Matthieu Schmittbuhl

Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations.

Background/Aims: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. Results: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. Conclusions: This au-tosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.

Symphyseal shape variation in extant and fossil hominoids, and the symphysis of Australopithecus bahrelghazali

The holotype of the species Australopithecus bahrelghazali is a mandibular fragment preserving left C-P(4) and right I(2)-P(4). One of the key features of the A. bahrelghazali mandible is its sagittally and transversally flat anterior region associated with a vertical, bulbous symphysis that is assumed to differ morphologically from the classic, more apelike eastern australopith morphology with its sloping symphysis, developed transverse tori, and distinct genioglossal fossa. Yet, close similarity has been suggested between A. bahrelghazali and A. afarensis. To date, no metrical comparison of the symphyseal morphology of east and west African australopiths has been performed. For the selected characters, this study attempts to test the following null hypothesis: A. bahrelghazali does not present significant differences from A. afarensis (i.e., A. bahrelghazali vs. A. afarensis variation does not depart from expected intraspecific variation for hominoid species). Analysis of the mandibular symphysis is difficult to undertake using conventional linear variables since few landmarks are available to make a precise quantitative assessment of its morphology. In addition, while a few studies have used outline-based techniques of analysis to address symphyseal shape variation, none has integrated data on early hominins. We present here a detailed comparative study of variation in the symphyseal outline of A. bahrelghazali and A. afarensis based on a quantitative characterization by elliptic Fourier coefficients. Original data on symphyseal variation in Pliocene hominins are provided and discussed within a comparative framework of extant and fossil hominoid representatives. We evaluate the relevance of our quantitative data describing the shape of the symphysis for discriminating hominoid taxa, and test for differences in symphyseal shape between A. bahrelghazali and A. afarensis. Elliptic Fourier coefficients appear to be well-suited descriptors for depicting symphyseal variation within hominoids. Our results confirm that symphyseal shape is a good indicator of taxonomic affinity within hominoids, enabling a clear distinction between great apes, early hominins, and modern humans. Furthermore, our results substantiate the unusual pattern of the A. bahrelghazali symphyses compared to A. afarensis and support the specific status of the west African australopith.

Sexual dimorphism of the human mandible: demonstration by elliptical Fourier analysis

Abstract A new quantitative approach of the mandibular sexual dimorphism, based on computer-aided image analysis and elliptical Fourier analysis of the mandibular outline in lateral view is presented. This method was applied to a series of 117 dentulous mandibles from 69 male and 48 female individuals native of Rhenish countries. Statistical discriminant analysis of the elliptical Fourier harmonics allowed the demonstration of a significant sexual dimorphism in 97.1% of males and 91.7% of females, i.e. in a higher proportion than in previous studies using classical metrical approaches. This original method opens interesting perspectives for increasing the accuracy of sex identification in current anthropological practice and in forensic procedures.

The human mandible in lateral view: elliptical fourier descriptors of the outline and their morphological analysis.

An original procedure based on new developments in elliptical Fourier methods associated with image analysis technics was applied to 117 human mandibles in lateral view (69 males, 48 females) in order to analyze interindividual variability and sexual dimorphism. Original parameters, called elliptical Fourier descriptors, allowed for the quantification of the shape of an outline irrespective of its morphological complexity, and provided a precise individual characterization. The use of step by step reconstructions with an increasing number of harmonics allowed for demonstration of the morphological contributions of the elliptical Fourier descriptors, and relationships to precise anatomical features were established. The first harmonics (1st to 8th) described the general mandibular shape, and the later harmonics (8th to 14th) characterized accessory and finer morphological features. The proportion of individuals presenting significant sexual dimorphism was 97.1% in males and 91.7% in females, and after size normalization 84.1% in males and 81.2% in females. Even after removal of the size component, these results in regard to mandibular dimorphism remained better than those found by classical approaches; this could be due to the use of elliptical Fourier analysis which takes into account all the information of the mandibular outline. Compared to the size component, the shape component seemed to be more important in the sexual dimorphism of the human mandible than previously recognized. The present approach opens interesting anthropological and clinical perspectives for the characterization of mandibular morphology.

Shape of the piriform aperture in Gorilla gorilla, Pan troglodytes, and modern Homo sapiens: Characterization and polymorphism analysis

By using new methodologies based on automatic image analysis, the shape of the piriform aperture was analyzed in Gorilla gorilla (33 males, 13 females), Pan troglodytes (35 males, 22 females), and modern Homo sapiens (30 males, 12 females). The determination of the piriform aperture index (breadth/height) allowed the authors to demonstrate a marked elongation of the aperture in Homo compared with Gorilla and Pan. Individual characterization of the shape was possible with great precision and without ambiguity by using Fourier analysis. An absolute, interspecific partition between Gorilla, Pan, and Homo resulted from the canonical discriminant analysis of the Fourier descriptors. However, a closeness of shape between some individuals in Pan and some in Gorilla and Homo was observed, demonstrating a morphological continuum of the shape of the piriform aperture in hominoids: Pan was in intermediate position between Gorilla and Homo. Interspecific differences between Homo and the group Pan-Gorilla were explained principally by the differences in elongation (amplitude of the second harmonic) and pentagonality (amplitude of the fifth harmonic) and by differences in orientation of quadrangularity (phase of the fourth harmonic). Differences in the shape of the piriform aperture between Pan and Gorilla were explained by differences in orientation of elongation (phase of the second harmonic) and by differences in the component of triangularity (amplitude of the third harmonic). In Gorilla and Pan, the little, elongated, and relatively trapezoidal piriform aperture seems to be a shared primitive feature (plesiomorphic), whereas an elongated piriform aperture seems to be a characteristic and derived feature (apomorphic) of modern Homo sapiens.

Handwriting Evidence Evaluation Based on the Shape of Characters: Application of Multivariate Likelihood Ratios*,†

Abstract:  A novel Bayesian methodology has been developed to quantitatively assess handwriting evidence by means of a likelihood ratio (LR) designed for multivariate data. This methodology is presented and its applicability is shown through a simulated case of a threatening anonymous text where a suspect is apprehended. The shape of handwritten characters a, d, o, and q of the threatening text was compared with characters of the true writer, and then with two other writers, one with similar and one with dissimilar characters shape compared to the true writer. In each of these three situations, 100 draws of characters were made and the resulting distributions of LR were established to consider the natural handwriting variation. LR values supported the correct hypothesis in every case. This original Bayesian methodology provides a coherent and rigorous tool for the assessment of handwriting evidence, contributing undoubtedly to integrate the field of handwriting examination into science.

Shape of the orbital opening: individual characterization and analysis of variability in modern humans, Gorilla gorilla, and Pan troglodytes

The description of the human orbital shape is principally qualitative in the classical literature, and characterised by adjectives such as circular, rectangular or quadrangular. In order to provide a precise quantification and interpretation of this shape, a study based on automatic image analysis and Fourier analysis was carried out on 45 human skulls (30 males, 15 females), and for comparison on 61 skulls of Gorilla gorilla (40 males, 21 females), and 34 skulls of Pan troglodytes (20 males, 14 females). Sexual dimorphism in the shape of the orbital opening was not demonstrated. Its dominant morphological features could be characterized by Fourier analysis; elliptical elongation and quadrangularity were dominant morphological features of the shape of the orbital opening in the three species. Elliptical elongation was more marked in humans and Pan, whereas quadrangularity was particularly emphasized in Gorilla. An intraspecific variability of the shape of the orbital opening existed in humans, Gorilla and Pan, and seemed close in the three species. Interspecific partition between humans, Gorilla and Pan was demonstrated despite the variability observed in the three species studied. Interspecific differences between Gorilla and the Pan-humans group were principally explained by the differences in quadrangularity, and by differences in orientation of triangularity and pentagonality. Differences in the shape of the orbital opening between humans and Pan were principally explained by differences in hexagonality, and by differences in orientation of quadrangularity. A closeness of shape between some humans and some individuals in Pan and, to a lesser degree, with some individuals in Gorilla was observed, demonstrating the existence of a morphological continuum of the shape of the orbital opening in hominoids.

RSK2 Is a Modulator of Craniofacial Development

Background The RSK2 gene is responsible for Coffin-Lowry syndrome, an X-linked dominant genetic disorder causing mental retardation, skeletal growth delays, with craniofacial and digital abnormalities typically associated with this syndrome. Craniofacial and dental anomalies encountered in this rare disease have been poorly characterized. Methodology/Principal Findings We examined, using X-Ray microtomographic analysis, the variable craniofacial dysmorphism and dental anomalies present in Rsk2 knockout mice, a model of Coffin-Lowry syndrome, as well as in triple Rsk1,2,3 knockout mutants. We report Rsk mutation produces surpernumerary teeth midline/mesial to the first molar. This highly penetrant phenotype recapitulates more ancestral tooth structures lost with evolution. Most likely this leads to a reduction of the maxillary diastema. Abnormalities of molar shape were generally restricted to the mesial part of both upper and lower first molars (M1). Expression analysis of the four Rsk genes (Rsk1, 2, 3 and 4) was performed at various stages of odontogenesis in wild-type (WT) mice. Rsk2 is expressed in the mesenchymal, neural crest-derived compartment, correlating with proliferative areas of the developing teeth. This is consistent with RSK2 functioning in cell cycle control and growth regulation, functions potentially responsible for severe dental phenotypes. To uncover molecular pathways involved in the etiology of these defects, we performed a comparative transcriptomic (DNA microarray) analysis of mandibular wild-type versus Rsk2-/Y molars. We further demonstrated a misregulation of several critical genes, using a Rsk2 shRNA knock-down strategy in molar tooth germs cultured in vitro. Conclusions This study reveals RSK2 regulates craniofacial development including tooth development and patterning via novel transcriptional targets.

New approaches to human facial morphology using automatic quantification of the relative positions of the orbital and nasal apertures

The purpose of this study was to define and quantify the relative positions of the orbital and nasal apertures in the human face. The material consisted of 44 skulls (32 males, 12 females). For each skull, an image of the projection of the face was captured perpendicular to the palatal plane, using a CCD camera. The orbital and nasal apertures were segmented and characterized using classical image analysis procedures. New quantitative parameters were automatically determined from the centres of area of the facial apertures, and from horizontal and vertical lines of reference. Sexual differences were only significant for orbital height, nasal height, and orbitonasal height. A medio-lateral orbitonasal overlap, as well as a vertical orbitonasal overlap, existed in all individuals; the vertical overlap was always much more marked than the medio-lateral overlap. Significant proportions of the human face were also demonstrated: on average, the interorbital breadth corresponded to a fifth of the biorbital breadth, and thus to half of the mean orbital breadth; the nasal breadth corresponded to one fourth of the biorbital breadth, and the vertical orbitonasal overlap to one fourth of the orbitonasal height. Some instructive significant correlations were observed between these new parameters. The applications of the present methodology seem of great potential interest in anthropology and clinical biometry.

Relative Position and Extent of the Nasal and Orbital Openings in Gorilla, Pan and the Human Species from the Study of Their Areas and Centres of Area

In order to quantify the relative position and extent of the nasal and orbital openings in hominoid primates, a new methodology based on image analysis was developed and applied to a series of 134 hominoid skulls (52 Gorilla gorilla; 30 Pan troglodytes; 44 Homo sapiens, and, as comparison material, 8 Pongo pygmaeus). The areas and the centres of area of the orbital and nasal openings were determined automatically. The orbitonasal triangle connecting these three centres of area was then constructed. This triangle was used to quantify the elongation of the face. It was most elongated in gorilla, shortest in the human species and intermediate in Pan; the elongation in Pongo was close to that in Gorilla. The proportions of the areas of the orbital and nasal openings in the face were related to the extent of the bony structures of the midface and were thus used to quantify the facial robustness. A robust face was demonstrated in Gorilla, but a gracile face in the human species. Robusticity in Pan was intermediate.