CLEIDOCRANIAL DYSPLASIA
ARTICLE ABSTRACT Cleidocranial dysplasia (CCD) is an autosomal-dominant disorder that occurs due to mutations in the Cbfa 1 gene, also called Runx 2, located on the short arm of chromosome 6, affecting osteoblast skeletal-specific bones that have intramembranous ossification. This condition is characterized by hypoplastic clavicles, short stature, and great clinical significance in the stomatognathic complex, with involvement of facial bones, changes in the eruption patterns, including multiple supernumerary and retained teeth. This study reports six subjects of the same family with CCD identified in the Dentistry Clinic of Oral Diagnosis Department, Universidade Paulista, Campus Sorocaba, Sao Paulo State, Brazil. All cases had clinical and radiographic aspects of this important condition, such as short stature, hypertelorism, severe mobility of the shoulders, and supernumerary and retained teeth. Due to the rare incidence and phenotypic manifestations, CCD can be easily misdiagnosed. The oral commitments are one of the main (functional and aesthetic) causes of complaints in these subjects; and a dentist must establish the diagnosis as early as possible, followed by behaviors and practices that can minimize harmful manifestations of the syndrome and improve health associated with oral and multidisciplinary integration offering improvements in quality of life of these subjects.
KEY WORDS: dental anomalies, oral pathology
Cleidocranial dysplasia: report of six clinical cases Rosemary Baptista Martins, MSc;* Ricardo Salgado de Souza, MSc; Elcio Magdalena Giovani, PhD School of Dentistry, Universidade Paulista (UNIP), Indianapolis Campus, Sao Paulo, Brazil. *Corresponding author e-mail: [email protected] Spec Care Dentist 34(3): 144-150, 2014
Int r od uct ion
The cleidocranial dysplasia (CCD), also known as Scheuthauer syndrome1 or mutational dysostosis, is a rare congenital bone disease with autosomal-dominant pattern of inheritance.2 Its prevalence is estimated at 1:1,000,000 with no sex predilection.3 Usually, it is an underdiagnosed disease because of the low incidence of medical complications, where oral manifestations are a major cause of morbidity.3,4 CCD occurs due to mutations in the Cbfa 1 gene, also called Runx 2, located on the short arm of chromosome 6. This gene is responsible for osteoblast differentiation. It is essential for the formation of bone tissue, both endochondral and membranous, and may be related to the delay in ossification of the skull, pelvis, and extremities in the CCD. This gene encodes a transcription factor that is osteoblast specific and maps to chromosome 6p21.4–6 However, although there are several different types of mutations in the Runx 2 in the CCD, it does not seem to relate to the severity of the disease. Range of phenotypes bone in CCD subjects is attributable to the quantitative reduction of the functional activity of Runx 2.4,7,8
C a s e r ep or t
Reports of clinical cases are based on six subjects of the same family following heredogram diagram with clinical and radiographic diagnosis of CCD. Highlighted and proofed features are meaningful and relevant to all subjects, such as short stature, clavicular hypoplasia with large mobility, ogival palate, absence of cleft palate, hypertelorism,
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supernumerary teeth, retained teeth, and prominent frontal bossing.
Her ed og r a m
Subject 1: A 45-year-old female, who attended the Dental Clinic of the Department of Oral Diagnosis, University Paulista, Sorocaba, SP, reported, as main complaint, a misfit of maxillary complete denture. Extra-oral clinical examination confirmed short stature (1 m and 40 cm tall), increased head circumference, hypertelorism, frontal protuberance, midface hypoplasia, pseudo-prognathism, discreet hearing loss, broad flattened nasal bridge, saddle nose, and large mobility of shoulders (Figure 1). Intraoral physical examination confirmed total absence of the upper and lower teeth because of extraction, narrow and deep ogival palate, and an increased volume of bone consistency in the anterior maxillary and painless palpation, which allowed the misfit of the denture. Panoramic radiograph showed retained supernumerary teeth, incomplete rhizogenesis, and maxillary atresia (Figure 2). Clinical and radiographic findings led to the diagnostic hypothesis of CCD. Based on clinical and
© 2013 Special Care Dentistry Association and Wiley Periodicals, Inc. DOI: 10.1111/scd.12045
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Figure 1. Subject 1.
radiographic findings, the subject was referred to the Department of Genetics where the CCD was confirmed. Given this diagnosis, we investigated the presence of these changes in the family due to autosomal-dominant characteristic of the syndrome. On analyzing all direct descendants (subjects 2–4), we found clinical and radiographic CCD features. Subjects were recorded through pictures with front view and panoramic radiograph. Subject 2: A 22-year-old male with same physical aspects, such as short stature (1 m and 51 cm tall), increased head circumference, mid-face hypoplasia, hypertelorism, prominent frontal, parietal and occipital bossing, saddle nose, and broad flattened nasal bridge (Figure 3). Intraoral clinical examination showed protruding jaw, narrow and deep ogival palate, maxillary atresia also observed in the panoramic radiography, partial absence of teeth in the upper and
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lower arches due to multiple previous dental extractions. Radiographic examination also showed multiple impacted teeth with abnormal morphologies and ectopic roots (Figure 4). Elements 53, 63, 73, and 83 had no exfoliation. Elements 13, 23, 33, and 43 were retained. This subject had extraction of deciduous elements, supernumerary elements, and third molars. A rapid maxillary expansion was performed with Haas expander. A space maintainer is being used. Orthodontic traction was performed on elements 13, 23, 33, 43, 21, and 22 for later rehabilitation. There is a possibility of placement of osteointegrable implant in the mandible, and installation of removable partial denture in the maxilla after the orthodontic therapy. However, osteointegrable implant depends on the computed tomography examination to ensure presence of enough alveolar bone. If it is not possible
Figure 2. Panoramic radiograph of Subject 1.
to place osteointegrable implant, the subject will have removable partial dentures in the maxilla and mandible. Subject 3: A 17-year-old female, who had short stature (1 m and 42 cm tall), increased head circumference, hypertelorism, prominent frontal, parietal and occipital bossing, mild exophthalmos, and mild pseudo-prognathism (Figure 5). Intraoral clinical examination showed narrow and deep ogival palate, maxillary atresia, absence of cleft palate, and permanent teeth, where some elements had morphological changes. Radiographic examination showed several retained teeth with abnormal morphologies and ectopic
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Figure 3. Subject 2.
Figure 5. Subject 3.
Figure 7. Subject 4.
Figure 4. Panoramic radiograph of Subject 2.
Figure 6. Panoramic radiograph of Subject 3.
Figure 8. Panoramic radiograph of Subject 4.
roots (Figure 6). It was observed that elements 28, 38, and 48 were retained. Elements 18, 34, and 44 were absent. Elements 13, 23, and 25 were impacted. Elements 32, 33, 42, and 43 were crowded. Elements 35, 45, 37, and 47 had incomplete rhizogenesis. Mandibular trabecular bone is poor in areas of greater radiographic density. Ascending branch of the mandible is narrow and delicate. Coronoid process was pointed. This subject received orthodontic therapy in which a rapid maxillary expansion was performed with Haas expander. A space maintainer is being used. She was considered for orthog-
nathic surgery, prosthesis, or orthodontic therapy seeking total repair. Subject 4: A 7-year-old male, who showed physical characteristics similar to his mother, such as hypertelorism, frontal and parietal protuberance, broad flattened nasal bridge, mild exophthalmos, large mobility of shoulders and short stature (1 m and 12 cm tall), and maxillary atresia (Figure 7). Intraoral clinical examination showed a mixed dentition not compatible with age, narrow and deep ogival palate, and absence of cleft palate. Radiographic examination showed a mixed dentition with delayed exfoliation of some deciduous teeth, delayed eruption of some
permanent teeth, and retained and supernumerary teeth (Figure 8). This subject was 7 years and 7 months old and has not suffered exfoliation of any deciduous tooth. Extractions of elements 51, 61, 71, 81, 52, 62, 72, and 82 were performed with surgical exposure. This procedure was an attempt to foster spontaneous eruption of upper permanent central and lateral incisors and lower permanent central and lateral incisors. These elements had evident delayed eruption because of the two-thirds of the roots of permanent elements were already formed and because of delayed rizolisis of deciduous teeth. It was also observed that elements 16, 26, 36, and 46 are in eruptive phase
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Figure 9. Subject 5.
Figure 11. Subject 6.
Figure 10. Panoramic radiograph of Subject 5.
Figure 12. Panoramic radiograph of Subject 6.
but with delayed rhizogenesis and extremely fibrous gingiva overlying these dental follicles. The follicle of elements 17, 27, 37, and 47 was also observed. Follicles 17 and 27 were in a phase of premature exfoliation with rupture of lamina dura not in a compatible stage with its rhizogenesis. There are signs of prognathism or pseudo-prognathism and maxillary atresia, severe malocclusion, and open bite. This patient received orthodontic therapy with use of maxillary expander. The patient was followed-up monthly by the Department of Orthodontics and annual panoramic radiographs were recommended for early detection of
supernumerary elements and best-case management. On investigating other family members, we identified two individuals with the same clinical and radiographic features described previously. Subject 5: A 32-year-old female who was sister of Subject 1. Physical examination showed same phenotypic features as Subject 1, such as short stature (1 m and 39 cm tall), hypertelorism, broad flattened nasal bridge, mild exophthalmos, prominent frontal bossing (Figure 9). Intraoral clinical examination showed absence of several elements, narrow and deep ogival palate, maxillary atresia, and mild mandibular protrusion.
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The presence of retained and ectopic elements in both arches with incomplete rhizogenesis, maxillary atresia, ectopic location of the retained elements, poor trabecular mandibular bone with large areas of greater radiographic density, extremely narrow ascending branch of the mandible, and slender coronoid process were observed through panoramic radiograph (Figure 10). At the request of the subject, all elements were extracted. Dental rehabilitation was performed with immediate upper and lower dentures that were replaced by dentures definitive about 1 year after the bone tissue remodeling. Subject 6: A 4-year-old female, daughter of Subject 5. She showed phenotypic features as 97 cm tall, mild mid-face hypoplasia, hypertelorism, prominent frontal, parietal and occipital bossing, saddle nose, broad flattened nasal bridge, and mild exophthalmos (Figure 11). Intraoral clinical examination showed signs of maxillary atresia with malocclusion, bilateral cross-bite, and slight anterior open-bite. However, chronological age seems to be compatible with patient’s dental age. Radiographic examination showed delay in the root resorption of deciduous teeth and permanent tooth germs in formation. Elements 16, 26, 36, and 46 are in a phase of premature exfoliation with incompatible rhizogenesis (Figure 12). This subject received orthodontic therapy with removable appliance, maxillary expander, and previous grid. No other dental interventions were conducted. Subject is being followed-up monthly by the Department of Orthodontics. Annual panoramic radiographs for early detection of supernumerary elements were recommended, which will help in evaluating the treatment needed at the appropriate time avoiding the worsening of conditions and improving the referral of this case. Surgical interventions, such as extractions, surgical exposures, orthodontic traction, and orthognathic surgery are not discarded, which depend on the development of the case. Some subjects reported that the father of Subjects 1 and 5 had characteristics
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similar to CCD. He died in a car accident. So we cannot confirm through clinical and radiographic examination whether father suffering from CCD. Given physical, clinical, and radiographic findings, subjects were referred to a geneticist for genetic counseling individually and with family. They were also informed about the risks of recurrence of this dominant genetic disease in future generations. A multidisciplinary assessment was conducted to establish appropriate surgical, orthodontic, and prosthetic treatment restoring each aesthetics and function. Important role prevention protocol was established for these subjects, where they were instructed about the cleaning and maintenance of desirable conditions of oral health. Subjects were referred to surgical and periodontal treatment followed by rehabilitation of decayed teeth and aesthetics. Subject 1 was referred for extracting retained teeth and later to the prosthesis rehabilitation of upper and lower denture. Subjects 2 and 6 were referred to orthodontic treatment through maxillary expander due to ogival palate. Corrective orthodontic appliances were installed later seeking better fit and positioning of the teeth. Subject 3 received clinical treatment from dentistry and periodontics and was referred to orthodontic treatment for maxillomandibular expansion for functional correctness. Subjects 4 and 5 received clinical treatment from dentistry and periodontics and extraction of retained teeth. Later, they were referred to prosthetic treatment for functional rehabilitation through both removable partial and complete dentures. These subjects were followed-up every 6 months in order to keep good maintenance of hygiene conditions and to see whether desirable effects are obtained with the approaches recommended.
D is cu s s io n
CCD is a disease caused by a bone disorder with inheritance pattern that shows
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phenotypic manifestations in different degrees. It may be confused with other bone pathologies but some manifestations are specific that will help determining the diagnosis of the syndrome.3,4,9 Among diseases that have differential diagnosis with CCD, pycnodysostosis or Maroteaux–Lamy syndrome, also known as mucopolysaccharidosis type VI, presents clinical features similar to CCD, such as short stature, craniofacial deformities, dysplasia of clavicles, and changes in tooth formation. However, this diagnosis was excluded as pycnodysostosis because it is an autosomal recessive skeletal dysplasia and presents other clinical aspects, such as dense and fragile bones, polydystrophic dwarfism, mild mental retardation, and also presents partial agenesis of the terminal phalanges of the hands and feet as multiple bone fractures, which was not found in the cases reported.10,11 Rubinstein–Taybi syndrome also has a differential diagnosis with CCD. However, subject presents mandatory retardation with variable degree of mental retardation, having the intelligence quotient usually between 40 and 50, and reduced life expectancy.12,13 In CCD, there is no loss of intellectual capacity.12,14 Usually diagnosis of CCD is delayed because these individuals usually have a normal life, without systemic complications. However, an extremely complex clinical condition can be presented at the first dental examination with presence of multiple supernumerary teeth, impacted teeth, eruption changed, ectopic dental morphology and location, malocclusion, maxillary atresic, and hindering successful treatment.4,15,16 Aplasia or hypoplasia of the clavicles, hypertelorism, short stature, prominent frontal, parietal and occipital bossing, brachycephalic head, mid-face hypoplasia, saddle nose, broad nasal bridge, hearing problems, and exophthalmos are clinical phenotypic characteristics of CCD.4,9,12,15,17 This article reports case of six subjects who presented aplasia of the clavicles leading to an accentuated mobility of shoulders, able to take
s houlders forward, and putting them together in the midline.4,18 All subjects had short stature, except Subject 6 who showed no visible signs of low height for age. The average low height in CCD (1 m and 56 cm for males and 1 m and 44 cm for females) can be observed in subjects over 4 years of age.19 Dental problems are major source of morbidity in the CCD patients, as it interferes with speech, chewing, swallowing, breathing, and hearing. Without treatment the retained deciduous teeth begin to deteriorate rapidly in the late youth or early adulthood, leading to an appearance of premature facial aging signs clearly found in patients 1, 3, 4, and 5.20,21 Permanent dentition is severely affected. There is predisposition to supernumerary teeth, failure in eruption, ectopic, and abnormal tooth morphology, mainly the roots. Delayed eruption of permanent teeth can be attributed to many factors, such as dilaceration of the roots and crowns with enamel hypoplastic and globular dentin, lack of root resorption of deciduous teeth, presence of a physical barrier represented by retained supernumerary teeth or by interposed fibrous tissue between dental follicle and mucosa, high bone density in maxillary and failure in the alveolar bone resorption, fibrous mucosa and presence of large amount of acellular cementum, and absence of cellular cementum on the roots of affected teeth.9,15,17,18 For better treatment of oral conditions of Subjects 2–4, we followed to the removal of retained deciduous teeth and supernumerary teeth.3,4,9 After maxillary expansion, obtaining an ideal format, and a solid anchor to the dental arch, efforts will be concentrated on impacted or unerupted teeth with orthodontic traction. This phase should extend for a long enough period of time.22,23 For Subjects 4 and 6, surgical and orthodontic treatment is being planned and executed so that they can coincide with the developmental stages of the permanent dentition.22 Orthognathic surgery for the correction of dentofacial deformities may be necessary in some cases as well as the prosthetic rehabilitation.14
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Eruption of first permanent molars appears spontaneously in most individuals with CCD due to a thin layer of bone tissue that needs to overcome, despite having extremely fibrotic gingiva overlying the dental follicles.24 In Subjects 4 and 6, it was observed that dental follicles of the first permanent molars were in exfoliative phase, even rhizogenesis showed slow development.24 Impacted and supernumerary teeth are clinical characteristics markedly found in the cases presented in this report. Generalized bone dysplasia present in CCD leads to changes in the bone tissue remodeling and the presence of supernumerary teeth. This explains the prolonged retention of teeth included, as well as retention of permanent teeth for much longer periods than usual.25 Subjects 1 and 5 were rehabilitated through upper and lower dentures. Removable partial denture was installed in Subject 4. Both total prosthesis as removable of partial dentures meet all the immediate needs for proper rehabilitation. However, as the bone height in these cases is very limited, with shallow grooves and a more slender bone, dentist should consider making dentures. Subject 2 can be rehabilitated through placement of osteointegrable implant. However, absence of alveolar bone and slender jaw often present in CCD precludes the use of implants. There is no treatment for cranial, clavicular, and other bone abnormalities associated with CCD. However, treatment of oral conditions is essential due to the occurrence of health problems related to the disease. This treatment should be based on aesthetic and functional rehabilitation through clinical care, surgery, orthodontics, and prosthodontics. Thus, oral problems resulting from this syndrome will be minimized and conditions of the stomatognathic system will be improved.15,26,27
C on clu s ion
Due to the rare incidence and phenotypic manifestations, CCD can be easily
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isdiagnosed. Dentist must have m the knowledge of disorders of the maxillofacial structures of this syndrome. Vast majority of affected subjects have oral problems (functional and aesthetic) as the main complaint. Dentist has to establish the diagnosis as early as possible. Other responsibility of a dentist is to make an immediate intervention in order to minimize oral changes, aiming at the functional adaptation of the individual, providing better quality of life with decreased comorbidities associated with oral problems. A multidisciplinary interaction is important in the handling and treatment of such subjects, composed of several experts in the dental field, associated with doctors, psychologists, and speech therapists, aiming a rehabilitation that provides a functional and aesthetic comfort for the subject. Multidisciplinary treatment of patients with CCD may also reduce the frequency of comorbidities associated with this syndrome.
References 1. Marie P, Sainton P. Sur la dysostose clidocranienne hereditaire. Rev Neurol 1898; 6:835-8. 2. Tanaka JL, Ono E, Filho EM, Castilho JC, Moraes LC, Moraes ME. Cleidocranial dysplasia: importance of radiographic images in diagnosis of the condition. J Oral Sci 2006;48(3):161-6. 3. Zabeen B, Mohsin F, Taher A, Khan M, Azad K, Nahar N. Cleidocranial dysplasia. Mymensingh Med J 2008;17(1):82-4. 4. Xuan D, Li S, Zhang X, Lin L, Wang C, Zhang J. A novel RUNX2 mutation in cleidocranial dysplasia patients. Biochen Genet 2008;46(11-12):702-7. 5. Suda N, Hamada T, Hattori M, Torii C, Kosaki K, Moriyama K. Diversity of supernumerary tooth formation in siblings with cleidocranial dysplasia having identical mutation in RUNX2: possible involvement of non-genetic or epigenetic regulation. Orthod Craniofac Rev 2007;10(4): 222-5. 6. Pamuk ON, Mundlos S, Cakir N. Cleidocranial dysplasia in a mother and her
two children. Join Bone Spine 2008;75(6): 725-7. 7. Purandare SM, Mendoza-Londono R, Yatsenko SA, et al. De novo three-way chrmose translocation 46,XY,t(4;6;21) (p16;p21.1;q21) in a male with cleidocranial dysplasia. Am J Med Genet A 2008;146A(4): 453-8. 8. Lou Y, Javed A, Hussain S, et al. A Runx2 threshold for the cleidocranial dysplasia phenotype. Hum Mol Genet 2009;18(3): 556-68. 9. Nagarathna C, Shakuntala BS, Mathew S, Krishnamurthy NH, Yumkham R. Cleidocranial dysplasia presenting with retained deciduous teeth in a 15-year-old girl: a case report. J Med Case Reports 2012; 6:25. Available at: http://www.ncbi.nlm.nih. gov/pmc/articles/PMC3292823/. Accessed December 11, 2012. 10. Osimani S, Husson I, Passemard S, et al. Craniosynostosis: A rare complication of pycnodysostosis. Eur J Med Genet 2010; 53(2):89-92. 11. Hernández-Alfaro F, Arenaz-Buá J, Serra Serrat M, Marenque Bueno J. Orthognatic surgery in pycnodusostosis: a case report. Int J Oral Maxillofac Surg 2011;40(1):110-3. 12. Smith DW. Síndromes de malformações congênitas: Aspectos genéticos, embriológicos e clínicos, 3rd ed. São Paulo: Manole; 1989; 310-1. 13. Golan I, Baumert U, Held P, Feuerbach S, Müssig D. Radiological findings and molecular genetic confirmation of cleidocranial dysplasia. Clin Radiol 2002; 57(6):525-9. 14. Regezi JA, Sciubba JJ. Patologia Bucal: Correlações Clinicopatológicas, 3rd ed. Rio de Janeiro: Guanabara Koogan; 2000; 389-90. 15. Hemalatha R, Balasubramaniam MR. Cleidocranial dysplasia: a case report. J Indian Soc Pedod Prev Dent 2008;26(1): 40-3. 16. Golan I, Baumert U, Hrala BP, Müßig D. Dentomaxillofacial variability of cleidocranial dysplasia: clinicoradiological presentation and systematic review. Dentomaxillofac Radiol 2003;32(6):347-54. 17. D’Alessandro G, Tagariello T, Piana G. Cleidocranial dysplasia: etiologu and stomatognathic and craniofacial a bnormalities. Minerva Stomatol 2010;59(3):117-27. 18. Manjunath K, Kavitha B, Saraswathi TR, Sivapathasundharam B, Manikandhan R.
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Cementum analysis in cleidocranial dysostosis. Indian J Dent Res 2008;19(3); 253-6. 19. Mundlos S. Cleidocranial dysplasia: clinical and molecular genetics. J Med Genet 1999; 36:177-82. 20. Neville BW, Damm DD, White DH. Atlas colorido de patologia oral clínica, 2nd ed. Rio de Janeiro: Guanabara Koogan; 2001; 336-7. 21. Neville BW, Damm DD, White DH. Oral & maxillofacial pathology, 2nd ed. United
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States of America: W.B. Saunders; 2002; 537-9. 22. Olszewska A. Dental treatment strategies in a 40-year-old patient with cleidocranial dysplasia. J Appl Genet 2006;47(2): 199-201. 23. Becker A. Tratamento ortodôntico de dentes impactados. São Paulo: Santos; 2004. 24. Jensen BL, Kreiborg S. Dental treatment strategies in cleidocranial dysplasia. Br Dent J 1992;172(6):243-7.
25. Jensen BL, Kreiborg S. Development of the dentition in cleidocranial dysplasia. J Oral Pathol Med 1990;19(2):89-93. 26. Mohan RP, Suma GN, Vashishth S, Goel S. Cleidocranial dysplasia: clinic-radiological illustration of a rare case. J Oral Sci 2010; 52(1):161-6. 27. Mata Zubillaga D, Lapena Lopez de Armentia S. Disostosis cleidocranial. Cleidocranial dysostosis. A review of 11 cases in five generations. An Pedriatr 2008; 69(2):162-6.
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ARTICLE ABSTRACT Cleidocranial dysplasia (CCD) is an autosomal-dominant disorder that occurs due to mutations in the Cbfa 1 gene, also called Runx 2, located on the short arm of chromosome 6, affecting osteoblast skeletal-specific bones that have intramembranous ossification. This condition is characterized by hypoplastic clavicles, short stature, and great clinical significance in the stomatognathic complex, with involvement of facial bones, changes in the eruption patterns, including multiple supernumerary and retained teeth. This study reports six subjects of the same family with CCD identified in the Dentistry Clinic of Oral Diagnosis Department, Universidade Paulista, Campus Sorocaba, Sao Paulo State, Brazil. All cases had clinical and radiographic aspects of this important condition, such as short stature, hypertelorism, severe mobility of the shoulders, and supernumerary and retained teeth. Due to the rare incidence and phenotypic manifestations, CCD can be easily misdiagnosed. The oral commitments are one of the main (functional and aesthetic) causes of complaints in these subjects; and a dentist must establish the diagnosis as early as possible, followed by behaviors and practices that can minimize harmful manifestations of the syndrome and improve health associated with oral and multidisciplinary integration offering improvements in quality of life of these subjects.
KEY WORDS: dental anomalies, oral pathology
Cleidocranial dysplasia: report of six clinical cases Rosemary Baptista Martins, MSc;* Ricardo Salgado de Souza, MSc; Elcio Magdalena Giovani, PhD School of Dentistry, Universidade Paulista (UNIP), Indianapolis Campus, Sao Paulo, Brazil. *Corresponding author e-mail: [email protected] Spec Care Dentist 34(3): 144-150, 2014
Int r od uct ion
The cleidocranial dysplasia (CCD), also known as Scheuthauer syndrome1 or mutational dysostosis, is a rare congenital bone disease with autosomal-dominant pattern of inheritance.2 Its prevalence is estimated at 1:1,000,000 with no sex predilection.3 Usually, it is an underdiagnosed disease because of the low incidence of medical complications, where oral manifestations are a major cause of morbidity.3,4 CCD occurs due to mutations in the Cbfa 1 gene, also called Runx 2, located on the short arm of chromosome 6. This gene is responsible for osteoblast differentiation. It is essential for the formation of bone tissue, both endochondral and membranous, and may be related to the delay in ossification of the skull, pelvis, and extremities in the CCD. This gene encodes a transcription factor that is osteoblast specific and maps to chromosome 6p21.4–6 However, although there are several different types of mutations in the Runx 2 in the CCD, it does not seem to relate to the severity of the disease. Range of phenotypes bone in CCD subjects is attributable to the quantitative reduction of the functional activity of Runx 2.4,7,8
C a s e r ep or t
Reports of clinical cases are based on six subjects of the same family following heredogram diagram with clinical and radiographic diagnosis of CCD. Highlighted and proofed features are meaningful and relevant to all subjects, such as short stature, clavicular hypoplasia with large mobility, ogival palate, absence of cleft palate, hypertelorism,
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supernumerary teeth, retained teeth, and prominent frontal bossing.
Her ed og r a m
Subject 1: A 45-year-old female, who attended the Dental Clinic of the Department of Oral Diagnosis, University Paulista, Sorocaba, SP, reported, as main complaint, a misfit of maxillary complete denture. Extra-oral clinical examination confirmed short stature (1 m and 40 cm tall), increased head circumference, hypertelorism, frontal protuberance, midface hypoplasia, pseudo-prognathism, discreet hearing loss, broad flattened nasal bridge, saddle nose, and large mobility of shoulders (Figure 1). Intraoral physical examination confirmed total absence of the upper and lower teeth because of extraction, narrow and deep ogival palate, and an increased volume of bone consistency in the anterior maxillary and painless palpation, which allowed the misfit of the denture. Panoramic radiograph showed retained supernumerary teeth, incomplete rhizogenesis, and maxillary atresia (Figure 2). Clinical and radiographic findings led to the diagnostic hypothesis of CCD. Based on clinical and
© 2013 Special Care Dentistry Association and Wiley Periodicals, Inc. DOI: 10.1111/scd.12045
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Figure 1. Subject 1.
radiographic findings, the subject was referred to the Department of Genetics where the CCD was confirmed. Given this diagnosis, we investigated the presence of these changes in the family due to autosomal-dominant characteristic of the syndrome. On analyzing all direct descendants (subjects 2–4), we found clinical and radiographic CCD features. Subjects were recorded through pictures with front view and panoramic radiograph. Subject 2: A 22-year-old male with same physical aspects, such as short stature (1 m and 51 cm tall), increased head circumference, mid-face hypoplasia, hypertelorism, prominent frontal, parietal and occipital bossing, saddle nose, and broad flattened nasal bridge (Figure 3). Intraoral clinical examination showed protruding jaw, narrow and deep ogival palate, maxillary atresia also observed in the panoramic radiography, partial absence of teeth in the upper and
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lower arches due to multiple previous dental extractions. Radiographic examination also showed multiple impacted teeth with abnormal morphologies and ectopic roots (Figure 4). Elements 53, 63, 73, and 83 had no exfoliation. Elements 13, 23, 33, and 43 were retained. This subject had extraction of deciduous elements, supernumerary elements, and third molars. A rapid maxillary expansion was performed with Haas expander. A space maintainer is being used. Orthodontic traction was performed on elements 13, 23, 33, 43, 21, and 22 for later rehabilitation. There is a possibility of placement of osteointegrable implant in the mandible, and installation of removable partial denture in the maxilla after the orthodontic therapy. However, osteointegrable implant depends on the computed tomography examination to ensure presence of enough alveolar bone. If it is not possible
Figure 2. Panoramic radiograph of Subject 1.
to place osteointegrable implant, the subject will have removable partial dentures in the maxilla and mandible. Subject 3: A 17-year-old female, who had short stature (1 m and 42 cm tall), increased head circumference, hypertelorism, prominent frontal, parietal and occipital bossing, mild exophthalmos, and mild pseudo-prognathism (Figure 5). Intraoral clinical examination showed narrow and deep ogival palate, maxillary atresia, absence of cleft palate, and permanent teeth, where some elements had morphological changes. Radiographic examination showed several retained teeth with abnormal morphologies and ectopic
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Figure 3. Subject 2.
Figure 5. Subject 3.
Figure 7. Subject 4.
Figure 4. Panoramic radiograph of Subject 2.
Figure 6. Panoramic radiograph of Subject 3.
Figure 8. Panoramic radiograph of Subject 4.
roots (Figure 6). It was observed that elements 28, 38, and 48 were retained. Elements 18, 34, and 44 were absent. Elements 13, 23, and 25 were impacted. Elements 32, 33, 42, and 43 were crowded. Elements 35, 45, 37, and 47 had incomplete rhizogenesis. Mandibular trabecular bone is poor in areas of greater radiographic density. Ascending branch of the mandible is narrow and delicate. Coronoid process was pointed. This subject received orthodontic therapy in which a rapid maxillary expansion was performed with Haas expander. A space maintainer is being used. She was considered for orthog-
nathic surgery, prosthesis, or orthodontic therapy seeking total repair. Subject 4: A 7-year-old male, who showed physical characteristics similar to his mother, such as hypertelorism, frontal and parietal protuberance, broad flattened nasal bridge, mild exophthalmos, large mobility of shoulders and short stature (1 m and 12 cm tall), and maxillary atresia (Figure 7). Intraoral clinical examination showed a mixed dentition not compatible with age, narrow and deep ogival palate, and absence of cleft palate. Radiographic examination showed a mixed dentition with delayed exfoliation of some deciduous teeth, delayed eruption of some
permanent teeth, and retained and supernumerary teeth (Figure 8). This subject was 7 years and 7 months old and has not suffered exfoliation of any deciduous tooth. Extractions of elements 51, 61, 71, 81, 52, 62, 72, and 82 were performed with surgical exposure. This procedure was an attempt to foster spontaneous eruption of upper permanent central and lateral incisors and lower permanent central and lateral incisors. These elements had evident delayed eruption because of the two-thirds of the roots of permanent elements were already formed and because of delayed rizolisis of deciduous teeth. It was also observed that elements 16, 26, 36, and 46 are in eruptive phase
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Figure 9. Subject 5.
Figure 11. Subject 6.
Figure 10. Panoramic radiograph of Subject 5.
Figure 12. Panoramic radiograph of Subject 6.
but with delayed rhizogenesis and extremely fibrous gingiva overlying these dental follicles. The follicle of elements 17, 27, 37, and 47 was also observed. Follicles 17 and 27 were in a phase of premature exfoliation with rupture of lamina dura not in a compatible stage with its rhizogenesis. There are signs of prognathism or pseudo-prognathism and maxillary atresia, severe malocclusion, and open bite. This patient received orthodontic therapy with use of maxillary expander. The patient was followed-up monthly by the Department of Orthodontics and annual panoramic radiographs were recommended for early detection of
supernumerary elements and best-case management. On investigating other family members, we identified two individuals with the same clinical and radiographic features described previously. Subject 5: A 32-year-old female who was sister of Subject 1. Physical examination showed same phenotypic features as Subject 1, such as short stature (1 m and 39 cm tall), hypertelorism, broad flattened nasal bridge, mild exophthalmos, prominent frontal bossing (Figure 9). Intraoral clinical examination showed absence of several elements, narrow and deep ogival palate, maxillary atresia, and mild mandibular protrusion.
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The presence of retained and ectopic elements in both arches with incomplete rhizogenesis, maxillary atresia, ectopic location of the retained elements, poor trabecular mandibular bone with large areas of greater radiographic density, extremely narrow ascending branch of the mandible, and slender coronoid process were observed through panoramic radiograph (Figure 10). At the request of the subject, all elements were extracted. Dental rehabilitation was performed with immediate upper and lower dentures that were replaced by dentures definitive about 1 year after the bone tissue remodeling. Subject 6: A 4-year-old female, daughter of Subject 5. She showed phenotypic features as 97 cm tall, mild mid-face hypoplasia, hypertelorism, prominent frontal, parietal and occipital bossing, saddle nose, broad flattened nasal bridge, and mild exophthalmos (Figure 11). Intraoral clinical examination showed signs of maxillary atresia with malocclusion, bilateral cross-bite, and slight anterior open-bite. However, chronological age seems to be compatible with patient’s dental age. Radiographic examination showed delay in the root resorption of deciduous teeth and permanent tooth germs in formation. Elements 16, 26, 36, and 46 are in a phase of premature exfoliation with incompatible rhizogenesis (Figure 12). This subject received orthodontic therapy with removable appliance, maxillary expander, and previous grid. No other dental interventions were conducted. Subject is being followed-up monthly by the Department of Orthodontics. Annual panoramic radiographs for early detection of supernumerary elements were recommended, which will help in evaluating the treatment needed at the appropriate time avoiding the worsening of conditions and improving the referral of this case. Surgical interventions, such as extractions, surgical exposures, orthodontic traction, and orthognathic surgery are not discarded, which depend on the development of the case. Some subjects reported that the father of Subjects 1 and 5 had characteristics
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similar to CCD. He died in a car accident. So we cannot confirm through clinical and radiographic examination whether father suffering from CCD. Given physical, clinical, and radiographic findings, subjects were referred to a geneticist for genetic counseling individually and with family. They were also informed about the risks of recurrence of this dominant genetic disease in future generations. A multidisciplinary assessment was conducted to establish appropriate surgical, orthodontic, and prosthetic treatment restoring each aesthetics and function. Important role prevention protocol was established for these subjects, where they were instructed about the cleaning and maintenance of desirable conditions of oral health. Subjects were referred to surgical and periodontal treatment followed by rehabilitation of decayed teeth and aesthetics. Subject 1 was referred for extracting retained teeth and later to the prosthesis rehabilitation of upper and lower denture. Subjects 2 and 6 were referred to orthodontic treatment through maxillary expander due to ogival palate. Corrective orthodontic appliances were installed later seeking better fit and positioning of the teeth. Subject 3 received clinical treatment from dentistry and periodontics and was referred to orthodontic treatment for maxillomandibular expansion for functional correctness. Subjects 4 and 5 received clinical treatment from dentistry and periodontics and extraction of retained teeth. Later, they were referred to prosthetic treatment for functional rehabilitation through both removable partial and complete dentures. These subjects were followed-up every 6 months in order to keep good maintenance of hygiene conditions and to see whether desirable effects are obtained with the approaches recommended.
D is cu s s io n
CCD is a disease caused by a bone disorder with inheritance pattern that shows
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phenotypic manifestations in different degrees. It may be confused with other bone pathologies but some manifestations are specific that will help determining the diagnosis of the syndrome.3,4,9 Among diseases that have differential diagnosis with CCD, pycnodysostosis or Maroteaux–Lamy syndrome, also known as mucopolysaccharidosis type VI, presents clinical features similar to CCD, such as short stature, craniofacial deformities, dysplasia of clavicles, and changes in tooth formation. However, this diagnosis was excluded as pycnodysostosis because it is an autosomal recessive skeletal dysplasia and presents other clinical aspects, such as dense and fragile bones, polydystrophic dwarfism, mild mental retardation, and also presents partial agenesis of the terminal phalanges of the hands and feet as multiple bone fractures, which was not found in the cases reported.10,11 Rubinstein–Taybi syndrome also has a differential diagnosis with CCD. However, subject presents mandatory retardation with variable degree of mental retardation, having the intelligence quotient usually between 40 and 50, and reduced life expectancy.12,13 In CCD, there is no loss of intellectual capacity.12,14 Usually diagnosis of CCD is delayed because these individuals usually have a normal life, without systemic complications. However, an extremely complex clinical condition can be presented at the first dental examination with presence of multiple supernumerary teeth, impacted teeth, eruption changed, ectopic dental morphology and location, malocclusion, maxillary atresic, and hindering successful treatment.4,15,16 Aplasia or hypoplasia of the clavicles, hypertelorism, short stature, prominent frontal, parietal and occipital bossing, brachycephalic head, mid-face hypoplasia, saddle nose, broad nasal bridge, hearing problems, and exophthalmos are clinical phenotypic characteristics of CCD.4,9,12,15,17 This article reports case of six subjects who presented aplasia of the clavicles leading to an accentuated mobility of shoulders, able to take
s houlders forward, and putting them together in the midline.4,18 All subjects had short stature, except Subject 6 who showed no visible signs of low height for age. The average low height in CCD (1 m and 56 cm for males and 1 m and 44 cm for females) can be observed in subjects over 4 years of age.19 Dental problems are major source of morbidity in the CCD patients, as it interferes with speech, chewing, swallowing, breathing, and hearing. Without treatment the retained deciduous teeth begin to deteriorate rapidly in the late youth or early adulthood, leading to an appearance of premature facial aging signs clearly found in patients 1, 3, 4, and 5.20,21 Permanent dentition is severely affected. There is predisposition to supernumerary teeth, failure in eruption, ectopic, and abnormal tooth morphology, mainly the roots. Delayed eruption of permanent teeth can be attributed to many factors, such as dilaceration of the roots and crowns with enamel hypoplastic and globular dentin, lack of root resorption of deciduous teeth, presence of a physical barrier represented by retained supernumerary teeth or by interposed fibrous tissue between dental follicle and mucosa, high bone density in maxillary and failure in the alveolar bone resorption, fibrous mucosa and presence of large amount of acellular cementum, and absence of cellular cementum on the roots of affected teeth.9,15,17,18 For better treatment of oral conditions of Subjects 2–4, we followed to the removal of retained deciduous teeth and supernumerary teeth.3,4,9 After maxillary expansion, obtaining an ideal format, and a solid anchor to the dental arch, efforts will be concentrated on impacted or unerupted teeth with orthodontic traction. This phase should extend for a long enough period of time.22,23 For Subjects 4 and 6, surgical and orthodontic treatment is being planned and executed so that they can coincide with the developmental stages of the permanent dentition.22 Orthognathic surgery for the correction of dentofacial deformities may be necessary in some cases as well as the prosthetic rehabilitation.14
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Eruption of first permanent molars appears spontaneously in most individuals with CCD due to a thin layer of bone tissue that needs to overcome, despite having extremely fibrotic gingiva overlying the dental follicles.24 In Subjects 4 and 6, it was observed that dental follicles of the first permanent molars were in exfoliative phase, even rhizogenesis showed slow development.24 Impacted and supernumerary teeth are clinical characteristics markedly found in the cases presented in this report. Generalized bone dysplasia present in CCD leads to changes in the bone tissue remodeling and the presence of supernumerary teeth. This explains the prolonged retention of teeth included, as well as retention of permanent teeth for much longer periods than usual.25 Subjects 1 and 5 were rehabilitated through upper and lower dentures. Removable partial denture was installed in Subject 4. Both total prosthesis as removable of partial dentures meet all the immediate needs for proper rehabilitation. However, as the bone height in these cases is very limited, with shallow grooves and a more slender bone, dentist should consider making dentures. Subject 2 can be rehabilitated through placement of osteointegrable implant. However, absence of alveolar bone and slender jaw often present in CCD precludes the use of implants. There is no treatment for cranial, clavicular, and other bone abnormalities associated with CCD. However, treatment of oral conditions is essential due to the occurrence of health problems related to the disease. This treatment should be based on aesthetic and functional rehabilitation through clinical care, surgery, orthodontics, and prosthodontics. Thus, oral problems resulting from this syndrome will be minimized and conditions of the stomatognathic system will be improved.15,26,27
C on clu s ion
Due to the rare incidence and phenotypic manifestations, CCD can be easily
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isdiagnosed. Dentist must have m the knowledge of disorders of the maxillofacial structures of this syndrome. Vast majority of affected subjects have oral problems (functional and aesthetic) as the main complaint. Dentist has to establish the diagnosis as early as possible. Other responsibility of a dentist is to make an immediate intervention in order to minimize oral changes, aiming at the functional adaptation of the individual, providing better quality of life with decreased comorbidities associated with oral problems. A multidisciplinary interaction is important in the handling and treatment of such subjects, composed of several experts in the dental field, associated with doctors, psychologists, and speech therapists, aiming a rehabilitation that provides a functional and aesthetic comfort for the subject. Multidisciplinary treatment of patients with CCD may also reduce the frequency of comorbidities associated with this syndrome.
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States of America: W.B. Saunders; 2002; 537-9. 22. Olszewska A. Dental treatment strategies in a 40-year-old patient with cleidocranial dysplasia. J Appl Genet 2006;47(2): 199-201. 23. Becker A. Tratamento ortodôntico de dentes impactados. São Paulo: Santos; 2004. 24. Jensen BL, Kreiborg S. Dental treatment strategies in cleidocranial dysplasia. Br Dent J 1992;172(6):243-7.
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