Skin Fragility and Blister Formation FREE

A 3-year-old girl native of the tribe Ngöbe-Buglé (Panama) was referred for evaluation of a history of skin fragility and blister formation since adoption 2 years earlier. The child's adoptive parents were unaware of the patient's or her family's medical history. Lesions were mainly located in sites of trauma and rapidly evolved to form crusts, ultimately leaving some pigmentary changes. Skin examination revealed erosions and crusts over the face and fingers. There was dyspigmentation with hyperpigmented and hypopigmented macules on both sun-exposed and non–sun-exposed areas. The skin was atrophic, with cigarette-paper–like wrinkling, especially over the dorsa of the hands and feet (Figure 1). Mild proximal syndactyly was present between the middle and ring fingers (Figure 2). There were no milia (Figure 3). Nails, gingiva, and mucous membranes were normal.

A . Do nothing; the lesions will resolve over time
B . Obtain a biopsy of the lesion
C . Prescribe oral antibiotics
D. Prescribe topical steroids

Kindler syndrome

B. Obtain a biopsy of the lesion

The key clinical feature in this case is making the diagnosis of Kindler syndrome in this adopted girl from Panama. Although this syndrome is extremely unusual in the rest of the world, the Ngöbe-Buglé or Guaymí tribe of Native Americans in Panama has the largest case series of Kindler syndrome described to date.² Kindler syndrome results from mutations in KIND1, the gene encoding kindlin-1, a novel protein involved in attachment of the actin cytoskeleton to the extracellular matrix.

Kindler syndrome is an autosomal recessive genophotodermatosis. It is considered a major type of inherited epidermolysis bullosa different from other epidermolysis bullosa types because of its unique features.³ Patients experience blisters in infancy following cutaneous trauma or exposure to sunlight. Unlike the other epidermolysis bullosa types, photosensitivity and blistering in Kindler syndrome improves with age, as progressive pigmentary changes and poikiloderma develop. Thin, wrinkled, and atrophic skin is most pronounced on the dorsa of the hands and feet. Typically, patients develop interdigital webbing but no scarring or milia. Other features may include nail dystrophy; keratoderma of the palms and soles; esophageal, anal, vaginal, and urethral stenosis; ectropion; and severe periodontal disease.⁴ Gastrointestinal symptoms and signs, such as colitis and bloody diarrhea, have been reported.⁵ There also appears to be an increased risk of nonmelanoma skin cancer, mostly squamous cell carcinomas that occur on acral skin or in the mouth.

Differential diagnosis can be difficult because Kindler syndrome has many clinical features that overlap with other diseases. In young children, this syndrome can be confused with variants of epidermolysis bullosa. When photosensitivity and poikiloderma develop, Kindler syndrome may be misdiagnosed as autosomal dominant Weary syndrome or other hereditary poikilodermas. Accurate diagnosis can be made using immunofluorescence antigenic mapping, electron microscopy, and genetic analysis. Diagnosis enables early intervention with photoprotection, surveillance for extracutaneous involvement, and genetic counseling.

In this child, a biopsy specimen showed slight orthokeratotic hyperkeratosis and atrophy. Ultrastructural examination revealed a normal-appearing epidermis, with 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 available. 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.⁶ In DNA analysis from a peripheral blood sample, homozygous mutation p.R271X in the FERMT1 gene, also known as KIND1, was detected. The FERMT1 gene is located on the short arm of chromosome 20 (20p12.3) and is the protein fermitin family homologue 1, a 77.3-kDa phosphoprotein that is a component of focal contacts in basal keratinocytes.^6- 7 Fermitin family homologue 1 links the actin cytoskeleton to the extracellular matrix and is supposed to have cell-signaling functions due to different domains.⁵ Therefore, Kindler syndrome is the first known 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 types.