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Biomedical subjects

J T Richtsmeier

Publications and source records attributed to J T Richtsmeier.

At least 19 recordsLinked to original sources
PubMed2001

Too much of a good thing: mechanisms of gene action in Down syndrome.

The molecular mechanisms underlying the specific traits in individuals with Down syndrome (DS) have been postulated to derive either from nonspecific perturbation of balanced genetic programs, or from the simple, mendelian-like influence of a small subset of genes on chromosome 21. However, these models do not provide a comprehensive explanation for experimental or clinical observations of the effects of trisomy 21. DS is best viewed as a complex genetic disorder, where the specific phenotypic manifestations in a given individual are products of genetic, environmental and stochastic influences. Mouse models that recapitulate both the genetic basis for and the phenotypic consequences of trisomy provide an experimental system to define these contributions.

Aneuploidy↗
PubMed2001

The effect of neurocranial surgery on basicranial morphology in isolated sagittal craniosynostosis.

OBJECTIVE: Isolated sagittal craniosynostosis produces a scaphocephalic neurocranium associated with abnormal basicranial morphology, providing additional evidence of the developmental relationship of the neurocranium and basicranium. Corrective surgical procedures vary, but the immediate impact of the surgical procedure is restricted to the neurocranium. This study addresses the secondary effects of neurocranial surgery on the cranial base. DESIGN: Three-dimensional (3-D) computed tomography (CT) scans were obtained for preoperative (n = 25) and postoperative (n = 12) patients with isolated sagittal synostosis. Landmark data from 14 landmarks on and around the cranial base were collected from 3-D CT reconstructions and analyzed using Euclidean distance matrix analysis. Subsamples of age-matched patients were used to identify basicranial differences in pre- and postoperative patients and to compare postoperative growth patterns identified in longitudinal data with preoperative growth patterns characterized in cross-sectional data. RESULTS: Statistically significant differences (p < or = 0.10) were found in the morphology of the cranial base in preoperative and postoperative patients. The relative positions of the landmarks nasion, right asterion, and left asterion are similar in preoperative and postoperative patients. However, the position of these landmarks relative to the cranial base is different in the two groups, being positioned relatively more anteriorly in postoperative patients. In addition, we found that the cranial base angle, on average, neither increases nor decreases in the first postoperative year. These morphological differences are associated with divergent growth trajectories in the operated and unoperated cranial base. CONCLUSION: Regardless of specific procedure, neurocranial surgery in sagittal synostosis patients affects growth patterns of the cranial base. The lack of change in the postoperative cranial base angle suggests that neurocranial surgery alleviates the occipital rotation and decreased cranial base angle described in the sagittal synostosis basicranium.

Case-Control Studies↗
PubMed2000

Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse.

Down syndrome (DS) is the most common genetic cause of mental retardation and affects many aspects of brain development. DS individuals exhibit an overall reduction in brain size with a disproportionately greater reduction in cerebellar volume. The Ts65Dn mouse is segmentally trisomic for the distal 12-15 Mb of mouse chromosome 16, a region that shows perfect conserved linkage with human chromosome 21, and therefore provides a genetic model for DS. In this study, high resolution magnetic resonance imaging and histological analysis demonstrate precise neuro- anatomical parallels between the DS and the Ts65Dn cerebellum. Cerebellar volume is significantly reduced in Ts65Dn mice due to reduction of both the internal granule layer and the molecular layer of the cerebellum. Granule cell number is further reduced by a decrease in cell density in the internal granule layer. Despite these changes in Ts65Dn cerebellar structure, motor deficits have not been detected in several tests. Reduction in granule cell density in Ts65Dn mice correctly predicts an analogous pathology in humans; a significant reduction in granule cell density in the DS cerebellum is reported here for the first time. The candidate region of genes on chromosome 21 affecting cerebellar development in DS is therefore delimited to the subset of genes whose orthologs are at dosage imbalance in Ts65Dn mice, providing the first localization of genes affecting a neuroanatomical phenotype in DS. The application of this model for analysis of developmental perturbations is extended by the accurate prediction of DS cerebellar phenotypes.

Animals↗
PubMed2000

Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice.

Mouse genetic models can be used to dissect molecular mechanisms that result in human disease. This approach requires detection and demonstration of compelling parallels between phenotypes in mouse and human. Ts65Dn mice are at dosage imbalance for many of the same genes duplicated in trisomy 21 or Down syndrome (DS), the most common live-born human aneuploidy. Analysis of the craniofacial skeleton of Ts65Dn mice using three-dimensional morphometric methods demonstrates an absolute correspondence between Ts65Dn and DS craniofacial dysmorphology, a distinctive and completely penetrant DS phenotype. The genes at dosage imbalance in Ts65Dn are localized to a small region of mouse chromosome 16 and, by comparative mapping, to the corresponding region of human Chromosome 21, providing independent experimental data supporting the contribution of genes in this region to this characteristic DS phenotype. This analysis establishes precise parallels in human and mouse skull phenotypes resulting from dosage imbalance for the same genes, revealing strong conservation of the evolved developmental genetic program that underlies mammalian skull morphology and validating the use of this mouse model in the analysis of this important DS phenotype. This evolutionary conservation further establishes the mouse as a valid model for a wide range of syndromes producing craniofacial maldevelopment.

Animals↗
PubMed1999

Three-dimensional morphological analysis of isolated metopic synostosis.

Morphological differences were quantified in three-dimensions among individuals with untreated isolated metopic synostosis and between those individuals and similar aged-matched normal dry skulls to test two hypotheses: first, that the dysmorphology is a self-correcting condition; and second, that a lack of vertical growth of the skull produces this dysmorphology. Three-dimensional (3D) coordinates were recorded for 22 craniofacial landmarks from CT scans of 15 metopic patients, ranging from 5- to 32-months-old, and of four normal dry skulls, ranging in age from 6- to 36-months-old. The patient population was diagnosed with isolated metopic synostosis at The Johns Hopkins Medical Institutions in Baltimore, Maryland or Children's Hospital in St. Louis, Missouri. Comparisons between the metopic age groups indicate that the trigonocephalic phenotype worsens through time. Between 5 and 14 months, the neurocranium displays an increase in vertical growth. This was followed by a lack of vertical growth between 14 and 32 months. The face displays a lack of vertical growth from 5 to 14 months and an increase in vertical growth after 14 months. Comparisons between the metopic age groups and the normal skulls indicate that the trigonocephalic head is taller superoinferiorly and longer anteroposteriorly. Relative to the normal phenotype, the inferior temporal region in the metopic phenotype is narrow. These findings enabled the rejection of both hypotheses and localized form differences between normal and metopic phenotypes. Based on these results, we suggest that the trigonocephalic phenotype worsens with age and the amount of vertical growth that produces the trigonocephalic phenotype varies throughout growth with respect to location within the skull and age.

Age Factors↗
PubMed1999

Three-dimensional analysis of craniofacial form in a familial rabbit model of nonsyndromic coronal suture synostosis using Euclidean distance matrix analysis.

OBJECTIVE: Simple craniosynostoses produce predictable morphologies of the cranial vault, with growth deficits in a direction parallel to the synostosed suture and compensatory growth at sutures that are perpendicular to and attached to the synostosed one. In coronal suture synostosis, anteroposterior growth is inhibited, with compensatory growth in a transverse direction. Information on growth patterns and influence on other craniofacial regions are not as clear. This study tested the hypotheses that (1), both juvenile and adult rabbits with familial, nonsyndromic coronal suture synostosis exhibit significant size and shape differences of the entire craniofacial region relative to normal rabbits as a result of altered growth patterns and that (2), shape differences of the calvaria will precede those of the basicranium. DESIGN: Fifty anatomic landmarks were located on 94 New Zealand white rabbit crania. The crania were divided into a juvenile, six-week-old age category (n = 53) and an adult, 18-week-old category (n = 41) in order to assess shape differences at different ages. Each age category was sorted into three groups based on growth at the coronal suture: normal sutural growth, delayed onset synostosis, and complete synostosis. Landmarks were digitized in three-dimensions, and statistical analyses on shape differences were carried out using Euclidean distance matrix analysis (EDMA). RESULTS AND CONCLUSIONS: Results showed that delayed onset synostosis did not produce craniofacial morphology that was different from normal at any age. However, complete synostosis yielded predictable and global craniofacial shape differences at both ages relative to normal skulls, producing an overall shorter, wider cranium with the most markedly compensating regions in a posterosuperior position of the skull. In addition, delayed onset synostosed crania showed no shape differences in the basicranium, relative to normal crania, suggesting primacy of the calvaria in this model of coronal synostosis. However, further investigations are necessary to verify primacy of the calvaria in this model.

Age Factors↗
PubMed1998

Capturing data from three-dimensional surfaces using fuzzy landmarks.

Anatomical landmarks are defined as biologically meaningful loci that can be unambiguously defined and repeatedly located with a high degree of accuracy and precision. The neurocranial surface is characteristically void of such loci. We define a new class of landmarks, termed fuzzy landmarks, that will allow us to represent the form of the neurocranium. A fuzzy landmark represents the position of a biological structure that is precisely delineated, but occupies an area that is larger than a single point in the observer's reference system. In this study, we present a test case in which the cranial bosses are evaluated as fuzzy landmarks. Five fuzzy landmarks (the cranial bosses) and three traditional landmarks were placed repeatedly by a single observer on three-dimensional (3D) computed tomography (CT) surface reconstructions of pediatric dry skulls and skulls of pediatric patients, and directly on four of the same dry skulls using a 3Space digitizer. Thirty landmark digitizing trials from CT scans show an average error of 1.15 mm local to each fuzzy landmark, while the average error for the last ten trials was 0.75 mm, suggesting a learning curve. Data collected with the 3Space digitizer was comparable. Measurement error of fuzzy landmarks is larger than that of traditional landmarks, but is acceptable, especially since fuzzy landmarks allow inclusion of areas that would otherwise go unsampled. The information obtained is valuable in growth studies, clinical evaluation, and volume measurements. Our method of fuzzy landmarking is not limited to cranial bosses, and can be applied to any other anatomical features with fuzzy boundaries.

Child↗
PubMed1998

A simple method for visualization of influential landmarks when using euclidean distance matrix analysis.

Euclidean distance matrix analysis (EDMA) differs from most other morphometric methods for the analysis of landmark coordinate data in that it is coordinate-system invariant. However, strict adherence to coordinate-system invariance (for both biological and statistical reasons) introduces some difficulty in using graphic aids for the analysis and interpretation of EDMA results. We present a simple and effective graphic method to help localize important differences in form, growth, or shape by identifying "influential" landmarks. Examples are presented using simulated data and real data involving both children with craniofacial dysmorphologies and sexual dimorphism in adult Macaca fascicularis.

Acrocephalosyndactylia↗
PubMed1995

Euclidean distance matrix analysis: confidence intervals for form and growth differences.

Analysis of biological forms using landmark data has received substantial attention recently. Much of the statistical work in this area has concentrated on the estimation of average form, average form difference, and average growth difference. From the statistical, as well as the scientific point of view, it is important that any estimate of a scientifically relevant quantity be accompanied by a statement regarding its accuracy. Such a statement is contained in a confidence interval. The purpose of this paper is to provide a method to obtain confidence intervals for form difference and growth difference estimators. The estimators are based on Euclidean distance matrix analysis. The confidence intervals are calculated using the model independent bootstrap method. We illustrate the method by using three examples: morphological differences between samples of craniofacial patients and normal controls using two dimensional data from head X-rays, sexual dimorphism of craniofacial morphology in Cebus apella, and sexual dimorphism of facial growth in Cebus apella using three-dimensional data.

Animals↗
PubMed1995

Interaction of craniofacial dysmorphology, growth, and prediction of surgical outcome.

Craniofacial surgery is a multidisciplinary specialty that often uses the expertise of many specialists including surgeons, orthodontists, geneticists, and anthropologists. The clinical experience gained by their collaboration enables predictions to be made of the ultimate success of the reconstructive surgery. Various patterns among surgical outcomes are noted as greater experience is gained. These observations prompted the following questions: Is there a way to classify patients according to surgical results? What factors underlie a successful response to surgery? In a clinical setting, we are faced with a spectrum of presentations of craniofacial dysmorphology. We propose that the results of surgical correction may be based on the cause of the condition and not necessarily on the degree or character of the dysmorphology. Craniofacial dysmorphologies are often grouped under the terms deformation, malformation, disruption, dysplasia, or syndrome. Our hypothesis is that a categorization of craniofacial dysmorphology can be proposed on the basis of the response of the individual to surgery. We propose that such a classification reflects real differences in cause. A poor response to surgery reflects a condition that includes a growth disorder. Alternatively, cases that respond best to surgery are those in which the growth process is not affected. In the latter cases, a dysmorphic face is surgically transformed into an acceptable morphology, and normative growth vectors maintain or improve postoperative facial appearance. It is our belief that the physiological differences underlying our categorization scheme have to do with embryological timing of insults or specific components of the ontogenic process. The divergence in the response to surgery among patients relates directly to the role of the growth process in the various types of dysmorphologies.

Child↗
PubMed1995

Precision, repeatability, and validation of the localization of cranial landmarks using computed tomography scans.

Computed tomography (CT) has brought to the craniofacial surgeon a three-dimensional representation of internal structures. CT scans provide visualization of anatomy for preoperative planning and postoperative evaluation. Beyond visualization, however, a CT scan enables assessment of measurements useful to clinicians and basic scientists. All measurement systems used with CT require the ability to accurately locate regions of interest on the image (i.e., areas, volumes, outlines, curves, surfaces, points). This study evaluates the precision and repeatability of locating anatomic landmarks in three dimensions on CT slice images, and validates these locations using an established measurement system. The average error of landmark position is always less than 0.5 mm and for some landmarks error is negligible. Repeatability studies show that less than 2% of the total variance in our data is due to measurement inaccuracy. Although data collected from CT scans are internally consistent, validation results caution the use of CT data in combination with data collected using calipers or other direct means of measurement.

Adult↗
PubMed1994

Cleft palate with autosomal recessive transmission in Brittany spaniels.

In the course of maintaining a large colony of Brittany spaniels for studying a dominantly inherited motor neuron trait, cases of sporadic complete cleft palate were observed. Without intervention, the pups with cleft palate that attempt to nurse, aspirate and die. In this study, we report on the incidence of cleft palate in this dog kindred, describe the gross morphologic characteristics of the cleft, and present a morphometric analysis of the skull of two of the cleft palate pups and one unaffected pup that died at birth. Our data thus far indicate 26.9% incidence of cleft palate in the colony. Pedigree analysis indicates that this cleft palate trait is inherited as an autosomal recessive. High resolution computed tomography scans of the pup heads were used in morphometric comparison of normal and cleft palate pups. We found specific morphologic differences between the cranial base and palate of normal and cleft palate pups. Plans for future studies of the genetics and growth and development of this animal model are discussed. This canine cleft palate trait provides an ideal model for studying a malformation common in humans.

Animals↗
PubMed1994

Perspectives on craniofacial growth.

This article underscores the importance of the growth process in the production of normal and abnormal craniofacial morphology. Although much has been learned over the past century, we still have only a limited appreciation of the 3D changes that occur in the skull during postnatal growth. We have also stressed that the current cooperation between reconstructive surgeons and radiologists is producing a substantive amount of data that could be used to further our understanding of the postnatal growth process. At The Johns Hopkins University we are putting our efforts toward the collection and organization of a large data base of craniofacial images that will allow us to study questions about the role growth plays in mediating the results of reconstructive surgery. Our ultimate goal is to provide information about the future appearance of craniofacial patients based on empirically derived growth patterns. In a recent article Dufresne and Richtsmeier proposed that the results of surgical correction may be predicted based on the etiology of the craniofacial condition, and not necessarily the degree or character of the dysmorphology. The authors hypothesize that a categorization or classification of craniofacial dysmorphology can be proposed, based on the response of individuals to surgery, and that such a classification reflects real differences in etiology. Hence, a poor response to surgery reflects a condition that includes a growth disorder, whereas cases that respond positively to reconstructive surgery are those in which the growth process is not part of the dysmorphology. In the latter cases, a dysmorphic face is surgically transformed into an acceptable morphology, and normative growth vectors maintain or improve postoperative facial appearance. Thus, Dufresne and Richtsmeier13 suggest that this divergence in the response to surgery among patients relates directly to the role of the growth process in various types of dysmorphologies. Using our tools and the data base we are forming, we envision a markedly different preoperative consultation for future craniofacial patients. When a patient is evaluated, images from the data base with a similar diagnosis will be used to calculate a growth pattern for the proper age interval. The patient's scan is then "grown" according to the appropriate growth pattern. The parents and patient can evaluate this new image and see what their child's skull will look like 2, 3, or 4 years from the present, both with and without reconstructive surgery. In addition, our tools will statistically compare the simulated (or "grown") skull to samples of craniofacial images of normal and affected children of an age/sex/ethnic population that matches the patient. This testing will determine whether growth results in the patient becoming more normal, or more different from normal, with time.(ABSTRACT TRUNCATED AT 400 WORDS)

Child↗
PubMed1993

Cranial growth and growth dimorphism in Ateles geoffroyi.

With the exception of the work of Schultz (1960), cranial growth in Ateles is not well documented. This paper describes the results of a detailed quantitative study of cranial ontogeny in male and female Ateles geoffroyi. Using Euclidean Distance Matrix Analysis (EDMA), local areas of form change due to growth within spider monkey crania are identified. We found substantial change local to the zygomatic region in the face, identified mediolaterally directed changes in the palate, detected relatively larger amounts of change local to the anterior neurocranium compared to the posterior neurocranium, and demonstrate a greater amount of basicranial growth along a mediolateral axis than previously reported. Cranial sexual dimorphism is also examined. A. geoffroyi is noted for being monomorphic, and we found a general similarity between male and female cranial forms at all developmental ages. However, differences in overall cranial size between the sexes were found in the oldest subadult age group but not between male and female adults. This difference suggests that A. geoffroyi females attain their adult cranial form slightly before males and implies a pattern of earlier onset of female maturity relative to males.

Animals↗
PubMed1993

A coordinate-free approach to the analysis of growth patterns: models and theoretical considerations.

Developmental biology holds keys to our understanding of morphological pattern formation whether these patterns are expressed in the fossil record or among extant species. Though much is known about osseous growth at the cellular level (e.g. Hall, 1991), we have minimal understanding of the coordinated processes that combine to produce a complex, three-dimensional form. We have proposed a framework for the coordinate-free representation of form, a statistical method for comparing and modelling growth trajectories for complex morphologies, and a means for the eventual elucidation of the role of growth in the evolution of morphology. Our method uses the coordinate locations of biological landmarks to represent form as a matrix of all possible linear distances between landmarks, the form matrix. When two forms are expressed in this way, comparison of these forms is accomplished by computing the ratios of like linear distances, the form difference matrix. When the forms being compared are from a growth series, the matrix of ratios is called a growth matrix. Patterns of growth for two groups can be compared by computing the growth difference matrix. We applied growth difference matrix analysis to the study of sexual dimorphism of ontogeny in the M. fascicularis craniofacial skeleton. Growth matrices describing growth in male and female M. fascicularis were presented along with the growth difference matrix that describes sexual dimorphism of growth to underscore the detailed information available from this analytical technique. The method is quite general and can be applied to two- or three-dimensional data sets of landmark coordinates (cross-sectional or longitudinal) collected from almost any developing structure. The methods that we propose enable us to go beyond a mathematical summary of the comparison of forms and the comparison of growth patterns. We provide examples of how growth patterns might be used in the study of phylogenetic relationships. Our plans for use of this method in the study of evolutionary change assumes that morphological change in the craniofacial skeleton results from evolutionary change in developmental units (as defined by Atchley & Hall, 1991) that underlie morphological structure. We believe we have the basic tools to ultimately propose informed phylogenies based solely on developmental data. This task requires the identification of 'growth features' and the polarization of these features as primitive or derived. It is also advisable to determine a set of primitive growth features for the groups of interest. This will necessitate the inclusion of outgroups in our growth analysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

Craniofacial growth following rigid fixation: suture excision, miniplating, and microplating.

The effects of plating the coronal and nasofrontal sutures on skull growth were studied in New Zealand white rabbits. Removal of the underlying coronal suture and reduction in the size of the plate were also studied with regard to their effect on growth. Three-dimensional coordinate landmarks located on the skulls were digitized and analyzed to determine the differences in form between operated and unoperated animals using Euclidian distance matrix analysis. Interlandmark distances in three dimensions were compared to demonstrate changes induced by plating. Coronal suture plating (n = 8) resulted in local decreases in dimensions of the plated bones and contralateral and adjacent skull size increases. Removal of the coronal suture without plating (n = 6) resulted in an increase in the size of the adjacent frontal bone and an increase in the width of the suture. Placement of a plate after removal of the underlying suture (n = 8) resulted in decreases in dimensions of the plated bones, with distant length and width increases in a pattern similar to that of the skulls that were simply plated. Plating across the nasofrontal suture (n = 6) resulted in decreases in dimensions in the plated bone, with some distant width increases at the midfrontal bone, the coronal suture, and the posterior parietal bone. In this group, no contralateral increase in dimensions was detected. This is unlike the pattern observed for the animals with a coronal suture plate only. Placing a microplate across the coronal suture (n = 6) resulted in morphologies similar to those with the use of miniplates across the coronal suture. We propose that the varying morphologies in these groups represent compensatory changes accompanying growth restriction induced by plating. We suggest that the lack of contralateral growth increases with nasofrontal suture plating results from lesser effects on the underlying growing cranial contents at this location, as compared with the coronal suture. We find consistent results despite suture removal, change in plate location, and change in plate size.

Animals↗
PubMed1992

Oculoauriculovertebral anomaly: segregation analysis.

Seventy-four families of probands with oculoauriculovertebral anomaly were evaluated, including 116 parents and 195 offspring. Relatives were examined to identify ear malformations, mandibular anomalies, and other craniofacial abnormalities. For segregation analysis using POINTER, selection of the sample was consistent with single ascertainment. Different population liabilities were used for probands and relatives, because affection was narrowly defined for probands and broadly defined for relatives. The hypothesis of no genetic transmission was rejected. The evidence favored autosomal dominant inheritance; recessive and polygenic models were not distinguishable.

Adult↗