Craniometaphyseal dysplasia (CMD) is a rare genetic skeletal disorder, whose biological understanding is not very well known. The disease manifests itself through bony hypertrophy of the skull base, craniofacial bones, and abnormal morphology of the long bones, present in the carrier of the disease. CMD has been previously determined through genetic analysis to be a result of one of 15 (to date) discovered mutations. Fourteen of those mutations are inherited in an autosomal dominant fashion, via mutations in the ANKH gene. One mutation has been discovered to result in CMD through autosomal recessive inheritance, via a locus found in the connexin 43 gene, coding for gap junction protein alpha-1. As the genetic foundation of CMD has become more clearly understood over time, there has been a lack of similar progress in understanding the clinical manifestations of CMD. To improve our understanding of the clinical characteristics of CMD, we propose a natural history of disease study to be conducted. This study serves as a pilot for this larger scale study, by using a smaller patient population comprised of CMD patient database at the Reichenberger Lab at University of Connecticut Health (UCH), and CMD patients reported in the literature, to understand what is currently known about the clinical manifestations of CMD, and what should be evaluated for further research. In this study, the existing literature on CMD has been compiled and sorted into distinct groups – created to guide those unfamiliar to the disease through the available information. Secondly, a set of 76 patient cases compiled at the Reichenberger lab at UCH were analyzed to determine what clinical information on CMD has already been collected. Lastly, from an in depth analysis of two specific case files from the Reichenberger Lab CMD patient database it was discovered that blood chemistry levels are an important parameter for analysis in future studies. From abnormalities in blood chemistry within both cases were found. . In both patients it was found that elevations in serum alkaline phosphatase were present congenitally, and persisted throughout the early childhood years. Specific attention to changing serum alkaline phosphatase concentrations over early childhood development is recommended. Additionally, from data present in patient case 2, blood urea nitrogen (BUN/creatinine) was found to be highly elevated through early childhood, though eventually slowly decreasing to the upwards bounds of the normal physiological reference range, by the time the patient grew from ages 1 to 12. No BUN/Creatinine data was provided by the first case. Lastly, from an analysis of the literature, the patient case files at the Reichenberger lab at UCH and an in depth study of two specific patient cases a list of clinical parameters useful for investigation in a full-scale natural history of disease study of CMD is presented.

Die Homöostase des Knochengewebes wird durch das balancierte Zusammenspiel von Ossifikation und Resorption gewährleistet. Eine in Relation zur Resorption zu starke Ossifikation führt zur Modellierungsstörung, Hyperostose und Sklerose. Knochenerkrankungen mit diesen Merkmalen werden als Sklerosierende Skelettdysplasien erfasst. Gegenstand der vorliegenden Arbeit sind fünf Skelettdysplasien aus dem Formenkreis der Sklerosierenden Skelettdysplasien: (1) Craniometaphysäre Dysplasie, autosomal dominante Form (MIM #123000); (2) Metaphysäre Dysplasie, Typ Braun-Tinschert (MIM *605946); (3) Caffey-Syndrom (MIM *114000); (4) McCune-Albright-Syndrom (MIM #174800); (5) Melorheostose (MIM 155950). Diese werden auf unterschiedlichen pathogenetischen Ebenen charakterisiert, die den Etappen des Weges entsprechen, der mit der Analyse des Phänotyps beginnt und zu einer Aufklärung des Basisdefektes führt. Die Arbeit gliedert sich ein in die Reihe von Bemühungen, zum molekularen Verständnis von Erkrankungen des Skelettsystems beizutragen. / Homeostasis of bone tissue is maintained by the balanced process of bone formation and resorption. Increased ossification in relation to resorption gives rise to conditions with modelling defects, hyperostosis and sclerosis. Skeletal diseases with these signs are classified as sclerosing bone dysplasias. The work presented here focuses on five skeletal dysplasias from the group of sclerosing bone dysplasias: (1) Craniometaphyseal dysplasia, autosomal dominant form (MIM #123000); (2) Metaphyseal dysplasia, Braun-Tinschert type (MIM *605946); (3) Caffey syndrome (MIM *114000); (4) McCune-Albright syndrome (MIM #174800); (5) Melorheostosis (MIM 155950). They were investigated at different pathogenetic levels that represent different steps on the path from phenotypic characterisation to clarification of the respective basic molecular defect. This work has contributed to our understanding of the molecular basis of skeletal diseases.