Unilateral focal polymicrogyria in a patient with classical Aarskog-Scott syndrome due to a novel missense mutation in an evolutionary conserved RhoGEF domain of the faciogenital dysplasia gene FGD1

Faciogenital dysplasia or Aarskog-Scott syndrome (AAS) is an X-linked disorder characterized by craniofacial, skeletal, and urogenital malformations and short stature. Mutations in the only known causative gene FGD1 are found in about one-fifth of the cases with the clinical diagnosis of AAS. FGD1 is a guanine nucleotide exchange factor (GEF) that specifically activates the Rho GTPase Cdc42 via its RhoGEF domain. The Cdc42 pathway is involved in skeletal formation and multiple aspects of neuronal development. We describe a boy with typical AAS and, in addition, unilateral focal polymicrogyria (PMG), a feature hitherto unreported in AAS. Sequencing of the FGD1 gene in the index case and his mother revealed the presence of a novel mutation (1396A>G; M466V), located in the evolutionary conserved alpha-helix 4 of the RhoGEF domain. M466V was not found in healthy family members, in >300 healthy controls and AAS patients, and has not been reported in the literature or mutation databases to date, indicating that this novel missense mutation causes AAS, and possibly PMG. Brain cortex malformations such as PMG could be initiated by mutations in the evolutionary conserved RhoGEF domain of FGD1, by perturbing the signaling via Rho GTPases such as Cdc42 known to cause brain malformation.

Pediatric craniofacial trauma

PURPOSE: Maxillofacial and skull fractures occur with concomitant injuries in pediatric trauma patients. The aim of this study was to determine the causes and distributions of maxillofacial and skull fractures as well as concomitant injuries of pediatric patients in Switzerland. Results were compared with worldwide studies. MATERIALS AND METHODS: A retrospective review was conducted of 291 pediatric patients with maxillofacial and skull fractures presenting to a level-I trauma center over a 3-year span. Data concerning the mechanism of the accident and the topographic location of the injuries were analyzed. RESULTS: The most common causes were falls (64%), followed by traffic (22%) and sports-related accidents (9%). Fifty-four percent of the fractures occurred in the skull vault and 37% in the upper and middle facial third. One third of the patients (n = 95) suffered concomitant injuries, mostly cerebral concussions (n = 94). CONCLUSIONS: The spectrum of craniofacial injuries is related to the specific developmental stage of the craniofacial skeleton. It is probable that national prevention programs will have a positive effect on reducing the incidence of falls. Standardization of studies is needed for international comparison.

Orbital venous malformation: percutaneous treatment using an electrolytically detachable fibred coil

PURPOSE: To report the efficacy of percutaneous treatment of an orbital venous malformation with an electrolytically detachable fibred coil. METHODS: We report an instance of radiography-guided percutaneous treatment with an electrolytically detachable fibred coil in a 16-year-old boy with acute, spontaneous, painless proptosis on the left side, which progressed with time. RESULTS: Magnetic resonance imaging, angiography and orbitophlebography revealed a low-flow, intraorbital venous malformation. Percutaneous puncture and drainage were followed by a short remission. Following an acute recurrence, a single detachable fibred coil was deployed via a percutaneous approach under angiographic guidance. No radiological or clinical recurrences were observed over 4 years. CONCLUSIONS: Embolization of a deep orbital venous malformation with detachable fibred coils via a percutaneous approach can be highly effective, and may be considered before proceeding with open surgery.

Bilateral malformation of maxillary third molars

A case of bilateral compound odontomas in the region of the third molars in the maxilla is reported. The differential diagnosis for this case is discussed.

Does hyoid bone resection according to Sistrunk influence normal craniofacial growth? A cephalometric study

PURPOSE: To retrospectively evaluate the influence of hyoid bone resection according to Sistrunk in early age due to a thyroglossal duct cyst on craniofacial growth. MATERIALS AND METHODS: We retrospectively examined 10 patients (2 females and 8 males) having had hyoid bone resection according to Sistrunk due to thyroglossal duct cysts by lateral cephalograms taken before orthodontic treatment (mean, 17.1 years; range, 8.6-31.9 years). Surgery was carried out at a mean age of 4.4 years (range, 0.37-9.8 years). All lateral cephalograms were evaluated and traced by hand. Descriptive statistics were calculated, and data from each patient were compared individually with corresponding standard values (age and gender) from Bathia and Leighton. RESULTS: With regard to sagittal parameters, the SNB angles were by trend too small and the ANB angles were too large. However, the ratio of mandibular to maxillary length showed that the patients had a mandible that was too large or maxilla that was too small. With regard to vertical parameters, large deviations from normal values in both directions (hyperdivergent to hypodivergent pattern) could be detected when we analyzed NSL/ML', NL/ML', and NSL/NL. With regard to dental parameters, the majority of the patients had retroclined upper (IsL/NL, IsL/N-A) and lower (IiL/ML, IiL/N-B) incisors. CONCLUSIONS: Several vertical and horizontal skeletal and dental cephalometric parameters were shown to be different by trend when compared with control values. A possible negative impact on craniofacial growth potential and direction as a result of hyoid resection in early age according to Sistrunk cannot be excluded.

Genetic analysis of factors regulating mesenchymal cell fates

Formation of cartilage and bone involves sequential processes in which undifferentiated mesenchyme aggregates into primordial condensations which subsequently grow and differentiate, resulting in morphogenesis of the adult skeleton. While much has been learned about the structural molecules which comprise cartilage and bone, little is known about the nuclear factors which regulate chondrogenesis and osteogenesis. MHox is a homeobox-containing gene which is expressed in the mesenchyme of facial, limb, and vertebral skeletal precursors during mouse embryogenesis. MHox expression has been shown to require epithelial-derived signals, suggesting that MHox may regulate the epithelial-mesenchymal interactions required for skeletal organogenesis. To determine the functions of MHox, we generated a loss-of-function mutation in the MHox gene. Mice homozygous for a mutant MHox allele exhibit defects of skeletogenesis, involving the loss or malformation of craniofacial, limb and vertebral skeletal structures. The affected skeletal elements are derived from the cranial neural crest, as well as somitic and lateral mesoderm. Analysis of the mutant phenotype during ontogeny demonstrated a defect in the formation or growth of chondrogenic and osteogenic precursors. These findings provide evidence that MHox regulates the formation of preskeletal condensations from undifferentiated mesenchyme. In addition, generation of mice doubly mutant for the MHox and S8 homeobox genes reveal that these two genes interact to control formation of the limb and craniofacial skeleton. Mice carrying mutant alleles for S8 and MHox exhibit an exaggeration of the craniofacial and limb phenotypes observed in the MHox mutant mouse. Thus, MHox and S8 are components of a combinatorial genetic code controlling generation of the skeleton of the skull and limbs. ^

A Deletion in the VLDLR Gene in Eurasier Dogs with Cerebellar Hypoplasia Resembling a Dandy-Walker-Like Malformation (DWLM).

Dandy-Walker-like malformation (DWLM) is the result of aberrant brain development and mainly characterized by cerebellar hypoplasia. DWLM affected dogs display a non-progressive cerebellar ataxia. Several DWLM cases were recently observed in the Eurasier dog breed, which strongly suggested a monogenic autosomal recessive inheritance in this breed. We performed a genome-wide association study (GWAS) with 9 cases and 11 controls and found the best association of DWLM with markers on chromosome 1. Subsequent homozygosity mapping confirmed that all 9 cases were homozygous for a shared haplotype in this region, which delineated a critical interval of 3.35 Mb. We sequenced the genome of an affected Eurasier and compared it with the Boxer reference genome and 47 control genomes of dogs from other breeds. This analysis revealed 4 private non-synonymous variants in the critical interval of the affected Eurasier. We genotyped these variants in additional dogs and found perfect association for only one of these variants, a single base deletion in the VLDLR gene encoding the very low density lipoprotein receptor. This variant, VLDLR:c.1713delC is predicted to cause a frameshift and premature stop codon (p.W572Gfs*10). Variants in the VLDLR gene have been shown to cause congenital cerebellar ataxia and mental retardation in human patients and Vldlr knockout mice also display an ataxia phenotype. Our combined genetic data together with the functional knowledge on the VLDLR gene from other species thus strongly suggest that VLDLR:c.1713delC is indeed causing DWLM in Eurasier dogs.

Pre-clinical in vivo models for the screening of bone biomaterials for oral/craniofacial indications: focus on small-animal models.

Preclinical in vivo experimental studies are performed for evaluating proof-of-principle concepts, safety and possible unwanted reactions of candidate bone biomaterials before proceeding to clinical testing. Specifically, models involving small animals have been developed for screening bone biomaterials for their potential to enhance bone formation. No single model can completely recreate the anatomic, physiologic, biomechanic and functional environment of the human mouth and jaws. Relevant aspects regarding physiology, anatomy, dimensions and handling are discussed in this paper to elucidate the advantages and disadvantages of small-animal models. Model selection should be based not on the 'expertise' or capacities of the team, but rather on a scientifically solid rationale, and the animal model selected should reflect the question for which an answer is sought. The rationale for using heterotopic or orthotopic testing sites, and intraosseous, periosseous or extraskeletal defect models, is discussed. The paper also discusses the relevance of critical size defect modeling, with focus on calvarial defects in rodents. In addition, the rabbit sinus model and the capsule model in the rat mandible are presented and discussed in detail. All animal experiments should be designed with care and include sample-size and study-power calculations, thus allowing generation of meaningful data. Moreover, animal experiments are subject to ethical approval by the relevant authority. All procedures and the postoperative handling and care, including postoperative analgesics, should follow best practice.

One-stage (Warsaw) and two-stage (Oslo) repair of unilateral cleft lip and palate: Craniofacial outcomes

The aim of this study was to compare facial development in subjects with complete unilateral cleft lip and palate (CUCLP) treated with two different surgical protocols. Lateral cephalometric radiographs of 61 patients (42 boys, 19 girls; mean age, 10.9 years; SD, 1) treated consecutively in Warsaw with one-stage repair and 61 age-matched and sex-matched patients treated in Oslo with two-stage surgery were selected to evaluate craniofacial morphology. On each radiograph 13 angular and two ratio variables were measured in order to describe hard and soft tissues of the facial region. The analysis showed that differences between the groups were limited to hard tissues – the maxillary prominence in subjects from the Warsaw group was decreased by almost 4° in comparison with the Oslo group (sella-nasion-A-point (SNA) = 75.3° and 79.1°, respectively) and maxillo-mandibular morphology was less favorable in the Warsaw group than the Oslo group (ANB angle = 0.8° and 2.8°, respectively). The soft tissue contour was comparable in both groups. In conclusion, inter-group differences suggest a more favorable outcome in the Oslo group. However, the distinctiveness of facial morphology in background populations (ie, in Poles and Norwegians) could have contributed to the observed results.