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Pediatric Dental Journal

journal homepage: www.elsevier.com/locate/pdj

Case Report

Early exfoliation of permanent tooth in patient with

hypophosphatasia

Rena Okawa a,*, Jiro Miura b, Kazuma Kokomoto a, Takuo Kubota c,

Taichi Kitaoka c, Keiichi Ozono c, Kazuhiko Nakano a
a
Department of Pediatric Dentistry, Osaka University Graduate School of Dentistry, Osaka, Japan
b
Division for Interdisciplinary Dentistry, Osaka University Dental Hospital, Osaka, Japan
c
Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan

article info abstract

Article history: Background: Hypophosphatasia (HPP) is a rare inherited skeletal disorder caused by muta-
Received 10 July 2017 tions in the ALPL gene encoding tissue-nonspecific alkaline phosphatase, with early
Received in revised form exfoliation of primary teeth due to disturbed formation of cementum often recognized as a
18 August 2017 major dental manifestation. However, reports regarding permanent teeth in HPP cases are
Accepted 30 August 2017 scant.
Available online xxx Case report: An 11-year-old boy diagnosed with childhood type HPP was referred to our
hospital for exfoliation of the maxillary right central incisor. Micro-computed tomography
Keywords: findings of the affected tooth revealed external root resorption, enamel hypoplasia, thin
Hypophosphatasia dentin, and a wide pulp chamber, while disturbed cementum formation, enamel hypo-
Early exfoliation plasia, dentin hypo-mineralization, and scant cementum around the enamel junction were
Hypo-mineralization observed by scanning electron microscopy.
Disturbed cementum Conclusion: Permanent teeth may have a risk of early exfoliation as well as other structural
Permanent teeth abnormalities in HPP patients, thus longitudinal dental follow-up examinations of affected
patients are required.
© 2017 Japanese Society of Pediatric Dentistry. Published by Elsevier Ltd. All rights reserved.

based on age at diagnosis, as well as severity of associated

1. Introduction signs and symptoms [1e5]. The frequency of the severe type in
newborns is estimated to be 1 per 100,000 [3]. Early exfoliation
Hypophosphatasia (HPP), an inherited skeletal disorder of primary teeth due to disturbed formation of cementum is
caused by mutations of the ALPL gene encoding tissue known to be a major feature of affected teeth in HPP patients
nonspecific alkaline phosphatase is characterized by defective [6e8]. In mild cases, such as childhood and odonto type,
bone mineralization and classified into 6 clinical types (peri- dental manifestations found by a dentist can occasionally lead
natal, benign prenatal, infantile, childhood, adult, odonto) to early diagnosis of HPP [7]. The site of early exfoliation is

* Corresponding author. Department of Pediatric Dentistry, Osaka University Graduate School of Dentistry, 1-8 Yamada-oka, Suita,
Osaka 565-0871, Japan.
E-mail address: [email protected] (R. Okawa).
http://dx.doi.org/10.1016/j.pdj.2017.08.005
0917-2394/© 2017 Japanese Society of Pediatric Dentistry. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Okawa R, et al., Early exfoliation of permanent tooth in patient with hypophosphatasia, Pediatric
Dental Journal (2017), http://dx.doi.org/10.1016/j.pdj.2017.08.005
2 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6

often the anterior primary teeth before the age of 4 years [6], premolar were identified, however, permanent tooth root
while early exfoliation of permanent teeth is considered to be formation was delayed, and the mandible and maxilla bone
rare. In the present report, we describe a patient with HPP who appeared to be thin (Fig. 3). In addition, a calcified area sized
showed early exfoliation of a permanent incisor and focus on 6.5 mm in diameter was observed close to the mesial root of
the morphological features of the affected tooth. Informed the mandibular right first molar. A periapical radiographic
consent was obtained from the patient for publication of this examination showed severe absorption of the alveolar bone in
case report and accompanying images. the regions of the maxillary right central incisor and
mandibular left central incisor (Fig. 4). We considered that it
would be difficult to preserve the maxillary right and
2. Case report mandibular left central incisors, though requested a local
general dental practitioner to follow the patient and maintain
An 11-year-6-month-old Japanese boy was referred to the his periodontal condition for preservation of the teeth for as
Pediatric Dentistry Clinic of Osaka University Dental Hospital long as possible.
by pediatricians of the Pediatric Clinic of Osaka University Unfortunately, the maxillary right central incisor was
Medical Hospital for consultation regarding mobility of per- exfoliated due to a traumatic injury caused by striking with his
manent teeth. He had been diagnosed with childhood type knee at the age of 11Y11M (Fig. 5a and b). The exfoliated tooth
hypophosphatasia at the age of 2Y2M due to a low serum showed enamel hypoplasia and external root resorption, and
alkaline phosphatase (ALP) level (66 IU/I), and radiological the apex of the root was incompletely closed. After fixing in
examination findings of the lower extremities and hands, 10% neutral buffered formalin, the tooth was analyzed using a
which revealed the metaphyseal irregularity of rickets. Ac- small-animal micro-computed (CT) tomography device
cording to his parents, 2 mandibular primary incisors had (R_mCT2; Rigaku®, Tokyo, Japan) to assess the morphology of
spontaneously exfoliated at 2Y2M, and 6 incisors and 2 ca- the enamel and dentin (Fig. 5cee). Those results revealed thin
nines were spontaneously lost by 3Y3M. An intraoral exami- dentin and a wide pulp chamber. External root resorption and
nation demonstrated that all incisors and canines, as well as enamel hypoplasia were also detected in three-dimensional
the first molar had emerged into the oral cavity, each of which images generated by reconstruction of the CT data (Fig. 5f
showed enamel hypoplasia, while all first molars were located and g).
in a prominently lower position (Fig. 1). In addition, the Following the micro-CT analysis, the tooth was hemi-
mandibular left primary and bilateral second molars showed sectioned, half of which was subjected to histological anal-
internal root resorption. Since the maxillary and mandibular ysis. The hemi-sectioned tooth was demineralized with 0.5 M
molars did not contact when biting, traumatic occlusion was EDTA at 4  C, conventionally processed for paraffin embed-
thought to have occurred in the incisors region. Furthermore, ding, cut into 5-mm-thick sagittal sections, and mounted on
a periodontal examination revealed deep pockets and severe silane-coated slides, then subjected to hematoxylin and eosin
mobility in the maxillary right central incisor and mandibular (H-E) staining. Histopathological findings revealed disturbed
left central incisor regions (Fig. 2). However, gingival inflam- cementum formation and incomplete cementum was
mation was mild. In an orthopantomographic examination, observed near the enamel region, though that was not
all permanent teeth except for the mandibular left second detected along the dentin of the root (Fig. 6aed). The

Fig. 1 e Oral photographs obtained at initial examination (patient age 11 years 5 months).

Please cite this article in press as: Okawa R, et al., Early exfoliation of permanent tooth in patient with hypophosphatasia, Pediatric
Dental Journal (2017), http://dx.doi.org/10.1016/j.pdj.2017.08.005
 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6 3

Mob 0 NE NE 0 0 2 1 0 0 NE NE 0

B 2 2 2 2 2 2 1 3 2 3 2 6 3 1 2 2 2 3 3 2 2 1 2 2
P
D
P 2 2 2 3 2 2 1 3 3 3 3 4 6 5 3 3 4 2 2 2 1 3 2 2

6 5 4 3 2 1 1 2 3 4 5 6

6 E 4 3 2 1 1 2 3 D E 6

L 2 2 2 2 2 2 1 3 2 3 2 6 3 1 2 2 2 3 3 2 2 1 2 2
P
D
B 4 2 3 3 1 3 3 1 1 1 1 2 3 2 3 2 1 2 3 1 3 3 2 2

Mob 0 1 NE 0 1 1 2 1 0 2 2 0

Fig. 2 e Periodontal scores at 11 years 5 months of age. PD: pocket index (circles indicate bleeding), B: buccal, P: palatal, L:
lingual, Mob: tooth mobility, NE: not erupted.

3. Discussion

Early exfoliation of primary teeth is a well-known major

dental manifestation of HPP [6,7]. However, few case reports
describing early exfoliation of a permanent tooth in HPP pa-
tients have been presented. It is possible that the number of
such cases is limited because of the longer root as compared to
that of a primary tooth. Moreover, primary incisors have an
excessive occlusal force burden, since edge to edge occlusion
is rather common in primary dentition. We found 9 previous
Fig. 3 e Orthopantomograph obtained at 11 years 5 months
reports describing both primary and permanent dentition in
of age.
HPP cases, all of which experienced early exfoliation of pri-
mary teeth [9e17]. In addition, early exfoliation or extraction
due to periodontitis of permanent teeth was described in 7 of
remaining half tooth was conventionally embedded with those reports [9e15], while the other 2 reports were regarding
methylmethacrylate (MMA). After embedding and cutting the HPP patients without early exfoliation of permanent teeth
specimen, and surface polishing, backscattered electron [16,17]. In one of those, absence of early exfoliation of a per-
images were obtained with a scanning electron microscope manent tooth with a reduced level of cementum in a male
(JSM-6510LV; JEOL, Tokyo, Japan) (Fig. 6eej), which revealed diagnosed with infantile HPP at the age of 26 years is described
hypoplasia, dentin hypo-mineralization, and scant cementum [16]. That patient had complete permanent dentition, though
formation around the enamel junction. prematurely lost all primary teeth. In another study, absence

Fig. 4 e Periapical radiographs obtained at 11 years 5 months of age.

Please cite this article in press as: Okawa R, et al., Early exfoliation of permanent tooth in patient with hypophosphatasia, Pediatric
Dental Journal (2017), http://dx.doi.org/10.1016/j.pdj.2017.08.005
4 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6

case, the dental phenotype was considered to be quite severe

as several primary teeth were exfoliated during the primary
dentition stage and the primary molars also showed signifi-
cant mobility soon after eruption. It is important to follow and
observe HPP patients, especially those who experience pri-
mary molar exfoliation, which is generally regarded to be
quite rare in these cases.
Early primary tooth exfoliation is considered to be caused
by disturbed cementum formation [7,8]. In the present case,
we noted disturbed formation in a permanent tooth, which
should be regarded as important information in dental find-
ings of HPP patients. Olsson et al. reported that cementum
could not be identified in histological findings of two maxillary
permanent central incisors extracted from a 23-year-old man,
though they found an area of previously resorbed cementum
that had been replaced by reparative fibrillary cementum in
the apical portion of the root and resorbed cementum
replaced by reparative cementum [13]. In addition, El-Labban
et al. analyzed a maxillary central incisor extracted from a
10-year-old patient, in which the cementum was found to be
absent from most of the root surface, while pre-cementum
and cementum were seen in repaired areas of apical root
resorption in histological findings, and afibrillar cementum
was detected by TEM and SEM [11]. In the present examined
tooth, we could only detect a scant amount of cementum
around the cervical portion of the root, which led us to
consider that only a small part of cellular cementum
remained and replacement of cementum in the apical absor-
bed root area could not be identified.
We consider the reason for exfoliation of permanent teeth
in our patient was mainly related to disturbed formation of
cementum. However, excessive pressure without adequate
molar occlusion might have caused traumatic occlusion,
which may be a secondary reason for that exfoliation. In
general, recovery of molar occlusion by use of a denture
appliance is quite difficult to achieve in patients with severe
dental manifestations, such as seen in the present case. The
presence of bacterial plaque along the coronal root dentine
has also been reported in histological findings [11,13]. In our
case, dental plaque was not detected, even though oral plaque
control was not adequate. Since the presence of bacterial
plaque can lead to exacerbation of periodontitis in weak
periodontal tissue, oral hygiene is especially important for the
severe dental phenotype of HPP. Watanabe et al. reported
regarding periodontal treatments performed over a period of 4
years for a 15-year-old boy [12]. Following the initial treatment
procedures, such as oral hygiene instruction, plaque control
evaluation, scaling, and root planing, a flap operation was
Fig. 5 e Exfoliated maxillary right central incisor. a: Labial conducted. In young patients with HPP, advanced periodontal
side. b: Palatal side. c: Micro-CT image, sagittal view. treatment, such as a flap operation, should be considered after
Vertical dotted line: coronal view (d). Cross dotted line: initial periodontal treatment following achievement of per-
axial view (e). d: Micro-CT image, coronal view. e: Micro-CT manent dentition and closing of the root apex.
image, axial view. f: 3D image, labial side. g: 3D image, Enamel and dentine dysplasia were detected in the present
palatal side. case. Six previous reports described hypoplasia of enamel,
dentin and cementum, wide pulp chamber, thin and short
roots, and premature root resorption in permanent teeth in
of dental anomalies in 3 brothers between 18 and 22 years of affected patients [10,12,13,15,16,18]. It is generally known that
age with familial odonto HPP is described, each of whom ALP plays an important role in not only bone but also tooth
experienced early exfoliation of anterior primary teeth and no mineralization. In addition, we previously experienced a case
problems with posterior primary teeth [17]. In the present of lower positioned primary teeth in a child patient with HPP

Please cite this article in press as: Okawa R, et al., Early exfoliation of permanent tooth in patient with hypophosphatasia, Pediatric
Dental Journal (2017), http://dx.doi.org/10.1016/j.pdj.2017.08.005
 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6 5

Fig. 6 e Histopathological appearance and SEM images. a: Image showing whole specimen. bed: Higher magnification. D:
dentin, P; pulp, C: cementum (arrow). e: Image showing whole specimen. fej: SEM images (Fig. 6i: higher magnification of
Fig. 6h). E: enamel, D: dentin, P; pulp, C: cementum.

[19]. It is speculated that ankylosis of these teeth could be underwent dental implant therapy for treatment of alveolar
derived from loss of attachment via the periodontal ligament bone in the mandible and maxilla [14], and it is considered
or insufficient dentine formation in the root. that use of implants may be a helpful modality for adult
An innovative treatment method for HPP patients termed patients with HPP. In the present case, enzyme replacement
“enzyme replacement therapy” has been introduced. therapy was recently started, and we intend to continue to
Although the dental effects in humans remain to be fully observe maxillary and mandibular bone for signs of
elucidated, that therapy has been reported to result in sig- improvement, and also perform treatments to promote
nificant recovery of bone mineralization [1,2,20,21]. In calcification in the area of the mesial root in the mandibular
another case report, a 20-year-old male HPP patient right first molar region.

Please cite this article in press as: Okawa R, et al., Early exfoliation of permanent tooth in patient with hypophosphatasia, Pediatric
Dental Journal (2017), http://dx.doi.org/10.1016/j.pdj.2017.08.005
6 p e d i a t r i c d e n t a l j o u r n a l x x x ( 2 0 1 7 ) 1 e6

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Please cite this article in press as: Okawa R, et al., Early exfoliation of permanent tooth in patient with hypophosphatasia, Pediatric
Dental Journal (2017), http://dx.doi.org/10.1016/j.pdj.2017.08.005