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JAMA CLINICAL CHALLENGE

Skin Fragility and Blister Formation

Huan J. Chang, MD, MPH

A3-YEAR-OLD GIRL NATIVE OF THE TRIBE NGBE-BUGL (PANAMA) WAS RE-ferred for evaluation of a history of skin fragility and blister formationsince adoption 2 years earlier. The childs adoptive parents were un-

aware of the patients or her familys medical history. Lesions were mainly lo-cated in sites of trauma and rapidly evolved to form crusts, ultimately leavingsome pigmentary changes. Skin examination revealed erosions and crusts overthe face and fingers. There was dyspigmentation with hyperpigmented and hy-

popigmented macules on both sun-exposed and nonsun-exposed areas. Theskin was atrophic, with cigarette-paperlike wrinkling, especially over the dorsaof the hands and feet (FIGURE 1). Mild proximal syndactyly was present be-tween the middle and ring fingers (FIGURE 2). There were no milia (FIGURE 3).Nails, gingiva, and mucous membranes were normal.

What Would You Do Next?

A. Do nothing; the lesions will re-solve over time

B. Obtain a biopsy of the lesionC. Prescribe oral antibioticsD. Prescribe topical steroids

See www.jama.com for online ClinicalChallenge.

Author Affiliation: Dr Chang (tina.chang@jama-archives.org) is Contributing Editor, JAMA.JAMA ClinicalChallenge SectionEditor: HuanJ. Chang, MD, ContributingEditor.We encourage authors to submit papers for considerationas a JAMAClinicalChallenge.Please contact Dr Chang at tina.chang@jama-archives.org.

Figure 1. Close-up of the feet demonstrates cigarette-paperlikewrinkling (figure reprinted from Arch Pediatr Adolesc Med.2010;164[9]:875-8761).

Figure 2. Interdigital webbing of the fingers. There also werehealing blisters and crusts over the dorsum of the hand (figurereprinted from Arch Pediatr Adolesc Med.2010;164[9]:875-8761).

Figure 3. Pigmentary changes over the legs (figure reprintedfrom Arch Pediatr Adolesc Med. 2010;164[9]:875-8761).

2011 American Medical Association. All rights reserved. JAMA, August 17, 2011Vol 306, No. 7 767

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DiagnosisKindler syndrome

What to Do Next

B. Obtain a biopsy of the lesion

The key clinical feature in this caseis making the diagnosis of Kindler syn-dromein this adoptedgirl fromPanama.Althoughthissyndromeis extremelyun-usual in therest of theworld, theNgobe-Bugle or Guaym tribe of Native Ameri-cans in Panamahas thelargestcase seriesof Kindler syndrome describedto date.2

Kindler syndrome results from muta-tions inKIND1, thegeneencoding kind-lin-1, a novel protein involvedin attach-ment of the actin cytoskeleton to theextracellular matrix.

CommentKindler syndrome is an autosomal re-cessive genophotodermatosis. It is con-sidered a major type of inherited epi-dermolysis bullosa different from otherepidermolysis bullosa types because ofits unique features.3 Patients experi-ence blisters in infancy following cu-taneous trauma or exposure to sun-light. Unlike the other epidermolysisbullosa types, photosensitivityand blis-tering in Kindler syndrome improveswith age, as progressive pigmentary

changes and poikiloderma develop.Thin, wrinkled, and atrophic skin ismost pronounced on the dorsa of thehands and feet. Typically, patients de-velop interdigital webbing but no scar-ring or milia. Other features may in-clude nail dystrophy; keratoderma ofthe palms and soles; esophageal, anal,vaginal, and urethral stenosis; ectro-pion; and severe periodontal disease.4

Gastrointestinal symptoms and signs,suchas colitisandbloody diarrhea, havebeen reported.5 There also appears to

be an increased risk of nonmelanoma

skin cancer, mostly squamous cell car-cinomas that occur on acral skin or inthe mouth.

Differential diagnosis can be diffi-cult because Kindler syndrome hasmany clinical features that overlap with

other diseases. In young children, thissyndrome can be confused with vari-ants of epidermolysis bullosa. Whenphotosensitivity and poikiloderma de-velop, Kindler syndrome may be mis-diagnosed as autosomal dominant

Weary syndrome or other hereditarypoikilodermas. Accurate diagnosis canbe madeusing immunofluorescence an-tigenic mapping, electron micros-copy, and genetic analysis. Diagnosisenables early intervention with photo-protection, surveillance for extracuta-neous involvement, and genetic coun-

seling.In this child, a biopsy specimen

showed slight orthokeratotic hyper-keratosis and atrophy. Ultrastructuralexamination revealed a normal-appearing epidermis, with markedduplication of the basal lamina, withbranching and folding that could betraced deep below the basement mem-brane zone. Immunofluorescencemapping of the basement membranedetected a significantly thickened typeVII collagen band, especially on the

papillary dermis. The other stains (6integrin, 4 integrin, laminin 5, andtype IV collagen) did not show altera-tions. C-terminal antifermitin familyhomologue 1 antibody, also known asantikindlin-1 antibody, was not avail-able. Immunofluorescence microscopylabeling using antifermitin familyhomologue 1 antibody shows anabsent or reduced fluorescence com-pared with control skin in mostpatients with Kindler syndrome.6

In DNA analysis from a peripheral

blood sample, homozygous mutation

p.R271X in the FERMT1 gene, alsoknown as KIND1, was detected. TheFERMT1 gene is located on the shortarm of chromosome 20 (20p12.3) andis the protein fermitin family homo-logue 1, a 77.3-kDa phosphoprotein

that is a component of focal contactsin basal keratinocytes.6,7 Fermitin fam-ily homologue 1 links the actin cyto-skeleton to the extracellular matrixand is supposed to have cell-signalingfunctions due to different domains.5

Therefore, Kindler syndrome is thefirst known genodermatosis caused bya defect in actin-extracellular matrixlinkage rather than the classic keratin-extracellular matrix linkage underly-ing the pathology of other epidermoly-sis bullosa types.

Conflict of Interest Disclosures: Theauthor hascom-pleted and submitted the ICMJE Form for Disclosureof Potential Conflicts of Interest and none were re-ported.Additional Information: This JAMA Clinical Chal-lenge is based on a previously published article (LealL, Vicente MA, Mascaro JM Jr, Bombi JA, Gonzalez-Ensenat MA. Picture of the month. ArchPediatr Ado-lesc Med. 2010;164[9]:875-876).

REFERENCES

1. Leal L, Vicente MA, Mascaro JM Jr, Bomb JA,Gonzalez-Ensenat MA. Picture of the monthquizcase: Kindler syndrome. Arch Pediatr Adolesc Med.2010;164(9):875-876.2. Penagos H, Jaen M, SanchoMT, et al.Kindler syn-drome in native Americans from Panama: report of26 cases. Arch Dermatol. 2004;140(8):939-944.

3. Fine JD, Eady RA, Bauer EA, et al. The classifica-tion of inherited epidermolysis bullosa (EB): report ofthe Third International Consensus Meeting on Diag-nosis and Classification of EB. J Am Acad Dermatol.2008;58(6):931-950.4. Mallo S, Rodrguez-DazE, BlancoS, Alvarez-CuestaC, Galache C, Nosti D. Kindler syndrome: presenta-tion of a case. Actas Dermosifiliogr. 2005;96(10):677-680.5. Sadler E,Klausegger A,MussW, etal. Novel KIND1gene mutation in Kindler syndrome with severe gas-trointestinal tractinvolvement. ArchDermatol. 2006;142(12):1619-1624.6. Lai-Cheong JE, Tanaka A, Hawche G, et al. Kin-dler syndrome: a focal adhesion genodermatosis. BrJ Dermatol. 2009;160(2):233-242.7. Jobard F, Bouadjar B, Caux F, et al. Identificationof mutations in a new gene encoding a FERM familyproteinwith a pleckstrinhomology domainin Kindlersyndrome. Hum Mol Genet. 2003;12(8):925-935.

JAMA CLINICAL CHALLENGE

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