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

Jani, Priyam; Nguyen, Quynh C.; Almpani, Konstantinia; Keyvanfar, Cyrus; Mishra, Rashmi; Liberton, Denise K.; Orzechowski, Pamela; Frischmeyer‐Guerrerio, Pamela A.; Duverger, Olivier; Lee, J.S.

doi:10.1136/jmedgenet-2019-106678

Cited by 12 publications

(22 citation statements)

References 45 publications

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“…We previously reported the oral manifestations in a cohort of 40 individuals with LDS from five subtypes (LDS1-5) and reported a high frequency of abnormal palate morphology, enamel defects, bifid uvula, or submucous cleft palate, malocclusion, dental crowding, and delayed eruption of permanent teeth (16). We concluded that individuals with LDS2 followed by LDS1 had the most severely affected oro-dental region, which is also true for the systemic manifestations reported in LDS literature.…”

Section: Introductionsupporting

confidence: 53%

Case Report: Rare Presentation of Dentin Abnormalities in Loeys-Dietz Syndrome Type I

et al. 2021

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Loeys-Dietz syndrome type 1 (LDS1) is caused by a mutation in the transforming growth factor-beta receptor 1 (TGFBR1) gene. We previously characterized the oral and dental anomalies in a cohort of individuals diagnosed with LDS and showed that LDS1 had a high frequency of oral manifestations, and most affected individuals had enamel defects. However, dentin anomalies were not apparent in most patients in the cohort. In this cohort, we had identified dentin anomalies in a patient with LDS1, harboring mutation TGFBR1 c.1459C>T (p.Arg487Trp), and in this report, we present clinical and radiographic findings to confirm the dentin anomaly. The proband had gray-brown discoloration of most teeth typical for dentinogenesis imperfecta (DI). A radiographic exam revealed obliterated or very narrow pulp canals, with maxillary anterior teeth being affected more than the posterior teeth. The son of the proband, who also has the same mutation variant, had a history of DI affecting the primary teeth; however, his permanent teeth were normal in appearance at the time of exam. TGFBR1 is expressed by odontoblasts throughout tooth development and deletion of TGFBR1 in mouse models is known to affect dentin development. In this report, we present a rare case of abnormal dentin in two individuals with LDS1. These dental anomalies may be the first obvious manifestation of a life-threatening systemic disease and demonstrate the variable and multi-organ phenotypic effects in rare diseases.

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Section: Introductionsupporting

confidence: 53%

Case Report: Rare Presentation of Dentin Abnormalities in Loeys-Dietz Syndrome Type I

et al. 2021

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“…Further investigations into TGFβ abrogation later in skeletal development could provide information relevant to skeletal diseases initiated later in life. Based on our mouse skeletal phenotype, we suggest that our CKO mice may provide a good model to investigate how TGFβ signaling contributes to the craniosynostosis and oro-dental anomalies demonstrated in Loeys-Dietz syndrome [ 44 , 48 , 49 , 50 , 51 , 52 ]. Future investigations should include in-depth static and kinetic morphometric analysis building upon our previous publication demonstrating rigorous quantification of histomorphometric changes in the CKO long bones, growth plates, and calvaria [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

Corps

Stanwick

Rectenwald

et al. 2021

Genes

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Transforming growth factor β (TGFβ) signaling plays an important role in skeletal development. We previously demonstrated that the loss of TGFβ receptor II (Tgfbr2) in Osterix-Cre-expressing mesenchyme results in defects in bones and teeth due to reduced proliferation and differentiation in pre-osteoblasts and pre-odontoblasts. These Osterix-Cre;Tgfbr2f/f mice typically die within approximately four weeks for unknown reasons. To investigate the cause of death, we performed extensive pathological analysis on Osterix-Cre- (Cre-), Osterix-Cre+;Tgfbr2f/wt (HET), and Osterix-Cre+;Tgfbr2f/f (CKO) mice. We also crossed Osterix-Cre mice with the ROSA26mTmG reporter line to identify potential off-target Cre expression. The findings recapitulated published skeletal and tooth abnormalities and revealed previously unreported osteochondral dysplasia throughout both the appendicular and axial skeletons in the CKO mice, including the calvaria. Alterations to the nasal area and teeth suggest a potentially reduced capacity to sense and process food, while off-target Cre expression in the gastrointestinal tract may indicate an inability to absorb nutrients. Additionally, altered nasal passages and unexplained changes in diaphragmatic muscle support the possibility of hypoxia. We conclude that these mice likely died due to a combination of breathing difficulties, malnutrition, and starvation resulting primarily from skeletal deformities that decreased their ability to sense, gather, and process food.

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“…The severity of enamel defects was graded using a classification system for enamel defects reported previously (Jani et al, 2020). The classification of dental enamel defects was applied for both deciduous and permanent dentitions.…”

Section: Methodsmentioning

confidence: 99%

The peroxisomal disorder spectrum and Heimler syndrome: Deep phenotyping and review of the literature

Varela

Jani

Zein

et al. 2020

American J of Med Genetics Pt C

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The spectrum of peroxisomal disorders is wide and comprises individuals that die in the first year of life, as well as people with sensorineural hearing loss, retinal dystrophy and amelogenesis imperfecta. In this article, we describe three patients; two diagnosed with Heimler syndrome and a third one with a mild-intermediate phenotype. We arrived at these diagnoses by conducting complete ophthalmic (National Eye Institute), auditory (National Institute of Deafness and Other Communication Disorders), and dental (National Institute of Dental and Craniofacial Research) evaluations, as well as laboratory and genetic testing. Retinal degeneration with macular cystic changes, amelogenesis imperfecta, and sensorineural hearing loss were features shared by the three patients. Patients A and C had pathogenic variants in PEX1 and Patient B, in PEX6. Besides analyzing these cases, we review the literature regarding mild peroxisomal disorders, their pathophysiology, genetics, differential diagnosis, diagnostic methods, and management. We suggest that peroxisomal disorders are considered in every child with sensorineural hearing loss and retinal degeneration. These patients should have a dental evaluation to rule out amelogenesis imperfecta as well as audiologic examination and laboratory testing including peroxisomal biomarkers and genetic testing. Appropriate diagnosis can lead to better genetic counseling and management of the associated comorbidities.

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

Cited by 12 publications

References 45 publications

Case Report: Rare Presentation of Dentin Abnormalities in Loeys-Dietz Syndrome Type I

Case Report: Rare Presentation of Dentin Abnormalities in Loeys-Dietz Syndrome Type I

Skeletal Deformities in Osterix-Cre;Tgfbr2f/f Mice May Cause Postnatal Death

The peroxisomal disorder spectrum and Heimler syndrome: Deep phenotyping and review of the literature

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