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. 2022 Oct;59(10):938-946.
doi: 10.1136/jmedgenet-2021-107695. Epub 2021 Dec 16.

Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-β-opathies with craniofacial manifestations using an innovative multimodality method

Konstantinia Almpani  1 , Denise K Liberton  1 , Priyam Jani  1 , Cyrus Keyvanfar  1 , Rashmi Mishra  1 , Natasha Curry  1 , Pamela Orzechowski  1 , Pamela A Frischmeyer-Guerrerio  2 , Janice S Lee  3
Affiliations

Loeys-Dietz and Shprintzen-Goldberg syndromes: analysis of TGF-β-opathies with craniofacial manifestations using an innovative multimodality method

Konstantinia Almpani et al. J Med Genet. 2022 Oct.

Abstract

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.

Keywords: aneurysm; cardiovascular abnormalities; genetic heterogeneity; human genetics; phenotype.

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Conflict of interest statement

Competing interests: None declared.

Figures

Figure 1
Figure 1
Clinical views of patients with LDS (subtypes 1–5) and SGS. This photo gallery illustrates the highly variable clinical craniofacial phenotype in TGF-β-opathies. LDS, Loeys-Dietz syndrome; SGS, Shprintzen-Goldberg syndrome; TGF-β, transforming growth factor-beta.
Figure 2
Figure 2
(A) Heatmap of Z-scores depicting the deviation of the soft tissue measurements in the different LDS subtypes and SGS, based on the normal values provided by FaceBase. The orange shades represent positive values, blue represents negative values. SGS, LDS2 and LDS1 are the subtypes with extreme Z-score values. LDS2, followed by LDS1, have the greatest variability. Facial depth, eyes and nose projection measurements were uniformly affected across the cohort. The facial depth and nasal projection were the most negatively affected features, while the eye measurements were increased. (B) The 3D mesh view of the face of an individual with LDS2 with the annotated landmarks used for the photo surface analysis. (C) PCA plot of the 3D photo surface landmark coordinate data depicting the variability of the soft tissue morphology among the different LDS subtypes, with the greatest variability in LDS2. 3D, three-dimensional; LDS, Loeys-Dietz syndrome; PCA, principal component analysis; SGS, Sphrintzen-Goldberg syndrome.
Figure 3
Figure 3
(A) Average Z-scores for each LDS subtype for each of the 2D cephalometric measurements, compared with normal values for the general population. The growth and position of the cranial base, maxilla and mandible are significantly affected in LDS, especially in LDS1 and LDS2. (B) The 3D craniofacial landmarks used for the cephalometric and geometric morphometric analysis annotated on a 3D view of a skull (C). PCA plot depicting the variation in the craniofacial shape in LDS. The variability in LDS2 and LDS1 can be appreciated, while all other subtypes are closer to the means of the axes. 2D, two-dimensional; 3D, three-dimensional; LDS, Loeys-Dietz syndrome; PCA, principal component analysis; SNA, sella–nasion–A point; SNB, sella–nasion–B point.
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