DOI: 10.1111/j.1365-263X.2012.01239.
REVIEW
Current concepts in hypophosphatasia: case report and
literature review
AMY HOLLIS1,2, PAUL ARUNDEL3, ALEC HIGH4 & RICHARD BALMER1,2
1
Paediatric Dentistry, Leeds Dental Institute, Leeds, UK, 2Harrogate and District NHS Foundation Trust, York, UK,
3
Paediatric Metabolic Bone Disease, Sheffield Children’s Hospital, Sheffield, UK and 4Pathologist (Head and Neck), Medical
and Dental School, University of Leeds, Leeds, UK
International Journal of Paediatric Dentistry 2013; 23:
153–159
Background. Hypophosphatasia (HP) is character-
ized by defective mineralization of bone and teeth
because of deficient alkaline phosphatase activity.
There are generally six recognized clinical forms, of
which the most severe is often lethal prenatally or
early in life. In milder forms, such as odontohypo-
phosphatasia (OHP), premature exfoliation of pri-
mary teeth may be the only clinical manifestation.
Case Report. A 20-month-old girl was referred to
the Specialist Paediatric Salaried Dental Service
within the Harrogate and District NHS Foundation
Trust with mobility of tooth numbers 71 and 81.
Clinical examination revealed grade III mobile 71
Introduction
Hypophosphatasia (HP) is a rare, inherited
disorder characterized by defective minerali-
zation of bone and teeth and deficient serum
and bone alkaline phosphatase (ALP) activ-
ity1. It is caused by mutations in the liver ⁄
bone ⁄ kidney ALP gene that encodes tissue
nonspecific alkaline phosphatase (TNSALP).
TNSALP cleaves phosphate from pyridoxal-5¢-
phosphate (PLP), phosphoethanolamine (PEA),
and inorganic pyrophosphate (PPi)2. If
TNSALP activity is reduced, these compounds
accumulate extracellularly and may prevent
skeletal mineralization3. PPi is thought to
have the most significant role in the patho-
genesis of HP. Six forms of HP have been
documented in the literature (Table 1) with
Correspondence to:
A. Hollis, Department of Paediatric Dentistry, Leeds Dental
Institute, Clarendon Way, Leeds LS2 9LU, UK.
E-mail: den1alh@leeds.ac.uk
 2012 John wiley & Sons Ltd, BSPD and IAPD
and 81, with minimal gingival inflammation and
plaque deposits. There were no other dental find-
ings and no significant medical history. Tooth
numbers 71 and 81 exfoliated prematurely with
no evidence of root resorption, shortly after pre-
sentation. Haematological and urinary investiga-
tions showed no abnormalities. Histological
examination showed a complete absence of
cementum. A diagnosis of OHP was made. After
10 months of dental follow-up, no further teeth
have increased mobility.
Conclusion. Odontohypophosphatasia should be
included as a differential diagnosis in children pre-
senting with early loss of primary teeth. The den-
tist may be the first health care professional to
whom the patient presents.
an incidence of around 1 ⁄ 100,000 for the
most severe forms9. This incidence was based
on children who had been referred to The
Hospital for Sick Children in Toronto. There-
fore, it is likely that the true incidence of HP
is higher as some of the milder forms may
have escaped formal diagnosis.
Diagnosis
The diagnosis of perinatal lethal and prenatal
benign forms can be made by antenatal ultra-
sonography and confirmed with postnatal
biochemical and ⁄ or genetic testing. Other
forms are often diagnosed following clinical
examination, supplemented by radiographs,
biochemical testing of blood and urine, and,
on occasion, molecular biology (Table 2). Lab-
oratory assays are directed at the TNSALP
substrates and often reveal reduced serum
ALP activity and increased urinary PEA10.
Neither of these findings are pathogno-
monic. However a sensitive marker for HP is
153
154 A. Hollis et al.

Table 1. Forms of hypophosphatasia.

Subtype Inheritance Clinical manifestations

Perinatal (lethal) (OMIM
#241500)
Prenatal (benign)
Infantile (OMIM #241500)
Childhood (OMIM #241510)
Adult (OMIM #146300)
Odontohypophosphatasia
(OMIM #146300)
Autosomal recessive Marked impaired bone mineralization in utero, blue sclerae, skin-covered
osteochondral projections affecting limbs (often diagnostic)4 respiratory
complications. Often lethal
Autosomal recessive or Limb deformities (may improve during 3rd trimester of pregnancy).
autosomal dominant Spontaneous improvement of skeletal defects reported5,6
Autosomal recessive Onset before 6 months of age. Respiratory complications, premature
craniosynostosis, demineralization, rachitic changes in the metaphyses,
hypercalcaemia1, short stature, premature loss of primary teeth. Mortality is
often related to respiratory complications
Autosomal recessive or Onset after 6 months. Skeletal deformities and fractures, short stature,
autosomal dominant premature loss of primary teeth. Often self-limiting but may re-appear in
adulthood1
Autosomal recessive or Presents in middle age often with stress fractures, thigh pain, chondrocalcinosis
autosomal dominant and osteoarthropathy. Patients may report premature loss of primary + ⁄ or
permanent teeth7,8
Autosomal recessive or Premature exfoliation of primary teeth (most commonly the incisors). Often no
autosomal dominant skeletal manifestations

Table 2. Medical investigations used to aid positives can also occur. As PLP is a derivative
hypophosphatasia diagnosis. of vitamin B6, patients under investigation
Investigation Specific tests Common findings
for HP should be advised not to take vitamin
supplements as this may result in misdiagno-
Skeletal Radiographs of Craniosynostosis, Distorted sis13.
radiographs skull, long bones trabeculation, reduced Molecular biology can be of use in cases
mineralization
Laboratory Serum ALP activity Reduced (N.B. reference where other investigations have been incon-
assays ranges for ALP are age- clusive as DNA sequencing may be used to
related with children detect mutations in the TNSALP gene1. Diag-
having higher activity
than adults)
nosis may be complicated by the wide spec-
Serum PLP Elevated trum of clinical manifestations observed both
concentration between and within the subtypes. Further-
Urinary PEA Elevated (N.B. levels
vary with age
more, transmission is variable and autosomal
and sex) dominant and autosomal recessive inheri-
Molecular TNSALP gene mutations tance has been reported.
analysis

ALP, alkaline phosphatase; PEA, phosphoethanolamine; PLP, General implications

pyridoxal-5¢-phosphate; TNSALP, tissue nonspecific alkaline
phosphatase.
increased plasma levels of pyridoxal-5-phos-
phate, one of the substrates that accumulates
as a result of reduced TNSALP activity11.
Even patients with milder forms of HP includ-
ing odontohypophosphatasia (OHP) show
elevated plasma PLP concentrations11. Bio-
chemical testing may not always be relied
upon. Reibel et al.12 documented a case of the
early loss of tooth number 81 in an infant
where initial laboratory assays did not reveal
abnormalities. Subsequent tests 2 years later
following further symptoms suggestive of HP
resulted in a diagnosis of childhood HP. False
The severity of the disease varies greatly.
Clinical expression ranges from stillbirth with-
out mineralized bone (perinatal form) to find-
ings in later life such as delayed walking,
short stature, skeletal deformities, bone pain,
and pathological fractures (childhood and
adult forms)8. In some cases, for example
OHP, the only clinical manifestation is the
early exfoliation of teeth. In general, the ear-
lier the presentation, the more severe the dis-
ease. However, despite the spectrum of
disease, there are symptoms common to more
than one subtype (Table 1) and it is impor-
tant to counsel some individuals that early
mild disease may be followed by osteomalacia

 2012 John wiley & Sons Ltd, BSPD and IAPD


and limb pains in adult life, in spite of appar-
ent good health in young adulthood.
Dental aspects
Premature loss of primary teeth is associated
with infantile, childhood, and OHP subtypes.
Fraser9 reported that 75% of the children in
whom skeletal manifestations became apparent
after 6 months of age experienced premature
loss of primary teeth (n = 15). The premature
loss of teeth results from agenesis or hypoplasia
of cementum so that the exfoliated teeth are
often lost before resorption occurs. Often the
primary incisor teeth are the only teeth
affected, and there are no associated inflamma-
tory periodontal changes or root resorption10.
In the more severe forms of HP, posterior teeth
may also exfoliate prematurely12. Enamel
hypoplasia, bulbous crowns, delayed dentine
formation, and delayed eruption have also been
reported12,14. Although some have reported
severe dental caries in association with HP1,15,
this may be an incidental finding. The perma-
nent dentition may be similarly affected16,17.
Radiographic findings include reduced alveolar
bone and enlarged pulp chambers and root
canals1. Histological analysis of exfoliated or
extracted teeth will show aplastic or hypoplastic
cementum. Whilst the only clinical manifesta-
tions in OHP are dental, the biochemical find-
ings may be indistinguishable from mild forms
of HP18.
Management
Medical management is generally aimed at
symptomatic relief with nonsteroidal anti-
inflammatory drugs. Orthopaedic intervention
may be necessary in cases of fracture or, per-
haps, skeletal deformity. Although there is
presently no approved medical treatment for
the condition, enzyme replacement therapy
may offer an effective treatment modality in
the future19. Recently, bone-targeted TNSALP
has been used on a research basis in a
number of severely affected infants as well as
some older children with some promising
provisional results20,21. Detailed trial results
including dental outcomes have not yet been
reported.
 2012 John wiley & Sons Ltd, BSPD and IAPD
Current concepts in hypophosphatasia 155
Case report
A fit and healthy girl (ER) of 20 months was
referred to Specialist Paediatric Dental Ser-
vices by her general dental practitioner after
her mother had noticed her front teeth mov-
ing when she brushed them. The mobility of
the teeth had increased since it was first
noted 4 weeks previously. Apart from a slight
delay in the onset of walking (19 months),
there was no suggestion of systemic involve-
ment at presentation. ER’s medical history
was unremarkable except for a bacterial skin
infection and a general systemic viral infec-
tion in the months preceding her presenta-
tion. ER had a 5-year-old brother, and no
family history of dental abnormalities was
given. The only reported skeletal disease in a
family member was a diagnosis of ankylosing
spondylitis reported in ER’s father.
Clinical examination revealed that all pri-
mary teeth were present except for second
primary molar teeth. Tooth numbers 71 and
81 were grade III mobile (Fig. 1). The remain-
ing dentition was sound. Soft tissue examina-
tion was unremarkable except for a minimal
amount of gingivitis associated with 71 and
81 where oral hygiene practises had been
complicated by the mobility of the teeth.
Generally, oral hygiene was optimal. Radio-
graphic examination revealed extensive bone
loss associated with 71 and 81 (Fig. 2).
Differential diagnoses
There are many potential causes for the early
exfoliation of primary teeth (Fig. 3). In this
case, the differential diagnoses included both
Fig. 1. Intraoral photograph of mobile 71 and 81 prior to
exfoliation.
156 A. Hollis et al.
Fig. 2. Lower occlusal radiograph showing extensive bone
loss and absence of root resorption associated with the
lower primary central incisors.
Fig. 3. Potential local and systemic causes of early
exfoliation of primary teeth.
local and systemic causes. The local differential
diagnosis was localized aggressive periodonti-
tis. Potential systemic causes included immune
diseases (neutrophil defects, Papillon-Lefèvre,
Chédiak-Higashi, Langerhans’ cell histiocyto-
sis) and diseases of the dental supporting
structures (such as HP and Ehlers-Danlos syn-
drome). In this case, because of the lack of sys-
temic involvement, differential diagnosis was
either localized aggressive periodontitis or a
mild form of HP and the patient was referred
for further medical investigation.
Management
ER was referred for biochemical testing of
blood (full blood count with differential white
cell count, C-reactive protein, liver function
test, magnesium, urea and electrolytes, thyroid
function test, and 25-hydroxy vitamin D)
and urine. No abnormalities, were detected
Fig. 4. Section of decalcified tooth showing regular
dentinal tubules surrounding vital pulp. No cellular or
acellular cementum was identified over the radicular
dentine. [H&E stain: Mag ·100 approximately].
(ALP 93 iu ⁄ L (ref range, 43–160 iu ⁄ L) and PEA
52 lmol ⁄ nmol(creat) [ref range, <55)]. Due to
the imminent exfoliation of 71 and 81, a deci-
sion was made to await for their loss then
request histopathological investigation. Macro-
scopic examination of the exfoliated teeth
revealed no abnormalities on the external sur-
face. Microscopic findings (Fig. 4) were consis-
tent with HP. There was no cellular or acellular
cementum over the radicular dentine. The
pulp chambers were not markedly enlarged,
but apices were wide, with an expanded pre-
dentine zone. Crossed polarisers showed a
number of accentuated incremental lines in
postnatal dentine.
Follow-up
Following the histopathology results, ER was
seen by a medical team specializing in paedi-
atric metabolic bone disease. Plain radio-
graphs of her wrists and knee did not show
any signs of mineralization defects. A repeat
measurement of ALP activity revealed a value
at the lower limit of the age-related normal
range at 76 U ⁄ L (76–398 U ⁄ L). As a result, a
definitive diagnosis of OHP was made and no
further follow-up was arranged except regular
dental examinations.
Discussion
Aetiology
The underlying pathological mechanism
involved in HP is reduced ALP activity and
 2012 John wiley & Sons Ltd, BSPD and IAPD

resultant defective mineralization of bone,
which explains the widespread skeletal mani-
festations that may be present. The most fre-
quently documented dental manifestation is
the premature loss of teeth as a result of hypo-
plasia or aplasia of cementum. Often there is
no evidence of inflammatory periodontal dis-
ease10, as was the case with ER. An alternative
mechanism to explain the early exfoliation of
teeth has been suggested. El-Labban et al.17
speculated that whilst the cementum may be
hypomineralized and hypoplastic, it is formed
initially but subsequently becomes resorbed
once the teeth erupt. The explanation offered
for this resorptive process related to bacterial
invasion and proliferation, although it is
unclear whether such an invasion could occur
in the absence of visible periodontal inflamma-
tion, as is often the case in HP.
Diagnosis
Early diagnosis of HP enables early support to
be provided, including genetic counselling
where applicable. Furthermore, accurate diag-
nosis of HP may prevent the misdiagnosis of
bone pain that could be wrongly attributed to
other causes with or without extensive and
poorly targeted investigations. To obtain a
definitive diagnosis, a careful patient and fam-
ily history needs to be taken. Questions
regarding any familial skeletal or dental
abnormalities (primarily the premature loss of
teeth) should be asked. An assessment of
extraoral findings such as height, weight, and
gait needs to be made followed by a detailed
intraoral clinical examination supported by
radiographs where possible. Examination of
the dental hard and soft tissues should include
an assessment of oral hygiene, tooth mobility,
and periodontal status as well as any abnor-
malities in the eruption pattern or tooth mor-
phology. Histopathological examination of
exfoliated or extracted teeth can greatly assist
diagnosis. Common findings are reduced or
absent cementum, wide zones of pre-dentine
within the pulp, irregular root resorption,
reduced numbers of odontoblasts, and fewer
dentinal tubules that may be enlarged10. The
mineralization defects seen in dentine, cemen-
tum, and bone are histologically similar10.
 2012 John wiley & Sons Ltd, BSPD and IAPD
Current concepts in hypophosphatasia 157
A referral to a paediatrician for further investi-
gation is indicated where systemic causes of
early exfoliation of teeth are included in the
differential diagnoses. Reduced serum ALP
activity and elevated serum and urine levels
of TNSALP substrates form the basis of HP
diagnosis although such findings are not
pathognomonic. A case where the diagnosis of
childhood HP was aided by the analysis of gin-
gival crevicular fluid using an ultrasensitive
chemiluminescent assay for ALP has been
described13. This technique does not appear to
be widely practiced, perhaps due to the com-
plexity of the test and the lack of published
data regarding the method.
In this case, the diagnosis of OHP was not
clear until the results of histopathology were
obtained as laboratory assays were inconclu-
sive. Whilst serum ALP activity is reduced in
OHP, values may lie towards the lower end of
the reference range22, as was the case with
ER. Furthermore, Hu et al.2 studied a kindred
of 21 family members with dominant HP and
concluded that serum ALP levels were a poor
predictor for children affected by HP (i.e., dis-
playing clinical symptoms of HP or having at
least two abnormal laboratory investigations)
under the age of 17 years. In their study,
urine PEA and serum PLP appeared to be
more reliable predictors for affected indi-
viduals. Despite normal laboratory assays, a
diagnosis of OHP was made following histo-
pathological examination.
Dental follow-up
Whilst there are numerous published reports
of HP, the dental management has not been
well documented. In primary, mixed, and
permanent dentitions, dental management
should be focused on rigorous oral hygiene
and preventive regimes aimed at minimizing
the exacerbation of periodontal pathology and
the prevention of other dental pathology.
Management may also include the replace-
ment of permanent exfoliated teeth, most
commonly with removable prostheses in
young patients. Careful monitoring is required
to identify periodontal disease progression,
which may be an indication of the degree of
systemic involvement. Early involvement and
158 A. Hollis et al.
regular review by the specialist paediatric
dental team is indicated because of the multi-
disciplinary approach that is required and the
unpredictable clinical course of the disease.
Summary
This case demonstrates the diagnostic difficul-
ties that may be associated with HP and high-
lights the importance of thorough investigation
of patients presenting with early loss of primary
teeth. Histological examination greatly aided
the definitive diagnosis. Whilst systemic com-
plications were not clinically apparent in this
case, it was important to obtain a definite
diagnosis to both exclude the risk of future
systemic manifestations and alleviate parental
anxiety associated with the premature exfolia-
tion of primary teeth. In addition to this, once a
diagnosis is confirmed, genetic counselling can
be arranged. In the future, enzyme replace-
ment therapy may provide a therapeutic option.
Recently, clinical trials have been undertaken
using bone-targeted TNSALP in a small number
of infants and young children with severe HP as
well as in juveniles and adults with the condi-
tion. The results of these trials, including its
effect on dentition, are awaited. At present,
there is no approved medical therapy for HP.
Why this clinical report is important to paediatric
dentists
d This report summarizes key aspects of hypophosphata-
sia and current concepts in its management
d The literature review and case report highlights the
importance of including hypophosphatasia amongst
the differential diagnoses for patients presenting with
premature exfoliation of primary teeth
d The case report provides a guide to the investigations
that are required to arrive at a diagnosis of hypophos-
phatasia and ⁄ or odontohypophosphatasia
Conflict of interest
There is no conflict of interest.
Acknowledgements
We would like to thank Medical and Dental
Illustration at Leeds Dental Institute for their
help with the figures.
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