Cleidocranial dysplasia and novel RUNX2 variants: dental, craniofacial, and osseous manifestations

Abstract Cleidocranial dysplasia (CCD) is a skeletal disorder affecting cranial sutures, teeth, and clavicles, and is associated with the RUNX2 mutations. Although numerous patients have been described, a direct genotype-phenotype correlation for RUNX2 has been difficult to establish. Further cases must be studied to understand the clinical and genetic spectra of CCD. Objectives To characterize detailed phenotypes and identify variants causing CCD in five unrelated patients and their family members. Methodology Clinical and radiographic examinations were performed. Genetic variants were identified by exome and Sanger sequencing, data were analyzed by bioinformatics tools. Results Three cases were sporadic and two were familial. Exome sequencing successfully detected the heterozygous pathogenic RUNX2 variants in all affected individuals. Three were novel, comprising a frameshift c.739delA (p.(Ser247Valfs*)) in exon 6 (Patient-1), a nonsense c.901C>T (p.(Gln301*)) in exon 7 (Patient-2 and affected mother), and a nonsense c.1081C>T (p.(Gln361*)) in exon 8 (Patient-3). Two previously reported variants were missense: the c.673C>T (p.(Arg225Trp)) (Patient-4) and c.674G>A (p.(Arg225Gln)) (Patient-5) in exon 5 within the Runt homology domain. Patient-1, Patient-2, and Patient-4 with permanent dentition had thirty, nineteen, and twenty unerupted teeth, respectively; whereas Patient-3 and Patient-5, with deciduous dentition, had normally developed teeth. All patients exhibited typical CCD features, but the following uncommon/unreported phenotypes were observed: left fourth ray brachymetatarsia (Patient-1), normal clavicles (Patient-2 and affected mother), phalangeal malformations (Patient-3), and normal primary dentition (Patient-3, Patient-5). Conclusions The study shows that exome sequencing is effective to detect mutation across ethnics. The two p.Arg225 variants confirm that the Runt homology domain is vital for RUNX2 function. Here, we report a new CCD feature, unilateral brachymetatarsia, and three novel truncating variants, expanding the phenotypic and genotypic spectra of RUNX2 , as well as show that the CCD patients can have normal deciduous teeth, but must be monitored for permanent teeth anomalies.

Síndrome de Saethre-Chotzen: a propósito de un caso / Saethre-Chotzen syndrome: a case report

El síndrome de Saethre-Chotzen es un síndrome malformativo craneofacial caracterizado por una sinostosis de las suturas coronales y alteraciones de extremidades. Tiene una prevalencia de 1 de cada 25 000-50 000 recién nacidos vivos. Se presenta el caso de un neonato sin antecedentes de interés con alteraciones craneofaciales al nacer. Ante los rasgos fenotípicos del paciente, se realizó una tomografía axial computada craneal, que mostró la fusión parcial de la sutura coronal y evidenció la presencia de huesos wormianos en localización metópica y lambdoidea derecha. Con la sospecha clínica de síndrome malformativo craneofacial, se solicitó análisis del exoma dirigido, que confirmó que el paciente era portador heterocigoto de la variante patogénica c.415C>A, que inducía un cambio de prolina a treonina en la posición 139 del gen TWIST1, responsable del síndrome. La presencia de huesos wormianos, hallazgo no descrito hasta ahora en la literatura, amplía la variabilidad fenotípica conocida de este síndrome.

The Saethre-Chotzen syndrome is a craniofacial malformation syndrome characterized by synostosis of coronal sutures and limb anomalies. The estimated prevalence of this syndrome is 1 in 25 000-50 000 live births. We present a case report of a neonate, without relevant family history, who presented craniofacial alterations at birth. Given the phenotypic features, a cranial computed tomography scan was performed, showing partial fusion of the coronal suture, evidencing the presence of wormian bones in the metopic and right lambdoid location. With the clinical suspicion of craniofacial malformation syndrome, an analysis of the directed exome was requested confirming that the patient is a heterozygous carrier of the pathogenic variant c.415C>A, which induces a change of proline to threonine at position 139 of the TWIST1 gene, responsible for Saethre-Chotzen syndrome.The presence of wormian bones, a finding not described so far in the literature, extends the well-known phenotypic variability of this syndrome.

Osteogenesis imperfecta: a case report

Osteogenesis imperfecta (OI) is a group of rare inherited disorders of connective tissue with the common feature of excessive fragility of bones caused by mutations in collagen. Diagnosis is mainly based on the clinical features of the disorder. We report a late preterm a male neonate born to a 20 years old primigravida. He had clinical features of a type II OI and severe birth asphyxia.

Study Of Wormian Bones In Adult Dry Skulls Of Human Cadaver

Introduction: Wormian bones are islands of small bones found at the sutures and fontanelles of the skull.Commonly appears in the lambdoid suture. This study reporting the incidence, location and morphology ofWormian bones as it may give the false impression as fractures and lead to confusion to the radiologists,surgeons and traumatologists to deal during surgeries.Materials and Methods: The study comprises the 100 human adult skulls. Measuring tape, Sliding calipers,sutural thread and scale were used for measuring the length of the suture, incidence, types, morphology andtopography of sutural bones were observed and compared with the studies done by previous authors. The boneswere obtained from the Department of Anatomy, sri venkata sai medical college Mahbubnagar, Telangana, India.Results: Wormian bones were found in Lambdoid suture (28%), Lambda (12%), Parietomastoid suture (0%),Coronal Suture (0%), Asterion (8%), Sagittal suture (12%), Occipitomastoid suture (0%), Parietosquamous (0%)and Pterion (8%). Three different shapes of WBs was witnessed; Quadrangular (4%), Irregular (36%), Triangular(8%).Discussion: the knowledge of wormian bones is important to radiologists, orthopedicians and traumatologistsas it can imitate fractures and lead to confusion and eventually differential diagnosis.

Huesos suturales umbilicados / Umbilicated sutural bones

Los huesos suturales son huesos supernumerarios observables en suturas y fontanelas del cráneo, variables en su número, forma, tamaño y posición. Formados desde centros de osificación normales y/o adicionales. Calleja en 1870, describe un hueso sutural en forma de anillo con un centro óseo (umbilicados). Nuestro objetivo de investigación, fue buscar y describir estos huesos. Se utilizaron 71 cráneos de adultos chilenos de ambos sexos, en los cuales se buscó, caracterizó, fotografió y midió a los huesos suturales umbilicados. Se hallaron dos cráneos con presencia de estos huesos, representando el 2,82 % del total de la muestra y el 8 % de los cráneos con huesos suturales. Los resultados concuerdan con la bibliografía, en cuanto a presencia de huesos suturales, así como su relación directa con el sexo y el tamaño del cráneo. También pudimos comprobar la observación y descripción de Calleja, encontrando huesos suturales que cumplían con su descripción. El conocimiento de estos huesos es de utilidad en la identificación médico legal.

The sutural bones are visible supernumerary bones in skull sutures and fontanelle, and are variable in number, shape, size and position. Formed from normal and /or additional ossification, Calleja in 1870, describes a sutural ring-shaped bone with a bone center (umbilicated). Our research objective was to look for and describe these bones. We used 71 skulls of Chilean adults of both sexes, in which we sought, marked, photographed and measured the molluscum sutural bones. Two (2) skulls were found with presence of these bones representing 2.82 % of the total sample and 8 % sutural skulls with bones. The results are consistent with the literature regarding presence of sutural bones, and their direct relationship to sex and size of the skull. We also noted the observation and description by Calleja, finding sutural bones that met their description. Knowledge of these bones is useful in forensic identification.

Frecuencia de huesos wormianos en población autóctona de Manzanillo / Frequency of the wormian bones in Manzanillo autochthonous population

Introducción: los huesos suturales del cráneo o wormianos son estructuras óseas supernumerarias, accesorias e inconstantes. El objetivo de la investigación fue determinar la presencia, número y localización de los huesos wormianos en población autóctona de Manzanillo. Materiales y métodos: se realizó un estudio cuantitativo, longitudinal, prospectivo, observacional y descriptivo, en 93 cráneos en buen estado de conservación, provenientes de cadáveres exhumados en la necrópolis de la ciudad de Manzanillo, Granma. Los cráneos pertenecían a fallecidos nacidos en Manzanillo y en los mismos se practicaron mensuraciones antropológicas. Resultados: los huesos wormianos se constataron en el 44,09 % de los cráneos estudiados. De 72 huesos wormianos el 62,5 % pertenecían a cráneos del sexo femenino. El 56,9 % de estos huesos se localizaron en el lado izquierdo. Los cráneos mesocéfalos e hiperbraquicéfalos tuvieron igual presencia de estos huesos (31 cráneos) pero el número de huesos fue mayor en cráneos hiperbraquicéfalos (33 huesos). Conclusiones: los huesos wormianos son formaciones óseas que aparecen en menos de la mitad de la población autóctona de Manzanillo, tuvieron mayor incidencia en mujeres, en el lado izquierdo del cuerpo y en cráneos hiperbraquicéfalos. El hueso lambdático fue el más frecuente.

Background: suture or wormian crania bones are supernumerary, accessorial and inconstant bone structures. The aim of this research was determining the presence, number and location of worm bones in Manzanillo autochthonous population. Materials and Methods: a quantitative, longitudinal, prospective, observational and descriptive study was carried out in 93 crania in good status of conservation, coming from corpses exhumed in the cemetery of Manzanillo, Granma. Crania belonged to dead people who were born in Manzanillo, and anthropologic measures were done on them. Outcomes: wormian bones were found in 44.09 % of the studied crania. 62.5 % of the 72 wormian bones belonged to female crania. 56.9 % of these bones were located in the left side. Both, mesocephalic and hyperbrachycephalic crania showed the presence of these bones (31 crania) but the number of bones was bigger in hyperbrachycephalic crania (33 bones). Conclusions: the wormian bones are bone formations appearing in less than half of the autochthonous population of Manzanillo, having more incidences in women, in the left side of the body and in hyperbrachycephalic crania. The lambdoid bone was the most frequent one.

Pyknodysostosis (Rare Skeletal Defect): A Case Report.

Pyknodysostosis is a defective bone disease that is responsible in many bone deformities. We report a case with recurrent urti, growth retardation, facial dysmorphism, delayed eruption of teeth & inability to gain weight properly since childhood and successful treatment of the patient by supportive measures.

Supernumerary Bones in the Walls of the Bony Orbit.

Occurrence of supernumerary bones in the walls of the orbit especially in the medial wall and the roof has been described in the literature. Studies of the prevalence of supernumerary bones in the bony wall of the orbit are scarce in the literature. Present study was undertaken to find the prevalence of supernumerary bones in the walls of the orbit in a collection of adult Indian skulls. In the present study three hundred and twenty six orbital walls from one hundred and sixty three skulls were examined for the presence of the sutural bones. Their location with reference to the sutures in the walls of the orbit and their size was noted. The supernumerary bones were found in 25 skulls (15.34 %) mainly in the lateral wall (11.04 %) and the roof of the orbit (4.29 %). Prevalence of such supernumerary bones in the walls of the bony orbit is of anthropological interest. Many of the bony ossicles were of sufficiently large size, enough to be visualized on lateral skull X-ray and could easily be mistaken for fracture of the bony wall of the orbit.

Sexual dimorphism among the wormian bones in adult human skulls.

This study was aimed at evaluating the sexual dimorphism with respect to overall incidence, number and location of wormian bones. Adult dry human skulls (n=180) of known age and sex available in the Department of Anatomy, St.John’s Medical College, Bangalore were included in the study. Overall incidence of wormian bones was more in female (64.80%) than in male skulls (40.20%). They occurred more frequently at lambdoid suture (60%). Wormian bones along the coronal suture and at bregma were seen only in male skulls, while intra- orbital wormian bones were seen only in female skulls. Wormian bones along the sagittal suture showed sexual dimorphism (27.78%, p= 0.045) while at lambda and lambdoid suture showed a good discriminating power of 17.65% (p=0.087) and 21.43% (p=0.089) respectively. This study concludes by stating that, there exists a moderate degree of sexual dimorphism among the wormian bones with respect to overall incidence, number and location.