RESUMO
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-ß) 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-ß receptor II mutations (LDS2) presented with the most severe enamel defects, followed by patients with TGF-ß 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.
Assuntos
Doenças do Tecido Conjuntivo/genética , Síndrome de Loeys-Dietz/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Anormalidades Dentárias/genética , Adolescente , Adulto , Criança , Doenças do Tecido Conjuntivo/classificação , Doenças do Tecido Conjuntivo/complicações , Feminino , Predisposição Genética para Doença , Humanos , Síndrome de Loeys-Dietz/classificação , Síndrome de Loeys-Dietz/complicações , Masculino , Pessoa de Meia-Idade , Mutação/genética , Fenótipo , Anormalidades Dentárias/classificação , Anormalidades Dentárias/complicações , Adulto JovemRESUMO
Loeys-Dietz syndrome (LDS) is a connective tissue disorder first described in 2005 featuring aortic/arterial aneurysms, dissections, and tortuosity associated with craniofacial, osteoarticular, musculoskeletal, and cutaneous manifestations. Heterozygous mutations in 6 genes (TGFBR1/2, TGFB2/3, SMAD2/3), encoding components of the TGF-ß pathway, cause LDS. Such genetic heterogeneity mirrors broad phenotypic variability with significant differences, especially in terms of the age of onset, penetrance, and severity of life-threatening vascular manifestations and multiorgan involvement, indicating the need to obtain genotype-to-phenotype correlations for personalized management and counseling. Herein, we report on a cohort of 34 LDS patients from 24 families all receiving a molecular diagnosis. Fifteen variants were novel, affecting the TGFBR1 (6), TGFBR2 (6), SMAD3 (2), and TGFB2 (1) genes. Clinical features were scored for each distinct gene and matched with literature data to strengthen genotype-phenotype correlations such as more severe vascular manifestations in TGFBR1/2-related LDS. Additional features included spontaneous pneumothorax in SMAD3-related LDS and cervical spine instability in TGFB2-related LDS. Our study broadens the clinical and molecular spectrum of LDS and indicates that a phenotypic continuum emerges as more patients are described, although genotype-phenotype correlations may still contribute to clinical management.
Assuntos
Síndrome de Loeys-Dietz/genética , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Síndrome de Loeys-Dietz/classificação , Síndrome de Loeys-Dietz/patologia , Pessoa de Meia-Idade , Linhagem , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta2/genéticaRESUMO
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