Focal palmoplantar and gingival keratosis: A distinct palmoplantar ectodermal dysplasia with epidermolytic alterations but lack of mutations in known keratins

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    Fhyperkeratosis syndrome or hereditary painful Since the first description of focal palmoplantarand gingival keratosis (FPGK) in 1964,2 only a fewcallosity syndrome, is a very rare disease that belongs

    to the heterogeneous group of inherited palmoplan-tar keratoderma with associated ectodermal mani-festations. The autosomal dominant disease (OnlineMendelian Inheritance in Man - OMIM *148730) wasfirst defined by Gorlin in 19761 and is characterizedby focal pressure-related and usually painful hyper-keratosis of the palms and soles, and hyperkeratosisof the attached gingiva presenting as leukoplakia. Inaddition to these findings, some of the affectedpatients were also reported to present nail changes,peri- and subungeal keratoses, follicular hyperkera-

    cases have been reported, including some familiesaffected by the disease in several consecutive gen-erations pointing to autosomal dominant inheri-tance.1,3-6 The clinical features of the diseaseremain to be defined in more detail. Furthermore,the light and electron microscopic alterations of thekeratotic palmoplantar and gingival lesions are notclear.We recently observed aGerman family affectedby FPGK in at least 3 consecutive generations.Histological and ultrastructural examinations of theplantar and gingival hyperkeratosis showed thefeatures of epidermolytic hyperkeratosis.7,8

    In the past several years, the underlying genedefects have been identified for many types ofpalmoplantar keratodermas.9,10 Mutations in keratingenes have been found in various forms of thediseases, including those characterized by epider-molytic alterations, such as epidermolytic palmo-plantar keratoderma of Vorner (OMIM #144200),pachyonychia congenita type I, the Jadassohn-Lewandowsky syndrome (OMIM #167200), andBrocqs generalized epidermolytic hyperkeratosis(OMIM #113800). By contrast, we demonstrate herethat FPGK is not caused by a mutation in one of the

    From the Departments of Dermatology and Allergy,a Oral Surgery

    and Dental Radiology,c Charite-University Medicine of Berlin,

    and the Department of Molecular Genetics and Gene Mapping

    Center, Max-Delbruck-Center for Molecular Medicine.b

    Funding sources: None.

    Conflicts of interest: None identified.

    Accepted for publication July 19, 2004.

    Reprint requests: Gerhard Kolde, MD, Department of Dermatology

    and Allergy, Charite-University Medicine of Berlin, Schumannstr.

    20/21, 10117 Berlin/Germany. E-mail:


    2005 by the American Academy of Dermatology, Inc.Focal palmoplantar and gipalmoplantar ectod

    epidermolytic alterationsknown

    Gerhard Kolde, MD,a Hans Christian Hennies, PhD


    Focal palmoplantar and gingival keratosis is a rare auin particular, pathologic alterations and moleculaobserved a German family affected by the diseaseexamined showed circumscribed and painful hypinfancy, rather mild palmar hyperkeratosis, and conmandibulary attached gingiva. There were nohyperkeratosis. Light and electron microscopy of thepidermolytic hyperkeratosis. Mutations in the knousing microsatellite markers. We conclude that focdistinct palmoplantar ectodermal dysplasia that is pabut is most probably not caused by a mutation in a

    ocal palmoplantar and gingival keratosis, alsotermed focal palmoplantar and oral mucosadoi:10.1016/j.jaad.2004.07.029gival keratosis: A distinctrmal dysplasia withbut lack of mutations ineratins

    Gudrun Bethke, MD,c and Peter A. Reichart, MDc


    somal dominant disease whose clinical features, andetiology remain to be well defined. Recently weat least 3 consecutive generations. The 4 patients

    keratosis at the weight-bearing plantar skin sincenuous leukokeratosis confined to the maxillary andail changes, subungeal keratoses, or follicularplantar and gingival lesions revealed alterations ofn keratin genes were excluded by linkage analysispalmoplantar and gingival keratosis is a clinically

    ologically characterized by epidermolytic alterations,eratin gene. ( J Am Acad Dermatol 2005;52:403-9.)

    tosis, hyperhidrosis, and oral keratotic lesions atother points of mechanical pressure.1-4known keratin genes.


  • CASA


    ons atothere wasus or

    fatherrately2, A).

    J AM ACAD DERMATOL404 Kolde et alE REPORTSs shown in the pedigree (Fig 1), the disease waserved in 4 members of a German family. Thex case (IV:2), an 11-year-old boy, was admittedhyperkeratosis of the soles and white lesions of

    gingiva, which were first noted two years earliersubsequently became more prominent. His 35-r-old mother and 58-year-old grandfather hadilar lesions of the skin and oral mucosa sincency. The fourth patient, a 6-year-old girl cousin of

    the index case, only demonstrated plantar lesifirst examination. The deceased great-grandmwas also said to have shown the disease. Therno family history of carcinoma of the esophagother tumor diseases.

    Clinical featuresThe index case and his mother and grand

    showed circumscribed areas of slightly tomodethick hyperkeratosis on the plantar skin (Fig

    Fig 1. Pedigree of the family with focal palmoplantar and gingival keratosis showingautosomal dominant inheritance in at least 3 consecutive generations. The deceased great-grandmother was also reported to have had the disease. Most likely haplotypes wereconstructed in the chromosomal regions of type II keratin genes (A), type I keratin genes(B), and the gene for focal palmoplantar keratoderma with esophageal cancer (C). Obligatoryrecombination events with focal palmoplantar and gingival keratosis were observed in thefamily described in all these regions.MARCH 2005

  • J AM ACAD DERMATOL Kolde et al 405The painful hyperkeratotic lesions were confined tothe weight-bearing heels and pads of the metacarpalheads. The labial and buccal surface of the attachedmaxillary and mandibular gingiva revealed sharplydelineated, continuous leukoplakic lesions whichdid not involve the basal and apical margins of thegingiva (Fig 2, B). The lingual surface of the attachedgingiva was also affected, but to a much lesserdegree. No leukoplakic lesions were seen on thefree gingiva and other areas of the oral mucosa.Primary and secondary dentition was normal. In thegrandfather, the oral hyperkeratosis hadbeen present until the prosthetic treatment with fulldentures.

    The mother and in particular the grandfatheradditionally demonstrated slight to moderate hyper-keratosis on the pressure points of the palmar skin(Fig 2, C), and slight circumungual hyperkeratosis atthe toe- and fingernails (Fig 2, D). These lesions hadonly developed in adulthood. There were, however,no subungual keratoses or nail changes. None of thepatients had follicular keratoses, hyperhidrosis, orhair abnormalities.

    The female cousin of the index case showed slightbut painful circumscribed hyperkeratotic areas onthe weight-bearing heels and metacarpal pads of thebig toes. There were no other lesions of the skin, andthe gingiva appeared initially normal. Some circum-scribed whitish lesions of the attached gingiva werefirst noted 3 years later. Primary dentition was reg-ular. Remarkably, examination of the parents of thisgirl did not reveal any sign of FPGK.

    All patients were otherwise healthy, and theroutine laboratory investigations were within normalrange.

    Histopathology and electron microscopyBiopsies of the plantar and gingival keratotic

    lesions were obtained from the index case and hismother and grandfather, and were processed forconventional histology and transmission electronmicroscopy as described in detail previously.11

    Histologic examinations of the affected plantarskin revealed a considerably acanthotic epidermis,with slightly increased mitotic activity of the basalcell layers, prominent granular cell layer, andmarkedhyperkeratosis (Fig 3, A). On both light and electronmicroscopy, most keratinocytes showed no struc-tural alterations. However, there were regularlysingle or small nests of keratinocytes in the su-prabasal epidermis demonstrating the features ofepidermolytic hyperkeratosis. These cells werehistopathologically characterized by perinuclear

    VOLUME 52, NUMBER 3edema, faintly eosinophilic globules in the periph-eral cytoplasm, and coarse keratohyalin materialsometimes resembling viral vacuolization. Electronmicroscopy showed edematous cytoplasm, whorl-like bundles of tonofilaments around the nucleus,some abnormal clumping of peripheral tonofila-ments, and irregularly shaped keratohyalin (Fig 4).A few mononuclear inflammatory cells were seen inthe upper dermis.

    The gingival lesions were histologically charac-terized by an acanthotic epithelium covered bya hyperkeratotic horny layer (Fig 3, B). The epithe-lium formed a small granular cell layer and some tinypapillary projections. Both light and electronmicroscopy revealed that nearly all suprabasal kerat-inocytes showed epidermolytic alterations. As in theepidermis, there were cytoplasmic edema, irregularshells and clumps of tonofilaments, and coarsekeratohyalin. The underlying connective tissue con-

    Fig 2. Clinical features of the cutaneous andoral lesions.A,Case 1: Slight to moderate hyperkeratosis on the weight-bearing plantar skin. B, Case 1: Continuous leukoplakiclesion on the labial surface of the attached gingiva. C, Case2: Focal hyperkeratosis on the pressure points of the palmarskin.D, Case 2: Rather normal fingernail with circumungealhyperkeratosis.tained only few histiocytes, lymphoid cells, andplasma cells in perivascular position.


    406 Kolde et alGenotyping and linkage analysisGenomic DNA was extracted from peripheral

    blood drawn after informed consent. Genotypingwas performed in the