Functional analysis of novel RUNX2 mutations identified in patients with cleidocranial dysplasia.

RUNX2 (Runt-related transcription factor 2) is a master regulator of osteoblast differentiation, cartilage and bone development. Pathogenic variants in RUNX2 have been linked to the Cleidocranial dysplasia (CCD), which is characterized by hypoplasia or aplasia of clavicles, delayed fontanelle closure, and dental anomalies. Here, we report 11 unrelated Polish patients with CCD caused by pathogenic alterations located in the Runt domain of RUNX2. In total, we identified eight different intragenic variants, including seven missense and one splicing mutation. Three of them are novel: c.407T>A p.(Leu136Gln), c.480C>G p.(Asn160Lys), c.659C>G p.(Thr220Arg), additional three were not functionally tested: c.391C>T p.(Arg131Cys), c.580+1G>T p.(Lys195_Arg229del), c.652A>G p.(Lys218Glu), and the remaining two: c.568C>T p.(Arg190Trp), c.673C>T p.(Arg225Trp) were previously reported and characterized. The performed transactivation and localization studies provide evidence of decreased transcriptional activity of RUNX2 due to mutations targeting the Runt domain and prove that impairment of nuclear localization signal (NLS) affects the subcellular localization of the protein. Presented data show that pathogenic variants discovered in our patients have a detrimental effect on RUNX2, triggering the CCD phenotype.

A 13-year-old Caucasian boy with cleidocranial dysplasia: a case report.

BACKGROUND: Cleidocranial dysplasia (CCD) is a rare congenital autosomal dominant skeletal disorder. The disorder is caused by heterozygosity of mutations in human RUNX2, which is present on the short arm of chromosome 6p21. The incidence of CCD is one per million births. CCD appears spontaneously with no apparent genetic cause in approximately 40% of affected patients, and one in three patients has unaffected parents. The most prevalent features associated with CCD are aplastic or hypoplastic clavicles, supernumerary teeth, failed eruption of permanent teeth, and a hypoplastic maxilla. CASE PRESENTATION: A 13-year-old Caucasian boy presented with a chief complaint of delayed eruption of the permanent anterior teeth. The patient was subsequently diagnosed with CCD based on the clinical examination, panoramic X-ray, anterior-posterior and lateral cephalogram, and chest radiograph findings. The details of this case are herein reported because of the extremely low incidence of this disorder. CONCLUSIONS: CCD is of clinical importance in dentistry and medicine because it affects the bones and teeth and is characterized by many changes in skeletal patterning and growth. Particularly in dentistry, CCD is of great clinical significance because is associated with delayed ossification of the skull sutures, delayed exfoliation of the primary teeth, lack of permanent teeth eruption, multiple supernumerary teeth, and morphological abnormalities of the maxilla and mandible. Patients with CCD seek treatment mainly for dental problems. Knowledge of the pathogenesis, clinical characteristics, and diagnostic tools of CCD will enable clinicians to render the appropriate treatment to improve function and aesthetics. Early diagnosis of CCD is crucial for timely initiation of an appropriate treatment approach.

Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience.

Cleidocranial dysplasia (CCD) is an uncommon but well-known genetic skeletal condition. Several hundred affected persons are members of a large extended family in the Cape Town Mixed Ancestry community of South Africa. The clinical manifestations are often innocuous, but hyperdontia and other developmental abnormalities of the teeth are a major feature and may require special dental management. Over the past 40 years, the authors have encountered more than 100 affected persons in Cape Town. Emphasis has been on dental management, but medical, genetic, and social problems have also been addressed. In this article, we have reviewed the manifestations of the disorder in the light of our own experience, and performed a literature search with emphasis on the various approaches to dental management and treatment options in CCD. Advances in the understanding of the biomolecular pathogenesis of CCD are outlined and the international and local history of the disorder is documented.

The management of ADHD and associated problems in a young person with cleidocranial dysostosis (CCD) and mild intellectual disability.

It is increasingly recognized that comorbidity is common in all fields of psychiatry, and furthermore, it is acknowledged that a large number of individuals with genetically determined conditions have associated behavioural phenotypes, and are more susceptible to particular psychiatric and psychological comorbidities than others. It is also recognized that the identification of such phenotypes enables clinicians to be more aware of the potential difficulties an individual may experience, and hence, facilitate early diagnosis, effective management and prevention, appropriate allocation of resources and psychoeducation for the individual and their family. We describe the case report of a girl with cleidocranial dysostosis (CCD), and comorbid intellectual disability and attention deficit hyperactivity disorder (ADHD), and suggest the possible existence of a behavioural phenotype. We also highlight the lack of an evidence base for the management of ADHD within the learning-disability population, and describe successful management utilizing the current evidence base, which exists for those of average intellectual ability.