Download Tooth developmental anomalies in severe combined

G. Cossellu*, R. Seramondi*, S. Benedicenti**,
G. Farronato***, G. Olivi****, F. Angiero**
*Department of Orthodontics, University of Milan,
Orthodontic Department, Fondazione IRCCS Cà Granda,
Ospedale Maggiore Policlinico, Milan, Italy
**University of Genoa, Department of Medical Science,
Dentistry, and Biophysics, University of Genoa, Italy
***School of Orthodontics, Department of Surgical,
Reconstructive and Diagnostic Sciences,
Fondazione IRCSS Cá Granda, University of Milan, Italy
****Department of Endodontics, University of Genoa, Italy
e-mail: [email protected]
Tooth developmental
anomalies in severe
combined
immunodeficiency
disease and juvenile
myelomonocytic
leukemia: common
clinical features and
treatment outcomes
abstract
Background
Human
Severe
Combined
Immunodeficiency (SCID) is a prenatal disorder of
T lymphocyte development that depends on the
expression of numerous genes. Juvenile myelomonocytic
leukemia (JMML), previously known as juvenile chronic
myeloid leukemia (JCML), is a rare, myelodysplastic/
myeloproliferative disease typically presenting in early
childhood.
Case Reports Two cases are described of
immunodeficiency
disorders,
both
treated
with
chemotherapeutic
drugs
(Busulfan
plus
cyclophosphamide) before bone marrow transplantation.
After treatment, these two different cases showed
several similar oral lesions: microdontia, root alterations,
numerous tooth ageneses, incomplete calcification,
enamel hypoplasia, premature apexification and
328
hypodontia. Both subjects underwent dental and
orthodontic treatment. The first phase comprised
orthopaedic treatment using a removable appliance
(Interim-G®) followed by rapid palatal expansion; in the
second phase patients underwent tooth extraction and
were treated using fixed appliances for 19 and 26 months,
respectively (mean 2 years) to obtain final alignment and
maximum intercuspation. In the third and final phase,
reconstruction of malformed teeth was completed, and
implant-supported protheses were applied.
Conclusion The difficulties of managing and treating
these diseases are discussed, with particular focus on tooth
anomalies and malocclusion disorders. Collaboration
between dentist and paediatrician in dealing with
patients with a variety of oral lesions and tooth anomalies
is important in order to prevent any other possible tooth
lesions and ensure correct jaw development.
Keywords Juvenile Myelomonocytic Leukemia;
Severe Combined Immunodeficiency; Tooth agenesis;
Tooth anomalies.
Introduction
Severe Combined Immunodeficiency Disease (SCID)
may be considered to be a primary immunodeficiency,
usually being based on genetic alterations; it is
characterised by an altered count and function of
lymphocytes T and B. Children with this disease show
defective growth and are repeatedly infected by bacteria,
viruses and other opportunistic pathogens. Genetic
alterations that can cause SCID have been described, and
may be summarized as:
• defects of the lymphocyte receptors;
• defects of the intracellular signaling molecules;
• defects of the transcription enzymes;
• defects of the enzymes of purine metabolism, such
as adenosine deaminase (ADA) and purine nucleoside
phosphorylase (PNP).
The incidence of SCID is between 1/50000 and
1/75000 live births [Fischer et al., 1997]. Without bonemarrow transplantation, patients die during the first year
of life [Friedrich, 1996]; they generally acquire infections
during the first three months, with rash or erythema
on the legs where the diaper ends, due to candida or
monilia. Even if growth and bone development may
progress normally during the first three months, after
that period an alteration of normal growth patterns is
seen.
Some of these children present a measles-like skin rash
immediately after birth, due to the transplacental diffusion
of lymphocytes from the mother to the newborn baby,
which may cause a graft-versus-host reaction (GFHR). If
the patient becomes infected by herpes virus, adenovirus
European Journal of Paediatric Dentistry vol. 14/4-2013
Tooth anomalies in patients with immunodeficiency disorders: report of two cases
or cytomegalovirus, death may supervene within a few
days. Diagnosis of severe combined immunodeficiency
disease should be considered, and must be treated as a
severe emergency; this disorder may lead very rapidly to
the patient’s death, although the infant can be treated by
restoring a correct immune system through bone-marrow
transplantation [Atkinson et al., 2000; SzczawinskaPoplonyk et al., 2009]. Infants affected by SCID typically
have severe lymphopenia (lymphocytes <1000 per m3).
Oral manifestations currently reported in the literature
include oral infections due to candida, herpes infections,
recurrent ulcers of the oral mucosa and tongue, and
necrotising gengivitis [Jaffe, 1991; Antoine, 2003;
Hoffmann 2009].
Chronic Myeloid Leukaemia (CML) is a bone-marrow
stem-cell deficiency characterised by severe accumulation
of granulocytes of differing degrees of maturation,
mainly in the bone marrow, but also in the extra-marrow
area, as well as in the blood, spleen and liver. From the
genetic standpoint, in 95% of patients the presence of
the Philadelphia chromosome has been demonstrated
(1969); this is derived from the translocation of genes
ABL and BCR, located on chromosomes 9 and 22, and
leads to the leukemic differentiation of other normal stem
cells [Hoffmann, 2009]. This is caused by an alteration of
stem-cell DNA and may be clinically expressed in adult
patients as well as in children: it is much common in
adults, with a predilection for the male gender 3:2 at
age 40-50.
CML may account for 15-20% of known cases of adult
leukemia and 4% of childhood leukemias; its incidence
increases with age (1 case in 1,000,000 among children
aged <10 years; 1:100,000 adults aged < 40 years;
1:10,000 adults aged < 80 years) [Hasle et al., 2003]. It
may be considered to have three main stages [Millot et
al., 2003]:
1)the chronic stage (lasting 3-5 years), or first phase,
characterised by a stable clinical aspect, with few if
any symptoms (e.g. abdominal pain, pallor, tiredness,
weight loss, anorexia, nocturnal sweating);
2) the accelerated phase (lasting weeks or months), an
intermediate phase during which there is a worsening
of clinical values (splenomegaly, arthralgia, asthenia,
fever) and blood chemistry values (leucocytosis with
immature granulocytes and a very marked increase in
the number of basophils and eosinophils, low levels
of leukocytic alkaline phosphatase, high blood/serum
levels of uricemia, LDH, vitamin B12 and histamine);
3)the blastic stage (if therapy fails, this stage lasts no
more than a few months); the last phase, characterised
by pain at the spleen (infarction), lymphoadenopathy,
hemorrhage, fever, arthralgia, myalgia with
characteristics of acute leukemia.
At onset, CML may be entirely asymptomatic: most
patients only notice a slow but progressive decline in
their general health, associated with skin pallor, fatigue,
breathlessness at the slightest effort, heavy feeling
European Journal of Paediatric Dentistry vol. 14/4-2013
at the left flank. Clinically, the most frequent finding
is enlarged spleen, which may cause a sensation of
abdominal tension and early satiety after meals; at the
oral cavity it manifests with lymphadenopathy, pain at
the larynx, mouth ulcer, bleeding and hypertrophy of
the gums [Nikoui and Lalonde, 1996; Hou et al., 1997;
Cousin,1997].
Diagnosis of CML is frequently achieved by chance
during the chronic phase of the disease (85% of cases),
during routine medical checkups (e.g. ECM) and/or
investigations for other diseases. Depending on the
severity and prognosis of CML, therapy may include
allogenic bone marrow transplant and/or of stem cells
from a HLA compatible donor (curative if performed
at an early phase of the disease), chemotherapy,
antineoplastic immunosuppressive drugs (e.g. busulfan,
hydroxy-urea, INF-a, imatinib), irradiation of the spleen,
and splenectomy [Goldamn and Melo, 2003; Ding et al.,
2010].
The juvenile form (JCML/JMML) in particular is a rare
neoplasm, without the acquired chromosome anomaly
typical of the adult form (Philadelphia chromosome).
It is characterised by irritability, lympho-adenomegaly,
hemorrhage, skin reactions (erythema, desquamation)
hepato-splenomegaly, bronchospasm, dyspnea, with
peaks of incidence below two years of age, and prevalence
in male infants (ratio 2-3:1) [Hasle et al., 2003].
This paper describes two cases with similar anomalies
in dental development in patients who had been treated
for systemic diseases with chemotherapy agents and
bone marrow transplantation.
Case reports
Two patients were referred to the Department of
Orthodontics, University of Milan, complaining of
malocclusion, difficulty in chewing and speech. One
patient had juvenile myelomonocytic leukemia (JMML)
and the other had severe combined immunodeficiency
disease (SCID). Both had been treated with chemotherapy
agents and bone marrow transplantation (BMT).
Case 1
A 7 years-old boy with a medical history of SCID, TB,
and with genetic alteration identified on the Artemis
locus, mutation exon I, T85C->116T; exon V, C381G ->
S119X and polymorphism on nucleoside 681, exon 8.
At the age of 7 months he had been treated with bone
marrow transplantation from a non-related donor; the
donated haematopoietic stem cells had fully taken.
The chemotherapy treatment before bone-marrow
transplantation entailed the administration of busulfan
for the first four days followed by cyclophosphamide for
the next four days. At the time of referral there was a
typical delay in his skeletal development, with persistent
infection of the upper airways, presence of skin nevi, and
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Cossellu G. et al.
fig. 1 Case 1. First OPG (2001) showing ageneses of 18, 15, 14, 12, 24, 25, 28, 34, 35, 38, 44, 45, 48.
fig. 2 Second OPG (2007): tooth 14 is inclined mesially, the roots of the first molars show altered development and appear short.
fig. 3 Intraoral views (2007) Conoid
aspect and microdontia: A. right view;
B. front view; C. left view; D. lower
occlusal view; E upper occlusal view.
non severe alteration of the left ventricle. He responded
well to all therapies and suffered no allergic episodes.
Orthopantamography at 6 years revealed many tooth
ageneses (Fig. 1) and the absence of the following teeth:
18, 15, 14, 12, 24, 25, 28, 34, 35, 38, 44, 45, 48. Intraoral
examination revealed poor oral hygiene, hypertonic lips,
normotrophic face, and hypertonic facial muscles.
In accordance with the paediatrician, the patient
entered an oral hygiene programme to improve his
periodontal health, with fluoride prophylaxis and
subsequent orthodontic treatment.
The orthodontic diagnosis was of biretrusion and
deficit of both maxilla and mandible, and was treated
with a one-piece orthodontic appliance constructed with
1 cm raised bite and upper and lower shields, in addition
to extraction of maxillary V teeth and maxillary IV teeth.
The subsequent OPG showed tooth 14 to be mesioinclined (Fig. 2). The permanent canines were anomalous
in shape, with microdontia and conoid aspect (Fig. 3).
The roots of the permanent teeth, particularly of the
first molars, showed altered development and appeared
short. A fixed appliance was then bonded onto the first
upper left molar, with a traction arm to the upper left
canine, for extrusion of the second upper left premolar. A
330
space maintenance device was applied until completion
of growth, when an implant-supported prosthesis could
be constructed. Malformed teeth were restored with
composite.
Case 2
A 14-year-old boy had undergone bone-marrow
transplantation
and
splenectomy
for
juvenile
myelomonocytic leukaemia (JMML). The chemotherapy
treatment before bone-marrow transplantation entailed
Busulfan plus cyclophosphamide and Melphalan. He
reported compensated arterial hypertension. The OPG
revealed the absence of teeth 12, 15, 18, 22, 25, 27,
28, 35, 38, 45, 47 and 48, with 13, 14, while tooth 23
was impacted (Fig. 4). The clinical examination showed
the presence of 55, 53, 52, 62, 63, 65, 75 and 85, with
microdontia and conoid shape of teeth 34 and 44 (Fig. 5).
The orthodontic treatment was started and it
consisted of rapid palatal expansion with bands on the
first molars and traction arms to extrude the impacted
teeth. A removable appliance (Interim-G®) was then
fitted. Surgical extrusion of the upper canines and of
the first upper right premolar was recently performed.
The case was re-evaluated after two year’s use of the
European Journal of Paediatric Dentistry vol. 14/4-2013
Tooth anomalies in patients with immunodeficiency disorders: report of two cases
orthodontic appliance, the correct vertical dimension
was restored and on completion of this treatment, an
implant-supported rehabilitation and the reconstructed
of the malformed teeth was planned
Orthodontic treatment
The treatment was performed in 2 phases. The first
phase consisted of orthopaedic treatment with a
removable appliance (Interim-G®); this was followed by
rapid palatal expansion with the device attached to the
maxillary first molars, and activated once or twice per day.
Each activation was 0.2 mm and the maximum expansion
possible was 10 mm. Expansion was terminated when
the first molars were in normal occlusion and when there
was sufficient space for the impacted teeth (on average
20 days). The appliance was stabilised and kept in place
as retention for at least 7 months (average 12 months).
In the second phase of the treatment, the permanent
dentition was completed and both patients were
treated using fixed appliances for a mean period of 2
years (19 to 26 months) to obtain final alignment and
maximal intercuspation. Due to the mechanics of fixed
orthodontic treatment, some movements are extrusive
and can alter the vertical dimension. The same occurs
with orthopaedic appliances, which guide the differential
extrusion of the teeth in order to correct the skeletal
malocclusions. However, this alteration of the vertical
dimension coincides with vertical facial development in
growing individuals; such alterations usually occur as a
consequence of the craniofacial growth process.
In the second case described here, surgical extrusion of
the upper canines and of the first upper right premolar
had been performed; the patient was re-evaluated after
fig. 4 Case 2: OPG with ageneses of 12, 15, 18, 22, 25, 27, 28, 35, 38,
45, 47, 48; conoid aspect, microdontia, anomalies in root calcification.
two year’s use of the orthodontic appliance, at which
time the correct vertical dimension was restored and
deciduous teeth were extracted.
The vertical dimension was assessed in both cases, by
measuring the SN–GoGn angle on lateral cephalograms
taken before treatment. The vertical dimension was
considered to be normal if the angle was between
30 and 36 degrees, low if the angle was less than
30 degrees, and high if the angle was more than 36
degrees. In both cases the new mandibular and maxillar
position improved the facial profile and corrected
the malocclusion. On completion of the orthopedic
treatment, the malformed teeth were reconstructed and
implant-supported rehabilitation was applied; patients
were monitored monthly throughout treatment.
Results and discussion
Immunodeficiency diseases, human SCID and JMML
are very often accompanied by oral diseases, that
include periodontitis, persistent candidiasis, and herpetic
infections, as well as prolonged or unusual dental
infections lympho-adenopathy, mouth ulcer, bleeding
and gingival hypertrophy. For these reasons, they must
be monitored monthly throughout treatment..
Tooth anomalies are generally reported in patients
after long-term chemotherapy [Welbury et al., 1984;
Rosenburg et al., 1987; Maguire et al., 1987; Macleod et
al., 1987; Pajari et al., 1995; Millot et al., 2003; Pedersen
et al., 2012], and in patients who have undergone
BMT, after total body irradiation [Dahllhof et al.1988].
Only a few cases of tooth alterations after SCID treated
with BMT have been reported, all were after long
chemotherapy treatment [Cole et al., 2000; Vaughan
et al., 2005; Maciel et al., 2009]. The tooth anomalies
observed in our two patients were very similar, and in our
opinion the cause of these alterations is not correlated
with the underlying disease (SCID – leukemia) but rather
with the treatment they have undergone. In view of
the high toxicity of chemotherapy agents, their action
on cell lines with rapid turnover, and the low separation
potential of tissues like tooth and dentine, it may be
hypothesised that such treatment is the main cause
of tooth developmental anomalies. This hypothesis
is supported by the fact that both patients had been
fig. 5 Intraoral photographs. Microdontia and conoid shape of teeth 34 and 44: A. right view; B. front view; C. left view.
European Journal of Paediatric Dentistry vol. 14/4-2013
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Cossellu G. et al.
treated with the same chemotherapic drugs (Busulfan
plus cyclophosphamide), and that both developed the
same tooth anomalies.
Development of the permanent teeth begins with the
crown (first molar) in the last few weeks of intra-uterine
growth, and is completed with root formation at age 1718 years. It is likely that chemotherapy treatment prior to
bone marrow transplantation, in the early months after
birth, could generate tooth developmental anomalies
like those observed in these two cases.
It is widely reported that oncologic paediatric patients
treated with long cycles of chemotherapy (6-30 months)
develop a series of tooth alterations that include
incomplete calcification, enamel hypoplasia, altered root
formation, premature apexification, microdontia, and
hypodontia. The two cases reported here show that, even
after a short period of chemotherapy, clinical evidence
comparable with many of these anomalies (microdontia,
root alterations, hypodontia) may be found. Both cases
were given dental and orthodontic treatment; mycoses,
herpes and periodontal disease were treated, and
malocclusion was corrected.
The patients were treated initially with orthopaedic
treatment with a removable appliance, followed by rapid
palatal expansion with a device attached to the maxillary
first molars and activated once or twice per day. Fixed
orthodontic treatment followed as the permanent
dentition was completed, for a mean period of 2 years
(19 to 26 months) to obtain final alignment and maximal
interdigitation. In both cases the new mandibular and
maxillary position improves the facial profile, corrects the
malocclusion and allows the teeth to function normally.
The final phase will comprise implant-supported
rehabilitation and reconstruction of malformed teeth.
In agreement with the paediatrician, our cases entered
the following treatment program: preventive dental
care, including oral hygiene instruction, nutritional
counseling, and fluoride gel applications to maintain
oral health. Collection of all data concerning current
medical history, recent hospitalisations, infections and
medications. Before complicated dental procedures can
be undertaken, a complete blood cell count with white
cell differential and platelet count is necessary. Additional
antibiotic prophylaxis is often warranted before invasive
dental treatment, since bacteremias from dental
procedures could be fatal to these patients. Since many
patients are maintained on continuous antibiotic therapy,
which permits the growth of penicillin-resistant oral
organisms, prophylaxis with another class of antibiotics
may be necessary. Consultation with infectious disease
specialists can help dental clinicians choose alternative
antibiotics. Viral, fungal, and bacterial cultures are thus
often needed to establish the causative agent of oral
infections, ulcerations, and lesions, and to help ascertain
the appropriate treatment. It is essential that the dentist
consults regularly with the pediatrician managing the
immunodeficient patient.
332
Conclusion
Oral lesions frequently accompany immunodeficiency
diseases, and teeth anomalies may be iatrogenic. They
thus demand particular awareness directed toward
diagnosis of an underlying disease of the immune
system, and care in deciding the therapy. It may thus be
appropriate a cooperation effort between dentists and
paediatricians dealing with patients exhibiting complex
oral lesions an adequate follow-up, in order to prevent
any other possible tooth anomalies and ensure correct
development of the jaws.
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