Articles scientifiques

Retinoic Acid Excess Impairs Amelogenesis Inducing Enamel Defects

2017 / English – Frontiers in Physiology 2017


S. Morkmued, V. Laugel-Haushalter, E. Mathieu, B. Schuhbaur, J. Hemmerlé, P. Dollé, A. Bloch-Zupan, K. Niederreither


« Abnormalities of enamel matrix proteins deposition, mineralization, or degradation during tooth development are responsible for a spectrum of either genetic diseases termed Amelogenesis imperfecta or acquired enamel defects. To assess if environmental/nutritional factors can exacerbate enamel defects, we investigated the role of the active form of vitamin A, retinoic acid (RA). Robust expression of RA-degrading enzymes Cyp26b1 and Cyp26c1 in developing murine teeth suggested RA excess would reduce tooth hard tissue mineralization, adversely affecting enamel. We employed a protocol where RA was supplied to pregnant mice as a food supplement, at a concentration estimated to result in moderate elevations in serum RA levels. This supplementation led to severe enamel defects in adult mice born from pregnant dams, with most severe alterations observed for treatments from embryonic day (E)12.5 to E16.5. We identified the enamel matrix proteins enamelin (Enam), ameloblastin (Ambn), and odontogenic ameloblast-associated protein (Odam) as target genes affected by excess RA, exhibiting mRNA reductions of over 20-fold in lower incisors at E16.5. RA treatments also affected bone formation, reducing mineralization. Accordingly, craniofacial ossification was drastically reduced after 2 days of treatment (E14.5). Massive RNA-sequencing (RNA-seq) was performed on E14.5 and E16.5 lower incisors. Reductions in Runx2 (a key transcriptional regulator of bone and enamel differentiation) and its targets were observed at E14.5 in RA-exposed embryos. RNA-seq analysis further indicated that bone growth factors, extracellular matrix, and calcium homeostasis were perturbed. Genes mutated in human AI (ENAM, AMBN, AMELX, AMTN, KLK4) were reduced in expression at E16.5. Our observations support a model in which elevated RA signaling at fetal stages affects dental cell lineages. Thereafter enamel protein production is impaired, leading to permanent enamel alterations. »

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SLC13A5 is the second gene associated with Kohlschütter–Tönz syndrome

2017 / English – Journal of Medical Genetics 2017; 54: 54-62


Schossig A, Bloch-Zupan A, Lussi A, Wolf NI, Raskin S, Cohen M, Giuliano F, Jurgens J, Krabichler B, Koolen DA, de Macena Sobreira NL, Maurer E, Muller-Bolla M, Penzien J, Zschocke J, Kapferer-Seebacher I.




Kohlschütter-Tönz syndrome (KTZS) is a rare autosomal-recessive disease characterised by epileptic encephalopathy, intellectual disability and amelogenesis imperfecta (AI). It is frequently caused by biallelic mutations in ROGDI. Here, we report on individuals with ROGDI-negative KTZS carrying biallelic SLC13A5 mutations.


In the present cohort study, nine individuals from four families with the clinical diagnosis of KTZS and absence of ROGDI mutations as well as one patient with unexplained epileptic encephalopathy were investigated by clinical and dental evaluation, parametric linkage analysis (one family), and exome and/or Sanger sequencing. Dental histological investigations were performed on teeth from individuals with SLC13A5-associated and ROGDI-associated KTZS.


Biallelic mutations in SLC13A5 were identified in 10 affected individuals. Epileptic encephalopathy usually presents in the neonatal and (less frequently) early infantile period. Yellowish to orange discolouration of both deciduous and permanent teeth, as well as wide interdental spaces and abnormal crown forms are major clinical signs of individuals with biallelic SLC13A5 mutations. Histological dental investigations confirmed the clinical diagnosis of hypoplastic AI. In comparison, the histological evaluation of a molar assessed from an individual with ROGDI-associated KTZS revealed hypocalcified AI.


We conclude that SLC13A5 is the second major gene associated with the clinical diagnosis of KTZS, characterised by neonatal epileptic encephalopathy and hypoplastic AI. Careful clinical and dental delineation provides clues whether ROGDI or SLC13A5 is the causative gene. Hypersensitivity of teeth as well as high caries risk requires individual dental prophylaxis and attentive dental management. »

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Hypophosphatasia: diagnosis and clinical signs – a dental surgeon perspective

2016 / English – International Journal of Paediatric Dentistry 2016; 26: 426–438


Agnès Bloch-Zupan


« Background. Hypophosphatasia (HPP) is a rareinherited metabolic disease in which mutations in the ALPL gene (encoding tissue-nonspecific alkaline phosphatase) result in varying degrees of enzyme deficiency. HPP manifests in a spectrum of symptoms, including early primary tooth loss (root intact) and alveolar bone mineralisation defects.
Objective. To provide an overview of HPP for dental professionals to help recognise and differentially diagnose patients for appropriate referral to a specialist team.
Methods. A non-systematic review of publications on HPP was performed. »

L’implantologie dans les cas de dysplasie ectodermique

2016 / Français – ROS – Septembre 2016 – Tome 45 – N° 3


F. Clauss, F. Obry, S. Jung, JC. Dahlet, E. Waltmann, A. Bloch-Zupan, V. Vogt, MC. Manière


« Les thérapeutiques implantaires précoces des patients atteints de dysplasie ectodermique présentent des spécificités chirurgicales, anatomiques et physiologiques en rapport avec le phénotype osseux et la croissance. Le degré de maturité squelettique et psychique, le phénotype dentaire et les antécédents prothétiques sont des éléments diagnostiques essentiels. L’imagerie sectionnelle CBCT pré-opératoire est essentielle dans ce contexte et permet une évaluation qualitative et mensurative du support osseux symphysaire. En fonction des observations cliniques et tomographiques, le praticien s’orientera vers la mise en place d’implants standards de faible dimension ou de mini-implants, dans les cas d’anodontie ou d’hypotrophie osseuse très marquée. La différence de taille entre ces deux approches est la nécessité de dépose des miniimplants à la fin de la croissance et leur remplacement par des implants ostéointégrés standards. Des études multi-centriques, un recul clinique et radiologique plus important sont nécessaires pour mieux étudier le comportement de ces mini-implants à long terme. Un suivi rigoureux de l’ostéointégration et un renouvellement prothétique régulier de la prothèse adjointe supra-implantaire, en fonction du rythme de croissance des bases osseuses, sont nécessaires. »

Diagnostic des anomalies bucco-dentaires associées aux maladies rares

2016 / Français – Réalités cliniques 2016, Vol. 27, n°3: pp.176-185


 F. Clauss, S. Jung, F. Bornert, A. Bloch-Zupan, M.C. Manière


« Le rôle de dépistage du chirurgien-dentiste est central dans les différents types d’anomalies du développement dentaire isolées ou syndromiques, comme les agénésies dentaires multiples, les anomalies de structure ou de morphologie. De nombreux syndromes polymalformatifs associent un phénotype dentaire à diverses atteintes systémiques, parmi lesquels on retrouve les dysplasies ectodermiques, les polyposes adénomateuses familiales, le syndrome ERS (Enamel-Renal syndrome), par exemple. Des signes cliniques dento-maxillaires sont retrouvés en association avec des formes de cancer cutané ou de tumeurs des systèmes nerveux ou endocrinien, citons par exemple la néoplasie endocrine multiple 2B ou le syndrome de Gorlin. Ces anomalies dentaires constituent autant de signes d’appel pour le praticien, permettant de suspecter des pathologies potentiellement sévères. »

Amelogenesis Imperfecta: 1 Family, 2 Phenotypes, and 2 Mutated Genes

2016 / English – Journal of Dental Research – Research Reports: Clinical


M.K. Prasad, S. Laouina, M. El Alloussi, H. Dollfus and A. Bloch-Zupan


« Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous group of diseases characterized by enamel defects. The authors have identified a large consanguineous Moroccan family segregating different clinical subtypes of hypoplastic and hypomineralized AI in different individuals within the family. Using targeted next-generation sequencing, the authors identified a novel heterozygous nonsense mutation in COL17A1 (c.1873C>T, p.R625*) segregating with hypoplastic AI and a novel homozygous 8-bp deletion in C4orf26 (c.39_46del, p.Cys14Glyfs*18) segregating with hypomineralized-hypoplastic AI in this family. This study highlights the phenotypic and genotypic heterogeneity of AI that can exist even within a single consanguineous family. Furthermore, the identification of novel mutations in COL17A1 and C4orf26 and their correlation with distinct AI phenotypes can contribute to a better understanding of the pathophysiology of AI and the contribution of these genes to amelogenesis. »

The spectrum of orofacial manifestations in systemic sclerosis: a challenging management

2016 / English – Oral Diseases 2017; 23: 424-439


Jung S, Martin T, Schmittbuhl M, Huck O.


« Systemic sclerosis (SSc) is a rare multisystem connective tissue disorder characterized by the triad fibrosis, vasculopathy and immune dysregulation. This chronic disease has a significant impact on the orofacial region that is involved in more than two-thirds of the cases. SSc patients can show a wide array of oral manifestations, which are usually associated with a severe impairment of the quality of life. They often present a decreased the salivary flow and a reduced mouth opening that contribute substantially to the worsening of the oral health status. Therefore, SSc patients require specific and multidisciplinary interventions that should be initiated as early as possible. The identification of specific radiological and clinical signs at the early stage will improve the management of such patients. This study reviews the wide spectrum of orofacial manifestations associated with SSc and suggests clues for the oral management that remains challenging. »

Detection of a Novel DSPP Mutation by NGS in a Population Isolate in Madagascar

March 2016 / English – Journal Frontiers in Physiology – Craniofacial Biology and Dental Research


Agnès Bloch-Zupan*, Mathilde Huckert, Corinne Stoetzel, Julia Meyer, Véronique Geoffroy, Rabisoa W. Razafindrakoto, Saholy N. Ralison, Jean-Claude Randrianaivo, Georgette Ralison, Rija O. Andriamasinoro, Rija H. Ramanampamaharana, Solofomanantsoa E. Randrianazary, Louise H. Ralimanana, Béatrice Richard, Philippe Gorry, Marie-Cécile Manière, Jeanne A. Rasoamananjara, Simone Rakoto Alson and Hélène Dollfus


« A large family from a small village in Madagascar, Antanetilava, is known to present with colored teeth. Through previous collaboration and 4 successive visits in 1994, 2004, 2005, and 2012, we provided dental care to the inhabitants and diagnosed dentinogenesis imperfecta. Recently, using whole exome sequencing we confirmed the clinical diagnosis by identifying a novel single nucleotide deletion in exon 5 of DSPP. This paper underlines the necessity of long run research, the importance of international and interpersonal collaborations as well as the major contribution of next generation sequencing tools in the genetic diagnosis of rare oro-dental anomalies. This study is registered in ClinicalTrials ( under the number NCT02397824. »

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