Heterozygous COL17A1 variants are a frequent cause of amelogenesis imperfecta.

BACKGROUND: Collagen XVII is most typically associated with human disease when biallelic COL17A1 variants (>230) cause junctional epidermolysis bullosa (JEB), a rare, genetically heterogeneous, mucocutaneous blistering disease with amelogenesis imperfecta (AI), a developmental enamel defect. Despite recognition that heterozygous carriers in JEB families can have AI, and that heterozygous COL17A1 variants also cause dominant corneal epithelial recurrent erosion dystrophy (ERED), the importance of heterozygous COL17A1 variants causing dominant non-syndromic AI is not widely recognised. METHODS: Probands from an AI cohort were screened by single molecule molecular inversion probes or targeted hybridisation capture (both a custom panel and whole exome sequencing) for COL17A1 variants. Patient phenotypes were assessed by clinical examination and analyses of affected teeth. RESULTS: Nineteen unrelated probands with isolated AI (no co-segregating features) had 17 heterozygous, potentially pathogenic COL17A1 variants, including missense, premature termination codons, frameshift and splice site variants in both the endo-domains and the ecto-domains of the protein. The AI phenotype was consistent with enamel of near normal thickness and variable focal hypoplasia with surface irregularities including pitting. CONCLUSION: These results indicate that COL17A1 variants are a frequent cause of dominantly inherited non-syndromic AI. Comparison of variants implicated in AI and JEB identifies similarities in type and distribution, with five identified in both conditions, one of which may also cause ERED. Increased availability of genetic testing means that more individuals will receive reports of heterozygous COL17A1 variants. We propose that patients with isolated AI or ERED, due to COL17A1 variants, should be considered as potential carriers for JEB and counselled accordingly, reflecting the importance of multidisciplinary care.

Characterization of ANKRD11 mutations in humans and mice related to KBG syndrome.

Mutations in ANKRD11 have recently been reported to cause KBG syndrome, an autosomal dominant condition characterized by intellectual disability (ID), behavioral problems, and macrodontia. To understand the pathogenic mechanism that relates ANKRD11 mutations with the phenotype of KBG syndrome, we studied the cellular characteristics of wild-type ANKRD11 and the effects of mutations in humans and mice. We show that the abundance of wild-type ANKRD11 is tightly regulated during the cell cycle, and that the ANKRD11 C-terminus is required for the degradation of the protein. Analysis of 11 pathogenic ANKRD11 variants in humans, including six reported in this study, and one reported in the Ankrd11 (Yod/+) mouse, shows that all mutations affect the C-terminal regions and that the mutant proteins accumulate aberrantly. In silico analysis shows the presence of D-box sequences that are signals for proteasome degradation. We suggest that ANKRD11 C-terminus plays an important role in regulating the abundance of the protein, and a disturbance of the protein abundance due to the mutations leads to KBG syndrome.

The dental management of children with congenital heart disease following the publication of Paediatric Congenital Heart Disease Standards and Specifications.

The Paediatric Congenital Heart Disease Standards and Specifications (PCHDSS) were published in May 2016 by NHS England. The standards describe in detail the cardiac care patients should expect in England. They are also the first cardiology standards to include an oral health section. The dental standards outline what oral health care patients should receive from both cardiology and dental healthcare professionals, with immediate effect. Children with congenital heart disease (CHD) are at increased risk of infective endocarditis and often have poorer oral health compared to healthy children. Children with cardiac disease can be complex to manage appropriately due to their increased dental anxiety and reduced access to dental care. The PCHDSS dental section highlights the importance of collaborative working between cardiology, primary care and paediatric dentistry. This should ensure preventive advice is delivered regularly, oral disease diagnosed early and patients managed or referred appropriately. This article will summarise CHD, the PCHDSS, its implications and discuss the oral health of children with a cardiac defect. The importance of treatment planning and dental management for this high risk group, in addition to informing readers when to refer to specialist care will also be described.

Intentional surgical repositioning of an ankylosed permanent maxillary incisor.

Replacement resorption (ankylosis) may be a significant complication after replantation of avulsed permanent incisor teeth. This report explains the aetiology, diagnosis, management and current treatment options in ankylosis and then describes an alternative surgical technique, intentional luxation and repositioning. This technique, in the presence of an acceptable root length, may be a realistic treatment option in adolescence until osseointegrated implants can be considered at the age of 18-20 years.