J Oral Patkol Med 19Vbi 25: .

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Frimeil in Denmark At! ri^hls rcsen'ec

Copyright Munksgaard

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JOURNAL OF

Oral Pa
ISSN 0904-2512

Case report

Hypophosphatasia affecting the

permanent dentition
Olsson A, Matsson L, Blomquist HK, Larsson A, Sjodin B. Hypophosphatasia
affecting the permanent dentition. J Oral Pathol Med 1996; 25: 343-347.
Munksgaard, 1996.
Repons on dental abnormalities in connection with bypophosphatasia almost exclusively describe changes in primary teeth, A 23-year-old man with hypophosphatasia,
first diagnosed at the age of 8 months, is described; histologically and radiographically verified signs of the condition were present in the permanent dentition. The
findings included a reduced level of the marginal alveolar bone supporting the upper
central incisors, which had to be extracted. The molars di.5p!ayed large coronal pulp
chambers. Histologically, the upper incisors demonstrated abnormal root cementum,
with areas of dentin resorption. as well as disturbances of the mineralization of the
coronal dentin. The patient also had signs of abnormal root resorption of molars. The
potential involvement of permanent teeth puts children with hypophosphatasia at
risk of developing oral complications during adolescent and adult life.

Hypophosphatasia is a rare inborn error

of metabolism characterized by deficient
activity of tissue-nonspecific (liver/
bone/kidney) alkaline phosphatase (1.
2). Four types of the disorder have been
described: perinatal, infantile, childhood
(or juvenile), and adult hypophosphatasia. The perinatal and infantile forms of
the disorder are serious, often lethal conditions. The childhood and adult forms
are milder and more variable in their expression. Individuals with adult hypophosphatasia often have a history of
symptoms in childhood (3, 4).
Hypophosphatasia occurs in all races
and is inherited as an autosomal trait.
The inheritance pattern of the infantile
form of the disorder is autosomal recessive (2, 5). The inheritance of the childhood and adult forms is, however, less
clear and there are reports of autosomal
recessive as well as autosomal dominant
inheritance (2, 5-7). The disorder has
recently been reviewed by CASWELL et
al. (2) and by CHAPFIE (5).

A prominent clinical finding in surviving subjects with infantile hypophosphatasia and in subjects with the milder
childhood hypophosphatasia is prema-

ture shedding of primary teeth. In childhood hypophosphatasia, dental changes

may be the only clinical expression of
the disorder, but may in more severe
cases also be coupled with skeletal disturbances.
The low activity of alkaline phosphatase results in a reduced entry of calcium and phosphate into the skeleton
(2), This is also believed to lead to dental changes, including hypopiasia or
aplasia of root cementum, irregular calcification of the dentin and large pulp
chambers, as well as to changes in the
marginal alveolar bone (8, 9). The cementum defects prevent a normal relationship between root surface and collagen fibrils (8, 9) and, along with loss of
alveolar bone, the disturbed formation
of cementum is thought to be the prime
aetiological factor in the early loss of
primary teeth (9). Recently, however,
this theory has been questioned, and it
has heen suggested that the cementum,
although hypomineralized or hypoplastic, is formed intially and then later becomes resorbed as a result of bacterial
invasion (10).
The vast majority of repons on dental

Anders Olsson\ Lars Matsson^,

Hans K. Blomquist^,
Ake Larsson'' and Bengt Sjodin^
^ Department ot Periodontology, Public Dental
Health Service, Lulei. ^Department of
Fedodontics and ^Department of Pediatrics,
Umei University, Umeit, 'Department ot Oral
Pathology, Lund University, H/lalmd and
^Department ot Postgraduate Dental
Education, Orebro. Sweden

Key words: alkaline phosphatase: dental

cementum: hypophosphatasia: permanent
dentition
Lars Matsson, Department of Pedodontics,
Centre lor Orai Health Sciences,
Lund University, Carl Gustavs vag 34,
S-214 21 Malmo, Sweden
Accepted tor publication February 7, 1996

abnormalities in connection with hypophosphatasia describe changes in primar>' teeth (8, 9, 11-16), leading to the
assumption that the dental changes
mainly affect the primary dentition (2,
17, 18). Based on reports that deciduous
incisors are most seriously affected, it
has been suggested that the dental effects of the biochemical defect are most
pronounced during the first year of life
(8). A few recent studies, however, report dental changes in the permanent
dentition (10, 19,20).
In the following report, a patient with
hypophosphatasia is described who had
histologically and radiographically verified signs of the condition in the permanent dentition. In addition, due to the
uncertainty regarding the inheritance
pattern of the disorder, a family study
was performed.
Case report
Medical history

The patient is the youngest child in a

family with three children living in the
northern part of Sweden. Parents, siblings and grandparents are healthy.

344

OLSSON et

al.

Fig. I. Panoramic radiograph (7 years of agei showing premature loss of primar\' teeth and
loss of marginal alveolar hone in area of remaining primar)' teeth. Note large pulp spaces in
lower first permanent molars.

At the age of 8 months the diagnosis

of childhood hypophosphatasia was
made after investigation of therapy-resistant rickets. During childhood, shortness of stature was noted (-2 SD), as
well as a weakness of muscles, early
loss of primary' teeth, enlargement of the
costochondral junction, "rachitic rosary", and thickening of the wrists and
ankles.
The patient was seen regularly by a
pediatrician but from the age of thirteen
years medical check-ups were not considered necessary. However, at 23 years
of age the patient still reported symptoms from the skeleton, including pain
from the knee-joints. He also described
difficulties in liffing heavy loads.
Repeated laboratory examinations
dttring childhood and at the age of 23
years revealed mainly normal serum
calcium and phosphate levels but the alkaline phosphatase levels were low or
very low compared to the reference values for the methods used. Phosphoethanolamine was invariably found in large
quantities in the urine.
Dental history

The earliest available dental radiographs were taken at the age of 7 years.
At this age all first permanent molars
had erupted and 28 permanent teeth or
tooth buds were present, all showing
normal chronological development (Fig.

1). Only 6 primary teeth were left, all

showing an apparent loss of marginal
alveolar bone. The first permanent
molars had abnormally large corona!
pulp chambers. At the age of 11 years
the upper right central incisor was subject to trauma: the tooth was recorded as
slightly mobile but no treatment was
indicated.
At 13 years of age. delay in the eruption of the second premolars led to a radiographic examination of these areas.
This revealed resorption of the mesial
root of both upper first molars and the
lower right molar {Fig. 2) and all 4 first
permanent molars were removed.

found, which seemed to reach the apex

of the root. Radiographic examination
revealed a reduced level of marginal
bone in the region of the upper incisors
(Fig. 3), with a widened periodontal ligament around the right central incisor.
In addition, large coronal ptilp chambers
were noted in the molars, as well as a
diverging root anatomy of the lower
incisors (not shown in the figures). The
upper right central incisor had to be
extracted and; for prosthetic reasons,
also the upper right lateral incisor. In
September 1993. external resorption of
the distobuccal root of the upper left
second molar was noted. It is likely that
this was induced by the eruption of the
third molar.
Histologic examination of the two incisors demonstrated signs of abnormal
root cementum (Figs. 4-7). In addition,
the dentin showed marked disturbances
of mineralization (Fig. 8). These included periodically occurring developmental lines from the coronal dentin to
the dentin in the apical pan of the roots.
The developmental disturbances were
most prominent in the proximity of the

Oral findings

Fig. 2. Radio^aph (13 years of age) showing external resorption of upper left first permanent molar.

In 1992. the now 23-year-old patient

was referred for consultation regarding
periodontai problems in the upper anterior area. The upper incisors had been
subjected to trauma one year earlier,
leading to a slight luxation of the two
central incisors. The incisors were
splinted for 4 weeks but mobility was
still increased after this period. Radiographic examination at the time of the
trauma revealed a significantly reduced
level of marginal bone in the area,
which was Judged not to be attributable
to the injury. Only minor signs of gingival infiammation were noted. However,
on the mesial surface of the right central
incisor a deep periodontal pocket was

Fig. 3. Radiograph of upper permanent incisors showing a reduced level of marginal

bone (arrows).

Hypophosphatasia in penttunent leeth

345

Fig. 4. Cervical portion of root covered by plaque. No cementum can be identified (x36Ol,
Fig. 5. Apical portion of root from same tooth as in Fig, 4. Resorption lacunae are not covered by plaque and are not accompanied by reparative
cementum formation {xl80).
Fig. 6. Apical portion of root, lacking plaque. Area of previously resorbed cementum now replaced hy repai'ative. iibrillai' cementum (x360).
Fig. 7. Midportion of root from same tooth as in Fig. 6. No cementum can be identified and the surface shows only a thin eosinophilic layer (x 180).

coronal pulp, where features of interglobular dentin were found.

Longitudinal sections of the two teeth
showed somewhat different root surface
morphologies. In one of the teeth, a thin
layer of plaque covered the buccal coronal root dentin, where no cementum and
no resorption could be seen (Fig. 4).
Along the buccal apical root surface
there was evidence of resorption into
the dentin. lacking plaque (Fig. 5). On
the lingual root surface there were thin,
plaque-covered dentin re,sorption cavities coronally, whereas the apical root
showed no plaque, no resorption and no
identifiable cementum. In the other
tooth, the buccal coronal root surface
lacked plaque but also lacked a cementum layer, whereas cenientutn was
clearly identified on the buccal apical
root surface, partly as reparative cemen-

tum in previously resorbed dentin (Fig.

6), No cementum was seen on the lingual root surface, which showed only a
thin eosinophilic layer (Fig. 7). Interestingly, the cervical portion of this tooth
showed superficial resorption. with no
evidence of plaque.
Family study

In addition to the proband. who displayed reduced serum alkaline phosphata.se activity and high quantities of
phosphoethanolamine in the urine, both
parents and both sisters showed a low
alkaline phosphatase level (Fig. 9).
However, their phosphoethanolamine
levels were normal and none of them
presented with a history of dental disturbances which could be related to hypophosphatasia. The biochemical analysis

of the remaining family members gave

normal results.
Discussion
Reports on dental abnonnalities in connection with hypophosphatasia almost
exclusively describe changes in primary
teeth, often leading to the assumption
that the dental changes affect only the
primary dentition (2.17.18), We report a
case with severe dental changes that
affect both dentitions, the diagnoses of
childhood and adult hypophosphatasia
being established clinically and biochemically at pre-school age and confirmed at the age of 23 years. Our
findings thus confirm recent reports that
permanent teeth may also be involved in
cases of hypophosphatasia (10. 19. 20).
The pos.sible involvement of permanent

346

OLSSON et al.

Fig. 8. Portion of circumpulpal dentin, exhibiting several incremental lines (arrows).

In addition, most recently formed dentin
shows features of globular dentin (XlOO).

" ' -x-'

teeth puts children with hypophosphatasia at risk of developing oral complications during adolescence and adult life,
which should be taken into consideration by the dentist when planning prevention and treatment.
Both parents and both sisters of the
proband had reduced alkaline phosphatase levels. However, the parents
and sisters showed normal levels of
phosphoethanolamine and therefore the
diagnosis of hypophosphatasia can be
made with confidence only in the
proband. However, the distribution of
reduced alkaline phosphatase levels in
the family is compatible with an autosoma! recessive inheritance pattern, the
parents and sisters of the proband possibly being heterozygote carriers.
The clinical and histological findings
in the permanent dentition of the present
patient resemble those reported for primary teeth (9, II, 15, 16). The findings
included disturbances of mineralization
of coronal dentin, hypopiasia or aplasia
of root cementum and external resorption of root dentin. Also, a reduced level
of marginal alveolar bone was seen. A
low level of alkaline phosphatase activity is associated with alterations in the

extracellular metabolism of various

compounds, including inorganic pyrophosphate. which seems to be of importance for the development of mineralization defects in patients with hypophosphatasia (2). In the present patient,
a low level of serum alkaline phosphatase activity was documented on
several occasions between the ages 7 13 years. The root development of the
permanent incisors takes place approximately between the ages 4-9 years and
thus the deficiency in alkaline phosphatase activity seems to have an impact on tooth formation not only during
infancy and early childhood but also
during the later part of childhood as
well. This contradicts the suggestion by
BEUMER et al. (8) that the dental effects
of the biochemical defect are most pronounced during the first year of life.
At the radiographic examination of
the patient at the age of 13 years, extensive external root resorption of all first
permanent molars was seen, and later, at
the age of 24 years, resorption of one
second permanent molar was revealed.
These changes may have been triggered
by the eruption of neighbouring teeth.
BoRAz (21) reported similar changes in

an 18-year-old man with hypophosphatasia, but apart from that, complications of this type do not seem to have
been reported earlier. Possibly, lack of
normal cementum on the first permanent molars, in which root development
chronologically coincides with that of
the incisors with verified cementum defects in the present case, makes these
teeth vulnerable to resorption. Hypotheticalty, the normal periodotital ligament with an intact cementum layer has
a protective function against eruption
pressure, and individuals with hypophosphatasia may run a greater risk of
developing changes of this type.
EL LABBAN et al, (10), in their study
of a 10-year-old boy with hypophosphatasia, reported that al 1 histologically
examined teeth presented with a thick
layer of bacterial plaque over the defective root surfaces and in most resorption
bays. Based on these finding.s they suggested that cementum, although hypomineralized or hypoplastic, is formed initially and then later becomes resorbed
as a result of bacterial invasion. In the
two teeth analysed in the present study,
bacterial plaque was a rare finding in areas of aplasia of eemetitum or dentin resorption. In one of the teeth, plaque was
totally absent, and in the other plaque
was found only on the coronal part of
the root. Aplasia of cementum as well as
dentin resorption was. however, a common finding in the apical as well as the
coronal part of the roots in both teeth.
This would indicate that bacteria were

NORMAL

[71 DiatASID, NOTIXAMIMD

HP

(^

POS5IBLX DIAGNOSIS OF HP

Fig. 9. Pedigree of the family. Serum alkaline phosphatase values (ALP. normal 1.4 5.1 ukat/1) and urinary phosphoethanolamine values (PEA. underlined, normal
<40 mmol/mol creatinine), HP = hypophosphatasia. In one boy, 14 months of age. no
serum sample could be taken. Asterisk indicates low ALP.

Hypophosphatasia in permanent ieeth

not a primary cause of lack of cementum or of resorption in the present case.
The presence of bacterial plaque in the
coronal part of the root in one of the
teeth could be .secondary to developmental defects of the cementum, which
may facilitate the down growth of bacteria along the root surface due to insufficient fiber attachment. However,
when established, bacterial plaque may
have a harmful effect in cases of cementum defects by inducing resorption.
PAGE & BAAB (22), discussing the etiology of prepubertal periodontitis in primary teeth, suggested that abnormal cementum or absence of cementum, as
seen in connection with hypophosphatasia, would result in disturbances in the
fiber attachment which might in turn
make way for invasion of bacteria.
When the periodontal problems of the
present patient became apparent at an
adult age. a systemic connection w as obvious due to his known history of disease. Still, loss of attachment in permanent teeth of seemingly healthy patients
may signal an underlying disorder of a
low activity of alkaline phosphatase.
GOTTLIEB (23) proposed cementum defects, "cementopathia". as an etiologic
factor in some types of early onset periodontitis and LiNDSKOG & BLOMLOF (24)
and BLOMLOF et al. [25) presented evidence recently, supporting this view.
They reported cementum hypopiasia in a
significant number of permanent teeth
affected by juvenile periodontitis and
hypothesized that varying degrees of hypophosphatasia may be of etiologic importance in these cases. No biochemical
analysis was performed in their patients
but their findings, along with the present
finding of an association between loss of
periodontal attachment and hypophosphatasia also in the permanent dentition,
suggest that measurement of serum alkaline phosphatase may be considered in
patients with an unusual pattern of loss

of tooth support and in studies of early

onset periodontitis.
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