Focal palmoplantar and gingival keratosis: A distinctpalmoplantar ectodermal dysplasia with

epidermolytic alterations but lack of mutations inknown keratins

Gerhard Kolde, MD,a Hans Christian Hennies, PhD,b Gudrun Bethke, MD,c and Peter A. Reichart, MDc

Berlin, Germany

Focal palmoplantar and gingival keratosis is a rare autosomal dominant disease whose clinical features, andin particular, pathologic alterations and molecular etiology remain to be well defined. Recently weobserved a German family affected by the disease in at least 3 consecutive generations. The 4 patientsexamined showed circumscribed and painful hyperkeratosis at the weight-bearing plantar skin sinceinfancy, rather mild palmar hyperkeratosis, and continuous leukokeratosis confined to the maxillary andmandibulary attached gingiva. There were no nail changes, subungeal keratoses, or follicularhyperkeratosis. Light and electron microscopy of the plantar and gingival lesions revealed alterations ofepidermolytic hyperkeratosis. Mutations in the known keratin genes were excluded by linkage analysisusing microsatellite markers. We conclude that focal palmoplantar and gingival keratosis is a clinicallydistinct 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.)

Focal palmoplantar and gingival keratosis, alsotermed focal palmoplantar and oral mucosahyperkeratosis syndrome or hereditary painful

callosity syndrome, is a very rare disease that belongsto 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-

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: gerhard.kolde@charite.de.

0190-9622/$30.00

ª 2005 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2004.07.029

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

Since the first description of focal palmoplantarand gingival keratosis (FPGK) in 1964,2 only a fewcases 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), andBrocq’s generalized epidermolytic hyperkeratosis(OMIM #113800). By contrast, we demonstrate herethat FPGK is not caused by a mutation in one of theknown keratin genes.

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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.

CASE REPORTSAs shown in the pedigree (Fig 1), the disease was

observed in 4 members of a German family. Theindex case (IV:2), an 11-year-old boy, was admittedwith hyperkeratosis of the soles and white lesions ofthe gingiva, which were first noted two years earlierand subsequently became more prominent. His 35-year-old mother and 58-year-old grandfather hadsimilar lesions of the skin and oral mucosa sinceinfancy. The fourth patient, a 6-year-old girl cousin of

the index case, only demonstrated plantar lesions atfirst examination. The deceased great-grandmotherwas also said to have shown the disease. There wasno family history of carcinoma of the esophagus orother tumor diseases.

Clinical featuresThe index case and his mother and grandfather

showed circumscribed areas of slightly tomoderatelythick hyperkeratosis on the plantar skin (Fig 2, A).

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The 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 perinuclearedema, faintly eosinophilic globules in the periph-eral cytoplasm, and coarse keratohyalin material

sometimes 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-tained only few histiocytes, lymphoid cells, andplasma cells in perivascular position.

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.

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Genotyping 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 D12S83were analyzed, and in the region of type I keratingenes on 17q21, markers at D17S1293, D17S946,

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.)

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 ımol/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 familypresented with circumscribed hyperkeratosis at theweight-bearing soles and continuous leukoplakic

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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.

lesions 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 patientsdemonstrated typical continuous leukokeratosis.

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 isa diagnostic hallmark of pachyonychia congenita.21

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Table I. Clinical features of focal palmoplantar keratoderma with oral lesions

Focal palmoplantar

and gingival

keratosis

Pachyonychia congenita

type I

Focal nonepidermolytic

palmoplantar keratoderma

with oral, genital, and

follicular lesions

Focal palmoplantar

keratoderma associated

with esophageal cancer

Inheritance Autosomaldominant

Autosomal dominant Autosomal dominant Autosomal dominant

Onset ( yearsof age)

4-7 1-2 6-7 7-8

Palmoplantarhyperkeratosis

Focal andpressure-related

Focal and pressure-related

Focal and pressure-related Focal andpressure-related

Oral hyperkeratosis Attachedgingiva

Tongue, buccalmucosa, palate

Buccal mucosa, palate Buccal mucosa,palate, gingiva

Genital lesions None None Leukokeratosis of glans penis NoneFollicularkeratosis

Rare and mild Usually pronounced Usually pronounced Usually mild

Nail changes Usually absent Thickening of mostfinger- and toenails

Widening of onychocornealband with splinterhemorrhages

Absent

Associateddisorders

None None None Esophageal carcinoma

The 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 ofour 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 lesspronounced in the oral epithelium of pachyonychiacongenita type I are caused by mutations of keratins

6A 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 molecularpathology is closely related to pachyonychia con-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 ofepidermolytic hyperkeratosis and might thus con-tribute to unravelling the question of why some

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keratin mutations cause such alterations but othersdo not.

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