Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Bacterial and parasite co-infection in Mexican golden trout (Oncorhynchus chrysogaster) by Aeromonas bestiarum, Aeromonas sobria, Plesiomonas shigelloides and Ichthyobodo necator.

BACKGROUND: Bacterial infections are responsible of high economic losses in aquaculture. Mexican golden trout (Oncorhynchus chrysogaster) is a threatened native trout species that has been introduced in aquaculture both for species conservation and breeding for production and for which no studies of bacterial infections have been reported. CASE PRESENTATION: Fish from juvenile stages of Mexican golden trout showed an infectious outbreak in a farm in co-culture with rainbow trout (Oncorhynchus mykiss), showing external puntiform red lesions around the mouth and caudal pedunculus resembling furuncles by Aeromonas spp. and causing an accumulated mortality of 91%. Isolation and molecular identification of bacteria from lesions and internal organs showed the presence of Aeromonas bestiarum, Aeromonas sobria, Plesiomonas shigelloides and Ichthyobodo necator isolated from a single individual. All bacterial isolates were resistant to amoxicillin-clavulanic acid and cefazoline. P. shigelloides was resistant to third generation ß-lactamics. CONCLUSIONS: This is the first report of coinfection by Aeromonas bestiarum, Aeromonas sobria, Plesiomonas shigelloides and Ichthyobodo necator in an individual of Mexican golden trout in co-culture with rainbow trout. Resistance to ß-lactams suggests the acquisition of genetic determinants from water contamination by human- or livestock-associated activities.

The ciliary Evc/Evc2 complex interacts with Smo and controls Hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia.

Hedgehog (Hh) signaling is involved in patterning and morphogenesis of most organs in the developing mammalian embryo. Despite many advances in understanding core components of the pathway, little is known about how the activity of the Hh pathway is adjusted in organ- and tissue-specific developmental processes. Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone development. Using mouse models, we show here that Evc and Evc2 are mutually required for localizing to primary cilia and also for maintaining their normal protein levels. Consistent with Evc and Evc2 functioning as a complex, the skeletal phenotypes in either single or double homozygous mutant mice are virtually indistinguishable. Smo translocation to the cilium was normal in Evc2-deficient chondrocytes following Hh activation with the Smo-agonist SAG. However, Gli3 recruitment to cilia tips was reduced and Sufu/Gli3 dissociation was impaired. Interestingly, we found Smo to co-precipitate with Evc/Evc2, indicating that in some cells Hh signaling requires direct interaction of Smo with the Evc/Evc2 complex. Expression of a dominantly acting Evc2 mutation previously identified in Weyer's acrodental dysostosis (Evc2Δ43) caused mislocalization of Evc/Evc2Δ43 within the cilium and also reproduced the Gli3-related molecular defects observed in Evc2(-/-) chondrocytes. Moreover, Evc silencing in Sufu(-/-) cells attenuated the output of the Hh pathway, suggesting that Evc/Evc2 also promote Hh signaling in the absence of Sufu. Together our data reveal that the Hh pathway involves Evc/Evc2-dependent modulations that are necessary for normal endochondral bone formation.

Identification of a frameshift mutation in Osterix in a patient with recessive osteogenesis imperfecta.

Osteogenesis imperfecta, or "brittle bone disease," is a type I collagen-related condition associated with osteoporosis and increased risk of bone fractures. Using a combination of homozygosity mapping and candidate gene approach, we have identified a homozygous single base pair deletion (c.1052delA) in SP7/Osterix (OSX) in an Egyptian child with recessive osteogenesis imperfecta. The clinical findings from this patient include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing, and white sclera. OSX encodes a transcription factor containing three Cys2-His2 zinc-finger DNA-binding domains at its C terminus, which, in mice, has been shown to be essential for bone formation. The frameshift caused by the c.1052delA deletion removes the last 81 amino acids of the protein, including the third zinc-finger motif. This finding adds another locus to the spectrum of genes associated with osteogenesis imperfecta and reveals that SP7/OSX also plays a key role in human bone development.

Oral Motor Treatment Efficacy: Feeding and Swallowing Skills in Children with Cerebral Palsy.

This study is aimed at identifying the relationship between oral motor treatment and the improvement of abilities for feeding and swallowing in boys and girls with CP residing in the state of Yucatán. The sample consisted of 30 patients with a diagnosis of CP and the presence of ADT, with gross motor function levels from II to V, between 3 and 14 years old, of which 50% received oral motor treatment. The predominant diagnosis was spastic CP and tetraplegia. An interview was carried out with the tutor, the application of the gross motor skills scale, and an assessment of feeding skills. The feeding and swallowing skills that improved significantly with the oral motor treatment were mandibular mobility, tongue activity, abnormal reflexes, control of breathing, and general oral motor skills (p ≤ 0.05). Within the sample that did not receive oral motor treatment, 46% presented low or very low weight and 40% referred recurrent respiratory diseases. In the end, it was concluded that feeding skills improve significantly with oral motor treatment, regardless of the severity of gross motor involvement. Likewise, oral motor treatment was associated with a lower presence of respiratory diseases and nutritional compromise.

Bisphosphonate-related osteonecrosis of the mandible and maxilla: clinical and imaging features.

OBJECTIVE: Bisphosphonate-related osteonecrosis of the jaws is a rare, but morbid, condition. We present the clinical and imaging features of 19 patients. METHODS: A review of 19 bisphosphonate-related osteonecrosis patients was performed. Patient demographics, diagnosis, dental procedures, symptoms and clinical findings, location and pattern of involvement, and presence of fractures, sequestra, and fistulae were documented. RESULTS: Patients included 14 women and 5 men aged 48 to 80 years. Diagnoses included breast carcinoma (n = 11), multiple myeloma (n = 4), osteoporosis (n = 4), prostate carcinoma (n = 2), and lymphoma (n = 1). Seventeen patients received intravenous and 2 received oral bisphosphonates for 2 to 5 years. Bone involvement was noted in the mandible (74%), maxilla (16%), and both (10%). A lytic and sclerotic pattern was most common (58%). Additional findings included fractures (n = 5), sequestra (n = 4), and oroantral fistulae (n = 2). CONCLUSIONS: Bisphosphonate-related osteonecrosis is a rare, but morbid, condition, and imaging features can mimic other conditions. It is important for the radiologist to consider this entity in the appropriate clinical setting.

Influencia del rofecoxib en los niveles de pg-e2 e il-1B; el movimiento dentario y el dolor durante la retracción de caninos / Influence of Rofecoxib on pg-e2 and Il-1â on tooth movement and pain during canine retraction

El propósito de este estudio fue comparar la cantidad de movimiento dentario, el dolor y los niveles de Interleuquina 1B y prostaglandina E2 en el fluido crevicular durante la retracción de caninos superiores en pacientes con y sin ingesta de un AINE específico para la COX-2 (Rofecoxib). Se evaluaron diez pacientes mayores de 18 años, divididos en dos grupos, un grupo experimental de cinco pacientes, quienes dos días antes de iniciar la activación del sistema de retracción, tomaron Rofecoxib y un grupo control, de cinco pacientes que en el mismo periodo tomaron un placebo. En total se realizaron tres activaciones y tres tomas del medicamento, cada mes durante tres meses. Se tomaron muestra de fluido crevicular a nivel de los caninos superiores, dos días después de ingerido el medicamento y antes de activar el sistema, a la primera, las 24 y 48 horas después de la activación. El movimiento dentario se midió en modelos dentales a los tres meses de iniciada la retracción y el dolor fue evaluado por medio de una escala análoga de dolor. Los niveles de IL-1B y PgE2 no mostraron diferencias significativas entre el grupo control y el experimental en ninguno de los tiempos de medición y tampoco al comparar ambos grupos. El movimiento dentario promedio y el nivel del dolor en el grupo experimental fue menor que el control, sin embargo esta diferencia no fue estadísticamente significativa (p>0.05). Se concluyó que el Rofecoxib no tuvo influencia en el movimiento dentario, el dolor ni en los niveles de IL-1B y PgE2 en los pacientes que participaron en este estudio...