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Special Feature
September 2010

Picture of the Month—Diagnosis

Arch Pediatr Adolesc Med. 2010;164(9):876. doi:10.1001/archpediatrics.2010.150-b

Denouement and Discussion: Kindler Syndrome

Kindler syndrome is an autosomal recessive genodermatosis, an inherited genetic disease with skin manifestations. Since the latest International Consensus Meeting of epidermolysis bullosa in 2008, Kindler syndrome is considered a major type of inherited epidermolysis bullosa separated from other epidermolysis bullosa types because of its unique features.1

Patients experience blisters in infancy that, similar to patients with epidermolysis bullosa, follow cutaneous trauma or exposure to sunlight. Blistering tends to improve with age, as progressive pigmentary changes and poikiloderma develop. The skin is thin, wrinkled, and atrophic, most pronounced on the dorsa of the hands and feet. Typically, they develop interdigital webbing but no scarring or milia.

Unlike the other epidermolysis bullosa types, photosensitivity in Kindler syndrome improves with age. Other features may include nail dystrophy; keratoderma of the palms and soles; esophageal, anal, vaginal, and urethral stenosis; ectropion; and severe periodontal disease.2Gastrointestinal symptoms and signs, such as colitis and bloody diarrhea, have been reported.3There also appears to be an increased risk of nonmelanoma skin cancer, mostly squamous cell carcinomas that occur on acral skin or in the mouth. The different complications that these patients may develop require the coordinated effort of a multidisciplinary team of professionals.

This entity has many clinical overlapping features with other diseases. In early life, it can be confused with variants of epidermolysis bullosa. When photosensitivity and poikiloderma develop, it may be misdiagnosed as autosomal dominant Weary syndrome and other hereditary poikilodermas. Accurate diagnosis, which used to be made only in later infancy when all features were present, nowadays can be made earlier with the support of immunofluorescence antigenic mapping, electron microscopy, and genetic analysis. This will enable early intervention with photoprotection, surveillance for extracutaneous involvement, and genetic counseling.

A biopsy specimen from the skin of the inner arm showed just slight orthokeratotic hyperkeratosis and atrophy. Ultrastructural examination revealed a normal-appearing epidermis, with a marked duplication of the basal lamina, with branching and folding that could be traced deep below the basement membrane zone.

Immunofluorescence mapping of the basement membrane detected a significantly thickened type VII collagen band, especially on the papillary dermis. The other stains (α6 integrin, β4 integrin, laminin 5, and type IV collagen) did not show alterations. C-terminal antifermitin family homologue 1 antibody, also known as anti–kindlin 1 antibody, was not readily available in our laboratory. Immunofluorescence microscopy labeling using antifermitin family homologue 1 antibody shows an absent or reduced fluorescence compared with control skin in most patients with Kindler syndrome.4

Following informed consent, DNA was extracted from a peripheral blood sample. The homozygous mutation p.R271X in the FERMT1gene, also known as KIND1, was detected. Located in the short arm of chromosome 20 (20p12.3), FERMT1is encoding for the protein fermitin family homologue 1, a 77.3-kDa phosphoprotein that is a component of focal contacts in basal keratinocytes.4,5Fermitin family homologue 1 links the actin cytoskeleton to the extracellular matrix and is supposed to have cell-signaling functions due to different domains.3Therefore, Kindler syndrome is the first genodermatosis caused by a defect in actin–extracellular matrix linkage rather than the classic keratin–extracellular matrix linkage underlying the pathology of other epidermolysis bullosa.

This child was adopted from an isolated population of Native Americans in Panama, the Ngöbe-Buglé or Guaymí. Although extremely unusual in the rest of the world, this tribe has the largest case series of Kindler syndrome described to date.6The high degree of consanguinity in this population may explain the high rate of this rare autosomal recessive disorder. The same mutation, R271X, was previously identified in affected individuals from that origin.6

This condition should be suspected in children with acral blistering, poikiloderma, and photosensitivity born to consanguineous parents or, as this case report illustrates, from countries with social or geographic peculiarities. Increasing adoptions and immigration from other countries require pediatricians to be able to recognize diseases that are rare in our environment.

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Correspondence:Lorena Leal, MD, Gran de Gràcia, 237, 2° 1ª B, Barcelona 08012, Spain (lorenalealcanosa@hotmail.com).

Accepted for Publication:February 1, 2010.

Author Contributions:Study concept and design: Leal, Vicente, and González-Enseñat. Acquisition of data: Leal, Mascaró, Bombí, and González-Enseñat. Analysis and interpretation of data: Leal, Vicente, and Mascaró. Drafting of the manuscript: Leal and Vicente. Critical revision of the manuscript for important intellectual content: Vicente, Mascaró, Bombí, and González-Enseñat. Administrative, technical, and material support: Leal, Vicente, and Mascaró. Study supervision: Vicente, Mascaró, Bombí, and González-Enseñat.

Financial Disclosure:None reported.

Fine  JDEady  RABauer  EA  et al.  The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB.  J Am Acad Dermatol 2008;58 (6) 931- 950PubMedGoogle ScholarCrossref
Mallo  SRodríguez-Díaz  EBlanco  SÁlvarez-Cuesta  CGalache  CNosti  C Kindler syndrome: presentation of a case.  Actas Dermosifiliogr 2005;96 (10) 677- 680PubMedGoogle ScholarCrossref
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Lai-Cheong  JETanaka  AHawche  G  et al.  Kindler syndrome: a focal adhesion genodermatosis.  Br J Dermatol 2009;160 (2) 233- 242PubMedGoogle ScholarCrossref
Jobard  FBouadjar  BCaux  F  et al.  Identification of mutations in a new gene encoding a FERM family protein with a pleckstrin homology domain in Kindler syndrome.  Hum Mol Genet 2003;12 (8) 925- 935PubMedGoogle ScholarCrossref
Penagos  HJaen  MSancho  MT  et al.  Kindler syndrome in native Americans from Panama: report of 26 cases.  Arch Dermatol 2004;140 (8) 939- 944PubMedGoogle ScholarCrossref