Strategy for Bone Conservation in the Two-Stage Correction of Hypertelorism in Craniofrontonasal Dysplasia.

Pre-emptive planning to optimize safety and outcome is a defining principle of pediatric craniofacial surgery, in which "procedures that come before" should enhance and not compromise procedures that are planned to follow.A technical modification of fronto-orbital advancement/remodeling in 2-stage hypertelorism surgery for craniofrontonasal dysplasia is presented, where orbital hypertelorism is accompanied by coronal craniosynostosis. Fronto-orbital advancement/remodeling undertaken by this approach preserves bone in the supero-lateral bandeau and provides optimal quality bone stock for the subsequent orbital box shift osteotomy. In this way the second procedure is protected and enhanced by optimal planning of the primary procedure, with potential benefits to safety, quality, and outcome of the final result.

Rapid degradation of progressive ankylosis protein (ANKH) in craniometaphyseal dysplasia.

Mutations in the progressive ankylosis protein (NP_473368, human ANKH) cause craniometaphyseal dysplasia (CMD), characterized by progressive thickening of craniofacial bones and widened metaphyses in long bones. The pathogenesis of CMD remains largely unknown, and treatment for CMD is limited to surgical intervention. We have reported that knock-in mice (AnkKI/KI) carrying a F377del mutation in ANK (NM_020332, mouse ANK) replicate many features of CMD. Interestingly, ablation of the Ank gene in AnkKO/KO mice also leads to several CMD-like phenotypes. Mutations causing CMD led to decreased steady-state levels of ANK/ANKH protein due to rapid degradation. While wild type (wt) ANK was mostly associated with plasma membranes, endoplasmic reticulum (ER), Golgi apparatus and lysosomes, CMD-linked mutant ANK was aberrantly localized in cytoplasm. Inhibitors of proteasomal degradation significantly restored levels of overexpressed mutant ANK, whereas endogenous CMD-mutant ANK/ANKH levels were more strongly increased by inhibitors of lysosomal degradation. However, these inhibitors do not correct the mislocalization of mutant ANK. Co-expressing wt and CMD-mutant ANK in cells showed that CMD-mutant ANK does not negatively affect wt ANK expression and localization, and vice versa. In conclusion, our finding that CMD mutant ANK/ANKH protein is short-lived and mislocalized in cells may be part of the CMD pathogenesis.

Hypertelorism Secondary to Mucocele in the Paranasal Sinuses.

Ocular hypertelorism was introduced by Greig as an increased interpupillary distance. The paranasal sinus mucoceles are acquired lesions for various reasons; however, their behavior is progressive, capable of eroding the bone and extending to the orbital and intracranial regions. The objective is to present a clinical case of orbital hypertelorism secondary to mucocele in the paranasal sinuses. This is a 72-year-old male patient who came presenting an increase in volume in the right nasoorbitoethmoidal region. The isodense lesion occupying the maxillary and right ethmoidal sinuses was confirmed by an intimate relationship with the ipsilateral frontal and sphenoidal sinus, with osteolytic involvement of the orbit and nasal region. After incisional biopsy with mucocele results, a wide resection plus facial reconstruction was performed with autologous grafts and osteosynthesis material. Currently, the patient has 1 year of evolution, without significant functional commitment. It is important to consider giant mucoceles as part of the differential diagnoses in patients with deformities in the middle and upper third of the face.

Etiology and pathogenesis of the cohesinopathies.

Cohesin is a chromosome-associated protein complex that plays many important roles in chromosome function. Genetic screens in yeast originally identified cohesin as a key regulator of chromosome segregation. Subsequently, work by various groups has identified cohesin as critical for additional processes such as DNA damage repair, insulator function, gene regulation, and chromosome condensation. Mutations in the genes encoding cohesin and its accessory factors result in a group of developmental and intellectual impairment diseases termed 'cohesinopathies.' How mutations in cohesin genes cause disease is not well understood as precocious chromosome segregation is not a common feature in cells derived from patients with these syndromes. In this review, the latest findings concerning cohesin's function in the organization of chromosome structure and gene regulation are discussed. We propose that the cohesinopathies are caused by changes in gene expression that can negatively impact translation. The similarities and differences between cohesinopathies and ribosomopathies, diseases caused by defects in ribosome biogenesis, are discussed. The contribution of cohesin and its accessory proteins to gene expression programs that support translation suggests that cohesin provides a means of coupling chromosome structure with the translational output of cells.

Is it time to change the neurofibromatosis 1 diagnostic criteria?

Neurofibromatosis 1 is a complex inherited neurocutaneous disease that is often difficult to diagnose early because of its age-dependent presentation. The diagnosis is also extremely difficult to communicate to patients and their parents because of the disease's clinical variability, unpredictable evolution, and uncertain prognosis. Since 1988, the year of publication of the last Consensus Conference statement concerning the diagnosis of neurofibromatosis 1, our understanding of the disease has naturally increased and, in addition to the availability of increasingly precise molecular analyses, some new clinical signs have been reported such as anaemic nevi, unidentified bright objects, choroidal hamartomas, and a typical neuropsychological phenotype. We critically review the current diagnostic criteria, and suggest the addition of new signs on the basis of published findings and our own clinical experience. This proposal aims to improve diagnostic power in paediatric age, securing a better and more reliable healthcare transition toward adult age. We finally recommend a new Consensus Conference in order to revise the diagnostic criteria, possibly differentiated by age of presentation.

Dental findings in Hamamy syndrome.

This paper highlights features of dental rehabilitation of patients with Hamamy syndrome. A 10-year-old boy patient with Hamamy syndrome reported pain in the maxillary left central incisor, and all mandibular incisors. Intraoral clinical and radiographical examination showed enamel hypoplasia, severe dilacerated maxillary left central incisor and mandibular incisors, malocclusion, delayed eruption of teeth, taurodontism, and loss of lamina dura. Root canal treatment, strip crown and composite restorations were performed.

Translational mechanisms at work in the cohesinopathies.

Chromosome cohesion, mediated by the cohesin complex, is essential for the process of chromosome segregation. Mutations in cohesin and its regulators are associated with a group of human diseases known as the cohesinopathies. These diseases are characterized by defects in head, face, limb, and heart development, mental retardation, and poor growth. The developmental features of the diseases are not well explained by defects in chromosome segregation, but instead are consistent with changes in gene expression during embryogenesis. Thus a central question to understanding the cohesinopathies is how mutations in cohesin lead to changes in gene expression. One of the prevailing models is that cohesin binding to promoters and enhancers directly regulates transcription. I propose that in addition cohesin may influence gene expression via translational mechanisms. If true, cohesinopathies may be related in etiology to another group of human diseases known as ribosomopathies, diseases caused by defects in ribosome biogenesis. By considering this possibility we can more fully evaluate causes and treatments for the cohesinopathies.

Orocraniofacial findings and dental management of a pediatric patient with Dubowitz syndrome.

Dubowitz syndrome is a rare genetic condition characterized by microcephaly, dysmorphic facial features and delayed general growth. It is transmitted through autosomal recessive inheritance. The purpose of this report is to describe the oral, craniofacial and systemic characteristics of a 7-year 11-month-old boy with Dubowitz syndrome and the dental management provided. The pediatric dentist should possess the ability to recognize this rare alteration, to provide dental treatment and to refer for the necessary medical and multidisciplinary treatment.

Waardenburg Syndrome type 1: A case report.

Waardenburg Syndrome (WS) is a rare hereditary disorder that is characterized by the clinical manifestations of oculocutaneous anomalies of pigmentation, congenital deafness, dystopia canthorum, and broad nasal root. It demonstrates both genetically and clinically heterogenous characteristics. In this article, we report an 11-month-old boy with WS1, one of four clinicat types of WS. He exhibited white forelock, hypopigmented macules and patches, heterochromia irides, and dystopia canthorum.

Canthal and cephalic indexes of children with homozygous sickle cell disease in Port-Harcourt.

INTRODUCTION: This research was conducted in view of the importance of anthropometric indices of the head and face in forensic medicine, surgery, paediatrics and medical imaging. This study was put forward to determine some of the effects of chronic diseases on head and face of children with homozygous sickle cell disease. METHOD: A comparative study on canthal and cephalic indexes were carried out on 100 patients, 54 males and 46 females who are homozygous for sickle cell anaemia, who attended the sickle cell clinic at the University of Port-HarcourtTeaching Hospital between the age ranges of 3-18 years. The same was also done for 500 normal growing children 291 males and 209 females between ages 3-18 years who are pupils of the University Kindergarten, Demonstration Primary and Secondary Schools as well as First International Academy Secondary School, Rumuokoro, Port Harcourt. The head length, head breadth, inner and outer canthal distances measured. The results showed a mean cephalic index value of 79.89 +/- 0.87 for the normal growing children while that of the sickle cell children was 79.54 +/- 2.14, which is not statistically significant (P>0.05). The mean canthal index for healthy children was 35.16 +/- 1.01 as against 37.28 +/- 1.65 for the sickle cell children, which is statistically significant. CONCLUSION: This research determined the possible effects of chronic diseases such as sickle cell anaemia on the diversity of head and face shapes in children.

Control of mTORC1 signaling by the Opitz syndrome protein MID1.

Mutations in the MID1 gene are causally linked to X-linked Opitz BBB/G syndrome (OS), a congenital disorder that primarily affects the formation of diverse ventral midline structures. The MID1 protein has been shown to function as an E3 ligase targeting the catalytic subunit of protein phosphatase 2A (PP2A-C) for ubiquitin-mediated degradation. However, the molecular pathways downstream of the MID1/PP2A axis that are dysregulated in OS and that translate dysfunctional MID1 and elevated levels of PP2A-C into the OS phenotype are poorly understood. Here, we show that perturbations in MID1/PP2A affect mTORC1 signaling. Increased PP2A levels, resulting from proteasome inhibition or depletion of MID1, lead to disruption of the mTOR/Raptor complex and down-regulated mTORC1 signaling. Congruously, cells derived from OS patients that carry MID1 mutations exhibit decreased mTORC1 formation, S6K1 phosphorylation, cell size, and cap-dependent translation, all of which is rescued by expression of wild-type MID1 or an activated mTOR allele. Our findings define mTORC1 signaling as a downstream pathway regulated by the MID1/PP2A axis, suggesting that mTORC1 plays a key role in OS pathogenesis.

Synchronous Paget disease of bone and hyperparathyroidism: report of a case with extensive craniofacial involvement.

Paget disease of bone (PDB) and hyperparathyroidism (HPT) are metabolic osseous disorders which affect ≥2% of the population. As these diseases may share clinical, radiographic, biochemical, and histopathologic features, knowledge of their phenotypic overlap may provide diagnostic utility and improve clinical outcome. Scant information is available in the dental literature regarding patients concurrently affected with both pathologies. We present an unusual case report of a 63-year-old woman coaffected with primary HPT, attributed to a functional oxyphilic parathyroid adenoma, and PDB. Bone scintigraphy revealed pagetoid lesions of the skull, humeral head, spine, sacrum, and hemipelvis. Salient craniofacial features noted were bony involvement of the calvarium and midface, resulting in extensive maxillary overgrowth, hearing loss, telecanthus and consequent visual impairment, nasal deformity, and leontiasis ossea. The patient underwent a partial parathyroidectomy and bisphosphonate administration was to be initiated upon extraction of the remaining dentition.

In situ fronto-orbital advancement with medial orbital osteotomies for trigonocephaly-associated hypotelorism.

In treating trigonocephaly, the value of direct surgical correction of orbital hypotelorism is controversial. In many cases of hypotelorism, the distance between the orbits increases over time after traditional fronto-orbital advancement. Still, more severe hypotelorism is not fully corrected and may benefit from a more definitive surgical intervention. We describe an in situ fronto-orbital advancement that improves severe hypotelorism and simplifies the surgical treatment of trigonocephaly. The key modification to traditional fronto-orbital advancement is an in situ medial orbital osteotomy that extends along the medial orbit, posterior to the medial canthus, and then across the inferior orbital rim into the piriform aperture. The procedure is indicated only in patients with more severe hypotelorism on physical examination. Rather than creating a freely removable bandeau during the operation, the bone segment composed of the supraorbital bar and superior orbits remains attached at the medial canthi. A midline osteotomy allows the respective orbital segments to be independently mobilized with the medial canthi left attached, and the space between them widened with gentle lateral traction and placement of an interpositional bone graft. Concomitantly, the lateral orbits and lateral supraorbital bar are contoured, advanced, and fixed with resorbable plates and screws. Representative results are shown. In situ fronto-orbital advancement with medial orbital osteotomies is a safe, efficient, and relatively simple technique that results in immediate improvement of hypotelorism and may be a worthwhile maneuver to consider in selected cases.

Ocular manifestations of Apert and Crouzon syndromes: qualitative and quantitative findings.

There are significant differences in the ocular manifestations of Apert and Crouzon syndromes. Here, we present qualitative and quantitative data about the oculo-orbital region to demonstrate these differences. Although ocular protosis and hypertelorism characterize both disorders, the nature of the orbital dystopia differs. In Crouzon syndrome, ocular proptosis is primarily caused by retrusion of the lateral and inferior orbital margins with a very short orbital floor. In Apert syndrome, the eyeglobe actually protrudes in relation to the cranial base and to the orbit, probably resulting from marked protrusion of the lateral orbital wall. The implications account for some of the differences encountered. Asymmetry is associated with Apert syndrome frequently. Exotropia is found in Crouzon syndrome, whereas the V pattern is more characteristic in Apert syndrome with divergent upgaze and esotropic downgaze. Subluxation of the eyeglobe is found in some cases of Crouzon syndrome but is not found in Apert syndrome. Optic atrophy found in approximately 20% of Crouzon syndrome patients is not characteristic of Apert syndrome. Structural alterations of the extraocular muscles have been associated with some cases of Apert syndrome, suggesting that ocular motility disturbances in Apert syndrome may not be caused solely by mechanical factors. Absence of the superior rectus and other extraocular muscles has been recorded. Furthermore, albinoid alterations of the fundus have also been associated with Apert syndrome.

Mid line craniofacial defects and morning glory disc anomaly with clinical anophthalmos-a distinct clinical entity.

Morning glory syndrome (MGS) is a congenital optic disc dysplasia often associated with craniofacial anomalies, especially basal encephalocele. We report a case of a 4-month-old male baby, who was referred to our institute with the complaints of decreased vision. This is the first report from Northeastern part of India as per our knowledge.

Craniometaphyseal dysplasia: a case report.

Craniometaphyseal dysplasia (CMD) is a rare genetically transmitted bone dysplasia characterized by alterations in the development of the craniofacial bones with abnormal remodeling of the metaphyses. Sclerosis of the skull bones can lead to cranial nerve compression that finally may result in hearing loss and facial palsy. CMD occurs in an autosomal dominant (AD) (MIM 123000) and an autosomal recessive (AR) form (MIM 218400). Sclerosis of cranial bones is usually much more severe in the AR form. We present a 36-year-old male with a previous diagnosis of Paget disease. The examination reveals prognathism, ocular hypertelorism, mixed bilateral hypoacusia, nasal bossing, a class III malocclusion and a narrow palatal vault. The patient necessitated several dental extractions, surgical procedures were conducted, and a biopsy of the alveolus was performed and the sample underwent histological examination. The histological report led to an exclusion of the previous diagnosis of Paget disease. The final diagnosis of autosomal dominant CMD was confirmed by the molecular testing of the CMD gene (ANKH).