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Focal palmoplantar and gingival keratosis: A distinct palmoplantar ectodermal dysplasia with epidermolytic alterations but lack of mutations in known keratins Gerhard Kolde, MD, a Hans Christian Hennies, PhD, b Gudrun Bethke, MD, c and Peter A. Reichart, MD c Berlin, Germany Focal palmoplantar and gingival keratosis is a rare autosomal dominant disease whose clinical features, and in particular, pathologic alterations and molecular etiology remain to be well defined. Recently we observed a German family affected by the disease in at least 3 consecutive generations. The 4 patients examined showed circumscribed and painful hyperkeratosis at the weight-bearing plantar skin since infancy, rather mild palmar hyperkeratosis, and continuous leukokeratosis confined to the maxillary and mandibulary attached gingiva. There were no nail changes, subungeal keratoses, or follicular hyperkeratosis. Light and electron microscopy of the plantar and gingival lesions revealed alterations of epidermolytic hyperkeratosis. Mutations in the known keratin genes were excluded by linkage analysis using microsatellite markers. We conclude that focal palmoplantar and gingival keratosis is a clinically distinct palmoplantar ectodermal dysplasia that is pathologically characterized by epidermolytic alterations, but is most probably not caused by a mutation in a keratin gene. ( J Am Acad Dermatol 2005;52:403-9.) F ocal palmoplantar and gingival keratosis, also termed focal palmoplantar and oral mucosa hyperkeratosis syndrome or hereditary painful callosity 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 (Online Mendelian Inheritance in Man - OMIM *148730) was first defined by Gorlin in 1976 1 and is characterized by focal pressure-related and usually painful hyper- keratosis of the palms and soles, and hyperkeratosis of the attached gingiva presenting as leukoplakia. In addition to these findings, some of the affected patients were also reported to present nail changes, peri- and subungeal keratoses, follicular hyperkera- tosis, hyperhidrosis, and oral keratotic lesions at other points of mechanical pressure. 1-4 Since the first description of focal palmoplantar and gingival keratosis (FPGK) in 1964, 2 only a few cases have been reported, including some families affected by the disease in several consecutive gen- erations pointing to autosomal dominant inheri- tance. 1,3-6 The clinical features of the disease remain to be defined in more detail. Furthermore, the light and electron microscopic alterations of the keratotic palmoplantar and gingival lesions are not clear. We recently observed a German family affected by FPGK in at least 3 consecutive generations. Histological and ultrastructural examinations of the plantar and gingival hyperkeratosis showed the features of epidermolytic hyperkeratosis. 7,8 In the past several years, the underlying gene defects have been identified for many types of palmoplantar keratodermas. 9,10 Mutations in keratin genes have been found in various forms of the diseases, including those characterized by epider- molytic alterations, such as epidermolytic palmo- plantar keratoderma of Vo ¨rner (OMIM #144200), pachyonychia congenita type I, the Jadassohn- Lewandowsky syndrome (OMIM #167200), and Brocq’s generalized epidermolytic hyperkeratosis (OMIM #113800). By contrast, we demonstrate here that FPGK is not caused by a mutation in one of the known keratin genes. 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-Delbru ¨ ck-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: [email protected] 0190-9622/$30.00 ª 2005 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2004.07.029 403

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: [email protected]

    0190-9622/$30.00

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

    epidermolytic alterationsknown

    Gerhard Kolde, MD,a Hans Christian Hennies, PhD

    Berlin,

    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

    ermany

    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.

    403

  • CASA

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    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.

  • J AM ACAD DERMATOLMARCH 2005

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

    blood drawn after informed consent. Genotypingwas performed in the 4 affected family members and3 unaffected subjects, the father of the index patientand the parents of his affected cousin (Fig 1).Microsatellite markers were chosen from theGenethon linkage map.12 In the region of the typeII keratin genes on chromosome 12q13, markers atD12S1661, D12S368, D12S96, D12S355, and D12S83

    Fig 3. Histopathology of the plantar and gingival hyper-keratosis. A, Plantar lesion showing acanthosis with nestsof epidermolytic keratinocytes in various suprabasal celllayers. B, Gingival lesion with acanthotic and hyperkera-totic epithelium forming papillary projections. The supra-basal keratinocytes demonstrate cytoplasmic edema andepidermolytic alterations. (A and B, Hematoxylin-eosinstain; original magnifications: A, 3200; B, 3200.)

    Fig 4. Electron-microscopy of plantar lesion showingepidermolytic keratinocytes with irregular bundles oftonofilaments around the nucleus and tonofilamentclumping in the peripheral cytoplasm. (Original magnifi-cation: 32600.)were analyzed, and in the region of type I keratingenes on 17q21, markers at D17S1293, D17S946,D17S1787, D17S791, and D17S943 were used. In thecandidate region for palmoplantar keratodermaassociated with esophageal cancer on chromosome17q25,13-17 markers at D17S789, D17S949, D17S939,D17S802, and D17S784 were genotyped. Markerswere amplified in singleplex reactions in a totalvolume of 15 L containing 10 mmol/L Tris, 1.5mmol/L MgCl2, 100 mol/L each dNTP, 0.5 U TaqDNA polymerase (Invitek, Berlin, Germany), 7 pmolof each primer, and 20 ng genomic DNA. One of theprimers was end-labelled with 6-FAM, TET, or HEX.The polymerase chain reaction (PCR) was performedin PTC-225 thermal cyclers (MJ Research, Waltham,Mass). Products were pooled and analyzed byelectrophoresis on MegaBACE 1000 fluorescentautomated DNA capillary sequencers (AmershamPharmacia Biotech, Freiburg, Germany). Data wereanalyzed using the computer program GeneticProfiler (Amersham). Linkage calculations weredone with the computer program packageLINKAGE version 5.218 with an autosomal dominantmodel and rating the penetrance as 95%. Multipointlinkage data were determined using GENEHUNTERversion2.0.19Most likelyhaplotypeswereconstructedmanually.

    All informative markers, ie, 4 of 5 markers in eachof the 3 regions analyzed, showed obligatory re-combination events with the phenotype of FPGK inthe family investigated (Fig 1). These findings weresignificantly confirmed by linkage analysis givinglogarithm of odds scores below e2 with multipointdata in each candidate interval (Fig 5). Because allknown keratin genes are clustered in two smallregions, on chromosomes 12q13 and 17q21, muta-tions could be clearly excluded from linkage.Moreover, no hint at linkage of FPGK was found inthe region of the unknown gene for palmoplantarkeratoderma associated with esophageal cancer,which is localized between D17S1839 andD17S939.16

    DISCUSSIONThe present family showed the clinical fea-

    tures reported to be typical for FPGK. Transmissionof the clinical signs through at least 3 consecutivegenerations was consistent with autosomal domi-nant inheritance. The penetrance of the phenotype,however, seems reduced since the parents of onepatient were not affected by the disease. There wasno evidence for amale-to-male transmission that wasobserved in the two families of Gorlin,1 but not in theother families reported so far.3,4,6

    Three of the 4 affected members of our family

    presented with circumscribed hyperkeratosis at theweight-bearing soles and continuous leukoplakic

  • J AM ACAD DERMATOL Kolde et al 407lesions confined to the attachedgingiva since infancy.The rather mild palmar hyperkeratosis only occurredin adulthood and was clearly related to mechanicalwork. The adult patients additionally demonstratedslight periungeal keratoses at several toe- and finger-nails, but there were no subungeal keratoses, nailchanges, hyperhidrosis, or follicular hyperkeratosisas described in some other cases of FPGK.1-4

    The fourth patient was a 6-year-old girl whoshowed slight and painful hyperkeratosis at theweight-bearing plantar skin, but no lesions of theoral mucosa at first examination. The definite di-agnosis of FPGK could only be made 3 years later,after the patient developed some circumscribedleukoplakic lesions of the attached gingiva. Suchcircumscribed lesions were also described in otherpatients of young age,3,4 whereas all adult patients

    Focal pressure-related palmoplantar and oralhyperkeratosis is also seen in pachyonychia con-genita type I;20-22 in focal nonepidermolytic palmo-plantar keratoderma with oral, genital, and follicularlesions (OMIM #600962);23,24 and in focal palmo-plantar keratoderma associated with esophagealcancer, the Howel-Evans syndrome (OMIM *148500)that was originally mistaken for tylosis or diffusepalmoplantar keratoderma.25,26 Like FPGK, thesediseases are inherited as autosomal dominant traitsand first occur in infancy, though with slightlydifferent ages of onset (Table I). All these diseasesdisplay, however, more widespread leukoplakiclesions of the oral mucosa, which often spare theattached gingiva. Furthermore, they are usually asso-ciated with follicular hyperkeratosis. Pro-nounced thickening of most finger- and toenails is

    Fig 5. Multipoint linkage data with focal palmoplantar and gingival keratosis in the 3 intervalsof type II (KRT type II; A) and type I keratin genes (KRT type I; B), and the gene for focalpalmoplantar keratoderma with esophageal cancer (TOC; C). Significant exclusion of linkagewas observed in all regions.VOLUME 52, NUMBER 3demonstrated typical continuous leukokeratosis. a diagnostic hallmark of pachyonychia congenita.21

  • pathology is closely related to pachyonychia con-

    er

    en

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    J AM ACAD DERMATOL408 Kolde et alour patients revealed the typical alterations ofepidermolytic hyperkeratosis in both the plantarand gingival lesions. These alterations were onlyfocal and rather inconspicuous in the plantar skinbut nearly all suprabasal keratinocytes demon-strated cytoplasmic edema, moderate condensationof the perinuclear tonofilament bundles, someclumping of the peripheral filaments, and coarsekeratohyaline in the gingival hyperkeratosis. Similartonofilament alterations of the gingival epithelium,though not classified as epidermolytic hyperkerato-sis, have also been observed in the cases reported byYoung et al.6

    The features of epidermolytic hyperkeratosis arefound in a variety of inherited and acquired dis-eases,27 including epidermolytic palmoplantar kera-toderma and pachyonychia congenita type I. In thediffuse epidermolytic palmoplantar hyperkeratosis,the tonofilament alterations are linked to mutationsof keratin 9.28,29 By contrast, the epidermolyticchanges seen in the palmoplantar skin and less

    genita type I. However, linkage analysis with micro-satellite markers in the chromosomal regions of typeI and type II keratin genes excluded a mutation inkeratins 6A or 16, or in any of the other knownkeratins as the cause for FPGK. Linkage analysesadditionally showed that the disease is not onlyclinically and pathologically, but also geneticallydifferent from focal nonepidermolytic palmoplantarkeratoderma with oral, genital, and follicular lesionsand from palmoplantar keratoderma associated withesophageal cancer. The family described was toosmall to perform a genome-wide screen for linkageof FPGK rather than the analysis of candidate loci.

    In conclusion, FPGK is a clinically distinct diseasethat belongs to the heterogeneous group of epider-molytic palmoplantar ectodermal dysplasia but is notassociated with a mutation in one of the knownkeratin genes. To elucidate the etiology of the dis-ease, further molecular genetic analyses are neces-sary. The identification of the gene defect underlyingFPGK will shed light on the development ofThe cases of focal nonepidermolytic palmoplantarkeratoderma with oral, genital, and follicular lesionsdescribed so far were additionally characterized bya widening of the onychocorneal bands of the nails,and by leukokeratosis of the glans penis in somemales.23,24

    The pathological alterations of FPGK have as yetbeen studied in only a few patients,4-6 including onlyone electron microscopic analysis.6 The histologicaland ultrastructural investigations performed in 3 of

    Table I. Clinical features of focal palmoplantar keratod

    Focal palmoplantar

    and gingival

    keratosis

    Pachyonychia cong

    type I

    Inheritance Autosomaldominant

    Autosomal domin

    Onset ( yearsof age)

    4-7 1-2

    Palmoplantarhyperkeratosis

    Focal andpressure-related

    Focal and pressurelated

    Oral hyperkeratosis Attachedgingiva

    Tongue, buccalmucosa, palate

    Genital lesions None NoneFollicular

    keratosisRare and mild Usually pronounc

    Nail changes Usually absent Thickening of mofinger- and toe

    Associateddisorders

    None Nonepronounced in the oral epithelium of pachyonychiacongenita type I are caused by mutations of keratins6A and 16.30-32 Keratin 16 mutations were alsoreported in two families with focal nonepidermolyticpalmoplantar keratoderma with oral, genital, andfollicular lesions.23,24 The absence of epidermolysisin this syndrome is thought to be caused by lessdisruptive keratin 16 mutations than in type Ipachyonychia congenita.24

    The clinical features and epidermolytic alterationsobserved in FPGK suggested that the molecular

    ma with oral lesions

    ita

    Focal nonepidermolytic

    palmoplantar keratoderma

    with oral, genital, and

    follicular lesions

    Focal palmoplantar

    keratoderma associated

    with esophageal cancer

    t Autosomal dominant Autosomal dominant

    6-7 7-8

    Focal and pressure-related Focal andpressure-related

    Buccal mucosa, palate Buccal mucosa,palate, gingiva

    Leukokeratosis of glans penis NoneUsually pronounced Usually mild

    ilsWidening of onychocorneal

    band with splinterhemorrhages

    Absent

    None Esophageal carcinoma

    MARCH 2005epidermolytic hyperkeratosis and might thus con-tribute to unravelling the question of why some

  • keratin mutations cause such alterations but othersdo not.

    REFERENCES

    1. Gorlin RJ. Focal palmoplantar and marginal gingival hyperker-

    atosis: a syndrome. Birth Defects 1976;12:239-42.

    2. Fred HL, Gieser RG, Berry WR, Erband JM. Keratosis palmaris

    et plantaris. Arch Intern Med 1964;113:866-71.

    Tylosis Oesophageal Cancer (TOC) locus. Oncogene 2002;21:

    6395-402.

    18. Lathrop GM, Lalouel JM. Easy calculations of lod scores and

    genetic risks on small computers. Am J Hum Genet 1984;

    36:460-5.

    19. Kruglyak L, Daly MJ, Reeve-Daly MP, Lander ES. Parametric and

    nonparametric linkage analysis: a unified multipoint approach.

    Am J Hum Genet 1996;58:1347-63.

    20. Jadassohn J, Lewandowsky F. Pachyonychia congenita.

    J AM ACAD DERMATOLVOLUME 52, NUMBER 3

    Kolde et al 4093. James P, Beggs D. Tylosis: a case report. Br J Oral Surg

    1973;11:143-5.

    4. Laskaris G, Vareltzidis A, Avgerinou G. Focal palmoplantar and

    oral mucosa hyperkeratosis syndrome: a report concerning

    five members of a family. Oral Surg 1980;50:250-3.

    5. Raphael AL, Baer PN, Lee WB. Hyperkeratosis of gingival and

    plantar surfaces. Periodontics 1968;6:118-20.

    6. Young WG, Newcomb GM, Daley TJ. Focal palmoplantar and

    gingival hyperkeratosis syndrome: report of a family, with

    cytologic, ultrastructural, and histochemical findings. Oral

    Surg 1982;53:473-82.

    7. Ackerman AB. Histopathologic concept of epidermolytic

    hyperkeratosis. Arch Dermatol 1970;102:253-9.

    8. Wilgram GF, Caulfield JB. An electron microscopic study of

    epidermolytic hyperkeratosis. Arch Dermatol 1966;94:127-43.

    9. Kelsell DP, Stevens HP. The palmoplantar keratodermas: much

    more than palms and soles. Mol Med Today 1999;5:107-13.

    10. Kimyai-Asadi A, Kotcher LB, Jih MH. The molecular basis of

    hereditary palmoplantar keratodermas. J Am Acad Dermatol

    2002;47:327-43.

    11. Kolde G, Knop J. Ultrastructural morphometry of epidermal

    Langerhans cells: Introduction of a simple method for

    a comprehensive quantitative analysis of the cells. Arch

    Dermatol Res 1986;278:298-301.

    12. Dib C, Faure S, Fizames C, Samson D, Drouot N, Vignal A, et al.

    A comprehensive genetic map of the human genome based

    on 5,264 microsatellites. Nature 1996;380:152-4.

    13. Risk JM, Field EA, Field JK, Whittaker J, Fryer A, Ellis A, et al.

    Tylosis oesophageal cancer mapped. Nat Genet 1994;8:319-21.

    14. Hennies HC, Hagedorn M, Reis A. Palmoplantar keratoderma

    in association with carcinoma of the esophagus maps to

    chromosome 17q distal to the keratin gene cluster. Genomics

    1995;29:537-40.

    15. Kelsell DP, Risk JM, Leigh IM, Stevens HP, Ellis A, Hennies HC,

    et al. Close mapping of the focal non-epidermolytic palmo-

    plantar keratoderma (PPK) locus associated with oesophageal

    cancer (TOC). Hum Molec Genet 1996;5:857-60.

    16. Risk JM, Ruhrberg C, Hennies H, Mills HS, Di Colandrea T,

    Evans KE, et al. Envoplakin, a possible candidate gene for

    focal NEPPK/Esophageal cancer (TOC): the integration of

    genetic and physical maps of the TOC region on 17q25.

    Genomics 1999;59:234-42.

    17. Risk JM, Evans KE, Jones J, Langan JE, Rowbottom L,

    McRonald FE, et al. Characterization of a 500 kb region on

    17q25 and the exclusion of candidate genes as the familialIn: Jacobs Ikonographia Dermatologica. Berlin: Urban und

    Schwarzenberg; 1906. p. 29.

    21. Kansky A, Basta-Juzbasic A, Videnic N, Ivankovic D, Stanimirovic

    A. Pachyonychia congenita (Jadassohn-Lewandowsky syn-

    drome)-evaluation of symptoms in 36 patients. Arch Dermatol

    Res 1993;285:36-7.

    22. Swensson O. Pachyonychia congenita. Keratingen-Mutationen

    mit pleiotroper Wirkung. Hautarzt 1999;50:483-90.

    23. Stevens HP, Kelsell DP, Spurr NK, Bishop DT, Purkins PE,

    Griffiths WAD, et al. Keratin staining and linkage of non-

    epidermolytic focal palmoplantar keratodermas (PPK) to 17q.

    Br J Dermatol 1994;131:425.

    24. Shamsher MK, Navsaria HA, Stevens HP, Ratnavel RC, Purkis PE,

    Kelsell DP, et al. Novel mutations in keratin 16 gene underly

    focal non-epidermolytic palmoplantar keratoderma (NEPPK) in

    two families. Hum Mol Genet 1995;4:1875-81.

    25. Howel-Evans W, McGonall RB, Clarke GA, Sheppard PM.

    Carcinoma of the oesophagus with keratosis palmaris

    et plantaris (tylosis). A study of 2 families. Q J Med 1958;

    27:415-29.

    26. Stevens HP, Kelsell DP, Bryant SP, Bishop DT, Spurr NK,

    Weissenbach J, et al. Linkage of an American pedigree with

    palmoplantar keratoderma and malignancy (palmoplantar

    ectodermal dysplasia type III) to 17q24. Literature survey

    and proposed updated classification of the keratodermas.

    Arch Dermatol 1996;132:640-51.

    27. Weedon D. Disorders of epidermal maturation and keratiniza-

    tion. In: Skin Pathology, Weedon D, editor. 2nd ed. New York:

    Churchill Livingstone; 2002. p. 281-320.

    28. Reis A, Hennies HC, Langbein L, Digweed M, Mischke D,

    Drechsler M, et al. Keratin 9 gene mutations in epidermolytic

    palmoplantar keratoderma (EPPK). Nat Genet 1994;6:174-9.

    29. Hennies HC, Zehender D, Kunze J, Kuster W, Reis A. Keratin 9

    gene mutational heterogeneity in patients with epidermolytic

    palmoplantar keratoderma. Hum Genet 1994;93:649-54.

    30. Bowden PE, Haley JL, Kansky A, Rothnagel JA, Jones DO,

    Turner RJ. Mutation of a type II keratin gene (K6a) in

    pachyonychia congenita. Nat Genet 1995;10:363-5.

    31. McLean WH, Rugg EL, Lunny DP, Morley SM, Lane EB,

    Swensson O, et al. Keratin 16 and keratin 17 mutations cause

    pachyonychia congenita. Nat Genet 1995;9:273-8.

    32. Smith FJ, Del Monaco M, Steijlen PM, Munro CS, Morvay M,

    Coleman CM, et al. Novel proline substitution mutations in

    keratin 16 in two cases of pachyonychia congenita type 1. Br J

    Dermatol 1999;141:1010-6.

    Focal palmoplantar and gingival keratosis: A distinct palmoplantar ectodermal dysplasia with epidermolytic alterations but...Case reportsClinical featuresHistopathology and electron microscopyGenotyping and linkage analysis

    DiscussionREFERENCES