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Mevalonic aciduria
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
Dysmorphic features were described in all but a few patients [7, 17], but were described as subtle in four [6]. The characteristic picture (Figures 85.6 and 85.7) is of dolichocephaly with frontal bossing, posteriorly rotated low-set ears, antimongoloid slanting of the eyes, a small mouth and jaw, and thin lips. One patient [1] had a small penis and a congenital hydrocele. In this boy, closure of fontanelles and sutures was delayed; by 19 months they were all widely patent. A third fontanelle may be present. Another of our patients had even more delayed closure of sutures, but she was found to have cleidocranial dysplasia and apparently independent mutations in the RUNX2 gene (Figure 85.8).
Genetic disorders, skeletal dysplasias and malformations
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Fergal Monsell, Martin Gargan, Deborah Eastwood, James Turner, Ryan Katchky
Cleidocranial dysplasia is a skeletal dysplasia which affects bones formed by intramembranous ossification. It is inherited in an autosomal dominant pattern and is due to a mutation in the RUNX2 gene causing an abnormality in the transcription factor regulating differentiation of osteoblasts.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Differential diagnosis:Parietal foramina with cleidocranial dysplasia: similar to CCD, the clavicular involvement is milder, there are no dental abnormalities, parietal foramina are typically present. Caused by mutations in MSX2. Crane-Heise syndrome: severe rare lethal syndrome characterised by disproportionately large and scarcely mineralized cranium, cleft lip and palate, low-set dysplastic ears, hypoplastic clavicles and scapulae, agenesis of some cervical vertebrae, talipes. Mandibuloacral dysplasia: progressive ageing disorder caused by recessive mutations of the genes LMNA or ZMPSTE24. Main features include: short stature, delayed closure of cranial sutures, mandibular hypoplasia, dysplastic clavicles. Over time the following features may develop: alopecia, stiff joints, acro-osteolysis, early tooth loss, atrophy of the skin, decreased subcutaneous fat. Pyknodysostosis (p. 325); Yunis Varon syndrome (p. 392); CDAGS syndrome: craniosynostosis and paradoxically delayed closure of the fontanelles, clavicular hypoplasia, anal and genitourinary malformations, and skin eruption (porokeratosis); hypophosphatasia (p. 367); congenital pseudarthrosis of the clavicle; cytogenetic abnormalities; 8p22 duplication; partial trisomy 11q, partial trisomy 11q/22q, trisomy 20p.
Interaction of bone and brain: osteocalcin and cognition
Published in International Journal of Neuroscience, 2021
Misa Nakamura, Masakazu Imaoka, Masatoshi Takeda
One of the most common skeletal dysplasias, cleidocranial dysplasia (CCD), is an autosomal dominant disorder associated with worse cognitive performance [44]. It is interesting that CCD is reported to be a mutation of the runt-related transcription factor 2 (RUNX2) gene, which is a key transcription factor gene associated with osteoblast differentiation [45–48]. RUNX2 is a master regulator of osteoblast differentiation and a primary regulator of OC expression [23,49]. In RUNX2+/- mice, bone resorption is lacking, OC levels in the blood are reduced, and the expression levels of OC target genes such as glutamate decarboxylase 1, tyrosine hydroxylase, and BDNF in the brain are changed. Furthermore, RUNX2+/- mice show decreased cognitive function and increased anxiety-like behavior [50]. These results strongly suggest that OC regulates cognitive function and anxiety-like behavior.
Molecular Genetics of Cleidocranial Dysplasia
Published in Fetal and Pediatric Pathology, 2021
Jamshid Motaei, Arash Salmaninejad, Ebrahim Jamali, Imaneh Khorsand, Mohammad Ahmadvand, Sasan Shabani, Farshid Karimi, Mohammad Sadegh Nazari, Golsa Ketabchi, Fatemeh Naqipour
Cleidocranial dysplasia (CCD) is associated with severe abnormalities in bone development. The main symptoms of the disease include hypoplasia, aplasia or lack of clavicles, sloping shoulders, open fontenelles, delayed bone formation of the skull, short stature and supernumerary teeth. Afflicted people with a lack of clavicle can put their shoulders close together [4]. Dental disorders include supernumerary teeth, maxillary hypoplasia, follicular cysts in the jaw, delayed tooth eruption, delay in the development of the root of permanent teeth and delay in the absorption of the roots of deciduous teeth [5,6]. Other characteristics of CCD are hypertelorism, hypoplasia the anterior part of the face, a short nasal bridge, and narrow thorax. Patients’ intelligence is usually normal, but in some cases, deafness has been mentioned [7,8]. The presence of anomalies in the clavicle bones has been considered in several studies as a clinical finding of this syndrome. Complete recognition of clinical symptoms and differential diagnosis of CCD from other diseases with similar clinical symptoms is necessary [9]. When the clinician suspects CCD, a skeletal survey and genetic analysis should be obtained. There are several therapeutic options for CCD. To address dental problems, extensive and comprehensive dental treatments such as extraction of teeth, surgery, and orthodontics are necessary to maintain proper mastication [10].
Bone dynamics and inflammation: lessons from rare diseases
Published in Immunological Medicine, 2020
Yoshinori Matsumoto, Robert Rottapel
We next generated and investigated conditional knockout mice, in which endogenous RNF146 was deleted in the osteoblast lineage (Rnf146fl/fl Osterix-Cre mice). Interestingly, Rnf146fl/fl Osterix-Cre mice have short stature, show failure to close their fontanelles, demonstrate general hypomineralization of the calvarium, have small or absent clavicles, and are generally osteopenic with low serum levels of osteocalcin. The abovementioned characteristics show phenotypic similarity to cleidocranial dysplasia (CCD), an autosomal dominant human disorder characterized by abnormal bone development that is primarily caused by defective intramembranous bone formation by osteoblasts. RUNX2 protein expression appears to be normal in these mice, although previous studies have revealed that loss-of-function mutations in a single allele of the Runx2 gene are detected in 60% of CCD patients and cause impaired osteoblast-mediated ossification [16,17,26–29].