STAT3 is critical for skeletal development and bone homeostasis by regulating osteogenesis

Skeletal deformities are typical AD-HIES manifestations, which are mainly caused by heterozygous and loss-of-function mutations in Signal transducer and activator of transcription 3 (STAT3). However, the mechanism is still unclear and the treatment strategy is limited. Herein, we reported that the mice with Stat3 deletion in osteoblasts, but not in osteoclasts, induced AD-HIES-like skeletal defects, including craniofacial malformation, osteoporosis, and spontaneous bone fracture. Mechanistic analyses revealed that STAT3 in cooperation with Msh homeobox 1(MSX1) drove osteoblast differentiation by promoting Distal-less homeobox 5(Dlx5) transcription. Furthermore, pharmacological activation of STAT3 partially rescued skeletal deformities in heterozygous knockout mice, while inhibition of STAT3 aggravated bone loss. Taken together, these data show that STAT3 is critical for modulating skeletal development and maintaining bone homeostasis through STAT3-indcued osteogenesis and suggest it may be a potential target for treatments.

Genetics of craniofacial anomalies

The birth of a child with a craniofacial malformation is usually an unexpected and devastating event for the parents. One of the first questions asked is ‘Why did this happen?’ Later, they may go on to ask ‘Could this happen again and if so, can it be avoided?’ A clinical genetics assessment can make an important contribution to answering these and other questions. In general, craniofacial malformations represent defects in embryogenesis, which can arise either from altered genetic information (abnormal developmental programming of the embryo), environmental insult (disruption of development), or a combination of adverse genetic and environmental factors. The clinical geneticist’s approach is primarily directed towards deciding which of these scenarios is most likely to be correct and, if a specific genetic cause is suspected, to advising on the most appropriate genetic tests to perform.

Ciliary Signalling and Mechanotransduction in the Pathophysiology of Craniosynostosis

Craniosynostosis (CS) is the second most prevalent inborn craniofacial malformation; it results from the premature fusion of cranial sutures and leads to dimorphisms of variable severity. CS is clinically heterogeneous, as it can be either a sporadic isolated defect, more frequently, or part of a syndromic phenotype with mendelian inheritance. The genetic basis of CS is also extremely heterogeneous, with nearly a hundred genes associated so far, mostly mutated in syndromic forms. Several genes can be categorised within partially overlapping pathways, including those causing defects of the primary cilium. The primary cilium is a cellular antenna serving as a signalling hub implicated in mechanotransduction, housing key molecular signals expressed on the ciliary membrane and in the cilioplasm. This mechanical property mediated by the primary cilium may also represent a cue to understand the pathophysiology of non-syndromic CS. In this review, we aimed to highlight the implication of the primary cilium components and active signalling in CS pathophysiology, dissecting their biological functions in craniofacial development and in suture biomechanics. Through an in-depth revision of the literature and computational annotation of disease-associated genes we categorised 18 ciliary genes involved in CS aetiology. Interestingly, a prevalent implication of midline sutures is observed in CS ciliopathies, possibly explained by the specific neural crest origin of the frontal bone.

Ethmoidal meningoencephalocele in a C57BL/6J mouse

An otherwise healthy two-month-old female C57BL/6J mouse presented with a left-sided head tilt. Differential diagnoses included idiopathic necrotizing arteritis, bacterial otitis media/interna ( Pasteurella pneumotropica, Pseudomonas aeruginosa, Streptococcus sp., Mycoplasma pulmonis and Burkholderia gladioli), encephalitis, an abscess, neoplasia, a congenital malformation and an accidental or iatrogenic head trauma. Magnetic resonance imaging (MRI) revealed a large space-occupying right olfactory lobe intra-axial lesion with severe secondary left-sided subfalcine herniation. Following imaging, the animal was euthanized due to poor prognosis. Histopathologic examination revealed a unilateral, full-thickness bone defect at the base of the cribriform plate and nasal conchae dysplasia, resulting in the herniation of the olfactory bulb into the nasal cavity. There was also a left midline-shift of the frontal cortex and moderate catarrhal sinusitis in the left mandibular sinus. The MRI and histopathologic changes are consistent with a congenital malformation of the nasal cavity and frontal aspect of the skull known as an ethmoidal meningoencephalocele. Encephaloceles are rare abnormalities caused by herniation of contents of the brain through a defect in the skull which occur due to disruption of the neural tube closure at the level anterior neuropore or secondary to trauma, surgical complications, cleft palate or increased intracranial pressure. The etiology is incompletely understood but hypotheses include genetics, vitamin deficiency, teratogens, infectious agents and environmental factors. Ethmoidal encephaloceles have been reported in multiple species including humans but have not been reported previously in mice. There are multiple models for spontaneous and induced craniofacial malformation in mice, but none described for ethmoidal encephaloceles.

Rare Facial Cleft: Surgical Treatment and Middle-Term Follow-up During Charity Operation

Facial cleft is a rare and challenging craniofacial malformation. Treatment of rare facial cleft is complex, and the evaluation of its long-term results is challenging because of the low incidence. In this article, we would like to present middle-term follow-up of 6 patients with facial cleft Tessier number 4, number 5, and number 7 who were treated in our center during charity surgical mission. We will discuss surgical option, difficulties, and complication that may arise in this surgery.

Severe head dysgenesis resulting from imbalance between anterior and posterior ontogenetic programs

Head dysgenesis is a major cause of fetal demise and craniofacial malformation. Although mutations in genes of the head ontogenetic program have been reported, many cases remain unexplained. Head dysgenesis has also been related to trisomy or amplification of the chromosomal region overlapping the CDX2 homeobox gene, a master element of the trunk ontogenetic program. Hence, we investigated the repercussion on head morphogenesis of the imbalance between the head and trunk ontogenetic programs, by means of ectopic rostral expression of CDX2 at gastrulation. This caused severe malformations affecting the forebrain and optic structures, and also the frontonasal process associated with defects in neural crest cells colonization. These malformations are the result of the downregulation of genes of the head program together with the abnormal induction of trunk program genes. Together, these data indicate that the imbalance between the anterior and posterior ontogenetic programs in embryos is a new possible cause of head dysgenesis during human development, linked to defects in setting up anterior neuroectodermal structures.

Risk factors of hearing defects and their relationship to the outcome of hearing screening among neonates

Background: Increased exposure to risk factors of hearing loss leads to a high susceptibility to deafness among neonates admitted to neonatal care units in developing countries. Objective: This article aims to study the prevalence of risk factors for neonatal hearing defect and determine their effect on the result of transient evoked otoacoustic emissions hearing test ( TEOAE). Methods: A longitudinal study was carried out for a period of one year from 1st October, 2016 to 30 th September, 2017 in the CWTH, Medical city, Baghdad, Iraq Demographic characteristics and certain risk factors were recorded for screened neonates. TEOAE test was done and if they failed to pass two steps, they were referred to autom ated auditory brainstem - response (AABR). Results: Out of 400 neonates, 342 (85.5%) passed from step 1TEOAE, while 58 (14.5%) were referred to step 2. From 58, 26 (44.8%) have passed step 2 and 32 (55.2%) not pass step 2 and were referred to AABR. From those 32 neonates with suspected hearing defect, NICU stay >7 days, ototoxic drugs >7days, use of ventilator >7 days, birth weight <1500gm, and craniofacial malformations were the main risk factors for hearing defects occurring in (90.6%), (90.6%), (59.4%), (40.6%), and (21.9%) respectively. Conclusions: Low birth weight , long intensive care stay, mechanical ventilation, drugs ototoxicity and craniofacial malformation of neonates are the main risk factors for failed TEOAE test

Regulatory Mechanisms of Soft Palate Development and Malformations

Orofacial clefting is the most common congenital craniofacial malformation, appearing in approximately 1 in 700 live births. Orofacial clefting includes several distinct anatomic malformations affecting the upper lip and hard and soft palate. The etiology of orofacial clefting is multifactorial, including genetic or environmental factors or their combination. A large body of work has focused on the molecular etiology of cleft lip and clefts of the hard palate, but study of the underlying etiology of soft palate clefts is an emerging field. Recent advances in the understanding of soft palate development suggest that it may be regulated by distinct pathways from those implicated in hard palate development. Soft palate clefting leads to muscle misorientation and oropharyngeal deficiency and adversely affects speech, swallowing, breathing, and hearing. Hence, there is an important need to investigate the regulatory mechanisms of soft palate development. Significantly, the anatomy, function, and development of soft palatal muscles are similar in humans and mice, rendering the mouse an excellent model for investigating molecular and cellular mechanisms of soft palate clefts. Cranial neural crest–derived cells provide important regulatory cues to guide myogenic progenitors to differentiate into muscles in the soft palate. Signals from the palatal epithelium also play key roles via tissue-tissue interactions mediated by Tgf-β, Wnt, Fgf, and Hh signaling molecules. Additionally, mutations in transcription factors, such as Dlx5, Tbx1, and Tbx22, have been associated with soft palate clefting in humans and mice, suggesting that they play important regulatory roles during soft palate development. Finally, we highlight the importance of distinguishing specific types of soft palate defects in patients and developing relevant animal models for each of these types to improve our understanding of the regulatory mechanism of soft palate development. This knowledge will provide a foundation for improving treatment for patients in the future.