Oral health in Autoimmune Polyendocrinopathy

Candidiasis Ectodermal Dystrophy (APECED)

E. McGovern*, P. Fleming*,** , C. Costigan***, M. Dominguez***, D. C. Coleman*, J. Nunn **

*Dental Dept., Our Ladys Childrens Hospital, Crumlin; **Division of Public and Child Dental Health, Dublin
Dental School and Hospital, University of Dublin, Trinity College; ***Dept. Endocrinology, Our Ladys Childrens
Hospital, Crumlin, *Microbiology Research Unit, Division of Oral Biosciences, Dublin Dental School and Hospital,
University of Dublin, Trinity College; Dublin, Ireland.

Abstract
Background: APECED (Autoimmune Polyendocrinopathy ectodermal disorders, including hypoplasia of dental enam-
Candidiasis Ectodermal Dystrophy) is a rare autosomal re- el. The presence of at least two of the following three major
cessive disease characterised primarily by sequential im- clinical signs are required to define the syndrome - Addisons
mune-mediated destruction of endocrine tissues, chronic disease, hypoparathyroidism, and chronic mucocutaneous
oral or mucocutaneous candidiasis and ectodermal disor- candidiasis [OMIM 240300].
ders, including hypoplasia of dental enamel. Aim: This was The most characteristic ectodermal manifestations of
to investigate the oral health and presence of enamel defects APECED are enamel defects (Figure 1), pitted nail dystro-
in a cohort of patients with APECED. Methods: 16 patients phy and alopecia. Perheentupa [2002] reported that enamel
with APECED (mean age of 13.9 years) were matched for defects were present in 75% of a cohort of patients in Fin-
age and gender with healthy controls. A comprehensive land. The aetiology of enamel defects in this disease remains
medical, dental and drug history was recorded, followed by a unclear [Perniola et al., 1998]. Porter et al., [1995] reported
clinical assessment of oral health which was determined by an association of enamel defects with hypoparathyroidism,
assessing periodontal treatment needs, prevalence of dental but Ahonen et al. [1990] suggested that there was no such
caries, erosion, fluorosis and enamel defects. The estimated association. The aim of the present study was to investigate
time of the development of the enamel defects and the con- the oral health and presence of enamel defects in a cohort
temporaneous medical diagnosis were recorded. Results: of Irish patients with APECED and to determine the medical
Oral health of patients with APECED was poor compared diagnosis if there was any, and the estimated time of devel-
with controls, with a higher prevalence of periodontal dis- opment of enamel defects.
ease, caries and erosion. There was a significantly (P < 0.05)
higher prevalence of enamel defects in the study group. The Fig 1. Extensive enamel defects in a patient with Autoimmune
enamel defects were mostly hypoplastic in the form of pits, Polyendocrinopathy Candidiasis Ectodermal Dystrophy.
missing enamel and grooves. The enamel defects occurred
in a chronological pattern. There was a strong association
between the estimated time of defective enamel formation
and a history of hypoparathyroidism. Gastrointestinal dys-
function and a history of chronic mucocutaneous candidiasis
were also associated with the presence of enamel defects.
Conclusion: The oral health of individuals with APECED was
poor compared with controls with a higher prevalence of
periodontal disease, caries, erosion and enamel defects. The
enamel defects in the study population occurred in a chrono-
logical pattern and some were associated with a history of
systemic disease during the period of tooth development.

Introduction Materials and methods

Autoimmune polyendocrinopathy candidiasis ectodermal
dystrophy (APECED) is a rare, but well-defined, monogenic
autosomal recessive disease associated with mutations in
the AIRE gene. There is defective tolerance to self-antigens
that is characterised primarily by endocrine organ-specific
autoimmunity, chronic mucocutaneous candidiasis and
Study group. A group of 16 Irish patients with APECED (all
patients had a confirmed mutation in the AIRE gene) were
matched for age and gender with an equal number of healthy
controls who volunteered to take part in this study. The con-
trol patients were chosen randomly from either the under-

Key words: Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy, Enamel defects, Hypoparathyroidism
Postal address: Dr. E. Mc Govern, Dental Dept., Our Ladys Childrens Hospital, Crumlin, Dublin 12, Ireland.
Email: eleanor.mcgovern@dental.tcd.ie

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 Oral health and APECED

graduate paediatric dentistry clinic or the dental trauma-
tology clinic at the Dublin Dental School and Hospital. The
examiner (EMcG) underwent training and calibration to the
National Standard in Dental Epidemiology. Patients, parents
or guardians as appropriate provided informed consent.
Examination and History. A comprehensive dental, medical,
and drug history was recorded. Patients underwent a clinical
examination (by EMG) seated in a dental chair with a con-
ventional dental light for illumination. A standardised visual
examination was undertaken of the oral mucosa, periodon-
tal tissues and teeth. A clinical assessment of oral candidi-
asis was undertaken along with laboratory investigations of
oral Candida species present, relative density and antifungal
drug susceptibility. Detailed results of clinical and laboratory
findings in relation to oral candidiasis and Candida species
will be reported in a separate paper.
The periodontal examination included a clinical assessment
of oral hygiene status, and a decision on the need for oral
hygiene instruction (OHI) only or OHI and plaque and calculus
removal. The need for urgent treatment was also determined.
Periodontal tissues were visually assessed and without prob-
ing of the tissues [National Childrens Oral Health Survey in
Ireland in 2002]. The prevalence of dental caries was deter-
mined using the WHO criteria [WHO, 1987], with the addition
of visual non-cavitated dental caries as used in the national
survey [National Childrens Oral Health Survey in Ireland,
2002]. DMFT/S, dmft/s were reported in the mixed dentition
until 8 years of age, after which age dft and dfs were reported
in conjunction with DMFT and DMFS. The teeth were exam-
ined wet and a periodontal probe used only to remove food
debris. The presence of erosion was recorded using the cri-
teria developed for the oral health examination as part of the
UK National Dietary and Nutrition Survey of 4-18 year olds
[Gregory et al., 2000]. Deans Index was used to determine
the prevalence of fluorosis [Dean et al., 1942].
The modified Developmental Defects of Enamel [DDE] in-
dex, for use in epidemiological studies, was used to assess
enamel defects [FDI, 1992]. The location of the defect was
recorded as occurring either in the gingival or the incisal one
half or the occlusal or cuspal areas. The estimated time of
development of each enamel defect was determined by cor-
relating the location of the defect with the estimated time of
development of that particular area of the tooth. The con-
temporaneous medical diagnosis (taken from patient files) of
any of the systemic/endocrine features of APECED for each
individual was correlated with the age range of timing of the
enamel defects. A schematic diagram of dental development
was used as an aid in determining the approximate timing
of the enamel defect [Hall, 1994]. Dental panoramic radio-
graphs were not available for many individuals, but dental
development and eruption sequence were noted clinically.
Results quoted in this study were mainly of a descriptive na-
ture with the exception of one Student T-Test.

Table 1. Characteristics of patients with Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy

Number Time of
Age Medical *Oral CMC Enamel Features of
Subject Sex of teeth enamel
(yrs) History candidiasis * defects APECED**
affected defects
1 7 M AI AH Y Y N 0 Not applicable Not applicable
2 15 F None N Y Y 1 0-3 yrs Not applicable
Autoimmune hepa-
3 18 M HPT AI AH GI Y Y Y 15 1-7 yrs
titis
4 17 F HPT AI Y Y Y 14 2-7 yrs Hypoparathyroidism
5 14 M HPT AI Di GI Y Y Y 4 1-6 yrs Diabetes
6 14 F HPT AI Y N Y 6 0-7 yrs Hypoparathyroidism
7 6 F HPT A GI Y Y N 0 NA Not applicable
8 2 M HPT AI GI Y Y N 0 NA Not applicable
9 11 M HPT AI GI Y Y Y 3 1-7 yrs Hypoparathyroidism
10 15 M HPT A N Y Y 24 1-7 yrs Hypoparathyroidism
11 9 M AI Y Y Y 1 In utero In utero
12 39 F HPT Di A GI Y Y Y 4 0-7 Hypoparathyroidism
13 13 F HPT AI A GI Y Y Y 4 0-2 yrs None
14 7 F HPT GI Y Y N 0 NA Not applicable
15 21 F HPT AI GI Y Y Y 18 0-7 yrs HPT
16 15 F HPT AI A Y Y Y 13 0-7 years HPT
*= History of ** = Features of APECED at time of development of enamel defects AI = Adrenal insufficiency, A = Alopecia, AH = Autoimmune hepatitis, CMC =
Chronic Mucocutaneous Candidiasis, Di = Diabetes, GI = Gastrointestinal, HPT = Hypoparathyroidism, F = Female, M = Male, Y = Yes, N = No

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McGovern et al.

Results Table 2. Frequency of occurrence of the main disease com-

The study and control population each consisted of 7 males ponents in 16 Irish patients with Autoimmune Polyendo-
and 9 females, ranging from 2 to 39 years of age, with a crinopathy Candidiasis Ectodermal Dystrophy.
mean and median age of 13.3 years and 14 years respec- Major disease component Number of patients
tively. All patients were Irish and Caucasian.
Chronic Mucocutaneous Candidiasis 15
Medical History. The gene mutations of the 16 patients with Hypoparathyroidism 13
APECED were identified in the Diagnostic Laboratory of Hel- Adrenal insufficiency 11
sinki University Hospital, Finland. The main features of the
Gastrointestinal dysfunction 9
patients with APECED are presented in Table 1. A summary
Alopecia 5
of the frequency of occurrence of the medical features for
the study group is presented in Table 2. None of those in the Autoimmune Hepatitis 2
control group had a significant history with the exception of Diabetes 2
one patient who had mild asthma. Gonadal failure 1
Pernicious anaemia 1

Table 3. Drug regime and oral health in a group of patients with Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy.

Erosion
Subject Drug regime Dental caries Periodontal treatment needs Presence Number of teeth
of erosion affected
Florinef
dmft 0
Itraconazole
dmfs 0
1 Neostatin drops Oral hygiene needed Y 6
DMFT 0
Miconazole oral gel
DMFS 0
Mycostatin liquid
DMFT 0
2 Nil Scaling and prophylaxis needed Y 1
DMFS 0
Hydrocortisone
DMFT 1
3 Florinef Scaling and prophylaxis needed Y 6
DMFS 1
Mycostatin liquid
Prednisilone
Florinef DMFT 9
4 Oral hygiene needed Y 12
One-alpha DMFS 13
Miconazole gel
Azothioprine
Hydrocortisone
DMFT 0
5 Florinef Oral hygiene needed N None
DMFS 0
One-alpha
Miconazole gel
Florinef
Hydrocortisone
Oestrogen DMFT 4
6 Oral hygiene needed Y 16
One-alpha DMTS 5
Becotide
Mycostatin
dmft 0
One-alpha dmfs 0
7 No treatment needed N None
Mycostatin DMFT 0
DMFT 0
One-alpha
Florinef dmft 0
8 No treatment needed N None
Mycostatin dmfs 0
Fluconazole

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 Oral health and APECED

Growth hormone
One-alpha
dft 2
Calcium
dfs 2
9 Itraconazole Oral hygiene needed N None
DMFT 2
Fluconazole
DMFS 2
Mycostatin liquid
Miconazole gel
DMFT 3
10 One-alpha Oral hygiene needed N None
DMFS 3
Florinef dft 4
Hydrocortisone dmfs 12
11 Oral hygiene needed Y 4
Miconazole gel DMFT 0
Fluconazole DMFS 0
B12 injections
Insulin
One-alpha
Vitamin D
DMFT 1
12 Daktarin gel Scaling and prophylaxis needed N None
DMFS 2
Mycostatin liquid
Fluconazole
Chlorhexidine
Itraconazole
Prednisilone
Potassium
Magnesium
Losec
DMFT 3
13 Adek Scaling and prophylaxis needed Y 16
DMFS 3
One-alpha
Florinef
Mycostatin liquid
Itraconazole
dft 7
One-alpha dfs 9
14 No treatment needed N None
Miconazole DMFT 0
DMFS 0
Hydrocortisone
Prednisilone
One-alpha
Magnesium
DMFT 2
15 Florinef Prophylaxis needed Y 2
DMFS 4
Delta cortical
Miconazole
Mycostatin
Fluconazole
Fluconazole
Mycostatin
Itraconazole DMFT 1
16 Oral hygiene needed Y 8
One-alpha DMFS 2
Hydrocortisone
Florinef
Y = yes N = No D/d =Decayed M/m = Missing F/f = Filled T= teeth S = surfaces

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Table 4. Comparison of oral health between patients with Autoimmune Polyendocrinopathy Candidiasis Ectodermal Dystrophy
(APECED) and control patients.

Oral health APECED patients Control patients

Periodontal treatment need *
No treatment needed 3 9
OHI required 8 5
OHI and plaque and calculus removal 5 2
Urgent treatment needed 0 0
Brushes at least twice daily 15 12
Caries
% caries free 31% 19%
DMFT 2 1.53
DMFT range 0-9 0-6
DMFS 2.3 2
dmft 0 -7 years old 0 5
dmft range 0 -7 years old 0-4 0-8
dmfs 0 -7 years old 0 8
**dft 8 years old 4.3 3.3
**dft range 8 years old 4-7 0-6
**dfs 8 years old 7.6 6.6
*** DMFT (8-15 year olds) (n = 9) 1.4 1.6
Erosion * 9 2
Range of teeth affected 1 - 16 6-7
Mean number of teeth affected 7.8 6.5
Fluorosis * 0 1
Enamel defects * 12 5
Range of teeth affected 1 - 24 1-5
Mean no. of teeth affected 10 1.8
Total number of teeth affected in group 118 9
Type of defect *
Opacities:
Demarcated Opacities 10 5
Diffuse Opacities 7 1
Hypoplasia:
No. of individuals affected 10 1
No. of teeth affected 95 1
Hypoplasia & Opacities Individuals with > 2 types of defects 10 1
Incisors
Teeth most commonly affected Premolars First permanent molars
Second permanent molars
* Number of individuals affected; ** m (missing) excluded for individuals 8 years old; *** National mean DMFT = 1.4 in fluoridated areas (North South Survey of
Childrens Oral Health 2002), OHI = oral hygiene instruction D/d = decayed M/m = missing F/f = filled

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 Oral health and APECED

Drug therapy. Of the 16 patients in the study group 15 were Fig 2. Severity/extent of enamel defects in 118 teeth with
taking a combination of systemic and/or topical medica- enamel defects in patients with Autoimmune Polyendo-
ments on a daily basis (Table 3). One person in the control crinopathy Candidiasis Ectodermal Dystrophy.
group reported the regular use of an inhaled corticosteroid
for the management of mild asthma.
Oral Health. The oral health of patients with APECED was
found to be poor compared with an age and gender matched
group of healthy controls in this study. The OH status of each
patient with APECED is presented in Table 3, and is sum-
marised for both study and control groups in Table 4. The
periodontal treatment need was greater among patients with
APECED with 81% requiring OHI with or without scaling and
polishing compared to 43% of controls. The mean DMFT,
dmft, and dft was 2.0, 0.0 and 4.3 for APECED patients re-
spectively, and 1.5, 5.0 and 3.3 for control group individuals,
respectively; 5 patients with APECED were caries-free, com-
pared with 3 in the control group.
There were 9 patients with APECED who had signs of ero-
Fig 3. Enamel defects in a patient with hypoparathyroidism.
sion affecting an average of 7.8 teeth per patient, compared
with 2 patients in the control group who had signs of erosion
with an average of 6.5 teeth affected per patient. The ero-
sion in both groups extended into enamel only and affected
over 2/3 of the tooth surface. The prevalence of erosion in
the study group could not be correlated with any particular
drug regime. One of the children in the control group dem-
onstrated clinical signs of generalised mild enamel opacities
consistent with a diagnosis of mild flourosis.

Enamel defects and medical history in

patients with APECED
Characteristics of Enamel defects. The characteristics of the
enamel defects are summarised in Table 1 for patients with
APECED and in Table 4 for both groups. Enamel defects oc-
curred in 12 patients with APECED with a mean number of Fig 4. Enamel defects in a patient with adrenal insufficiency,
10 teeth affected per patient, compared with 5 patients in the hypoparathyroidism and gastrointestinal dysfunction.
control group with a mean of 1.8 teeth affected per patient (P
< 0.05). Enamel defects (118 affected teeth in the APECED
group) included both hypomineralised and hypoplastic de-
fects. Enamel hypoplasia was more prevalent in the APECED
group with 95 (80%) of the 118 affected teeth displaying hy-
poplastic enamel. Enamel hypoplasia occurred in 10 of the
12 patients with APECED and enamel defects (mean 9.5 hy-
poplastic teeth per patient) compared with one patient (one
tooth) in the control group.
The extent of the enamel defects in the 118 teeth of patients
with APECED is summarised in Figure 2; 83 (70%) teeth had
less than 1/3 of the total tooth surfaces affected. The teeth
most commonly affected in the study group were incisors,
premolars and second permanent molars. First permanent
molars were more frequently affected in the control group.
The estimated time of development of enamel defects was
between 4 and 7 years of age in the APECED group, with the
gingival 1/3 the most frequently affected site (83% of cases).

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McGovern et al.
Enamel defects and Hypoparathyroidism (HPT). Of the 13
patients with Hypoparathyroidism (HPT) 10 had enamel de-
fects (Figure 3). The estimated time of development of the
enamel defects coincided with the diagnosis of HPT in 6 pa-
tients. A diagnosis of HPT was made one year later than the
estimated time of the development of enamel defects in two
patients and approximately 6 years later than the estimated
time of development of enamel defects in another 2 patients.
There were 3 patients with HPT who did not demonstrate
clinical signs of enamel defects. One of these patients was
still in the primary dentition and the other two in the very
early mixed dentition stage of dental development (Table 1).
Enamel defects and gastrointestinal disturbance (GI). Enamel
defects occurred in 6 of the 9 children with a history of GI
disturbance. One of the 3 children with a history of GI distur-
bance, but with no enamel defects, was in the primary stage
of dental development and the other two children in the early
mixed dentition stage (Table 1).
Enamel defects and Adrenal insufficiency (AI). Of the 11 pa-
tients with AI, 9 had enamel defects (Figure 4). The estimated
time of development of enamel defects did not coincide with
the time of diagnosis of AI in any of these patients. There
were 4 patients diagnosed with AI approximately one year
later than the estimated maximum age range of development
of enamel defects. The remaining 5 patients were diagnosed
with AI approximately 2, 4, 6, 9 and 10 years later than the
maximum age range for the development of enamel defects.
There were 8 of the 9 patients in the mixed or permanent
dentition and 1 was in the early mixed dentition with enamel
defects on the primary incisors. The other 2 patients with
adrenal insufficiency and without clinical signs of enamel de-
fects were in the primary dentition stage of dental develop-
ment (Table 1); 8 of the 9 patients with AI and enamel defects
also had hypoparathyroidism.
Enamel defects and Candida history. There were 14/16 pa-
tients with APECED with a history of oral candidiasis and
15/16 had a history of chronic mucocutaneous candidiasis
(Table 1). 10 of the patients with a history of oral candidiasis
and 11 with a history of chronic mucocutaneous candidiasis
had enamel defects. (Table 1).
History of APECED and estimated time of development of
enamel defects. Of the patients with APECED 10 had enamel
defects and 9 of these patients had a feature of APECED at
the estimated time of the occurrence of the enamel defect;
7 had hypoparathyroidism (HPT), 1 had diabetes (Di) and 1
had autoimmune hepatitis (AH). There were 3 patients with
APECED and enamel defects did not have a specific fea-
ture of APECED at the estimated time of development of the
enamel defects (Table 1).
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European Archives of Paediatric Dentistry // 9 (4). 2008
Discussion
In this study there was difficulty in accessing patients with
APECED in Ireland for inclusion in the study. The prevalence
of APECED in the Irish population is 1 in 130,000 [Dominguez
et al., 2006]. A number of patients with known oral manifes-
tations of APECED, and in some cases severe oropharyngeal
candidiasis and enamel defects, declined to participate in
this study. The study numbers were therefore limited to 16
patients with APECED and 16 control patients.
The periodontal treatment needs among patients with
APECED were high despite the reported history of regular
tooth brushing. This finding may be due to the increased
prevalence of enamel defects and the associated problems
of increased plaque accumulation in the APECED group.
Longstanding oral candidiasis and an associated sore mouth
may also challenge the maintenance of good oral hygiene.
The caries experience of patients with APECED was gener-
ally higher than that of controls, except in children less than
8 years of age, who had a lower caries experience in the
primary dentition than that found in the controls. The study
group were age and gender matched with patients (con-
trols) attending the Dublin Dental School and Hospital. The
younger controls were generally recruited from undergradu-
ate treatment clinics and the older controls from trauma clin-
ics. Management of dental caries is usually one of the main
reasons for attending undergraduate dental treatment clin-
ics. This may account for the high caries experience in the
primary dentition of the control group.
Enamel erosion was more prevalent among patients with
APECED (56%) than in controls (12%). However, the severity
and extent of erosion in affected patients was similar in both
groups. 15/16 patients with APECED were taking medication
on a daily basis but the increased prevalence of erosion was
not associated with any particular drug regime. The acidity
and sugar content of liquid medicines have been previously
reported [Maguire et al., 2007; Nunn et al., 2001; Maguire
and Rugg-Gunn, 1996]. Many medicaments consumed by
patients with APECED are potentially cariogenic and erosive.
Fluconazole suspension contains, among other ingredients,
sucrose and citric acid, mycostatin oral suspension contains
sucrose and hydrochloric acid and nystatin pastilles contains
glucose, sucrose and hydrochloric acid. Further research
into the acidity and sugar levels of the drug combinations
used by this patient group is indicated. In addition consid-
eration should also be given to the frequent consumption of
sugary and acidic drinks, particularly during times of illness,
as a possible aetiological factor in the erosion and caries
observed in patients with APECED.
The prevalence of enamel defects differed significantly (P<
0.05) between the two groups, with the largest number of
enamel defects present in patients with APECED. Enamel
hypoplasia in the form of pits, groves or missing enamel was
the most prevalent defect, affecting 80% of affected teeth in

the study group. Where there was missing enamel the hyp-
oplasia was often of the thin, hard and rough type. Perniola
et al. [1998] assessed enamel hypoplasia in 4 individuals
with APECED. They described the defects as occurring as
grooves or rows of pits of variable width and depth, but
sometimes a larger portion of the crown was hypoplastic.
In such cases they concluded that there was prolonged dis-
ruption in amelogenesis during most of the period of crown
development. In our study the extent of the enamel defects
varied among patients with APECED, with the majority of de-
fects (70%) affecting less than 1/3 of the tooth surface. This
would suggest that the development of the enamel hypopla-
sia was attributable to a systemic or metabolic upset that oc-
curred during that period of tooth formation. Similar findings
were reported by Myllarniemi et al. [1978] who described
enamel hypoplasia in patients with APECED as appearing
as bands on the teeth corresponding to defined periods of
enamel formation.
Hypoparathyroidism (HPT) is associated with a reduction in
the concentration of calcium ions in the peripheral blood.
Enamel defects in association with a history of HPT have
been previously described [Greenberg et al., 1969; Welbury
et al., 1986]. In our study 10 of the 13 patients with HPT
had enamel defects; 8/10 of these patients were diagnosed
with HPT within +/- 1 year of the estimated timing of the de-
velopment of the enamel defect. The other 2 patients were
not diagnosed with HPT until 6 years after the estimated oc-
currence of the enamel defects. The 3 children in our study
with APECED and HPT and with no enamel defects were in
the primary dentition or early mixed dentition stage of devel-
opment. Enamel defects could be present in the unerupted
premolar and second permanent molar teeth that developed
during the time of potential hypocalcaemia associated with
HPT.
Welbury et al. [1986] reported on two cases of APECED and
concluded that enamel hypoplasia can both pre-date and
post-date the onset of clinical hypocalcaemia, even when
there is adequate replacement therapy and biochemical
evidence of normal serum calcium levels. Myllarniemi et
al. [1978] who described enamel defects in patients with
APECED, similar to those found in our study, concluded
that enamel defects were not attributable to HPT. Greenberg
et al. [1969] carried out a review of published literature on
HPT and enamel hypoplasia. In half of the cases, enamel
hypoplasia was reported to affect regions of the teeth that
had formed many years before there was clinical evidence
of hypocalcaemia. A number of potential causes of enamel
hypoplasia were proposed by Greenberg et al. [1969]. One
suggestion was that serum calcium levels were low enough
to cause enamel mineralisation defects but not low enough
to affect neuromuscular excitability. Another suggestion was
that endocrine/renal mechanisms may maintain serum calci-
um and phosphorous in the normal range, even though there
may be marked mobility of these inorganic components at
Oral health and APECED
tissue level causing enamel defects. Alternatively the enamel
hypoplasia may be the result of an immune response, mani-
fested as early enamel hypoplasia and mucosal candidiasis,
that subsequently leads to hypoparathyroidism [Greenberg
et al. 1969]. Finally Greenberg suggested that the enamel
defects might be attributed to childhood illness.
In our study Adrenal Insufficiency (AI) and enamel defects
occurred in 9/11 patients with APECED. The 2 patients with-
out enamel defects and with AI were children in the primary
dentition stage of dental development. Although AI fre-
quently occurs in APECED [Beeterle et al., 1998], there has
been very little speculation on its direct association with the
enamel defects in APECED. Despite the strong association
in our study between AI and enamel defects, the diagnosis
of AI did not coincide with the timing of the development of
the enamel defects in any of the patients. In fact, AI was di-
agnosed from between 1 to 10 years following the estimated
time of development of enamel defects. AI can commence
development but not manifest clinically from a few months
of age to several years of age if a patients serum contains
antiadrenocortical antibodies [Peerhentuba, 2002]. The un-
derlying development of AI could therefore be sufficient to
interfere with amelogenesis but not to cause clinical signs of
AI. Mineralocorticoid deficiency was often observed as the
first manifestation of AI in our study group [Dominguez et al.,
2006]. The frequent occurrence of HPT in patients with AI and
enamel defects has however reduced the significance of AI
as an aetiological factor in the enamel defects in APECED.
Pindborg [1982] has reviewed many factors associated with
enamel defects. Hypothyroidism, HPT, APECED and diabe-
tes were described in association with enamel defects. In
his review of enamel defects, Pindborg also included the
concept of infectious disease as a causative factor. He de-
scribed reports of viral infections (e.g. rubella) in association
with enamel defects in the primary dentition. He reported on
bacterial infections (e.g. syphilis) and the associated enamel
defects of mulberry molars. In the present study there was
a strong association between oral/chronic mucocutaneous
candidiasis (CMC) and enamel defects. It could be suggest-
ed that the actual fungal infection, systemic or local, could
be the insult, or at least a significant contributory factor, or
perhaps just the marker of illness that interferes with the very
delicate process of amelogenesis. It is not clear if autoim-
mune disease predisposes to CMC or if CMC predisposes
to autoimmune disease, or indeed if both diseases have a
common underlying cause. Greater than 50% of cases of
CMC are associated with an endocrine disease [Coleman et
al., 1997], thus, the enamel defects could be attributed to the
autoimmune disease itself or the CMC.
In this study 6/9 patients with APECED and a history of gas-
trointestinal disturbance had enamel defects in the perma-
nent dentition. The other 3 patients were either in the pri-
mary or early mixed dentition stage of dental development
and enamel defects may therefore be present on unerupted
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European Archives of Paediatric Dentistry // 9 (4). 2008
McGovern et al.
teeth. Gastrointestinal disturbances associated with APECED
include diarrhoea, steatorhea, constipation and malabsorp-
tion. A case report of a patient with APECED [Hogenaur et
al., 2001] describes severe malabsorption caused by a defi-
ciency of cholecystokinin-producing enteroendocrine cells in
the mucosa of the proximal small intestine. Cholecystokinin
(CCK) is a gastrointestinal hormone stimulated by fats and
amino acids and stimulates gallbladder contraction. Poor
gallbladder emptying attributed to low CCK levels may lead
to fat malabsorption. This may in turn affect absorption of
fat-soluble vitamins such as Vitamin D that are essential for
calcium homeostasis. Disturbances of calcium homeostasis
may impact on tooth development. It would appear from the
case reported by Hogenaur et al., [2001], that the patient
also experienced periods of remission from malabsorption.
It may be that autoimmunity to GI-associated endocrine cells
has a fluctuating pattern [Gianani and Eisenbarth, 2003] and
therefore that calcium imbalance associated with fat mal-
absorption may also fluctuate. This might offer an explana-
tion for the development of enamel defects in patients with
APECED and for their chronological nature.
Conclusion
The oral health of 16 patients with APECED was poor com-
pared with age and gender matched controls with a higher
prevalence of periodontal disease, caries in the late primary
dentition and in the permanent dentition, erosion and enamel
defects. The enamel defects in patients with APECED were
mostly hypoplastic and occurred in a chronological pattern,
most likely reflecting a transient disturbance of tooth devel-
opment. There was a strong association between the esti-
mated timing of development of enamel defects in patients
with APECED and the diagnosis of hypoparathyroidism. Ga-
trointestinal dysfunction, and a history of oral or chronic mu-
cocutaneous candidiasis were also associated with enamel
defects.
Acknowlegements
We would like to express our gratitude to the National Centre for Medical Ge-
netics, Our Ladys Childrens Hospital, Crumlin, Dublin for their role in confirm-
ing the diagnosis of APECED in our patients. We would also like to thank Pro-
fessor Hilary Hoey, (The Adelaide and Meath Hospital incorporating National
Childrens Hospital, Tallaght, Dublin) for permission to access the children with
APECED in her care. Permission was granted by the paediatric endocrinolo-
gists (from Our Ladys Childrens Hospital, Crumlin, Dublin and The Adelaide
and Meath Hospital incorporating The National Childrens Hospital, Tallaght,
Dublin) involved in the care of these patients to access the Irish APECED data-
base. Ethical approval for this study was obtained from the research commit-
tee in Our Ladys Childrens Hospital, Crumlin, Dublin and from the St. Jamess
Hospital and Adelaide and Meath Hospital, Dublin incorporating The National
Childrens Hospital research ethics committee.
244
European Archives of Paediatric Dentistry // 9 (4). 2008
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