GENERAL DENTISTRY

The key role of the dental practitioner in early diagnosis

of periodontal Ehlers-Danlos syndromes: a rare case report
of siblings
Jorge Cortés-Bretón Brinkmann, DMD, PhD/Ignacio García-Gil, DMD/Diana Marina Lobato-Peña, DMD/
Constanza Martínez-Mera, MD/Maria Jesús Suárez-García, DMD, MD, PhD/Jose María Martínez-González,
DMD, MD, PhD, MDV/Maria Rioboo Crespo, DMD, PhD

Ehlers-Danlos syndromes (EDS) are a group of diverse heredi-
tary connective tissue disorders. Various EDS subtypes present
as different diseases. Periodontitis of early onset is a major cri-
terion of periodontal EDS (pEDS). This article reports the clinical
case of two siblings, young adults, who came to the clinic for
diagnosis and treatment of periodontal disease. The patients
had already been diagnosed with pEDS several months earlier
after being referred for genetic testing by a dermatologist. It
should be noted that in these siblings pEDS had been misinter-
preted for years by health care specialists despite the patients’
periodontal disease, which had appeared at the age of 3 years.
The subsequent effects of periodontal disease in these patients
jeopardized the survival prognosis of their teeth. It may be
stated that, in spite of pEDS’s status as a rare syndrome, the den-
tal practitioner can play a key role in the early diagnosis by re-
sponding appropriately to periodontal manifestations at early
stages. (Quintessence Int 2021;52:166–174; doi: 10.3290/j.qi.a45263)

Key words: connective tissue, early diagnosis, Ehlers-Danlos syndromes, periodontal disease, siblings

Ehlers-Danlos syndromes (EDS) comprise a group of hetero-
genous hereditary clinical connective tissue disorders, named
after two dermatologists, Edvard Ehlers and Henri-Alexandre
Danlos, in the early years of the 20th century. Later, various sub-
types were identified one by one, until in 1988 a revised classi-
fication was published known as the “Berlin nosology,” which
defined 11 EDS subtypes based on clinical findings, mode of
inheritance, and biochemical characteristics.1 Classification of
EDS is largely based on defects in the primary structure of col-
lagen (types I, III, or V) or modifications in collagen enzymes.
Subsequently, further reports were published that led to a new
classification with 13 EDS subtypes, due to the appearance of
different noncollagenous extracellular matrix proteins and
intracellular processes.2-8 As the knowledge of this pathology
increases, the incidence of EDS seems to be growing, reaching
a prevalence today of one in every 5,000 births.9
The involvement of EDS in the organism varies, affecting
different structures: ligaments, skin, blood vessels, and even
internal organs. It can manifest as: joint laxity, hyperextensibil-
ity, scars, and facial bruising. In dentistry and oral medicine, the
most relevant aspect of this pathology is the affectation of lig-
aments and collagen closely related to the periodontium sur-
rounding teeth, since it is composed of collagen fibers (pre-
dominantly collagen type I, III, and XII). This is how EDS mainly
affect the oral cavity (depending on EDS subtype). In classic or
vascular EDS, oral disorders are marked by the structure of the
connective tissue of the periodontium, while periodontal EDS
(pEDS) are caused by hyperinflammatory innate immune
response (complement C1r or C1s mutations) rather than by
connective tissue pathology. This will cause severe periodontal
involvement at an early age.10-12 The major criteria for diagnos-
ing pEDS are: severe and intractable periodontitis of early onset

166 QUINTESSENCE INTERNATIONAL | volume 52 • number 2 • February 2021


1a 1b
Figs 1a to 1e Patient 1. Intraoral situation
in maxilla and mandible, showing gingival
rash and redness, plaque accumulation,
and absence of keratinized tissue in many
vestibular areas. 1d
(during childhood or adolescence), lack of attached gingiva,
pretibial plaques, family history of a first-degree relative who
meets clinical criteria. Minor criteria consist of easy bruising,
joint hypermobility (mostly distal joints), skin hyperextensibil-
ity and fragility, abnormal scarring (wide or atrophic), increased
rate of infection, hernia, marfanoid facial features, acrogeria, or
prominent vasculature. All these criteria contribute to an accu-
rate diagnosis of pEDS.8
This report describes the cases of two siblings presenting
pEDS misdiagnosed for years by health care specialists in spite of
the patients having presented periodontal disease from the age
of 3 years. The article also highlights the importance of inter-
disciplinary diagnosis and proposes specific treatment guide-
lines for this type of patient.
Case presentation
A Caucasian 18-year-old man (Patient 1) and 21-year-old woman
(Patient 2) were referred by the Department of Dermatology at
Puerta de Hierro University Hospital (Majadahonda, Madrid,
Spain) to a dental clinic specializing in periodontics, for diag-
nosis and treatment of periodontal disease and other possible
oral pathologies. Both patients underwent full periodontal
examination. This included an anamnesis and photographic
records, intra- and extraoral examination, panoramic radiog-
raphy, full mouth series, and periodontograms aided by the
Florida Probe System. In addition, microbiologic samples were
QUINTESSENCE INTERNATIONAL | volume 52 • number 2 • February 2021
Cortés-Bretón Brinkmann et al
1c
1e
collected for analysis and sent to the Microbiology Laboratory
at the Complutense University of Madrid (Madrid, Spain).
The patients were brother and sister. Their father had pre-
viously undergone genetic testing, which identified pEDS
(C1R [c.1014C>G, p.Cys338Thr]). It should be noted that the
father, diagnosed with pEDS late in life and completely eden-
tulous, had also lost all the implants subsequently placed in
both arches as a result of peri-implantitis within 1 year after
placement.
For this reason, the Department of Dermatology at Puerta
de Hierro University Hospital carried out a genetic study of
both offspring confirming the presumed diagnosis of pEDS
(according to the 2017 international classification of the Ehlers-
Danlos syndromes).8
Patient 1
Patient 1, aged 19 years and classified as ASA (American Society
of Anesthesiologists classification status) II, was not taking any
medication, and not allergic to any drug. He did not smoke or
have any other addictive habits. Regarding his dental history,
he reported suffering gingival problems from a young age (3
years) associated with recurrent gingivitis, dental mobility,
plaque accumulation, and loss of the mandibular right central
incisor, which was replaced with a Maryland partial denture.
Generalized gingival inflammation was observed in intraoral
examination, with high levels of plaque deposits and malocclu-
167
 GENERAL DENTISTRY

Bleeding

Probing depth
≥ 4.4

Smoker

Systemic Missing teeth

Bone Loss / Age

2b

Figs 2a and 2b Patient 1. Periodontal examination with

Florida probe and risk analysis, with 100% bleeding on
2a probing and 100% Plaque Index.

Fig 3 Patient 1. Maxillary and mandibular periapical radiograph series, with generalized moderate horizontal bone loss around teeth.

sion (Fig 1). The gingiva was red, presenting a rash and a fragile Periodontal charting showed attachment loss of 4 to 6 mm
consistency with loss of gingival architecture, especially in the in several locations, 100% bleeding on probing (BOP), and a
mandibular anterior region. Complete absence of keratinized Plaque Index (PI) of 100% (Fig 2). In addition, seven teeth pre-
tissue was observed in many vestibular areas. sented mobility degree I to II. Panoramic and full-mouth radio-

168 QUINTESSENCE INTERNATIONAL | volume 52 • number 2 • February 2021


4b
4a
Figs 4a to 4e Patient 2. Intraoral situation
in maxilla and mandible, showing plaque
accumulation, generalized inflammatory
redness of the gingiva, presence of gingival
recessions, and absence of keratinized tissue
in almost all the sextants. 4d
graphs (Fig 3) revealed a moderate generalized horizontal bone
loss pattern with severe periodontal bone loss around the man-
dibular incisors; however, no images compatible with furcation
defects or apical radiolucencies were observed.
Patient 2
Patient 2, aged 21 years, was classified as ASA II (like her brother),
was not taking any medication, and was not allergic to any drug.
She did not smoke or have any other addictive habits. Regarding
her dental history, she too reported gingival problems from an
early age, mainly bleeding, dental mobility, and plaque accumu-
lation, although she had not suffered any dental loss. In the
intraoral examination generalized gingival inflammation was
observed with high levels of plaque deposits, different restor-
ations in mandibular molars, as well as generalized malocclu-
sion (Fig 4). During the periodontal examination, a generalized
inflammatory redness of the gingiva was observed with loss of
architecture. The presence of gingival recessions and absence
of keratinized tissue were noted in almost all the sextants,
being more pronounced at the level of the mandibular incisors.
In the periodontal chart attachment loss between 4 to 7 mm,
75% BOP, 40% to 60% PI, and grade I and II mobility in nine
teeth were noted (Fig 5). In this case it was possible to collect
microbiologic samples, which had been impossible in the case
of Patient 1 because of the excessive calculus and generalized
plaque accumulation. Microbiologic analysis showed the fol-
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Cortés-Bretón Brinkmann et al
4c
4e
lowing data: presence of Porphyromonas gingivalis (30.53%),
Prevotella intermedia (30.53%), Fusobacterium nucleatum (0.37%),
and a total flora count of 19,000,000 CFU/mL (Table 1). Both
panoramic and full-mouth radiographs (Fig 6) showed a mod-
erate generalized horizontal bone loss pattern and no images
compatible with furcation defects or apical radiolucencies.
Nevertheless, the patient presented severe periodontal bone
loss around the mandibular incisors.
Based on these findings and according to the Consensus
report of workgroup 3 of the 2017 World Workshop on the Classi-
fication of Periodontal and Peri-Implant Diseases and Conditions,
periodontitis as a direct manifestation of systemic disease was
suspected in both siblings (with a high risk prognosis of advanc-
ing periodontal disease), classified among the systemic genetic
disorders that affect the connective tissue and cause the loss of
periodontal tissues by influencing periodontal inflammation.13
Diagnosis of pEDS was established by means of both major
and minor criteria.8 In addition to periodontal manifestations
and a family history of a first-degree relative who met all clinical
criteria, the siblings also presented several systemic features of
pEDS such as pretibial discoloration (Fig 7), hypermobility of
the joints, easy bruising, and marfanoid facial features.
Discussion
EDS are syndromes with different subcategories. Periodontitis
of early onset is a major criterion of periodontal EDS. Bone
169
 GENERAL DENTISTRY

Bleeding

Probing depth

≥ 4.4
Smoker

Systemic Missing teeth

Bone Loss / Age

5b

Figs 5a and 5b Patient 2. (a) Periodontal examination with

Florida probe, with 75% bleeding on probing, and 40–60%
5a Plaque Index. (b) Risk analysis.

Fig 6 Patient 2. Maxillary and mandibular periapical radiograph, showing generalized moderate horizontal bone loss around teeth.

loss follows a pattern without any preferred anatomical develop as a consequence of plaque accumulation during
region and a sequential progression in a domino effect from childhood, which, as adolescence approaches, progresses to
one location to another. It appears at an early age and can early-onset periodontitis with destruction of periodontal
cause dental loss before the age of 30 years. Gingivitis can attachment.10

170 QUINTESSENCE INTERNATIONAL | volume 52 • number 2 • February 2021


To establish an accurate diagnosis of pEDS, a series of major
and minor criteria should be considered.8 Nevertheless, not all
the described manifestations of pEDS were found in these two
cases, although several of them were present. Mucosal disor-
ders were observed, together with an absence of keratinized
tissue, and periodontitis of early onset (from the age of 3 years).
Also some systemic features of pEDS were observed includ-
ing pretibial discoloration, hypermobility of the joints, easy
bruising, and marfanoid facial features.
The microbiologic study of Patient 2 revealed the presence
of P gingivalis, P intermedia, and F nucleatum; however, no spe-
cific microbiologic pattern has been described in pEDS patients.
Periodontal EDS is transmitted by a dominant autosomal pat-
tern that would appear to be genetically heterogenous. Never-
theless, analyses of various families have led to the identification
of a gene locus (genes C1R and C1S).11,14,15 It has been shown in
more than 100 affected individuals that pEDS is caused by het-
erozygous pathogenic variants in C1R (MIM 613785) or C1SS (MIM
120580) encoding complement 1 and subcomponents r and s.15
No specific treatment exists for this disease but early treat-
ment of periodontal manifestations is essential.10,16-18
Initial diagnosis is based on an exhaustive anamnesis and
thorough periodontal examination, the results of which may
constitute the first signs indicating this type of systemic dis-
ease. Early diagnosis of pEDS takes on vital importance, as
treatment and stabilization of periodontal pathology at its ear-
liest stages will optimize dental prognosis.
It is remarkable that in the present cases, clinical manifesta-
tions of both siblings were misinterpreted for years by health
care specialists in spite of them having suffered periodontal
diseases from early ages. The evolution of untreated periodon-
tal disease in these high-risk patients caused severe irreversible
periodontal support breakdown.
The treatment of this pathology by the periodontist will not
differ greatly from the treatment received by any patient present-
ing periodontal disease, but in these cases the high susceptibility
of this type of patient to periodontal diseases makes the mainte-
nance of a strict protocol a matter of paramount importance.
Microbiologic study may prove helpful when it comes to choos-
ing the right antibiotic when this is needed to boost the out-
comes of periodontal treatment.19 However, regardless of micro-
biologic information, additional therapy with a combination of
amoxicillin and metronidazole will have a beneficial effect.20
When it comes to treating periodontal EDS, the primary
objective should be to conserve teeth for as long as possible;
dental implant-supported solutions are not straightforward, as
dental implants in pEDS patients suffer a high risk of failure. In
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Cortés-Bretón Brinkmann et al
7
Fig 7 Patient 2. Right leg with atrophic pretibial skin with areas of
hyperpigmentation.
this sense, Rinner et al21 report that implant treatment failed in
three affected individuals in the same family. As far as the pres-
ent authors are aware, Rinner et al21 is the only published work
about dental implants and pEDS patients. It should be noted
that in the present cases, the patients’ father had also suffered
implant loss in both arches after approximately 1 year.
Another relevant aspect, which has not been much dis-
cussed in the literature, is the need for communication between
specialists in different fields (dentistry, medical genetics, der-
matology, pediatrics, internal medicine) in order to establish an
early diagnosis and treatment protocol
A protocol is proposed for interdisciplinary action between
specialties as well as a treatment guide for these patients. This
places emphasis on the importance of early detection of a pos-
sible systemic disease, which initiates or alters the response
and the pathophysiology of periodontitis at a premature age.
For this reason, it is essential to establish early periodontal con-
trol and to prevent tooth loss at very early ages.
In the context of pEDS, dental practitioners play an import-
ant role in recognizing and diagnosing the onset of gingival or
periodontal diseases, in terms of performing the right treat-
ment and referring the patient to the pertinent specialist. For
this reason, it is essential to carry out effective screening in chil-
dren and adolescents and to be aware of suitable types of treat-
ment. When the presence of systemic disease with oral or peri-
odontal manifestation is suspected, the case should be referred
to a specialist. Regarding the periodontal management and
screening of children and adolescents in the dental clinic, the
British Society of Periodontology and the British Society of
171
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Table 1 Patient 2. Microbiologic study, showing the presence The dental practitioner should provide the patient or his/her
of Porphyromonas gingivalis, Prevotella intermedia, and
Fusobacterium nucleatum
doctor with a list of the most commonly used medications that
can trigger oral mucosa/cavity affectation so that the doctor is
Count aware of the risk of exacerbating periodontal pathology when
Bacteria (CFU/mL) Percentage prescribing medication to this type of patient, especially when
Anaerobic bacteria 19,000,000 administration is to be chronic.
Aggregatibacter actinomycetemcomitans 0 0.00% At the same time, when medical specialists suspect a case
Porphyromonas gingivalis 5,800,000 30.53% of EDS (because the case fulfills the clinical criteria), a genetic
Prevotella intermedia 600,000 3.16% study should be carried out to confirm diagnosis, and when
Tannerella forsythia 0 0.00% confirmed, the presence of any other cases among the patient’s
Parvimonas micra 0 0.00% family members should be investigated.
Fusobacterium nucleatum 70,000 0.37% When EDS is suspected, assessment should be carried out by
Campylobacter rectus 0 0.00% a multidisciplinary team. The role of the dermatologist is to
Eikenella corrodens 0 0.00% assess the cutaneous stigmas8 that may be found in cases of EDS,
Capnocytophaga species 0 0.00% such as skin hyperextensibility, the aspect and texture of the skin
Actinomyces odontolyticus 0 0.00%
(fine, translucent, soft, doughy), marfanoid facial features, acro-
Streptococcus mutans 0 0.00%
geria, palmar wrinkling, nonphysiologic striae (not associated
Candida species 0 0.00%
with weight change), pretibial hyperpigmented plaques or atro-
CFU, colony-forming unit.
phic scarring, piezogenic papules, molluscoid pseudotumors, or
subcutaneous spheroids. Among the cutaneous signs of pEDS,
the most characteristic is pretibial hyperpigmented plaques, in
which case differential diagnosis must be performed to discount
necrobiosis lipoidica, diabetic dermopathy, chronic lipodermato-
Paediatric Dentistry22 proposed consensus guidelines under sclerosis, vasculopathies, pretibial myxedema, or child abuse,
the umbrella of the established classification of periodontal among others.24,25
diseases.23 However, there are no specific guidelines and/or rec- When a case belonging to the spectrum of hypermobility
ommendations available as to if and when dental practitioners disorders is suspected, the Beighton score may be used to iden-
should refer a young patient directly to a specialist doctor tify the presence of generalized articular hypermobility (or
(pediatricians, dermatologists) for a more in-depth exploration whether this has presented previously) and investigate any
of their systemic state. Nevertheless, this is essential, since the affectation in other systems (musculoskeletal, neurologic, diges-
results and expected prognoses of periodontal treatment may tive, ophthalmologic, pneumologic, gynecoobstetric).24
differ in the presence of pEDS. Other types of EDS that often present pretibial lesions are
Based on the only guidelines proposed to date21 and on the the classic hypermobile and vascular subtypes.8
current classification of periodontal diseases,13 it is suggested In patient management, the avoidance of direct and indirect
that the following clinical situations indicate the need to refer trauma is important (in small children the areas at high risk of
the patient to a specialist medical service (pediatrics, dermatol- knocks should be protected: shins, knees, forehead, etc). Only low
ogy, internal medicine, medical genetics) to establish the pres- impact exercise should be allowed (for example, cycling, swim-
ence of some systemic disease that would explain specific pre- ming, walking, etc). The administration of medication that inter-
mature oral or periodontal signs or symptoms, and determine feres in platelet aggregation (ie, aspirin) should also be avoided.26
a more specific and personalized periodontal monitoring in In the same way, surgical procedures should be avoided
collaboration with pediatricians or medical management: unless absolutely essential, due to the increased risk of wound
■ Diagnosis of any periodontitis, whether localized or gener- dehiscence, bleeding, and infection. When surgery is necessary,
alized GRADE C (phenotype). double layer wound closure should be performed and the sutures
■ Gingivitis or periodontitis that do not respond to standard left for double the usual healing period, with the use of wound
bacterial control therapies. closure strips and an adhesive bandage to help reduce surface
■ Dysmorphic fascie. tension. In cases requiring grafting or skin flaps for closure, each
■ Disorders of other foci, skin, hair, nails, or genital mucosa. must be assessed individually as few cases have been docu-

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 Cortés-Bretón Brinkmann et al

mented.24 As for the prevention of hematoma in EDS patients, the
use of oral vitamin C has been proposed to reduce its occurrence.24
There should also be preparation for health centers and
medical services (pediatrics, dermatology, internal medicine) to
refer to the periodontist any young patients (children, adoles-
cents) displaying periodontal signs or symptoms. It is known
that, even with the correct specific medical and pharmacologic
treatment of a systemic disease, the control of the bacterial
load through biofilm elimination is essential for improving the
prognosis of and survival of teeth. As these patients are at risk
and are systemically compromised, periodontal maintenance
visits will be more or less frequent depending on the patient’s
plaque control and periodontal disease activity.
In addition, communication and interdisciplinary consulta-
tion between the periodontist and the specialist doctor must
be continuous. It is recommended that consultations are made
at the time of periodontal diagnosis, after periodontal treat-
ment and during maintenance visits, so that if and when peri-
odontal stability worsens, the specialist doctor is aware of the
patient’s oral situation and patient motivation can be stepped
up for the purposes of periodontal treatment and control.
Conclusions
This clinical case report describes two siblings with pEDS. Peri-
odontal EDS, although uncommon, should not be overlooked
by dental practitioners, as early diagnosis improves the prog-
nosis for oral and periodontal health substantially and preven-
tative and therapeutic measures can be implemented at once.
Health care professionals must adopt an interdisciplinary
approach to pEDS, the dental practitioner often being the first
specialist to recognize the possible presence of the syndrome,
whose diagnosis then requires genetic testing and consultation
across different medical fields to reach a definitive diagnosis.
Declaration
The authors declare there are no conflicts of interest.

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Jorge Cortés-Bretón Brinkmann Diana Marina Lobato-Peña Masters Program in Orthodontics

and Orthopedic, Faculty of Dentistry, University of Oviedo, Oviedo,
Spain

Constanza Martínez-Mera Adjunct Doctor, Department of

Dermatology, Puerta de Hierro University Hospital, Madrid, Spain

Maria Jesús Suárez-García Full Professor of Oral Prosthodon-

Jorge Cortés-Bretón Brinkmann Researcher/Assistant Profes-
sor, Department of dental Clinical Specialties, Faculty of Dentistry,
Complutense University of Madrid, Madrid, Spain
Ignacio García-Gil Master Program Advanced Oral Implantolo-
gy, Europea University of Madrid, Madrid, Spain; Master Program
Buccofacial Prostheses and Occlusion, Faculty of Dentistry, Com-
plutense University of Madrid, Madrid, Spain
tics, Department of Conservative Dentistry and Orofacial Prostho-
dontics. Faculty of Dentistry, Complutense University of Madrid,
Madrid, Spain
Jose María Martínez-González Full Professor of Maxillofacial
Surgery, Department of Dental Clinical Specialties, Faculty of Den-
tistry, Complutense University of Madrid, Madrid, Spain
Maria Rioboo Crespo Assistant Professor, Department of Dental
Clinical Specialties, Faculty of Dentistry, Complutense University of
Madrid, Madrid, Spain

Correspondence: Dr Jorge Cortés-Bretón Brinkmann, Department of Dental Clinical Specialties, Faculty of Dentistry, Complutense Uni-
versity of Madrid, Pza Ramon y Cajal s/n, 28040 Madrid, Spain. Email: brinkmann55@hotmail.com

174 QUINTESSENCE INTERNATIONAL | volume 52 • number 2 • February 2021