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Clinical dermatology • Original article
Oro-dental manifestations in Hallopeau-Siemens-type recessive
dystrophic epidermolysis bullosa
M. De Benedittis, M. Petruzzi, G. Favia and R. Serpico
Department of Odontostomatology and Surgery, School of Dentistry, University of Bari, Bari, Italy
Summary
Recessive dystrophic epidermolysis bullosa of Hallopeau-Siemens (RDEB-HS) is a
rare genetic disorder characterized by trauma-induced blisters, milia, acral
pseudosyndactyly, and scarring. RDEB-HS patients present with a distinct pattern of
oral involvement consisting of microstomia, ankyloglossia, vestibule obliteration and
dental caries. In this review, we describe the orodental manifestations of RDEB-HS and
present our experience in a cohort of six new cases of RDEB-HS in children aged
6–10 years, documenting the presence of microstomia, ankyloglossia and vestibule
obliteration in childhood. We also show that compared with unaffected control
children, RDEB-HS subjects have a greater risk of developing high caries indices with
early onset, both for permanent or deciduous teeth, and a worse oral hygiene index
(scored as OHI). Tooth malpositions and the cross-bite relationship between maxilla
and mandible could play a major role in promoting these events. We propose that
dental management of RDEB-HS subjects should commence as soon as tooth eruption
begins.
manifestations of RDEB-HS and present our experience
in a series of six paediatric cases.
Introduction
There are few reports in the literature of the oro-dental
manifestations of recessive dystrophic epidermolysis
bullosa (RDEB).1–5 This is not surprising given the
rarity of the disease which makes it difficult to perform
large-scale studies in this population and limits information to reports of case-series. It is particularly difficult
to provide evidence for the benefits and risks of certain
treatment or management procedures given the difficulty of performing large therapeutic trials in these
populations. Additionally, until 1999 when diagnostic
and classification criteria for all forms of epidermolysis
bullosa (EB) were clarified, reports about this topic
included all RDEB subtypes.6 Of particular interest is the
management of oro-dental manifestations in the most
severe variant of RDEB (the Hallopeau-Siemens, RDEBHS, subtype). In this review, we focus on the oro-dental
Correspondence: M. De Benedittis, Via Pitagora 2 ⁄ A, 70033 Corato (Bari),
Italy. Tel. ⁄ Fax: +39 80 547 8388.
E-mail: [email protected] or [email protected]
Accepted for publication 31 October 2003
128
Rdeb-hs
RDEB-HS is a subtype of inherited EB with an autosomal
recessive pattern of transmission.6 It is one of the rarest
forms of EB, with 0.41 per million live births observed in
the USA.7,8 In Scotland it has been reported that the
incidence of RDEB-HS is currently 3.0 per million live
births.9 Mutations of the gene encoding type VII
collagen are found in RDEB-HS patients resulting in
absence of anchoring fibrils in the anchor complex of
the epithelia; skin cleavage occurs at the level of the
sublamina densa.6,10 RDEB-HS is the most severe
phenotype of RDEB. Blistering starts at birth or within
24 h of delivery and involves large areas of skin and the
anal, ocular, gastrointestinal and oral mucosae with
secondary dysphagia.7,11 Cutaneous lesions heal leaving scars associated with milia formation. Repeated
blistering with progressive scarring also results in severe
mutilating deformities.7 Moreover, RDEB-HS patients
are at higher risk of developing cutaneous and mucosal
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Oro-dental lesions in Hallopeau-Siemens-type EB • M. De Benedittis et al.
squamous cell carcinomas.12,13 Because RDEB-HS
implies multiorgan involvement, a team approach by
health professionals is generally needed. Management
includes extreme care in handling the skin and skin
protection by avoidance of mechanical trauma.7 As scar
formation causes flexion deformities of limbs and digits,
plastic surgery may be necessary.14,15 Mucosal blistering and scarring of the oesophagus cause oesophageal
dysmotility and eventually dysphagia. When dysphagia
prevents adequate oral nutrition many children now
undergo oesophageal dilatation or gastrostomy and
feeding with nutritional supplements.16,17
series of 27 cases. These displayed microstomia,
ankyloglossia, vestibule obliteration and a mean commissure-to-commissure distance with the mouth maximally open of 33.6 mm. No specific data relating to
age, sex and the general medical condition of these
patients were provided in this report. Only three
additional studies have been published on this topic.
Two focused on caries index and jaw growth and were
published in Europe3,4 the third one was reported in
Australia and described severe dental caries and oral
tissue distortion in an 11-year-old patient with RDEB.5
Oro-dental manifestations of RDEB-HS
Orodental findings in six new cases
of RDEB-HS: personal experience
RDEB-HS patients show marked oral involvement with
tissue distortions and abnormalities, including tooth
crowding, decreased maxillary growth, ankyloglossia,
microstomia, vestibular obliteration, loss of palatal
rugae and ⁄ or lingual papillae, extensive dental caries
and poor oral hygiene.1–4
Ankyloglossia and vestibular obliteration are related
to traumatic injury by food intake and talking while
microstomia results from intraoral and ⁄ or perioral
blistering.1 Poor oral hygiene conditions result from
the inability to brush the teeth as this procedure is
painful and evokes blister formation; this eventually
leads to an early and more severe onset of caries.2
Moreover, a role in precipitating this event could be
played by the impairment of oral secretory immunity
which affects RDEB-HS patients.18 It has been speculated in the literature that RDEB-HS patients’ higher
caries indices were due to structural abnormalities of
the teeth.5,19,20 The debate has partly come to an end
after the recent demonstration that the chemical
composition of enamel in RDEB patients is normal.21
It was then proposed that the high caries indices found
in RDEB patients are related not only to poor oral
hygiene but also to underestimation of oral care needs.2
In fact it has been observed that, given the severity of
the other manifestations of RDEB-HS, oro-dental examination is not considered a major need by either the
parents or the physicians and there are major delays in
starting dental treatment.2
Tooth malpositions and smaller maxillae in their turn
could result from chronic inflammation and malnutrition secondary to dysphagia which affects these
patients.3
Oro-dental manifestations as a whole in RDEB-HS
have been seldom described in detail. Oral soft tissue
involvement was first described in the American literature by Wright et al.1 who reported and analysed a
We investigated oral hard and soft tissue involvement in
a cohort of six children (three male, three female) with
RDEB-HS referred to our clinic by the Centre for Rare
Diseases at the Giovanni XXIII Hospital in Bari, Italy, for
oro-dental examination. Their demographic characteristics at the time of the initial visit are presented in
Table 1. All patients in this study had been diagnosed as
having RDEB-HS according to the guidelines established
by the Second International Consensus Meeting on
Diagnosis and Classification of EB.6 These include
pedigree analysis, skin biopsy (transmission electron
microscopy and specific monoclonal antibodies) and
clinical evaluation of cutaneous and extracutaneous
lesions (Table 1). Personal medical history and dental
history were collected for each patient; subsequently,
oral panoramic radiograms were taken. Oral evaluations were conducted by two independent dental examiners (MDB, MP) using artificial light, a dental mirror
and a dental explorer. The extent of caries was
quantified and scored as decayed, missing, filled teeth,
either for permanent (DMFT) or deciduous teeth (dmft).
The oral hygiene habits of each patient were quantified
and scored according to the simplified oral hygiene
index (OHI-S) by Greene and Vermillon.24 The OHI-S is
obtained by examining and scoring on a scale of 0–3 for
debris and calculus on six surfaces of the teeth, four
posterior and two anterior. The debris and calculus
scores are totalled and divided by the number of surfaces
scored. The average individual or group debris and
calculus scores are combined to obtain the OHI-S. Teeth
were examined for developmental dental abnormalities,
including missing or malformed teeth and enamel
hypoplasia. The size, characteristics and location of oral
lesions were also documented. Microstomia was quantified by measuring the commissure-to-commissure
distance with the mouth maximally open. As a control
for this selected cohort, we also used a local school
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Oro-dental lesions in Hallopeau-Siemens-type EB • M. De Benedittis et al.
Table 1 Demographic characteristics, pedigree analysis and histopathology of six patients with RDEB-HS.
Patient
Sex
Age (years)*
Type of inheritance
Electron microscopy analysis
Immunohistopathology†
1
2
3
4
5
6
Female
Female
Male
Male
Male
Female
6
7
8
9
9
10
Autosomal
Autosomal
Autosomal
Autosomal
Autosomal
Autosomal
Absence
Absence
Absence
Absence
Absence
Absence
Staining
Staining
Staining
Staining
Staining
Staining
recessive
recessive
recessive
recessive
recessive
recessive
of
of
of
of
of
of
AF
AF
AF
AF
AF
AF
absent
absent
absent
absent
absent
absent
AF, anchoring fibrils. *Mean ± SD ¼ 8.2 ± 1.5 years. †Using the LH 7.2 monoclonal antibody which reacts with the N-terminal of type VII
collagen.22,23
registry to select a random sample of 36 healthy school
children (18 male, 18 female). Oral opening measurements, dental caries score and OHI-S in this randomly
selected cohort were compared with the findings in the
six RDEB-HS children. Ethical approval was obtained
from the local Human Subjects Committee (University of
Bari, Italy), permission was obtained from schools and
informed subject and parental consent were obtained.
All patients had a past medical history significant for
continuous, generalized cutaneous blistering since
birth. On physical examination, they showed signs
consistent with the diagnosis of RDEB-HS7,8,11 including
digit involvement which varied from loss of the nails to
complete digital webbing and atrophic scars and widespread milia on the skin. Scarring alopecia was also a
common feature of these patients. All individuals
suffered from dysphagia secondary to oesophageal
involvement and two of them (patients 5 and 6, aged
9 and 10 years, respectively) had undergone oesophageal dilatation for strictures.
All six cases had severe intraoral involvement with
continuous blistering and erosions and also presented a
reduction in depth of the oral vestibule and ankyloglossia (Fig. 1). These features were more pronounced in the
two older children (patients 4 and 6). Palatal and lingual
mucosal involvement resulted in a distortion or complete
loss of normal tissue landmarks, such as palatal rugae
and lingual papillae (Fig. 1). The oral opening of these
RDEB-HS patients determined by commissure-to-commissure measurements with the mouth maximally open
was reduced compared with that of healthy controls
(Table 2; Figs 1 and 2). No patient had generalized
developmental defects or enamel hypoplasia of the teeth,
which were normal in colour, shape and size. Despite
this, dental caries scoring by dmft and DMFT were
higher than control values (Table 2). OHI-S scoring
showed that these patients had worse dental care habits
when compared to healthy individuals (Table 2). Four
patients (2, 3, 4 and 5) had tooth crowding in the upper
and ⁄ or lower jaw (Fig. 1) and two (patients 1 and 5)
showed cross-bite relationship between the maxilla and
130
Figure 1 Microstomia, ankyloglossia, loss of lingual papillae and
tooth crowding in RDEB-HS.
mandible, i.e. upper teeth biting under lower teeth
(Fig. 3). Finally, from the medical history, intraoral
examination and radiographic imaging, it was clear that
none of our patients had ever undergone professional
dental care and ⁄ or prophylaxis. To the best of our
knowledge, we are the first to report early onset of
inversion in the alignment between the maxilla and
mandible, i.e. cross-bite, in RDEB-HS patients.
Conclusion
RDEB-HS is the most severe phenotype of RDEB. It is a
multisystem disease causing blisters and scar formation.7 In the oral cavity, these events lead to severe
tissue abnormalities and microstomia.1 In our own
experience and from the literature, we have no exact
idea of when soft tissue anomalies are established in
these patients. We therefore suggest that dental prophylaxis should commence as soon as tooth eruption
begins. This is particularly important because the high
caries index, tooth malpositions and the precocious
onset of tissue distortions (mostly microstomia), lower
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Oro-dental lesions in Hallopeau-Siemens-type EB • M. De Benedittis et al.
Table 2 DMFT, dmft, commissure-tocommissure distance with the mouth
maximally open and simplified oral
hygiene index in six patients with RDEBHS and 36 controls aged 6–10 years.
RDEB-HS
(n ¼ 6)
Control†
(n ¼ 36)
DMFT
(mean ± SD)
dmft
(mean ± SD)
Commissure-to-commissure
distance (mm) with the mouth
maximally open (mean ± SD)
Simplified oral
hygiene index*
(mean ± SD)
3.0 ± 0.7
6.0 ± 1.9
38.0 ± 2.3
5.0 ± 0.1
1.0 ± 1.1
3.0 ± 1.4
50.0 ± 5.3
2.0 ± 0.6
*According to Greene and Vermillon.24 †Random selection from a cohort of 360 non RDEBHS school children aged 8.0 ± 1.4 years.
diagnosed according to the guidelines established in
1999 by the Second International Consensus Meeting
on Diagnosis and Classification of EB6 and that they
should be reported in the literature.
Acknowledgements
We thank H. M. Horn of the Department of Dermatology
of the Royal Infirmary of Edinburgh for critical reading
of the manuscript.
References
Figure 2 Diffuse facial blistering and microstomia in RDEB-HS.
Figure 3 Cross-bite relationship between jaws and perioral
blistering in RDEB-HS.
patients’ compliance with oral hygiene procedures and
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which easily evokes painful erosions. Both physicians
and parents should be aware of the limited possibilities
of intervention in these patients. To improve knowledge
and increase research in this area, it should be
recommended that that all cases of EB should be
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