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Original research
Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation
  1. Priyam Jani1,
  2. Quynh C Nguyen1,
  3. Konstantinia Almpani1,
  4. Cyrus Keyvanfar1,
  5. Rashmi Mishra1,
  6. Denise Liberton1,
  7. Pamela Orzechowski1,
  8. Pamela A Frischmeyer-Guerrerio2,
  9. Olivier Duverger1,
  10. Janice S Lee1
  1. 1Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, Bethesda, Maryland, USA
  2. 2Food Allergy Research Unit, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
  1. Correspondence to Dr Olivier Duverger, Craniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, Bethesda, MD 20892, USA; olivier.duverger{at}; Dr Janice S Lee, Craniofacial Anomalies and Regenration Section, National Institute of Dental and Craniofacial Research, Bethesda, MD, 20892; janice.lee{at}


Background Loeys-Dietz syndrome (LDS), an autosomal dominant rare connective tissue disorder, has multisystemic manifestations, characterised by vascular tortuosity, aneurysms and craniofacial manifestations. Based on the associated gene mutations along the transforming growth factor-beta (TGF-β) pathway, LDS is presently classified into six subtypes. Methods We present the oro-dental features of a cohort of 40 patients with LDS from five subtypes. Results The most common oro-dental manifestations were the presence of a high-arched and narrow palate, and enamel defects. Other common characteristics included bifid uvula, submucous cleft palate, malocclusion, dental crowding and delayed eruption of permanent teeth. Both deciduous and permanent teeth had enamel defects in some individuals. We established a grading system to measure the severity of enamel defects, and we determined that the severity of the enamel anomalies in LDS is subtype-dependent. In specific, patients with TGF-β receptor II mutations (LDS2) presented with the most severe enamel defects, followed by patients with TGF-β receptor I mutations (LDS1). LDS2 patients had higher frequency of oro-dental deformities in general. Across all five subtypes, as well as within each subtype, enamel defects exhibited incomplete penetrance and variable expression, which is not associated with the location of the gene mutations. Conclusion This study describes, in detail, the oro-dental manifestations in a cohort of LDS, and we conclude that LDS2 has the most severely affected phenotype. This extensive characterisation, as well as some identified distinguishing features can significantly aid dental and medical care providers in the diagnosis and clinical management of patients with this rare connective tissue disorder.

  • connective tissue disease
  • diagnosis
  • genetics
  • getting research into practice

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  • Contributors PJ, RM and JSL performed the clinical evaluation of patients. PO recruited and consented the patients. PJ, QN, KA, CK, DL and OD performed the analysis and interpretation of data. JSL and PAF-G obtained IRB approval and secured research funding, identified and recruited patients with LDS. PJ, QN, OD and JSL wrote the manuscript. All authors reviewed the manuscript critically for important intellectual content and approved the version to be published.

  • Funding This research was funded by the Intramural Research Program of the National Institute of Dental and Craniofacial Research (PI: JSL, DDS, MD, FACS, ZIA DE000746 04 and ZID DE000728 10) and National Institute of Allery and Infectious Diseases (PI: PAF-G, MD, PhD, ZIA AI001203 04).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval The main study and the collaborated study protocols were approved by the institutional review boards at their respective institute ( numbers, NCT02639312 for the Natural History of Craniofacial Anomalies and Developmental Growth Variants study and NCT02504853 for the Natural History and Genetics of Food Allergy and Related Conditions study). A signed informed consent was obtained from all the participating patients and/or their guardians.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Deidentified participant data will be shared on request by contacting either the primary or the corresponding author.

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