American Journal of Medical Genetics 79:134–139 (1998)

Sublocalization of the Papillon-Lefevre Syndrome

Locus on 11q14−q21
Thomas C. Hart,1,2* Donald W. Bowden,3 Khaled A. Ghaffar,4 Wei Wang,1 Christopher W. Cutler,5
Irfan Cebeci,6 Ahmet Efeoglu,6 and Erhan Firatli6
1
Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina
2
Department of Dentistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
3
Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina
4
Department of Oral Diagnosis and Periodontology, Ein-Shams University, Cairo, Egypt
5
Department of Periodontics, Baylor College of Dentistry, Dallas, Texas
6
Department of Periodontology, University of Istanbul School of Dentistry, Istanbul, Turkey

Papillon-Lefevre syndrome (PLS) is an au- INTRODUCTION

tosomal recessive form of palmoplantar ec-
todermal dysplasia, characterized by pal-
moplantar hyperkeratosis and severe early-
onset periodontitis. The presence of severe
periodontitis distinguishes PLS from other
palmoplantar keratodermas. As part of our
efforts to study the genetic basis of peri-
odontitis susceptibility, we performed a ge-
nome-wide search to identify major loci for
PLS in 44 individuals (14 affected) from 10
consanguineous PLS families. We have iden-
tified evidence for linkage of a PLS gene on
11q14–q21. A maximum two-point logarithm
of the odds (LOD) score of 8.24 was obtained
for D11S1367 at a recombination fraction of
␪ = 0.00. Multipoint analysis resulted in a
LOD score of 10.45 and placed the gene for
PLS within a 4–5 cM genetic interval. This
genetic interval, flanked by D11S4197 and
D11S931, contains more than 50 cDNAs and
200 expressed sequence tags (ESTs). This re-
finement of the candidate region for a PLS
gene is in agreement with other recent re-
ports of linkage for PLS to chromosome
11q14–q21 and should help in identification
of the gene for PLS. Am. J. Med. Genet. 79:
134–139, 1998. © 1998 Wiley-Liss, Inc.
KEY WORDS: linkage; Papillon-Lefevre
syndrome; periodontitis; pal-
moplantar keratoderma;
chromosome band 11q
Contract grant sponsor: National Institute for Dental Re-
search; Contract grant number: R29DE10990 and R03 DE 10563.
*Correspondence to: Thomas C. Hart, D.D.S., Ph.D., Wake For-
est University School of Medicine, Department of Pediatrics, Sec-
tion on Medical Genetics, Medical Center Boulevard, Winston-
Salem, NC 27157-1093. E-mail: thart@bgsm.edu
Received 10 March 1998; Accepted 20 May 1998
© 1998 Wiley-Liss, Inc.
In 1924, Papillon and Lefevre described two sibs
from a first-cousin mating, with a condition character-
ized by diffuse transgradient palmoplantar keratosis
and the premature loss of the deciduous and perma-
nent teeth. The condition became known as Papillon-
Lefevre syndrome (PLS) (Mendelian Inheritance in
Man no. 245000) and subsequently more than 250
cases have been described [Gorlin et al., 1964]. The
hereditary palmoplantar keratodermas (PPKs) com-
prise a heterogeneous group of skin disorders, and clas-
sifications based on morphology and distribution of the
hyperkeratosis, histopathological findings, mode of in-
heritance, and associated clinical findings resulted in
considerable confusion [Griffiths et al., 1992; Zemtsov
and Veitschegger, 1993]. The identification of specific
keratin gene mutations in several forms of PPK per-
mitted development of a more reliable classification
[Lind et al., 1994]. Recently, Stevens et al. [1996] de-
scribed an alternative classification of the primary
PPKs, suggesting that PLS is one of 19 palmoplantar
ectodermal dysplasias. PLS is distinguished from the
other palmoplantar ectodermal dysplasias by the se-
vere periodontitis that follows eruption of the decidu-
ous teeth and reoccurs with eruption of the permanent
teeth. This rapidly destructive periodontitis usually re-
sults in premature loss of all teeth. The PPK is usually
diffuse, but focal callosities have been reported in the
creases with punctate lesions over the palms, and ex-
tension onto the elbows and knees has been reported.
Recurrent infections have been reported to occur in ap-
proximately 20% of cases [Haneke et al., 1979; Haneke,
1975]. It is unknown whether the severe periodontal
destruction seen in PLS is a manifestation of increased
susceptibility to specific microbial infections or a gen-
eral susceptibility to infection by Gram-negative mi-
crobes that are commonly found in the gingival sulcus
surrounding the teeth [Preus, 1988; Hart, 1996].
With the genetic mapping of PPK conditions to at
least five distinct genetic loci, it has become apparent
that the PPKs are heterogeneous [Stevens et al., 1996].
After excluding the Type 1 keratin gene family on chro-

mosome 17 and the Type 2 keratin gene family on chro-
mosome 12 as candidate loci for PLS in these 10 fami-
lies [Firatli et al., 1997], we began a genome-wide
search for the gene(s) responsible for PLS. Utilizing a
homozygosity linkage mapping approach, we have
identified linkage for PLS to 11q14–q21.
MATERIALS AND METHODS
Ascertainment of Families
Ten families were identified when the index case pre-
sented for treatment of severe, early-onset periodontal
disease. Fig. 1 shows pedigrees of affected individuals.
Eight of the families are from Turkey (families 1-8),
and 2 are from Egypt (families 9 and 10). Informed
consent was provided by all participants prior to inclu-
sion into the study. All available relatives were exam-
ined by a dentist and a dermatologist. To be classified
as affected, an individual needed to show clinical evi-
dence of severe early-onset periodontitis (radiographic
evidence of >50% alveolar bone loss, and/or at least four
teeth with periodontal probing depth of at least 5 mm);
palmoplantar hyperkeratosis had to be present on the
palms of the hands and or soles of the feet.
DNA-Marker Analysis
Peripheral venous blood (7.5 ml) was obtained by ve-
nipuncture. Genomic DNA was extracted using the
QIAmp blood kit (QIAMP, Inc., Valencia, CA) accord-
ing to manufacturer’s protocol. An initial genome-wide
scan was performed using the Weber version 6A low-
density markers (Research Genetics, Huntsville AL)
Fig. 1. Pedigrees of 10 families segregating the PLS phenotype. Squares and circles represent males and females, respectively. Affected individuals
are represented by filled symbols and nonaffected family members by open symbols. Consanguineous relations are shown by double lines. Numbered
individuals were examined clinically and sampled.
Sublocalization of PLS to 11q14–q21 135
using standard techniques for polymerase chain reac-
tion (PCR) amplification with radioactively labeled (␥-
32P) primers according to manufacturer’s protocol us-
ing a PCR 9600 thermocycler (Applied Biosystems,
Foster City, CA) as previously reported [Hart et al.,
1997]. After identification of a linkage relationship to
D11S901 on chromosome 11q, a high-density array of
DNA markers was selected from available genetic
maps of the region. These maps included the Coopera-
tive Human Linkage Center chromosome 2 version
v8c7 integrated marker map (www.chlc.org) and the
Genethon Map [Gyapay et al., 1994]. Following PCR
amplification, individual samples were separated on a
6% polyacrylamide gel electrophoresis urea gel (30 W,
1500 V). An M13 sequencing ladder (Sequenase kit,
USB, Cleveland, OH) was loaded onto each gel to per-
mit sizing of individual alleles. Following electrophore-
sis, gels were wrapped in cellophane and exposed in a
phosphorimaging cassette for 15 min, and scanned
(Molecular Dynamics, Inc., Sunnyvale, CA). Alleles
were scored and genotype data entered into a pedigree
file for linkage analysis.
Linkage Analysis
LOD scores were generated assuming autosomal re-
cessive inheritance with 95% penetrance. The mutant
allele frequency was taken as 0.0001. Marker allele
frequencies were assumed to be uniformly distributed.
The families were of Turkish and Egyptian origin, and
allele frequencies for the markers used in these popu-
lations, are unreported. Two-point and multipoint link-
136 Hart et al.

age analyses were carried out using the MAPMAKER/ TABLE I. Combined Pairwise LOD Scores at Standard
HOMOZ [Kruglyak et al., 1995] software package, Recombination Rates for Chromosome 11q Markersa
which allows rapid multipoint mapping of disease LOD score (Z) at
genes in nuclear pedigrees. The order of genetic mark- recombination fraction (␪)
ers on chromosome 11 was evaluated with CRI-MAP Locus 0.00 0.10 0.20 0.30 0.40
[Lander and Green, 1987] analysis of available genetic
D11S916 −16.68 0.53 0.94 0.85 0.67
mapping data from Centre d’Etude du Polymorphisme
D11S937 −11.41 1.22 1.28 0.99 0.70
Humain (CEPH) families [Dib et al., 1996] (http:// D11S918 −12.35 0.84 1.01 0.83 0.61
landru.cephb.fr/). Genotype data for the markers was D11S911 −2.71 3.07 2.51 1.87 1.33
downloaded and the BUILD option was used to create D11S901 1.88 3.26 2.47 1.75 1.19
a map. The highest-likelihood map was compared to D11S4187 −0.28 4.02 3.15 2.27 1.56
alternative orders of loci using the FIXED option in the D11S4135 3.47 4.09 2.92 1.92 1.19
D11S4147 2.15 5.64 4.31 3.05 2.08
multipoint homozygosity mapping analysis. Using a
D11S4197 2.57 3.72 2.76 1.92 1.29
criterion of LOD minus 1.0, a 95% confidence interval D11S1887 6.52 4.95 3.54 2.43 1.61
was determined [Conneally et al., 1985]. D11S1367 8.24 6.38 4.67 3.25 2.19
D11S1780 3.81 5.04 3.83 2.73 1.86
RESULTS D11S1979 7.64 5.90 4.33 3.04 2.08
Clinical Findings D11S931 −2.79 3.29 2.57 1.83 1.25
D11S4675 3.35 4.86 3.68 2.62 1.80
Forty-four persons available for study were exam- D11S1332 3.06 4.12 3.07 2.14 1.43
ined. Fourteen individuals were classified as affected D11S1311 1.27 3.01 2.34 1.48 1.16
with PLS based on a significant history/presence of se- D11S919 −0.66 2.90 2.18 1.46 0.93
vere early-onset periodontitis and palmoplantar hyper- D11S917 −18.89 −0.01 0.61 0.56 0.40
kerotosis. In none of the 10 families did a parent have a
The shared region of the nonrecombinant loci is shown in bold.
a history for early-onset periodontitis or palmoplantar
keratosis, suggesting that all parents were carriers,
nation events by haplotype reconstruction. The mini-
but none was affected. Parental consanguinity was pre-
mum interval containing the PLS locus, defined by re-
sent in all 10 families. Equal numbers of males and
combination between chromosome 11q STRPs and the
females were affected (7 males, 7 females). These find-
PLS locus, is shown for each family in Table III. The
ings are consistent with autosomal recessive transmis-
cosegregating segment in which recombination was not
sion of PLS in these families. No family members
detected was flanked by the markers D11S4197 and
showed evidence of partial expression of PLS, as has
D11S931. Multipoint linkage analysis using 19 STRP
been reported to occur infrequently in PLS [Kotzot and
markers yielded a maximum multipoint LOD score of
Pfeiffer, 1993; Bullon et al., 1993; Soskolne et al., 1996].
10.45 at D11S1367. Utilizing a criterion of LOD minus
Both early-onset periodontitis and palmoplantar hyper-
1.0 to determine the 95% confidence interval, the PLS
keratosis were present in all 14 affected individuals.
locus lies in a 4–5-cM genetic interval flanked by
Two-Point Linkage D11S4197 and D11S931 (Fig. 2).
Utilizing a genome-wide search strategy, all indi-
viduals were genotyped for a low-density short tandem DISCUSSION
repeat polymorphism (STRP) locus screening panel Findings of this analysis confirm recent reports of
(Weber version 6a). Two-point LOD scores supporting linkage for PLS to chromosome 11q14–q21 [Laass et
linkage were obtained for only one STRP locus, al., 1997; Fischer et al., 1997]. All affected individuals
D11S901 (Zmax ⳱ 3.58; ␪ ⳱ 0.04). All individuals were
then genotyped for a high-density array of markers
TABLE II. Family-Specific LOD Scores for D11S1367 Showing
that flanked the genetic region surrounding D11S901.
All Families Consistent With Linkage to D11S1367 and No
Two-point LOD scores for markers spanning the can- Evidence of Any Family Not Linked to This Marker, Suggesting
didate interval are summarized in Table I. The great- a Common Linkage to All Families With No Suggestion of
est two-point LOD score was obtained for D11S1367 Genetic Heterogeneity
(Zmax ⳱ 8.24; ␪ ⳱ 0.00). Two additional markers
Recombination fraction (␪)a
showed complete evidence for linkage with Zmax at ␪
⳱ 0.00 (D22S1887, Zmax ⳱ 6.82, ␪ ⳱ 0.00; D11S1979, Family 0.00 0.1 0.2 0.3 0.4 Zmaxb
Zmax ⳱7.64; ␪ ⳱ 0.00). No support for linkage was 1 0.70 0.55 0.41 0.30 0.20 0.70
found for any marker outside the 11q14–q21 genetic 2 0.70 0.53 0.38 0.25 0.16 0.70
interval (no LOD score > 1.0). All families appeared 3 0.18 0.13 0.08 0.05 0.02 0.18
4 0.53 0.38 0.25 0.16 0.10 0.53
linked to the 11q14–q21 chromosomal region, with no
5 1.18 0.93 0.69 0.47 0.31 1.18
evidence for heterogeneity. To illustrate this, Table II 6 0.93 0.70 0.50 0.33 0.21 0.93
shows two-point LOD scores for all 10 families with the 7 0.68 0.53 0.40 0.28 0.20 0.68
STRP marker D11S1367. The Zmax for each family 8 0.63 0.49 0.35 0.25 0.17 0.63
was at ␪ ⳱ 0.00 for this locus. 9 0.82 0.65 0.50 0.36 0.26 0.82
10 1.88 1.47 1.10 0.77 0.52 1.88
Haplotype and Multipoint Linkage Analysis Total Zmax 8.23
In order to define the smallest interval containing a
Two-point LOD scores for D11S1367 and PLS.
the PLS locus, individuals were analyzed for recombi- b
Theta at Zmax for all families was at 0.00.
 Sublocalization of PLS to 11q14–q21 137

TABLE III. Summary of Family-Specific Recombination Between 11q STRPs and the PLS Locusa
Family no.
STRP 1 2 3 4 5 6 7 8 9 10
D11S916 R R R N R N N N − R
D11S911 R − N N − N N N − −
D11S937 R R − N R N N N − R
D11S918 R − − N R − N N − −
D11S901 N N N N − − − N R R
D11S4187 − N − N N − N − − R
D11S4135 − N − N N N − − R R
D11S4147 N N N N N N N N R −
D11S4197 − N N N − − − N R −
D11S1887 N − − N N − N N N −
D11S1367 − N − N N N N − − −
D11S1780 − N N N N − N − N N
D11S1970 − N N − N − − N N −
D11S931 N N N N R N − − R −
D11S4675 N N N N R − − − R −
D11S1332 − − − − − N N − − R
D11S1311 R N N N − − − − − R
D11S919 − − N N R − N N − R
D11S917 R R R N R − − − R R
a
R, recombinant; N, nonrecombinant; −, uninformative or partially informative meiosis. The shared region of the nonrecombinant loci is shown in bold.

from the 10 families identified in the present report
appear to share common alleles consistent with inher-
itance of two copies of the PLS gene ‘‘identical by de-
scent’’ from a common ancestor in each family. How-
ever, the lack of a common haplotype reasons against a
recent, and possibly a common, allelic mutation in
these families. Recent linkage studies have identified a
genetic candidate region bounded by the STRP loci
D11S1761 and D11S1342, a candidate region of ap-
proximately 9 cM. Although Fischer et al. [1997] re-
ported the candidate region as between D11S901 and
D11S4175, their data show that recombinants were
identified with markers D11S1761 and D11S1342,
markers that lie outside the candidate region from
D11S901 to D11S4175. Therefore, the PLS candidate
region they defined is more accurately defined as the
9-cM region (based on their genetic map) from
D11S1761 to D11S1342. Results of our haplotype re-
construction and multipoint analysis refines the PLS
candidate region to a 4–5-cM genetic distance within
the previously reported candidate region. This refined
candidate region is bounded by D11S4197 and
D11S931. The precise size of the candidate region is not
clear. Published maps of 11q have the order D11S4197-
D11S4147-D11S1887-D11S1780-D11S1367-
D11S1979-D11S931 [Gyapay et al., 1994] in the candi-
date region, which would place the PLS gene in a 2–3-
cM interval. However, our CRI-MAP analysis of the
available genetic mapping data from CEPH families
(http://landru.cephb.fr/) with these markers shows that
the order D11S4197-D11S4147-D11S1887-D11S1367-
D11S1780-D11S1979-D11S931 is 69-fold more likely,
which would increase the PLS interval to 4–5 cM. Al-
though we have reduced the genetic map interval for
PLS, additional development of correlated physical and
genetic maps of the region will be necessary to define
precisely the size of the interval. This candidate region
is a gene-dense region of the genome and contains ap-
proximately 20 genes, 50 cDNAs, and 200 ESTs. This
reduction of the candidate region should help to reduce
the number of potential candidate genes/ESTs for PLS.
The hereditary PPKs are a heterogeneous group of
skin disorders characterized by hyperkeratosis (thick-
ening of the stratum corneum, the uppermost layer of
the epidermis) primarily of the palms and soles. The
recent classification system of Stevens et al. [1996] for
PPK conditions proposes 19 different types of PPK with
ectodermal dysplasia. PLS is classified as Type IV of
the palmoplantar ectodermal dysplasia group. The se-
vere early-onset periodontitis with resultant loss of
teeth is the primary trait that distinguishes PLS from
other conditions in the ectodermal dysplasia group,
with the exception of the Haim-Munk syndrome [Haim
and Munk, 1965], which may be a variant of the PLS
[Gorlin et al., 1990]. Preus has suggested that the peri-
odontal component of PLS may simply be a casual as-
sociation with PPK, so that individuals without peri-
odontal destruction will be diagnosed with a different
form of PPK, and those with periodontal destruction
will be diagnosed with PLS [Preus, 1988]. Although
apparent partial expression of PLS has been reported
[Kotzot and Pfeiffer, 1993; Bullon et al., 1993; Soskolne
et al., 1996], the apparent complete segregation of se-
vere early-onset periodontitis with palmoplantar hy-
perkeratosis in the 19 families reportedly linked to the
chromosome 11q14 region in three independent studies
to date suggests that the periodontal disease compo-
nent is not simply an occasional associated finding
[present report, Laass et al., 1997; Fischer et al., 1997].
Destruction of the oral tissues in PLS is somewhat
unique; the process is characterized by severe inflam-
mation of the gingival/periodontal tissues, destruction
of collagen fibers of the periodontal ligament, and al-
veolar bone loss, resulting in loss of the teeth. The on-
set is reported to begin at the time of eruption of the
primary dentition through the periodontium. After ex-
foliation of the primary dentition, the gingival tissues
return to a noninflamed state. However, upon eruption
138 Hart et al.
Fig. 2. Multipoint LOD score calculations between the PLS phenotype
and nineteen chromosome 11q markers. The multipoint LOD score is rep-
resented on the x-axis. The DNA marker loci tested are identified numeri-
cally as follows: 1 ⳱ D11S916, 2 ⳱ DS11S911, 3 ⳱ D11S937, 4 ⳱
D11S918, 5 ⳱ D11S901, 6 ⳱ D11S4187, 7 ⳱ D11S4135, 8 ⳱ D11S4147, 9
⳱ D11S4197, 10 ⳱ D11S1887, 11 ⳱ D11S1367, 12 ⳱ D11S1780, 13 ⳱
D11S1979, 14 ⳱ D11S931, 15 ⳱ D11S4675, 16 ⳱ D11S1332, 17 ⳱
D11S1311, 18 ⳱ D11S919, and 19 ⳱ D11S917. Relative genetic distances
are in cM.
of the permanent dentition, the cycle of severe gingival
inflammation, alveolar bone loss, and tooth exfoliation
recurs. Usually, all permanent teeth with the exception
of the third molars are affected [Haneke, 1979]. When
the teeth are not present, gingival inflammation is un-
remarkable, and destruction of the periodontium
ceases. The genetic defect in PLS appears to profoundly
alter host susceptibility to periodontal destruction. The
molecular basis for this increased susceptibility for
periodontal destruction is unknown.
Periodontal diseases are generally thought to result
from inflammation-driven destruction of the periodon-
tal tissues. Genetic factors appear to be significant
determinants of risk in several forms of periodontal
diseases, particularly some early-onset forms of peri-
odontal diseases [Hart, 1996]. Recently, genetic deter-
minants of inflammatory responses to Gram-negative
microbial infections have been associated with peri-
odontal disease susceptibility [Offenbacher, 1996;
Kornman et al., 1997]. Periodontitis has also been as-
sociated with systemic diseases (e.g., diabetes) and
with genetically inherited conditions that result in sig-
nificant susceptibility to microbial infections (e.g., leu-
kocyte adhesion deficiency and neutropenias) [Genco et
al., 1986]. The biologic basis for the increased propen-
sity for periodontal destruction in PLS is unknown, but
alterations of inflammatory cells, cellular response,
and structural integrity of epithelium have been re-
ported in PLS [Hart and Shapira, 1994]. Specific aber-
rations of epithelial integrity have been identified in
several PPKs [Stevens et al., 1996]. It is unknown
whether PLS results from a structural alteration in
epithelium, but it is possible that an epithelial defect,
perhaps of the junctional epithelium, may predispose
to microbial infections in the unique ecological and
structural tissues of this part of the periodontium. To
date, no genetic loci for periodontal diseases have been
linked to chromosome region 11q14–q21 [Hart and
Kornman, 1997]. Identification of the gene muta-
tions(s) responsible for PLS will permit elucidation of
the molecular basis of PLS. This should enable devel-
opment of effective, cause-based treatments for PLS.
Understanding the pathogenesis in PLS may also per-
mit identification of genetic factors important to peri-
odontitis susceptibility, particularly for the early-onset
forms of disease and forms of periodontitis resistant to
traditional therapies.
A number of potential candidate genes have been
localized to this region of chromosome 11q, including
several that could affect inflammatory cell response
and structural integrity of the epithelium. These in-
clude collagen-binding protein 2 (CBP2); keratin, hair
cuticle, ultrahigh-sulfur 1 (KRN1); tyrosinase (TYR);
esterase-A4 (ESA4); and two matrix metalloproteinase
(MMPs), MMP7 and MMP8. MMP8 is also called neu-
trophil collagenase, and it is of interest that aberrant
neutrophil function has been reported in PLS patients.
The pathogenetic basis of PLS must await identifica-
tion of the specific gene mutation involved. Refinement
of the candidate genetic region will permit identifica-
tion of those genes/ESTs that lie within the candidate
region to determine which are candidates for PLS.
ACKNOWLEDGMENTS
We thank Ruby Griffin for her assistance in manu-
script preparation.
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