Severity of oro-dental anomalies in Loeys-Dietz syndrome segregates by gene mutation

Abstract

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.

Keywords: connective tissue disease; diagnosis; genetics; getting research into practice.

Figure 1

Common phenotypical characteristics in patients with Loeys-Dietz syndrome (LDS). (A) Narrow and high-arched palate in patient XIX with LDS2 and a high-arched palate in patient IIB with LDS1. The narrow palate in XIX resulted in severe crowding of teeth, malocclusion and posterior crossbite. (B) Bifid uvula in patient XVII with LDS2 and broad uvula in patient IIB. (C) Crowding of lower anterior teeth in patient XXV with LDS2. The crowding resulted from lack of space for permanent teeth mostly due to small (retrognathic) mandible. (D) Increased overjet of anterior teeth (double arrow) and class II dental malocclusion in patient VI with LDS1. (E) Bilateral posterior crossbite in patient IV. (F) Delayed dental eruption pattern in patient XVI with LDS2 with multiple retained deciduous teeth. The incisor was not visible in the oral cavity during patient’s first visit at 10 years of age (top image, arrowhead) but was partially erupted in the visit after 1 year (bottom image, arrowhead). Also notable is the presence of several deciduous teeth at 11 years of age (bottom image, asterisk). (G) Panoramic X-ray of a patient 11 years of age with LDS2 having congenitally missing teeth #4, #20 and #29, along with retained deciduous teeth (asterisk), unerupted permanent teeth (black arrows) and impacted tooth #11 (black arrowhead).

Figure 2

Grading of enamel defects in Loeys-Dietz syndrome (LDS). (A) Representative photos of various grades of enamel defects seen in patients with LDS, with the inset showing a magnified view of the boxed area of each tooth. Grade 0 shows normal incisors with no defects. Grade 1 shows the teeth with discolouration of enamel and white spots. Grade 2 shows mild enamel structural defects including pits and grooves. Grade 3 shows severe pitting of the enamel involving more than two-thirds of the surface. Severe structural defects leading to loss of enamel and dentin exposure was classified as grade 4. The dotted line shows the extent of enamel loss and underlying dentin becoming visible. E, enamel, D, dentin. (B) Distribution of the different grades of enamel defects in patients with LDS. LDS2 has the most severe defects with two patients having grade 4 and three patients having grade 3 defects. LDS1 only had one patient with grade 2, while six had grade 1 defects. Grade 1 enamel defects were seen in two out of three LDS3 patients and three LDS4 patients.

Figure 3

Mutations in transforming growth factor-beta (TGF-β) receptor type 2 (TGFBR2) lead to varying degrees of enamel defects. (A) Varying degrees of severity of enamel defects seen in LDS2 patients with patient XIV showing severe loss of enamel (grade 4), patient XX showing generalised discolouration of both upper and lower teeth (grade 2) and patient XVII only exhibiting mild discolouration and localised white spot lesions (grade 1). (B) Graphic representation of the TGF-β receptor 2 protein (TGFR-2) showing the distribution of pathogenic variants in the LDS2 patients in this study. All LDS-causing mutations reported so far in TGFBR2 are in the region of the gene that encodes the intracellular protein kinase domain. We also mapped the severity of enamel defects to each variant and did not find any correlation between defect severity and variant position. EC, extracellular domain, IC, intracellular domain. (C) LDS2 patients with same pathogenic variant (p.R528H) presenting varying severity of enamel defects, once again showing the variability in LDS phenotype. (D) Patients in the same family with p.V419E mutation showing different grades of enamel defects with father (top image) having grade 1 defects and daughter (bottom image) having no evident enamel defects. LDS, Loeys-Dietz syndrome.