Molecular Characterization of Three Canine Models of Human Rare Bone Diseases: Caffey, van den Ende-Gupta, and Raine Syndromes.

One to two percent of all children are born with a developmental disorder requiring pediatric hospital admissions. For many such syndromes, the molecular pathogenesis remains poorly characterized. Parallel developmental disorders in other species could provide complementary models for human rare diseases by uncovering new candidate genes, improving the understanding of the molecular mechanisms and opening possibilities for therapeutic trials. We performed various experiments, e.g. combined genome-wide association and next generation sequencing, to investigate the clinico-pathological features and genetic causes of three developmental syndromes in dogs, including craniomandibular osteopathy (CMO), a previously undescribed skeletal syndrome, and dental hypomineralization, for which we identified pathogenic variants in the canine SLC37A2 (truncating splicing enhancer variant), SCARF2 (truncating 2-bp deletion) and FAM20C (missense variant) genes, respectively. CMO is a clinical equivalent to an infantile cortical hyperostosis (Caffey disease), for which SLC37A2 is a new candidate gene. SLC37A2 is a poorly characterized member of a glucose-phosphate transporter family without previous disease associations. It is expressed in many tissues, including cells of the macrophage lineage, e.g. osteoclasts, and suggests a disease mechanism, in which an impaired glucose homeostasis in osteoclasts compromises their function in the developing bone, leading to hyperostosis. Mutations in SCARF2 and FAM20C have been associated with the human van den Ende-Gupta and Raine syndromes that include numerous features similar to the affected dogs. Given the growing interest in the molecular characterization and treatment of human rare diseases, our study presents three novel physiologically relevant models for further research and therapy approaches, while providing the molecular identity for the canine conditions.

[Craniomandibular disorder/dysfunction. Characteristics and disorders of the masticatory organ]. / Craniomandibularis diszfunkció. A rágószerv sajátosságai és muködési zavarai.

The practising physician often meets patients with pain located in different parts of the face and facial skull, mouth opening restriction or other motion disorder of the mandible. It is not always easy to identify and explain the cause. It is not widely known among doctors that most of these problems are due to masticatory dysfunction. There is a special group of patients showing functional disorders and there are some others who present a variety of different symptoms and visit several doctors. The masticatory organ, a functional unit of the human organism has a definite and separate task and function. In the early years of life it is capable of adaptation, while later on it tends to compensation. The authors outline the functional anatomy of the masticatory organ and the characteristics of multicausal pathology, the dynamics of the process of the disease and their interdisciplinary aspects. They discuss the basic elements of craniomandibular dysfunction. Based on the diagnostic algorithm, they summarize treatment options for masticatory function disorders. They emphasize the importance that physicians should offer treatment, especially an irreversible treatment, without a diagnosis. It occurs very often that the causes are identified after the patients become symptom-free due to treatment. The aim of this report is to help the general practitioners, dentists, neurologists, ear-nose-throat specialists, rheumatologists or any other specialists in the everyday practice who have patients with different symptoms such as pain in the skull, acoustic phenomenon of the joint or craniomandibular dysfunction.

Changes in cortical activation in craniomandibular disorders during splint therapy - a single subject fMRI study.

There is some controversial discussion within the therapy of craniomandibular disorders (CMDs) about the mode of action of occlusal splints. Here we present a case report on one CMD-patient measuring cerebral activation changes with functional magnetic resonance imaging (fMRI) before and after therapy with a stabilization splint. Wearing the Michigan splint for 11 nights and partially days resulted in substantial pain relief and changes in occlusal movement performance. Cerebral activation during occlusion was decreased after therapy (PRE-POST) in bilateral sensorimotor regions but also additional areas such as left posterior insula, right superior temporal cortex and bilateral occipital lobe. During the first usage of the splint in the scanner (PRE) increased activation in the left dorsolateral prefrontal lobe (BA 9) was observed. After splint training occlusion with the splint compared to without a splint increasingly involved the left superior parietal lobe (BA 7, POST). Whereas BA 9 might be associated with increasing working memory load due to the manipulation with an unusual object, the BA 7 activation in the POST session might document increased sensorimotor interaction after getting used to the splint. Our findings indicate that wearing an occlusion splint triggers activation in parietal sensorimotor integration areas, also observed after long periods of sensorimotor training. These additional recourses might improve coordination and physiological handling of the masticatory system.

Correlation analysis of craniomandibular index and gothic arch tracing in patients with craniomandibular disorders.

BACKGROUND/AIM: Complex etiology and symptomatology of craniomandibular dysfunction make the diagnosing and therapy of this disorder more difficult. The aim of this work was to assess the value of clinical and instrumental functional analyses in diagnosing of this type of disorders. METHODS: In this study 200 subjects were examined, 15 with temporomandibular joint disorder. They were subjected to clinical functional analysis (Fricton-Shiffman) and instrumental functional analysis by using the method of gothic arch. The parameters of the gothic arch records were analyzed and subsequently compared among the subjects of the observed groups. RESULTS: In the examined group of the population 7.5% of them were with craniomandibular dysfunction. The most frequent symptoms were sound in temporomandibular joint, painful sensitivity of the muscles on palpation and lateral turning of the lower jaw while opening the mouth. By analyzing the gothic arch records and comparing the obtained values between the observed groups it was assessed that: lateral and protrusion movements, lateral amplitude and the size of gothic arch were much bigger in the healthy subjects, and latero-lateral asymmetry was larger in the sick subjects. Latero-lateral dislocation of apex was recorded only in the sick subjects with average values of 0.22 +/- 0.130 mm. The correlation between the values of Fricton-Shiffman craniomandibular index and the parameters of the gothic arch records and latero-lateral amplitude and dislocation of apex records were established by correlative statistical analysis. CONCLUSION: Functional analysis of orofacial system and instrumental analysis of lower jaw movements (gothic arch method) can be recommended as precise and simple methods in diagnosing craniomandibular dysfunctions.

Does head posture have a significant effect on the hyoid bone position and sternocleidomastoid electromyographic activity in young adults?

The aim of this study was to evaluate the associations between head posture (head extension, normal head posture, and head flexion) and anteroposterior head position, hyoid bone position, and the sternocleidomastoid integrated electromyographic (IEMG) activity in a sample of young adults. The study included 50 individuals with natural dentition and bilateral molar support. A lateral craniocervical radiograph was taken for each subject and a cephalometric analysis was performed. Head posture was measured by means of the craniovertebral angle formed by the MacGregor plane and the odontoid plane. According to the value of this angle, the sample was divided into the following three groups: head extension (less than 95 degrees); normal head posture (between 95 degrees and 106 degrees); and head flexion (more than 106 degrees). The following cephalometric measurements were taken to compare the three groups: anteroposterior head position (true vertical plane/pterygoid distance), anteroposterior hyoid bone position (true vertical plane-Ha distance), vertical hyoid bone position (H-H' distance in the hyoid triangle), and CO-C2 distance. In the three groups, IEMG recordings at rest and during swallowing of saliva and maximal voluntary clenching were performed by placing bipolar surface electrodes on the right and left sternocleidomastoid muscles. In addition, the condition with/without craniomandibular dysfunction (CMD) in each group was also assessed. Head posture showed no significant association with anteroposterior head position, anteroposterior hyoid bone position, vertical hyoid bone position, or sternocleidomastoid IEMG activity. There was no association to head posture with/without the condition of CMD. Clinical relevance of the results is discussed.

Desordem crânio-mandibular em idosos: revisäo da literatura / Cranio-mandibular disorder in elderly people: review of the literature

A populaçäo de idosos vêm aumentando rapidamente em diversas partes do mundo, o que coloca a atençäo à saúde do idoso em evidência. Neste contexto, o papel do cirurgiäo-dentista é de grande importância, uma vez que o estado de saúde oral dos indivíduos idosos contribui em grande parte para sua saúde em geral. Numerosos estudos têm sido feitos para identificar as modificaçöes patológicas e fisiológicas da senescência no sistema mastigatório. No trabalho que ora se apresenta, os autores realizam uma revisäo da literatura inerente às desordens crânio-mandibulares em pacientes de idade avançada, abordando os vários fatores envolvidos neste tipo de alteraçäo

A comparison of the craniofacial morphology in 2-month-old unoperated infants with unilateral complete cleft lip and palate, and unilateral incomplete cleft lip.

This paper reports a cephalometric analysis of the craniofacial morphology in infants with unoperated unilateral complete cleft lip and palate (UCCLP) and unoperated unilateral incomplete cleft lip (UICL). The purpose of the study was to determine the nature and extent of the craniofacial deviations in UCCLP as compared to the morphology in UICL, which has previously been shown to be close to normal. The samples comprised 82 infants with UCCLP (58 males and 24 females) and 75 with UICL (48 males and 27 females). The mean age was about 2 months in both groups. The cephalometric analysis of craniofacial morphology included the lateral, frontal, and axial projections. The data were presented as mean plots of the craniofacial region including the calvaria, cranial base, orbits, nasal bone, maxilla, mandible, cervical column, pharynx, and soft-tissue profile. The most pronounced deviations in the UCCLP group were observed in the maxillary complex and the mandible. The most striking findings were: markedly increased width of the maxilla, a short mandible, and bimaxillary retrognathia except for the premaxillary area, which was relatively protruding and asymmetric. The study did not support the hypothesis previously suggested in the literature that cleft lip and palate is a craniofacial anomaly as size and shape of the calvaria and cranial base were found to be normal. The etiology of cleft lip and palate is still incompletely understood. Based on the present study, we suggest that facial type may be a liability factor that could represent a developmental threshold increasing the probability of cleft lip and palate.

Craniomandibular osteopathy in two Pyrenean mountain dogs.

Craniomandibular osteopathy was diagnosed in two Pyrenean mountain dogs with a history of mandibular swelling, pain, fever and, in dog 1, lameness. Radiographs demonstrated extensive, active new bone formation on the ventral aspect of the mandibular bodies of both dogs. Dog 2 responded well to treatment but dog 1 was euthanased owing to severe pain, dysphagia and unsuccessful treatment. The mandibles were examined by means of back-scattered scanning electron microscopy and a well arranged mineralised trabecular network of chondroid tissue and woven bone was observed. The mandibular cortical bone under the areas of periosteal proliferation was also affected, showing a looseness of the characteristic compact appearance of lamellar bone. This is the first report of craniomandibular osteopathy in this breed.

Disfunción craneomandibular: revisión actualizada de los factores etiopatogénicos / Craniomandibular dysfunction: a current review of the etiopathogenic factors

A partir de un modelo presuntivo que involucra seis factores etiopatogénicos asociados a la DCM: oclusales, psicosociales, parafunción, genéticos, hipermovilidad articular sistémica (HAS) y trauma, se analizan los trabajos de publicación reciente referidos a cada uno de ellos evaluándose su posible contribución etiopatogénica. Se especifican algunos hallazgos controversiales, sobre todo los referidos a los factores oclusales que, a partir de revisiones y nuevas publicaciones, han puesto en duda su carácter relevante asociado a la DCM. Los aspectos psicológicos parecen mantener su valor contributivo, históricamente considerado, advirtiéndose cierto énfasis para los denominados "psicosociales", involucrando aspectos contingentes y cicunstancias referidos al entorno socioeconómico. En cuanto a la parafunción, en particular el bruxismo, se señalan las dificultades metodológicas para evaluar su frecuencia y el grado de certeza de su valor contributivo asociado a la DCM. Los factores genéticos y la HAS, asociada a patologías intracapsulares, deberán ser estudiadas más ampliamente en el futuro, pues pueden ser la clave para el reconocimeinto de aspectos aún no aclarados sobre mecanismos etiopatogénicos de la DCM. En cuanto a los factores traumáticos, la posibles deformación de los resultados por razones económicas secundarias, propias de los litigios legales, habría "sobreinterpretado" algunos hallazgos. Aún así, hay un importante número de trabajos asociándolos a la DCM (AU)

Disfunción craneomandibular: revisión actualizada de los factores etiopatogénicos / Craniomandibular dysfunction: a current review of the etiopathogenic factors

A partir de un modelo presuntivo que involucra seis factores etiopatogénicos asociados a la DCM: oclusales, psicosociales, parafunción, genéticos, hipermovilidad articular sistémica (HAS) y trauma, se analizan los trabajos de publicación reciente referidos a cada uno de ellos evaluándose su posible contribución etiopatogénica. Se especifican algunos hallazgos controversiales, sobre todo los referidos a los factores oclusales que, a partir de revisiones y nuevas publicaciones, han puesto en duda su carácter relevante asociado a la DCM. Los aspectos psicológicos parecen mantener su valor contributivo, históricamente considerado, advirtiéndose cierto énfasis para los denominados "psicosociales", involucrando aspectos contingentes y cicunstancias referidos al entorno socioeconómico. En cuanto a la parafunción, en particular el bruxismo, se señalan las dificultades metodológicas para evaluar su frecuencia y el grado de certeza de su valor contributivo asociado a la DCM. Los factores genéticos y la HAS, asociada a patologías intracapsulares, deberán ser estudiadas más ampliamente en el futuro, pues pueden ser la clave para el reconocimeinto de aspectos aún no aclarados sobre mecanismos etiopatogénicos de la DCM. En cuanto a los factores traumáticos, la posibles deformación de los resultados por razones económicas secundarias, propias de los litigios legales, habría "sobreinterpretado" algunos hallazgos. Aún así, hay un importante número de trabajos asociándolos a la DCM

[Histopathological effects of overextended opening of the mouth on the temporomandibular joint and masticatory muscles].

The purpose of this study is to explore the effects and the pathogenicity of overextended mouth opening on the temporomandibular joint (TMJ) and the masticatory muscles. In this experiment, the animal model of overextended opening was, established by overly opening the miniature pigs' mouths for certain periods with mouth gag, and then the TMJ and the masticatory muscles were studied histopathologically. The results showed that the histosytes of the TMJ and the masticatory muscles had suffered injury, proliferation, atrophy and degeneration from the overextended opening, and the extents of deterioration became greater with the increase of frequency and duration of overextended opening. Among the injured tissues, the cartilage of the condyle, the posterior and anterior portions of the articular disc, the anterior extenting tissue of the disc, the lateral perygoid muscles and the temporalises underwent the most obvious histopathological changes. The result of this study confirms that overextended mouth opening is one of the pathogenic factors of CMD, and it has great significance for the clinical diagnosis, treatment and prevention for CMD.

Craniomandibular stiffness in myogenous and arthrogenous CMD patients, and control subjects: a clinical and experimental investigation.

The purpose of this study was to compare active maximum mouth opening, endfeel distance, and craniomandibular stiffness values of three craniomandibular disorder (CMD) patient subgroups and a control group. The CMD patient subgroups consisted of myogenous pain patients and arthrogenous pain patients with a 'closed lock' and arthrogenous pain patients without a 'closed lock'. Both myogenous pain patients and the 'closed lock' patients showed great differences on all parameters (P < 0.05-P < 0.001). However, the arthrogenous pain patients without a 'closed lock' revealed no statistical differences with the control group on any of the tested parameters.

[MRI of the semicircular canals in cranio-facial asymmetries and craniomandibular syndrome]. / IRM des canaux semi-circulaires dans les asymétries crânio-faciales et le syndrome crânio-mandibulaire.

The cranio-mandibular syndrome (CMS) is often secondary to an cranio-facial asymmetry (CFA); it associate a painful masticatory dysfunction syndrome with functional and aching clinical signs in relation with a functional torticollis required for oculo-labyrinthal equilibration maintenance. Our anatomical and functional MRI protocol uses tridimensional study of semi-circular canals (SCC) up relation to the medial cerebral axis (MCA), and permit to measure precisely these CFA and propose, with a multispecialist approach, an adapted treatment of the SCM. Application of MRI to SCC asymmetry looks to its future use for spatial intracranial referencial of cerebral structures.

Craniomandibular disorders and skeletal mineral status.

Values for bone mineral density of the femoral neck and lumbar spine were determined by dual-energy x-ray absorptiometry for 355 postmenopausal women 48 to 56 years of age. The bone mineral density in three regions of the mandible was measured by quantitative computed tomography for 77 of the 355 women. Existing symptoms of craniomandibular dysfunction were recorded in both an anamnestic inquiry and a clinical examination. The purpose of this study was to determine whether the bone mineral density of the skeleton and mandible is associated with symptoms of craniomandibular dysfunctions. The results suggest that the habits and conditions that provoke development of general bone loss in the skeleton may disturb the functional harmony of the masticatory system and, thus, increase the possibility for craniomandibular disorders (CMD).

Duraçäo do período de silêncio (PS) eletromiográfico masseterino em indivíduos com desordens crâniomandibulares após a terapia oclusal / The electromyographic silent period duration of the masseter muscles in patients with dysfunction of the temporomandibular joint after occlusal therapy

O período de silêncio (PS) eletromiográfico dos músculos masséteres tem sido objeto de inúmeras investigaçöes desde que se observou estar a sua duraçäo alterada em indivíduos com desarmonias oclusais. A partir dessa observaçäo, vários pesquisadores propuseram o uso da medida da duraçäo do PS como teste fisiológico da condiçäo neuromuscular do sistema mastigatório, sendo, portanto, de grande utilidade para o diagnóstico das desordens crâniomandibulares, bem como para a avaliaçäo da efetividade do tratamento realizado. Tais proposiçöes säo, no entanto, questionadas na literatura existente sobre o assunto. Devido à inexistência de consenso a respeito, o presente trabalho teve como objetivo analisar as variaçöes observadas na duraçäo do PS eletromiográfico de um grupo de pacientes (n=21) com desordens crâniomandibulares após a terapia oclusal convencional. Os registros foram feitos em um eletromiógrafo DISA 1500 EMG-System que captava os potenciais de açäo através de eletrodos de superfície fixados sobre os músculos masséteres dos indivíduos que eram instruídos a manter-se com os dentes em máxima intercuspidaçäo habitual e com a musculatura em estado de contraçäo voluntária isométrica máxima. Neste estado, aplicavam-se ao mento 10 percurssöes de cima para baixo, com um martelo de teste de reflexos, para estimular-se o aparecimento do PS. As medidas de duraçäo dos PS obtidos foram realizadas em uma mesa digitalizadora acoplada a um microcomputador. Os resultados mostraram que as médias de duraçäo do PS eletromiográfico, no grupo de normais, foram de 24,14ñ4,31 ms e de 24,79ñ4,08 ms para os músculos masséteres direito e esquerdo, respectivamente. No grupo de pacientes com desordens crâniomandibulares, as médias obtidas para os músculos masséteres direito e esquerdo, respectivamente, foram de 43,13ñ8,43 ms e 44,56ñ7,97 ms na situaçäo inicial, de 45,80ñ13,62 ms e 46,50ñ12,66 ms após o uso da placa parcial anterior por uma semana e de 41,25ñ9,45 ms e 42,85ñ9,32 ms um mês após o ajuste oclusal. A análise de variância mostrou näo haver diferença significante entre os valores de duraçäo do PS eletromiográfico do grupo de pacientes com desordens crâniomandibulares, nas situaçöes pré-tratamento, pós uso da placa parcial anterior e pós ajuste oclusal. Encontrou-se diferença significante entre os valores obtidos no grupo normal e no grupo com desordens crâniomandibulares (pré-tratamento). Pela análise dos dados, conclui-se que: 1) A duraçäo do PS...

Influência da terapia oclusal na duraçäo do período de silêncio eletromiográfico / Influence of occlusion therapy in the electromyographic silent period duration

O presente trabalho teve por objetivos determinar a duraçäo do período de silêncio eletromiográfico (PS) em um grupo de pacientes portadores de disfunçäo craniomandibular (DCM, n=10) e em outro que necessitava de reabilitaçäo oral protética (ROP, n=6). No grupo com DCM, a duraçäo de PS foi analisada na fase pré-tratamento, após o uso por um mês da placa oclusal total miorrelaxante e após um mês da realizaçäo do ajuste oclusal. O exame físico, a confecçäo das placas oclusais e os ajustes foram realizados na Clínica de DCM da FOB-USP, por alunos de pós-graduaçäo em reabilitaçäo oral-prótese. No grupo com ROP, a duraçäo do PS foi analisada numa fase inicial, antes da colocaçäo dos provisórios, e um mês após o posicionamento dos mesmos, efetuado na Clínica de Pós-Graduaçäo em Reabilitaçäo Oral da FOB-USP. O PS foi induzido pela percussäo do mento, pela percussäo voluntária e rítmica dos dentes, pela percussäo direta do dente incisivo central superior direito, pelo estímulo elétrico aplicado ao lábio inferior e pela aplicaçäo de jato de ar aplicado na papila gengival entre os dentes incisivos inferiores. A atividade bioelétrica dos músculos masséteres e temporais foi captada por meio de eletródios bipolares de superfície (DISA tipo 13L26) conectados a um eletromiógrafo (DISA 1500 EMG-System). Avaliando os dados por meio de análise de variância a três critérios, podê-se verificar que: 1) na fase pré-tratamento, a duraçäo do PS eletromiográfico tanto no grupo com DCM quanto no grupo com ROP foi significativamente maior que no grupo de indivíduos normais (n=7), 2) näo houve diferença significante, na duraçäo do PS eletromiográfico, nas fases de tratamento, tanto no grupo com DCM quanto no com ROP e 3) näo houve correlaçäo entre os valores de duraçäo do PS eletromiográfico com o índice anamnésico de disfunçäo craniomandibular. Com base nesses resultados sugere-se afirmar que o parâmetro duraçäo do PS eletromiográfico é um índice efetivo auxiliar no diagnóstico das alteraçöes neuromusculares do sistema estomatognático, presentes nos casos de DCM e de ROP, näo podendo, entretanto, ser utilizado como índice de acompanhamento de tratamento