The phenotypic overlap of syndromes associated with hereditary

gingival fibromatosis: follow-up of a family for five years

M. Cenk Haytaca and Onur Ozcelik,b, Adana, Turkey
CUKUROVA UNIVERSITY FACULTY OF DENTISTRY

Hereditary gingival fibromatosis (HGF) is characterized by the slowly progressive fibrous enlargement of
gingival tissue. It usually develops as an isolated disorder but can also be one feature of various syndromes. The
currently preferred terminology of these syndromes mainly describes the clinical features of the disorder without
identifying the cause. In this report, we present the 5-year follow up of a family with HGF and features of 3 previously
described syndromes: Jones syndrome, Zimmerman-Laband syndrome, and HGF-hypertrichosis syndrome. The 45year-old father had HGF, hypertrichosis, hearing loss, and short stubby fingers and toes with hypoplasia of the terminal
phalanges and hypoplasia of the nails on the thumbs. The features of 13-year-old son were almost identical to those of
his father except for hypertrichosis, but in addition he was mentally retarded. Although the 10-day-old son had HGF
and defective fingers, the mother and 7-year-old daughter were unaffected. Owing to the overlap of these syndromes,
we argue that the identification of the genetic pathways and mechanisms will be the most important factor in
classifying these disorders, with the phenotype playing a minor role. (Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 2007;103:521-7)

Hereditary gingival fibromatosis (HGF) is a rare disorder characterized by the slowly progressive, nonhemorrhagic, fibrous enlargement of gingival tissue.1,2 The
clinical presentation of HGF is variable in both the
distribution and the severity of expression.3,4 The hyperplastic gingiva may be localized or generalized,
usually with normal color and firm consistency with
abundant stippling.4,5 The enlargement usually begins
at the time of the eruption of the permanent dentition,
although it may occur during the eruption of deciduous
teeth or even at birth.3,6,7 HGF is reported under at least
25 different names in the literature, mainly referring to
generalized forms.8
HGF is usually seen as an isolated disorder9-12 but it
may also develop as one feature of several rare multisystem syndromes such as Zimmerman-Laband
(ZLS),13,14 Jones,15,16 Ramon,17 and Rutherford6 syndromes, Juvenile hyaline fibromatosis,18 systemic infantile hyalinosis,19 and mannosidosis20,21 (Table I). In
the comprehensive review by Hart et al.,3 more than 18
different genetic forms of HGF are presented with
highly variable systemic findings. On the other hand,
numerous case reports describe varying combinations
of the systemic manifestations, suggesting overlap between these genetic disorders.5,9,14,22,23
a

Associate Professor, Department of Periodontology.

Research Assistant, Department of Periodonology.
Received for publication Dec. 2, 2005; returned for revision Jan. 20,
2006; accepted for publication Feb. 16, 2006.
1079-2104/$ - see front matter
2007 Mosby, Inc. All rights reserved.
doi:10.1016/j.tripleo.2006.02.021

Genetic heterogeneity of HGF also exists by the

presence of both autosomal-dominant and autosomalrecessive inheritances.3 To date, several responsible
gene loci of isolated HGF have been identified at chromosomal locations of 2p21-p22,24 2p13-p16,10 and
5q13-q22.25. A mutation in the SOS1 gene, which has
been mapped to 2p21-p22, has recently been discovered.24 Hart et al.3 suggested that the isolated HGF may
result from a single gene mutation and the syndromic
forms may result from alterations of multiple genes or
a gene dosage effect.
This study presents HGF in a family with a combination of systemic findings which overlap 3 previously
described syndromes: Zimmerman-Laband syndrome,
Jones syndrome, and gingival fibromatosis-hypertrichosis syndrome.
CASE DESCRIPTION AND RESULTS
The family was first seen in June 2000. The father
(42 years old) was referred to the periodontology department with a complaint of gingival enlargement. His
medical history included moderate hearing deficit
which was diagnosed at age 14. He denied taking any
medication which may cause gingival enlargement or
deafness. Because his parents were deceased when he
was 3 years old he did not know if either of them had
a similar situation. He reported that he had had the
problem since childhood and gingivectomy, serial extractions, and a bridge fixed in the maxillary anterior
region at 20 years of age.
The extraoral examination revealed a broad nose,
thick floppy ears, thick eyelashes and eyebrows, short
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Haytac and Ozcelik

Table I. Conditions associated with gingival fibromatosis

Condition
Gingival fibromatosis3,9
Gingival fibromatosis and mental
retardation3,9,10
Gingival fibromatosis with
hypertrichosis3,11
Gingival fibromatosis with distinctive
facies3,12
Zimmerman-Laband syndrome3,13,14:
gingival fibromatosis with abnormal
fingers, fingernails, nose, and ears and
splenomegaly
Jones syndrome: gingival fibromatosis with
progressive deafness3,15,16
Ramon syndrome3,17
Rutherfurd syndrome: gingival hypertrophy
with corneal dystrophy3,6
Juvenile hyaline fibromatosis3,18
Systemic infantile hyalinosis3,19
Mannosidosis3,20,21

Findings
Gingival fibromatosis
Gingival fibromatosis and mental retardation
Gingival fibromatosis, hypertrichosis, mental retardation, muscular hypotonia
Gingival fibromatosis, macrocephaly, bushy eyebrows, synophys, hypertelorism,
dolynslantedpalpebral fissures, flat nasal bridge, hypoplastic nares, cupid-bow mouth, high
arched palate
Gingival fibromatosis, abnormal fingers, fingernails, nose, and ears, splenomegaly,
hepatomegaly, hyperextensible metacarpophalangela joints

Gingival fibromatosis, progressive sensorineural hearing loss

Gingival fibromatosis, cherubism, seizures, mental deficiency, hypertricosis, stunted growth,
juvenile rheumatoid artritis
Gingival hypertrophy, corneal opacity, mental retardation, failure of tooth eruption, aggressive
behavior
Gingival fibromatosis, multiple subcutaneous tumors, dysseborrhea, sclerodermiform atrophy,
whitish nodules, osteolytic and osteoclastic skeletal lesions
Gingival fibromatosis, thickened skin, focal skin nodularity, restricted movement, joint,
contractures, osteoporosis, failure to thrive
Gingival hypertrophy, deafness, muscle hypotonia, craniofacial dysmorphism, mental
retardation, immunoglobulin deficiency

stubby fingers and toes with hypoplasia of the terminal

phalanges, hypoplasia of the nails on the thumbs, and
mild hypertrichosis especially affecting the face and
upper limbs (Fig. 1).
Intraorally, there was generalized severe gingival
enlargement in both the mandible and the maxilla involving the palate. The gingiva was pink with a firm
and dense consistency covering the crowns of several
teeth (Fig. 2, A). Although there was no overgrowth of
gingiva in the edentulous posterior of the mandible, the
posterior maxilla was the most severely affected region,
with the bulky enlargement of maxillary tuberosities
contacting the mandibulardibler ridges (Fig. 3). There
was spacing of the teeth, which the patient stated as
having started about 5 years before. There were clinically observable root fragments that were embedded in
the overgrown tissue in the maxillary posterior (Fig. 3).
The amount of the enlarged gingival tissue could easily
be traced from the panoramic radiograph. The radiograph also showed the teeth and root fragments covered
by the gingiva (Fig. 4, A).
The son was 9 years old at the initial visit. His
medical history was remarkable in that he had mild
mental retardation and attended a special school. He did
not have a hearing deficit at that time. His extraoral
findings were almost identical to those of his father but
he did not have hypertrichosis. The intraoral examination revealed prolonged retention of primary teeth with
permanent first molars and mandibulardibler incisors

Fig 1. The extraoral view of the father with hypertrichosis,

prominent ears, hypoplasia of the terminal phalanges of the
fingers, and hypoplasia of the nail on the thumb.

only, which were partially erupted. The primary teeth

had no mobility. He also had pink firm overgrown
gingiva generalized in both arches, which prevented

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Haytac and Ozcelik 523

Fig 3. The initial intraoral view of the father in June 2000.

Note the severe enlargement on the tuberosities contacting
mandibler ridges and the root fragments in the overgrown
tissue.

Fig 2. The intraoral view of the father in 2000 (A), 2003 (B),
and 2005 (C). Note that the bridge on the anterior region has
been lost.

adequate lip closure (Figs. 5, A, and 6, A). There were

no signs of gingival inflammation. The radiographic
assessment revealed the presence of all permanent
teeth; however, the physiologic root resorptions of the
primary teeth were delayed (Fig. 7, A).
The mother and 6-yr-old daughter were not affected,
with no signs of HGF or any other systemic findings.
A treatment schedule which included gingivectomy
and extractions either under local or general anesthesia
was planned; however, the father only agreed to have
extractions and refused any treatment for gingival fibromatosis both for his son and for himself. He stated
that severe pain that he suffered after his previous

Fig 4. The panoramic radiographs of the father in 2000 (A)

and 2005 (B), showing the teeth and the root fragments
covered by the gingiva. The amount of enlargement on the
maxilla can be traced in the radiograph (arrows).

operation and highly probable recurrence rate of

HGF were the reasons for his refusal of treatment.
After 3.5 years, the family was re-examined in December 2003. The intraoral examination of the father

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complicated breastfeeding for the mother. The terminal

phalanges of the fingers of the baby were hypoplastic,
but he did not have any other systemic findings, such as
hypertrichosis.
The intraoral views of the patients in November 2005
are shown in Figs. 2, C; 5, C; 6, C; and 8, B; and the
panoramic radiographs of the father and the older son
are shown in Figs. 4, B, and 7, B. The father again
refused periodontal treatment as well as a chromosal
study of his family.

Fig 5. The intraoral view of the son in 2000 (A), 2003 (B),
and 2005 (C). Note the malocclusion and prolonged retention
of primary teeth owing to gingival hyperplasia.

(Fig. 2, B) showed that the anterior bridge was broken

and the gingiva had covered the prepared teeth. The
overgrowth of the palatal gingival tissue was not increased significantly compared to the initial examination. The patient stated that he had been biting and
chewing on the gingiva and he had encountered no
problems. The son, now 12 years old, still retained
many of his primary teeth (Fig. 6, B). The mandibular
incisors were still partially erupted. During the ensuing
years, his maxillary primary central incisor had exfoliated and the incisal edge of the permanent incisor could
be observed. The physiologic root resorptions of the
primary teeth were still defective. One important development of the boys case was that he was diagnosed
as having mild hearing deficit at the age of 11.
The mother gave birth to a healthy boy in December
2003. The intraoral examination of this 10-day-old boy
also revealed gingival enlargement, especially affecting
the maxillary anterior and tuberosities (Fig. 8, A). The
tissue was pink, firm, and dense in consistency, which

DISCUSSION
Patients with isolated or syndromic forms of HGF
have been widely described in medical and dental literature. Although the various syndromes with HGF are
considered to be distinct entities, significant overlap of
symptoms has been noted occasionally.13,14,22,23,26 Furthermore, the phenotypic expression of the syndromes
may even vary within the same family,1,26 such as in
the one reported here. For the last 20 years, most of the
published cases of syndromic HGF do not appear to fall
exactly into any recognized patterns. The commonly
reported systemic manifestations of syndromes associated with HGF include hypertrichosis,3,22,26 mental retardation,17,22 abnormal fingers, fingernails, nose, and
ears,13,26,27 epilepsy,17,28 hearing loss,15,16 and supernumerary teeth.1,13 The systemic findings of the present
family with HGF overlap with 3 previously described
syndromes. The features of the father fit ZimmermanLaband syndrome29 (ZLS, Online Mendelian Inheritance n Man (OMIM) catalog number 135500) with
the hypoplasia of the terminal phalanges and nails of
the extremities; HGF-hypertrichosis syndrome29
(OMIM 135400) with the hypertrichosis; and Jones
syndrome29 (OMIM 135550) with the hearing loss. The
elder son also had characteristics of ZLS and Jones
syndromes, whereas the features of the younger son
only fits ZLS. Besides the overlapping findings of this
family, Zimmerman-Laband syndrome with hypertrichosis,17,22 in the forms of confluent and thick eyebrows, hairy arms, back, and legs, with mental deficiency17,30 and with hearing loss14 has been reported in
sporadic cases. On the other hand, congenital hypertrichosis and deafness without HGF has also been described recently.31 Thus, it seems reasonable to assume
that the highly variable phenotypic overlap of these
syndromes may represent a spectrum of a single disorder. The currently preferred terminology of these syndromes mainly describes the clinical features of the
disorder without any attempt to identify the cause.
The father-to-son transmission observed in our family clearly demonstrates that the responsible genetic
defect is autosomal dominantly inherited. The presence
of hearing loss, which is unusual in HGF except for

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Haytac and Ozcelik 525

Fig 6. The intraoral view of the son in 2000 (A), 2003 (B), and 2005 (C). Note the gingival enlargement in the maxillary
tuberosities.

Jones syndrome, in both father and son most likely

suggests that it is an internal feature of the genetic
condition and not a mere association. Although 3 gene
loci and 1 gene (SOS1) have been are described for
isolated HGF,24,10,25 there are only a few studies performed to clear the causative genes of syndromic HGF.
Mangino et al.32 showed that linkage analysis excluded
linkage to previously mapped HGF loci on chromosomes 2p21 and 5q13-q22 for HGF associated with
hypertrichosis. If it is assumed that the clinical condition described in our family is an allelic variant of
HGF-hypertrichosis syndrome, because of the abovementioned overlap, the genetic defect in our family
should be at another chromosomal locus. It is possible
that different mutations in 1 gene may cause different
phenotypes considered to be ZLS, Jones, or HGFhypertrichosis syndromes. Another possibility would
be the presence of deletions involving 2 or more neighboring genes, the phenotypic consequence of which
would be bred true in a given family and heterogeneous
phenotypes would be observed in unrelated patients.
This situation is called contiguous gene syndrome
and described as a syndrome, which results owing to
the abnormalities of 2 or more genes that map next to
each other on a chromosome. Recently, an apparently

balanced reciprocal translocation of chromosomes

3p21.2 and 8q24.3 has been described for patients with
ZLS,33 suggesting that the responsible genetic defect
may be at one of these chromosomal positions. One
autosomal recessive nonsyndromic deafness gene,
TMIE (transmembrane inner ear expressed gene), maps
to 3p14-p21,34 which is found to be mutant in ZLS.33
Furthermore, several reports have linked isolated nail
dysplasias35,36 to the same region: 3p21. It will be
interesting to observe if an alteration in this gene is
involved in the pathogenesis of phenotypic defects detected in our family.
It was of interest that although the father did not have
HGF on the edentulous posterior ridges of the mandible, he had the most severe enlargement on the posterior maxilla, with teeth and root fragments completely
covered by the overgrown tissue. Although we have no
explanation for this finding; maxillary posterior and
palatal regions are reported to be the most affected
regions in previous cases.2,29 Another interesting finding was the prolonged retention of primary teeth in the
13-year-old son. Apart from the retentive effect of
dense overgrown gingiva, further analyses are needed
to clear the reasons of delayed root resorption of the
primary teeth and delayed emergence of permanent

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Haytac and Ozcelik

Fig 7. The panoramic radiograph of the son in 2000 (A) and

2005 (B), showing the prolonged retention and delayed root
resorption of the primary teeth.

teeth from alveolar bone. And the 10-day-old child is,

to our knowledge, the youngest patient with GF in the
literature. The long-term follow-up of this family may
highlight some important characteristics of the natural
progress of HGF, because the father strongly refuses
any treatment.
In conclusion, the findings from this family provide
further evidence that the clinical presentation of the
syndromic forms of HGF is highly variable. The complexity of reviewing cases such as this family is based
on different mutations causing the same syndrome (genetic heterogeneity), the same essential mutation being
expressed differently from case to case (variable expression), and the fact that neighboring mutations
sometimes can be inherited as a block (contiguous gene
syndromes). Owing to the clinical overlap between
diagnosed and undiagnosed (or unclassified) syndromes, the identification of the genetic pathways and
mechanisms will be the most important factor in classifying these disorders, with the phenotype playing a
minor role.
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Fig 8. The gingival enlargement of the son born in June

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Reprint requests:
Dr. Onur Ozcelik
Cukurova University Faculty of Dentistry
Balcali/Adana 01330
Turkey
oozcelik@cu.edu.tr