Papillon-Lefevre syndrome with albinism: A review of the literature

and report of 2 brothers

Faiez N. Hattab, BDS, PhD,a and Wala M. Amin, BDS, MSc, PhD,b Doha, State of Qatar,and Amman, JordanFAMILY DENTAL CLINIC AND UNIVERSITY OF JORDAN

Background. Papillon-Lefevre syndrome (PLS) is a very rare autosomal recessive disorder characterized by palmoplantar

hyperkeratosis and severe early onset of destructive periodontitis leading to premature loss of both primary and permanent

dentitions. The etiopathogenesis of the condition suggests that there is a genetic basis for susceptibility to specific virulent

pathogens. Variation in the clinical presentation of PLS has recently been observed.

Objective. The objective was to present the first report, which describes the concurrence of PLS and albinism. The etiology,

pathology, and management of the condition were reviewed and genetic analysis was performed.

Subjects and clinical presentation. The probands are Jordanian brothers aged 13 and 20 years on their initial presentation.

The parents were second cousins and not affected. The patients exhibited the typical clinical features of PLS with type 1

oculocutaneous albinism (OCA1). They also had increased susceptibility to infection manifested in recurrent tonsillitis,

respiratory tract infection, pyoderma, onychogryphosis, and other pathosis. Skin biopsy demonstrated hyperkeratosis, focal

parakeratosis, hypergranulosis, and acanthosis. Ectopic calcification of the dura was noticed in one of the probands.

Hematological parameters tested were within the normal limits. The probands were tested for mutations in the causative genes

of PLS and OCA1, cathepsin C (CTSC), and tyrosinase, respectively. Independent mutations (c.318-1G>A and c.817G>C/

p.W272C) were identified in CTSC and tyrosinase, respectively. The probands were homozygous and their sister who had only

PLS was homozygous for the same (CTSC) mutation but heterozygous for tyrosinase gene.

Conclusion. We hope that this report of coinheritance PLS and albinism will initiate further investigations to disclose other

possible variations that may enhance our knowledge on gene mutations of this intriguing syndrome.

(Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:709-16)

In 1924, Papillon and Lefevre1 described a brother andsister with a condition characterized by palmoplantarhyperkeratosis (keratoderma) associated with severe,early onset periodontitis and premature loss of primaryand permanent teeth. Gorlin et al2 added calcification ofthe falx cerebri to the syndrome, converting it intoa triad. An increased susceptibility to infection has beenreported in approximately 25% of Papillon-Lefevrepatients.3 Variable findings in the syndrome includeretardation of somatic development, follicular hyper-keratosis, nail dystrophy, and hyperhidrosis.2-5

Papillon-Lefevre syndrome (PLS) usually manifestsitself between the ages of 6 months to 4 years,coinciding with the eruption of primary teeth.4,5 The

We are grateful to Professor Nalin Thakker at the Unit of Medical

Genetics, University of Manchester, UK, for contribution to this

work.aConsultant, Family Dental Clinic, Doha, State of Qatar.bAssociate Professor, Department of Conservative Dentistry and

Prosthodontics, Faculty of Dentistry, University of Jordan, Amman,

Jordan.

Received for publication Apr 23, 2004; returned for revision Jun 23,

2004; accepted for publication Aug 27, 2004.

1079-2104/$ - see front matter

� 2005 Elsevier Inc. All rights reserved.

doi:10.1016/j.tripleo.2004.08.030

soles of the feet are more severely affected than thehands, and erythema always precedes hyperkeratosis.The skin lesions are aggravated during cold weather andat times of severe periodontal involvement.2,4-8

More than 250 cases of PLS have been publishedincluding about 80 Arab probands.4,6-12 Because ofincreased awareness of the disease, mainly dentists havediagnosed over half of the reported cases during the past2 decades. The prevalence of PLS in the general popu-lation is 1 to 4 cases per million.2 Haneke3 reviewed atotal of 124 cases published until the mid 1970s andfound that males and females were equally affected andno racial predominance of the condition was evident.One third of the cases had consanguineous parents.3 Ourreview on Arab probands revealed as high as 75% hada history of close parental consanguinity (first or secondcousins). The relatively high prevalence of PLS in Arabsand its frequency in families with parental consanguin-ity could partly be related to the high rate of consanguin-eous marriage in Arab communities, accounting for onethird or more of the total marriages.13,14

PLS is a genetically homogeneous autosomal re-cessive disorder with a locus mapped on chromosome11q14-q21.15 In 1999, 2 independent groups16,17

identified germline missense and truncating mutationsof the gene with loss of function of cathepsin C,

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a lysosomal protease enzyme. This enzyme plays animportant role in maintaining the balance between theoral microflora and the immune system through proteindegradation and proenzyme activation.17,18 Lack ofcathepsin activity in PLS may be associated with areduced host response against virulent pathogens indental plaque and possibly at other sites. It is welldocumented that mutations of the cathepsin C gene(CTSC) are implicated in PLS and prepubertal peri-odontitis.18,19 In addition to genetic alterations, severalenvironmental and host factors are involved in thePLS periodontitis including (1) specific virulent bacte-rial and viral infection of periodontium, particularlyActinobacillus actinomycetemcomitans,20,21 cytomega-lovirus, and Epstein-Barr type 1 virus22; (2) impairedneutrophil chemotaxis, migration, and phagocytoxicfunctions,10,20,23-25 and increased superoxide produc-tion23,26; (3) reduced functional activity of monocyteselicited by decreased phagocytosis, increased tendencyto aggregate, and impaired Fc-receptor function27;(4) decreased mitogenic activity of lymphocytes,28,29

and reversed ratio of T-helper to T-killer cells30,31;(5) degenerative changes of plasma cells32 and elevation

Fig 1. Occulocutaneous albinism with snow-white hair,erythema of the face, and blue-gray irides (Case 1).

of serum immunoglobulin (IgG)31; and (6) disruptionof fibroblast and cementoblast function combined withdefective periodontal ligament attachment and gingivalepithelium,29,33 and imbalance of collagenolytic activ-ity in the periodontal ligament.34,35 Accumulated evi-dence indicates that the etiopathogenesis of PLS is acomplex interaction between immune-mediated defi-ciencies in the host defense mechanism and inheritedgenetic defects.

Variation in the clinical presentation of PLS hasrecently been observed. Willett et al36 described a casewith mild, late onset of periodontitis and early onset ofpalmoplantar hyperkeratosis. Brown et al37 presented3 cases in which periodontal inflammation was rela-tively mild and both the periodontal and skin lesionswere of late onset, starting around the third decade.Bullon et al23 presented 2 sisters exhibiting early onsetof palmoplantar hyperkeratosis, but their primarydentition was not affected. Fardal et al38 describeda case in which palmoplantar hyperkeratosis started atabout the age of 2 years with no periodontal involvementobserved until the age of 14. Soskolne et al39 examined2 families with multiple affected members. In eachfamily one individual had either hyperkeratotic lesionwith no periodontal changes or early onset periodontitisin the absence of palmoplantar keratosis. We add to theliterature the first report of concurrence of PLS and type1 oculocutaneous albinism (OCA1) in 2 brothers.Clinical and histopathological features are describedand mutations in the CTSC gene and tyrosinase genewere investigated.

CASE REPORTSCase 1

A 20-year-old Jordanian male was referred to our cliniccomplaining of the early loss of teeth, esthetic problems, anddifficulty in eating. From the history, periodontal breakdownand palmoplantar hyperkeratosis were reported. The patientwas diagnosed as having PLS with OCA1. The proband andhis family members were initially seen in 1993.

Family history revealed the patient was the eldest of6 siblings, 5 males and a female, of whom the fourth brother(age 13) also had PLS with OCA1 and the youngest sister(age 3) had only PLS. A sixth sibling, a brother, was also analbino but died at the age of 2 years because of respiratory tractinfection. The parents, who are second cousins, and the secondand third brothers were free of similar oral and cutaneouspathology. Pregnancy, labor, and delivery were normal.According to his mother, the skin of the palms and soles wasred and rough at birth. The primary teeth had erupted at theexpected age. At the age of approximately 1.5 years, thegingiva around the erupted teeth became inflamed and sorefollowed by looseness and migration of teeth. A few monthslater, the teeth started to exfoliate one after another and at theage of 5 years he was completely edentulous. Cutaneouslesions became markedly evident at the age of 1 year, in which

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the skin of the palms and soles was red, thickened, and painful.At the age of 6 years, the permanent teeth started to erupt andthe cycle of destructive periodontitis and aggravated palmo-plantar hyperkeratosis was repeated. The patient lost all of histeeth by the age of 15 years. Therewas a history of hospitaliza-tion at the age of 5 years because of severe pneumonia.

Physical examination revealed that the development of thepatient, both physically andmentally, was within normal limits(height 170 cm,weight 63 kg). His hearingwas normal. He hadsnow-white hair, erythema of the face with pustules, and blue-gray irides (Fig 1). Visual acuity was poor and the patientexperienced photophobia and rotary movements of the eyes.Ophthalmoscopic examination showed lack of retinal pig-mentation, prominent choroidal vessels, foveal hypoplasia,and a pale optic disc. These findings are consistent with classicOCA1 (tyrosinase negative type). The skin on the palms of thehands (Fig 2) and on the soles of the feet (Fig 3) showed well-demarcated hyperkeratotic, erythematous, scaly, and fissuredlesions with a spillover onto the dorsal surface of the hands(Fig 4) and ankles (Fig 5). The knees and elbows were alsoaffected, but to a less severe degree than the palmoplantarsurfaces. The skin lesions aggravated during cold weather andthe patient experienced pain on walking.

Intraoral examination revealed that only the maxillarythird molars were present. The gingiva around the teeth wasinflamed, swollen, and tender while the oral mucosa coveringthe edentulous area appeared normal. The teeth were mobilewith pathological periodontal pockets from which pus exudedupon probing. Panoramic radiograph showed gross atrophy ofthe alveolar bone. Skull radiographs (PA) showed ectopiccalcification of the dura (Fig 6).

Histological examination of the skin lesion disclosedhyperkeratosis, focal parakeratosis, hypergranulosis, acantho-sis, and irregular epidermal rete pegs. In papillary dermisvessels, proliferation and perivascular mononuclear infiltrateare present (Fig 7).

Mutation of CTSC and tyrosinase genes were tested bydirect sequencing of both forward and reverse standards on anABI 373 or 377 sequencer using the Applied Biosystems ABIPRISMA BigDye Terminator Cycle Sequencing ReadyReaction Kit. The primer sequences for CTSC and tyrosinase

Fig 2. Palms of the hands showing diffuse hyperkeratosis,erythematous, scaly, and cracked lesions (Case 1).

were reported previously.16 Results indicate that the probandsaffected by both PLS and OCA1 were homozygous forc.318-1G>A mutation in CTSC and c.817G>C/p.W272Cmutation in tyrosinase gene. The sister who had PLS onlywas homozygous for the same CTSC mutation but heterozy-gous for tyrosinase gene. The 2 affected genes lie closetogether on chromosome bands 11q14.2-14.3.

Hematologic examination included differential white cellcount, erythrocyte count, hemoglobin, glucose and serumcalcium, phosphate, alkaline phosphatase, immunoglobulins(IgM, IgA, IgG), triglycerides, cholestrol, and albumin; all ofwhich were normal values.

Clinical treatment comprised the extraction of mobilemaxillary third molars and construction of complete upper andlower dentures. Five years after denture delivery, the patientreturned to our clinic with a complaint of loose dentures. Onexamination, he exhibited severe loss of bone support. Therewas remission of the skin lesions on the knees and elbows, butnot on the palmar and plantar surfaces.

Case 2A 13-year-old boy, brother to Case 1, presented with

a complaint of teeth mobility and swollen and sore gingivaewith difficulty chewing.

Fig 3. Soles of the feet showing extensive hyperkeratosissimilar to those of the palms. Crustations and fissures areevident (Case 1).

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Medical and dental histories were, in general, similar toCase 1. He was born after an uneventful full-term pregnancy.A history of recurrent tonsillitis and respiratory infectionswas reported. His primary teeth started to erupt at the age of6 months and he had his full dentition by the age of 2.5 years.After teeth eruption, the gingivae became red and swollen, andbled easily, followed by teeth mobility and exfoliation. Allprimary teeth were lost by the age of 4 years. According to hismother, the skin lesions were first noticed at birth, when thepalms and soles appeared red and roughened. The permanentteeth erupted within a normal chronological time. A few yearslater, some of the teeth began to exfoliate.

Physical examination revealed a normally developed sub-ject with albinism presentation similar to that of Case 1. Hehad erythematous, hyperkeratotic, scaly, and cracked lesionson the palms and soles. The skin lesions were also obvious onthe knees and elbows, but less prominent than on the hands andfeet. Seasonal variations of skin lesions were also noted in thispatient. Onychogryphosis was evident. He had purulentcutaneous infection (pyoderma) on the thighs.

Intraoral examination showed that the following teeth hadexfoliated: 16, 22, 26, 32, and 46 (FDI numbering system). Thegingivae around the teeth were red, swollen, hemorrhagic, and

Fig 4. Hyperkeratotic lesions on the dorsal sides of the palms(Case 1).

Fig 5. Mild hyperkeratosis affecting the heel (Case 1).

tender with a gingival abscess present around the maxillaryincisors (Fig 8). Plaque accumulation was evident. There weregeneralized deep periodontal pockets ranging from 4 to 7 mmin depth. The teeth were sensitive to touch and upon slightpressure pus exuded from periodontal pockets and periodontalabscesses. Almost all of the teeth showed signs of mobilityranging from grade 2 to 3 and were malposed. Offensivehalitosis was present. Submandibular lymph nodes werepalpable and painful. Follow-up observations indicated thatthe severity of periodontitis coincided with the exacerbationof the cutaneous lesions.

Radiographic examination (panoramic) revealed severealveolar bone loss around the teeth with no root resorption. Thislosswas particularly extensive on themandibular left firstmolars,where virtually no alveolus remained (Fig 9). Skull radiographswerewithin normal and did not reveal ectopic calcification of thefalx cerebri or tentorium. Hematologic parameters tested, asstated in Case 1, were within the normal limits.

Treatment was initiated with tetracycline administeredorally (250 mg every 6 hours for 1 month) combined withperiodontal therapy consisting of mechanical and chemical(0.2% chlorhexidine mouth rinse) plaque control, scaling androot planing, and oral hygiene instructions. The periodontalcondition was temporarily improved. Six years later, thepatient was seen again (at age of 19). All his teeth wereexfoliated, except the maxillary left third molar.

DISCUSSIONPLS is inherited and appears to follow an autosomal

recessive pattern; that is, both parents are phenotypi-cally healthy and there is no family history of thedisease, other than the affected person and possiblysome siblings. Both parents must carry the autosomalgene for the syndrome to appear in their offspring.When2 such carriers mate, there is a 25% chance of produc-ing affected offspring. In our family, 2 brothers of the6 siblings had PLS and OCA1, a sister had only PLS,and an albino brother had died at 2 years of age withunknown history of PLS involvement.

Fig 6. Skull radiograph showing ectopic calcification(arrows) of the dura (Case 1).

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The concurrence of 2 rare recessive genetic con-ditions, PLS and OCA1, strongly suggested that thegenes underlying the conditions are located very closetogether on the same chromosome. This was evident inthe genetic analysis of our patients and an Egyptianprobandwith similar clinical features.40 In 1989, Tomitaet al41 reported that mutations in the tyrosinase gene atchromosome location 11q14.3 were the cause of OCA1.In 1999, Toomes et al17 identified the genetic cause ofPLS as a result of loss-of-function mutations in theCTSC. They revealed all affected individuals in 8familieswerehomozygous, theparentswereheterozygous,and the other nonaffected members were either hetero-zygous or homozygous. Nusier et al42 have reported thesame PLS mutation, IVS3-1G>A, in another JordanianPLS family in which the affected individuals did nothave albinism. A review of the literature on the numberof mutations of CTSC shows a total of 40 mutationsof this gene, with the majority of mutations located inexons 5 to 7.16,17,19,42-45 An interesting feature of theCTSC is that mutations of this gene also result in 2

Fig 7. Skin lesion revealed hyperkeratosis, focal paraker-atosis, hypergranulosis, and acanthosis of epidermis. Inpapillary dermis, vessel proliferation and mononuclear in-filtrate are present (Case 1).

other closely related conditions: the Haim-Munksyndrome18,43 and prepubertal/aggressive periodonti-tis.44,45 A common clinical manifestation in all 3conditions is severe early-onset periodontitis. Haim-Munk syndrome is an ethnically specific disorderdescribed only in Jews of South Indian origin (the socalled ‘‘Cochin Jews’’). It is a recessive inheritance traitof congenital diffuse palmoplantar keratoderma associ-ated with periodontitis, onychogryposis, arachnodac-tyly, and recurrent abscess formation. Thus, PLS,prepubertal periodontitis, and Haim-Munk syndromeseem to be allelic variants. Mutation in the CTSC,however, had not been identified in patients with late-onset PLS.46

The 2 brothers in the present family exhibited the2 main diagnostic features of the PLS: palmoplantarhyperkeratosis and early onset of generalized rapidlyprogressing periodontitis. In addition, they also hadtypical features of OCA1; a disorder due to genetic

Fig 8. Generalized severe gingival inflammation with gingi-val abscesses associated with migration of teeth (Case 2).

Fig 9. Panoramic radiograph showing generalized alveolarbone loss and migration of teeth with no evidence of rootresorption. Note a large dentoalveolar abscess around themandibular left first molar (Case 2).

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defect in tyrosinase—the enzyme responsible formetabolizing and converting tyrosine to melanin. Allvarieties of albinism have an autosomal recessivepattern of inheritance, with the exception of X-linkedocular albinism. Both sexes are affected equally, witha prevalence of 1:39 000 among American whites.47

Our patients showed the following common features.Skin lesions: (1) palmoplantar hyperkeratosis appearedas well-demarcated, erythematous, scaly lesions, whichundergo cracking, deep fissuring, and crustation; (2)lesions exacerbate at times of increased severity ofperiodontitis; (3) lesions aggravate during the coldcondition; (4) lesions subside after exfoliation of thedentition; and (5) biopsy showed hyperkeratosis, hyper-granulosis, and acanthosis. Oral aspects: (1) teethdevelopment, form, and eruption were normal; (2) attimes of tooth eruption the gingiva becomes red andedematous, and shortly before tooth eruption the gingivabecomes red and edematous and after eruption it swellsand bleeds easily; (3) rapidly progressing periodontitisassociated with pathologically deep pockets, severealveolar bone loss, and teeth mobility; (4) plaqueaccumulation, gingival abscesses, purulent exudates,offensive halitosis; and (5) after exfoliation or extractionof teeth, the oral mucosa resumes the normal appear-ance. Both patients also showed increased susceptibilityto infection (recurrent tonsillitis, respiratory tractinfections, and pyoderma), ectopic intracranial calcifi-cation, submandibular lymphadenopathy, erythema ofthe face, and onychogryphosis, but free from otheroccasional manifestations of this syndrome such ashyperkeratosis of cheeks, lips, and thighs. Ectopicintacranial calcification was evident in Case 1. Incontrast to the present findings and other reports,2,4-6,8

Ullbro et al11 found no association between the degreeof palmoplantar hyperkeratosis and the severity ofperiodontitis, suggesting that these 2 major componentsof PLS are unrelated to each other.

PLS should be differentiated from other conditionsshowing similar oral or cutaneous clinical features.Diseases with oral manifestations such as acrodynia,hypophosphatasia, histiocytosis X, leukemia, cyclicneutropenia, and Takahara’s syndrome are associatedwith periodontitis and premature loss of teeth. PLS wasdifferentiated from them by the presence of the palmo-plantar hyperkeratosis. PLS can also be distinguishedfrom palmoplantar keratoderma of Unna Thost, mal deMeleda, Howel-Evans syndrome, keratosis punctata,keratoderma hereditarium mutilans (Vohwinkel’s syn-drome), and Greither’s syndrome as these entities arenot associated with periodontopathy.

Efforts to treat PLS have been traditionally directedeither to reducing the hyperkeratotic skin lesions orhalting the periodontal destruction. The therapeutic goal

for skin lesions is to remove sufficient callus to preservefunction and to relieve pain over pressure points fromfissures and cracks. Treatments were based on topicalapplication of lubricants, keratolytic agents such as 6%salicylic acid (Keralyt gel) or 7% to 10% lactic acid inpetrolatum, anti-inflammatory steroids, and antibiotics.Gention violet, Castellani’s paint, or flexible collodionwas used to seal painful fissures. Local betamethasoneand 3% salicylic acid ointment combined with systemicmethoxypsoralen and UVA radiation were also tried butwith limited success.46 The therapeutic effects of thesetreatments were not satisfactory. Oral retinoids (analogsof vitamin A) that have proven effective in the treatmentof various types of keratinizing disorders have beeninstalled in the treatment of PLS. Etretinate (a syntheticretinoid of acitretin; Tigason [Tegison in the UnitedStates] is available in 10- and 25-mg capsules) has beensuccessfully used for treatment of palmoplantar kerato-derma8,9,48 and periodontitis49-51 in PLS.

There are controversial reports regarding the effec-tiveness of systemic antibiotics combined with mechan-ical and chemical periodontal methods for treatmentof periodontal components of PLS. Tinanoff et al20

reported that administration of tetracycline (250 mgtid for 28 days) followed by erythromycin (400 mg tidfor 28 days) was ineffective in halting periodontitisin this syndrome. Failure or partial success of tetracy-cline therapy has been reported in many studies,4,38,48

including the present one. Glenwright and Rock51

treated a case with penicillin, tetracycline, and metro-nidazole at different times over 8 years but did not arrestperiodontal destruction of primary and permanent teeth.De Vree et al52 followed 2 PLS siblings for 15 years andreported that continuous and intensive periodontaltreatment along with systemic metronidazole (250 mg/qid for 5 days during periods of exacerbations) wassuccessful in maintaining a number of permanent teethin one of the patients but not able to prevent completetooth loss in the other sibling. Preus and Gjermo53

reported successful treatment of periodontitis over a 4.5-year follow-up study period in 2 siblings receivingtetracycline intermittently (2-4 weeks) in periods ofexacerbation and continuously during the last 2 yearsof the study. They suggested that the combination ofcareful plaque control, periodontal surgery, antibiotictherapy, and A actinomycetemcomitans monitoringwas important in successful treatment. Brown et al37

reported a favorable response for a patient using tetra-cycline (250 mg/qid for 3 weeks) combined with rootplaning and scaling. Eronat et al,54 treated 2 cases(aged 7 and 9 years) with amoxicillin/clavulanic acid(Augmentin) at a dosage of 1 g per day for 10 days every6 months. No tooth loss was observed in either patientafter more than 2 years of follow-up. On the contrary,

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Bullon et al23 found no response to amoxicillin withclavulanic acid (500 mg/tid for 15 days) of a patienttreated at regular intervals for 22 months. Successfultreatment of PLS periodontitis using both amoxicillinand metronidazole (250 mg/tid for10 days or 6 weeks)followed by supportive periodontal therapy every 3 to4 months was recently reported.55-57

These conflicting findings on PLSmanagement couldbe related to the severity of the condition, the age atwhich treatment was instituted, timing and duration ofantibiotic therapy, professional supervision, follow-upsupportive treatment, and home care. The complexetiopathogenesis of PLS renders that successful treat-ment of the periodontal component of this syndromeremains challenging. However, 2 promising approachesfor the management of PLS periodontitis have beendocumented, one aimed at eradication of A actino-mycetemcomitans with a meticulous professional andindividual oral hygiene regimen, and another usingsynthetic retinoids. Recently, osseointegrated implantshave been successfully used in PLS patients.58,59

In conclusion, 2 cases of coinheritance PLS andOCA1 are presented for the first time. Theymanifest thetypical features of these disorders in addition to othersporadic findings. The present cases had a close parentalconsanguinity, common clinical features, and shared thesamemutations of CTSC and tyrosinase genes.We hopethat this study will help to identify other PLS variantsand to investigate the association between suchvariations and mutations of the CTSC causative gene.

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Reprint requests:

Faiez N. Hattab, BDS, PhD

PO Box 31664

Doha

State of Qatar

f_hattab@hotmail.com