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

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


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.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Arachnodactyly* / genetics
  • Craniosynostoses
  • Humans
  • Loeys-Dietz Syndrome* / diagnosis
  • Loeys-Dietz Syndrome* / genetics
  • Marfan Syndrome
  • Receptor, Transforming Growth Factor-beta Type II / genetics
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factors


  • Transforming Growth Factor beta
  • Transforming Growth Factors
  • Receptor, Transforming Growth Factor-beta Type II

Supplementary concepts

  • Shprintzen Golberg craniosynostosis