Journal of medical genetics · 2021
Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-β-opathies with craniofacial manifestations using an innovative multimodality method.
СтатьяResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод в очереди
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Almpani Konstantinia, Liberton Denise K, Jani Priyam, Keyvanfar Cyrus, Mishra Rashmi, Curry Natasha, Orzechowski Pamela, Frischmeyer-Guerrerio Pamela A, Lee Janice S
Аннотация
BACKGROUND: Elevated transforming growth factor-beta (TGF-β) signalling has been implicated in the pathogenesis of Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). In this study, we provide a qualitative and quantitative analysis of the craniofacial and functional features among the LDS subtypes and SGS.
METHODS: We explore the variability within and across a cohort of 44 patients through deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, cephalometric and geometric morphometric analyses of cone-beam CT scans.
RESULTS: The most common craniofacial features detected in this cohort include mandibular retrognathism (84%), flat midface projection (84%), abnormal eye shape (73%), low-set ears (73%), abnormal nose (66%) and lip shape (64%), hypertelorism (41%) and a relatively high prevalence of nystagmus/strabismus (43%), temporomandibular joint disorders (38%) and obstructive sleep apnoea (23%). 3D cephalometric analysis demonstrated an increased cranial base angle with shortened anterior cranial base and underdevelopment of the maxilla and mandible, with evidence of a reduced pharyngeal airway in 55% of those analysed. Geometric morphometric analysis confirmed that the greatest craniofacial shape variation was among patients with LDS type 2, with distinct clustering of patients with SGS.
CONCLUSIONS: This comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-β signalling pathway, with a particularly severe phenotype associated with TGFBR2 and SKI mutations. Multimodality assessment of craniofacial anomalies objectively reveals the impact of mutations of the TGF-β pathway with perturbations associated with the cranium and cranial base with severe downstream effects on the orbit, maxilla and mandible with the resultant clinical phenotypes.
METHODS: We explore the variability within and across a cohort of 44 patients through deep clinical phenotyping, three-dimensional (3D) facial photo surface analysis, cephalometric and geometric morphometric analyses of cone-beam CT scans.
RESULTS: The most common craniofacial features detected in this cohort include mandibular retrognathism (84%), flat midface projection (84%), abnormal eye shape (73%), low-set ears (73%), abnormal nose (66%) and lip shape (64%), hypertelorism (41%) and a relatively high prevalence of nystagmus/strabismus (43%), temporomandibular joint disorders (38%) and obstructive sleep apnoea (23%). 3D cephalometric analysis demonstrated an increased cranial base angle with shortened anterior cranial base and underdevelopment of the maxilla and mandible, with evidence of a reduced pharyngeal airway in 55% of those analysed. Geometric morphometric analysis confirmed that the greatest craniofacial shape variation was among patients with LDS type 2, with distinct clustering of patients with SGS.
CONCLUSIONS: This comprehensive phenotypic approach identifies developmental abnormalities that segregate to mutation variants along the TGF-β signalling pathway, with a particularly severe phenotype associated with TGFBR2 and SKI mutations. Multimodality assessment of craniofacial anomalies objectively reveals the impact of mutations of the TGF-β pathway with perturbations associated with the cranium and cranial base with severe downstream effects on the orbit, maxilla and mandible with the resultant clinical phenotypes.