Sven Kreiborg

Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism

Cherubism (MIM 118400) is an autosomal dominant inherited syndrome characterized by excessive bone degradation of the upper and lower jaws followed by development of fibrous tissue masses, which causes a characteristic facial swelling. Here we describe seven mutations in the SH3-binding protein SH3BP2 (MIM 602104) on chromosome 4p16.3 that cause cherubism.

The BoneXpert Method for Automated Determination of Skeletal Maturity

Bone age rating is associated with a considerable variability from the human interpretation, and this is the motivation for presenting a new method for automated determination of bone age (skeletal maturity). The method, called BoneXpert, reconstructs, from radiographs of the hand, the borders of 15 bones automatically and then computes ldquointrinsicrdquo bone ages for each of 13 bones (radius, ulna, and 11 short bones). Finally, it transforms the intrinsic bone ages into Greulich Pyle (GP) or Tanner Whitehouse (TW) bone age. The bone reconstruction method automatically rejects images with abnormal bone morphology or very poor image quality. From the methodological point of view, BoneXpert contains the following innovations: 1) a generative model (active appearance model) for the bone reconstruction; 2) the prediction of bone age from shape, intensity, and texture scores derived from principal component analysis; 3) the consensus bone age concept that defines bone age of each bone as the best estimate of the bone age of the other bones in the hand; 4) a common bone age model for males and females; and 5) the unified modelling of TW and GP bone age. BoneXpert is developed on 1559 images. It is validated on the Greulich Pyle atlas in the age range 2-17 years yielding an SD of 0.42 years [0.37; 0.47] 95% conf, and on 84 clinical TW-rated images yielding an SD of 0.80 years [0.68; 0.93] 95% conf. The precision of the GP bone age determination (its ability to yield the same result on a repeated radiograph) is inferred under suitable assumptions from six longitudinal series of radiographs. The result is an SD on a single determination of 0.17 years [0.13; 0.21] 95% conf.

Comparative three-dimensional analysis of CT-scans of the calvaria and cranial base in Apert and Crouzon syndromes

The purpose of this study is to describe and analyze Apert and Crouzon skulls from three-dimensional (3-D) reconstructions of CT-scans. 12 Apert patients and 19 with Crouzon syndrome were included in the study. The age range was 0 to 23 years. All CT-scannings were carried out according to the same protocol with a slice thickness of 2 or 4 mm and 3-D reconstructions of the craniofacial region included midsagittal and horizontal cuts. A number of qualitative characteristics of the calvaria and cranial base were recorded and the cranial base angle was measured on the 3-D models. Our results showed that Apert and Crouzon syndromes are very different in cranial development and their dysmorphology is highly age dependent. We suggest that cartilage abnormalities, especially in the anterior cranial base, play a primary role in cranial development in the Apert syndrome from very early intrauterine life. Several cranial anomalies observed postnatally, however, are caused by the resultant dysmorphic and compensatory growth and are probably compounded by early cranial deformation. The primary abnormality in Crouzon syndrome appears to be premature fusion of sutures and synchondroses. Based on the findings at birth and early infancy it would seem that such fusions occur relatively late in fetal life. The adult cranial form in Crouzons patients is explainable by resultant dysmorphic and compensatory growth changes. Very early release of the coronal suture areas with advancement of the frontal bone is advocated in both syndromes but for somewhat different reasons.(ABSTRACT TRUNCATED AT 250 WORDS)

Surface-bounded growth modeling applied to human mandibles

From a set of longitudinal three-dimensional scans of the same anatomical structure, the authors have accurately modeled the temporal shape and size changes using a linear shape model. On a total of 31 computed tomography scans of the mandible from six patients, 14,851 semilandmarks are found automatically using shape features and a new algorithm called geometry-constrained diffusion. The semilandmarks are mapped into Procrustes space. Principal component analysis extracts a one-dimensional subspace, which is used to construct a linear growth model. The worst case mean modeling error in a cross validation study is 3.7 mm.

Novel Mutation of the Initiation Codon of PAX9 Causes Oligodontia

Tooth development is under strict genetic control. Oligodontia is defined as the congenital absence of 6 or more permanent teeth, excluding the third molar. The occurrence of non-syndromic oligodontia is poorly understood, but in recent years several cases have been described where a single gene mutation is associated with oligodontia. Several studies have shown that MSX1 and PAX9 play a role in early tooth development. We screened one family with non-syndromic oligodontia for mutations in MSX1 and PAX9. The pedigree showed an autosomal-dominant pattern of inheritance. Direct sequencing and restriction enzyme analysis revealed a novel heterozygous A to G transition mutation in the AUG initiation codon of PAX9 in exon 1 in the affected members of the family. This is the first mutation found in the initiation codon of PAX9, and we suggest that it causes haploinsufficiency.

A clinical study of the craniofacial features in Apert syndrome.

A clinical study of the craniofacial features in Apert syndrome is based on our experience with 136 cases. Characteristics included hyperacrobrachycephaly, steep wide forehead, flat occiput, common craniofacial asymmetry, ocular hypertelorism and proptosis, downslanting palpebral fissures, divergent upgaze and esotropic downgaze, a tendency towards large ears, and marked depression of the nasal bridge. The nose is short and wide with a bulbous tip, and the anterior facial height is reduced. Common features during infancy included horizontal grooves above the supraorbital ridges that disappear with age, a break in the continuity of the eyebrows, and a trapezoidal-shaped mouth at rest. Radiographic aspects of Apert syndrome were also assessed. Tables are provided which compare the craniofacial features of Apert and Crouzon syndromes.

Craniofacial growth in a case of congenital muscular dystrophy

S trong activity in the masseter muscles during maximal bite in the intercuspal position is associated with an anteriorly inclined, prognathous mandible with a curved base and a tendency to a large overbite. On the other hand, in normal subjects weak activity in the masseter muscles is associated with a mandible which is posteriorly inclined and retrognathous; its base is flattened, and there is a tendency toward an anterior openbite. Furthermore, strong activity in the masseter muscles during swallowing coincides with prognathism and anterior inclination of both jaws.6 Recordings of maximal bite force 7 have demonstrated associations between facial morphology and the total strength of the elevators corresponding to those observed with maximal electrical activity in the masseter. In patients with progressive muscular dystrophy a specific malocclusion, an anterior open-bite, may occur as described by Brown and Losch4 and White and Sackler.8 In both of the latter investigations the morphologic observations were limited to the occlusion of the teeth. The present report deals with craniofacial growth as determined by roentgencephalometry and muscle activity assessed by electromyography in a girl with congenital muscular dystrophy. It was our aim to clarify the effect on facial morphology of progressive wasting of the elevators of the mandible without impairment of craniofacial growth per se. Survey of examinations The patient was born at term. When she was 3 months old action potentials were recorded from the left tibialis anticus and right deltoid muscles and biopsy specimens from her triceps and tibialis anticus were studied histologically. At the age of 3 years she was subjected to a general medical examination. The patient was referred to the Institute of Orthodontics at the age of 4 years 9 months because of severe malocclusion. Here she was followed longitudinally with annual or

Inactivation of IL11 Signaling Causes Craniosynostosis, Delayed Tooth Eruption, and Supernumerary Teeth

Craniosynostosis and supernumerary teeth most often occur as isolated developmental anomalies, but they are also separately manifested in several malformation syndromes. Here, we describe a human syndrome featuring craniosynostosis, maxillary hypoplasia, delayed tooth eruption, and supernumerary teeth. We performed homozygosity mapping in three unrelated consanguineous Pakistani families and localized the syndrome to a region in chromosome 9. Mutational analysis of candidate genes in the region revealed that all affected children harbored homozygous missense mutations (c.662C>G [p.Pro221Arg], c.734C>G [p.Ser245Cys], or c.886C>T [p.Arg296Trp]) in IL11RA (encoding interleukin 11 receptor, alpha) on chromosome 9p13.3. In addition, a homozygous nonsense mutation, c.475C>T (p.Gln159X), and a homozygous duplication, c.916_924dup (p.Thr306_Ser308dup), were observed in two north European families. In cell-transfection experiments, the p.Arg296Trp mutation rendered the receptor unable to mediate the IL11 signal, indicating that the mutation causes loss of IL11RA function. We also observed disturbed cranial growth and suture activity in the Il11ra null mutant mice, in which reduced size and remodeling of limb bones has been previously described. We conclude that IL11 signaling is essential for the normal development of craniofacial bones and teeth and that its function is to restrict suture fusion and tooth number. The results open up the possibility of modulation of IL11 signaling for the treatment of craniosynostosis.

The Craniofacial Phenotype of the Crouzon Mouse: Analysis of a Model for Syndromic Craniosynostosis Using Three-Dimensional MicroCT

Objective: To characterize the craniofacial phenotype of a mouse model for Crouzon syndrome by a quantitative analysis of skull morphology in mutant and wild-type mice and to compare the findings with skull features observed in humans with Crouzon syndrome. Methods: MicroCT scans and skeletal preparations were obtained on previously described Fgfr2C342Y/+ Crouzon mutant mice and wild-type mice at 6 weeks of age. Three-dimensional coordinate data from biologically relevant landmarks on the skulls were collected. Euclidean Distance Matrix Analysis was used to quantify and compare skull shapes using these landmark data. Results: Obliteration of bilateral coronal sutures was observed in 80% of skulls, and complete synostosis of the sagittal suture was observed in 70%. In contrast, fewer than 40% of lambdoid sutures were found to be fully fused. In each of the 10 Fgfr2C342Y/+ mutant mice analyzed, the presphenoid-basisphenoid synchondrosis was fused. Skull height and width were increased in mutant mice, whereas skull length was decreased. Interorbital distance was also increased in Fgfr2C342Y/+ mice as compared with wild-type littermates. Upper-jaw length was shorter in the Fgfr2C342Y/+ mutant skulls, as was mandibular length. Conclusion: Skulls of Fgfr2C342Y/+ mice differ from normal littermates in a comparable manner with differences between the skulls of humans with Crouzon syndrome and those of unaffected individuals. These findings were consistent across several regions of anatomic interest. Further investigation into the molecular mechanisms underlying the anomalies seen in the Crouzon mouse model is currently under way.

Parameters of Care for Craniosynostosis

Background A multidisciplinary meeting was held from March 4 to 6, 2010, in Atlanta, Georgia, entitled “Craniosynostosis: Developing Parameters for Diagnosis, Treatment, and Management.” The goal of this meeting was to create parameters of care for individuals with craniosynostosis. Methods Fifty-two conference attendees represented a broad range of expertise, including anesthesiology, craniofacial surgery, dentistry, genetics, hand surgery, neurosurgery, nursing, ophthalmology, oral and maxillofacial surgery, orthodontics, otolaryngology, pediatrics, psychology, public health, radiology, and speech-language pathology. These attendees also represented 16 professional societies and peer-reviewed journals. The current state of knowledge related to each discipline was reviewed. Based on areas of expertise, four breakout groups were created to reach a consensus and draft specialty-specific parameters of care based on the literature or, in the absence of literature, broad clinical experience. In an iterative manner, the specialty-specific draft recommendations were presented to all conference attendees. Participants discussed the recommendations in multidisciplinary groups to facilitate exchange and consensus across disciplines. After the conference, a pediatric intensivist and social worker reviewed the recommendations. Results Consensus was reached among the 52 conference attendees and two post hoc reviewers. Longitudinal parameters of care were developed for the diagnosis, treatment, and management of craniosynostosis in each of the 18 specialty areas of care from prenatal evaluation to adulthood. Conclusions To our knowledge, this is the first multidisciplinary effort to develop parameters of care for craniosynostosis. These parameters were designed to help facilitate the development of educational programs for the patient, families, and health-care professionals; stimulate the creation of a national database and registry to promote research, especially in the area of outcome studies; improve credentialing of interdisciplinary craniofacial clinical teams; and improve the availability of health insurance coverage for all individuals with craniosynostosis.