetic condition are urged to consult with a qualified physician for diagnosis and for answers to person

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[PubMed 13149722 related citations]

8 Larregue M Prigent F Lorette G Canuel C Ramdenee P Acrokeratose poikilodermique bulleuse et hereditaire de Weary‑Kindler

Ann Derm Venerol 108 69‑76 1981

9 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 related citations] [Full Text]

10 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 WessagowitV 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 images related citations] [Full

Text]

11 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 related citations] [Full Text]

12 Wallach D Vignon‑Pennamen M‑D Cottenot F Poikilodermie congenitale avec bulles type Weary Ann Derm Venerol 108 79‑83 1981

13 Weary P E Manley W F Jr Graham G F Hereditary acrokeratotic poikiloderma Arch Derm 103 409‑422 1971 [PubMed 4253719

related citations] [Full Text]

14 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 related citations]

Contributors Marla J F OʹNeill ‑ updated 9142011

Creation Date Victor A McKusick 621986

Edit History carol 09142011