Genotypes and Craniofacial Phenotypes in Orthodontic Patients With Marfan and Loeys-Dietz Syndromes

Genotypes and Craniofacial Phenotypes in Orthodontic Patients With Marfan and Loeys-Dietz Syndromes: Observational Retrospective Study

The aim of this retrospective observational study is to investigate the association between genotype and craniofacial phenotype in orthodontic patients affected by Marfan and Loeys-Dietz syndromes. A total of 39 patients aged between 4 and 18 years were enrolled and stratified into four groups according to the underlying pathogenic genetic variants. Lateral cephalometric radiographs were analyzed to assess sagittal, vertical, and cranial base skeletal relationships. Each patient group was compared with age- and sex-matched controls, as well as between syndromes and among Marfan subgroups. Statistical analyses were performed to evaluate differences in craniofacial parameters and to explore potential genotype-phenotype correlations relevant for orthodontic diagnosis.

Study Overview

• Status: Completed
• Conditions: Marfan Syndrome; Loeys-Dietz Syndrome
• Intervention / Treatment: Diagnostic test: Cephalometric analysis

Detailed Description

This retrospective observational study aims to investigate the association between genotype and craniofacial phenotypic variation in orthodontic patients affected by Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS). Patients aged between 4 and 18 years who referred to the Unit of Orthodontics and Paediatric Dentistry and had a confirmed genetic diagnosis were considered eligible for inclusion. Parents or legal guardians provided informed consent prior to data collection.

A total of 39 patients were enrolled and divided into four groups according to the underlying pathogenic genetic variant:

• Group FBN1Cys: Marfan patients with missense cysteine variants of the FBN1 gene.
• Group FBN1m: Marfan patients with missense non-cysteine variants of the FBN1 gene.
• Group FBN1tp: Marfan patients with truncating FBN1 variants (nonsense, frameshift or splicing mutations).
• Group LD: Patients with Loeys-Dietz syndrome carrying pathogenic variants in TGFBR1 or TGFBR2 genes.

An age- and sex-matched control group without genetic disorders and without previous orthodontic treatment was selected for each study group. All patients underwent orthodontic diagnostic records including lateral cephalometric radiographs. Due to the retrospective nature of the study and the use of different radiographic units, only angular cephalometric measurements were considered.

Cephalometric analysis was performed using dedicated software according to Giannì's method, evaluating sagittal, vertical and cranial base relationships. Each patient was compared with the corresponding control group, between MFS and LDS patients, and among the Marfan subgroups. All measurements were performed by a single operator and intra-rater reliability was assessed.

Sample size was defined by the availability of patients affected by these rare genetic disorders who met the inclusion criteria during the study period. Descriptive statistics were calculated for all cephalometric parameters. Shapiro-Wilk test was applied to assess data normality. Differences between groups were evaluated using ANOVA, followed by Tukey's post-hoc test when appropriate.

Statistical analysis was conducted using R software, with significance for all tests predetermined at p < 0.05.

• Study Type: Observational
• Enrollment (Actual): 39

Contacts and Locations

Study Locations

• Italy
  • Lombardy
    • Pavia, Lombardy, Italy, 27100
      • Unit of Orthodontics and Pediatric Dentistry - Section of Dentistry - Department of Clinical, Surgical, Diagnostic and Pediatrics - University of Pavia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients referring for orthodontic consultation from the Unit Centre for Inherited Cardiovascular Diseases, IRCCS Foundation, University Hospital Policlinico San Matteo, Pavia, Italy

Description

Inclusion Criteria:

• Diagnosis of Marfan/Loeys-Dietz syndrome;
• formal request of parents or legal guardians for orthodontic evaluation;
• aged between 4 and 18;
• no previous orthopaedic or orthodontic treatment.

Exclusion Criteria:

• History of craniofacial anomalies (e.g., cleft lip/palate, craniosynostosis) or syndromic conditions other than Marfan/Loeys-Dietz syndrome;
• previous orthopaedic or orthodontic treatment;
• poor quality cephalograms.

Study Plan

How is the study designed?

Number of groups / cohorts

5

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
FBN1Cys (Marfan syndrome, cysteine missense variants); This arm included patients diagnosed with Marfan syndrome carrying missense variants affecting cysteine residues of the FBN1 gene.	Diagnostic test: Cephalometric analysis; Lateral cephalometric radiographs with cephalometric tracings were performed to evaluate craniofacial patterns.
FBN1m (Marfan syndrome, non-cysteine missense variants); This arm comprised patients with Marfan syndrome carrying missense FBN1 variants not involving cysteine residues.	Diagnostic test: Cephalometric analysis; Lateral cephalometric radiographs with cephalometric tracings were performed to evaluate craniofacial patterns.
FBN1tp (Marfan syndrome, truncating variants); Patients in this arm were affected by Marfan syndrome and carried truncating FBN1 variants, including nonsense, frameshift, or splicing mutations.	Diagnostic test: Cephalometric analysis; Lateral cephalometric radiographs with cephalometric tracings were performed to evaluate craniofacial patterns.
LD (Loeys-Dietz syndrome); This arm included patients diagnosed with Loeys-Dietz syndrome carrying pathogenic variants in TGFBR1 or TGFBR2 genes.	Diagnostic test: Cephalometric analysis; Lateral cephalometric radiographs with cephalometric tracings were performed to evaluate craniofacial patterns.
Control group; A control group matched for age and sex was added for all syndromic patients.	Diagnostic test: Cephalometric analysis; Lateral cephalometric radiographs with cephalometric tracings were performed to evaluate craniofacial patterns.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ANB angle	The ANB angle will be measured on lateral cephalometric radiographs to assess the sagittal skeletal relationship between the maxilla and mandible. Comparisons will be performed between genotype-based case groups and age- and sex-matched controls, as well as among case groups when applicable.	Baseline

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SNA angle	SNA angle will be measured to assess maxillary position relative to the cranial base.	Baseline
SNB angle	SNB angle will be measured to assess mandibular position relative to the cranial base.	Baseline
Vertical skeletal pattern (SN-MP angle)	SN-MP angle will be measured to evaluate mandibular plane inclination and vertical skeletal pattern.	Baseline
Intermaxillary vertical relationship (PP-MP angle)	PP-MP angle will be measured to assess vertical discrepancy between the palatal plane and the mandibular plane.	Baseline
Occlusal plane relationships (Occ-MP and Occ-PP angles)	Occ-MP and Occ-PP angles will be measured to assess occlusal plane inclination relative to the mandibular and palatal planes.	Baseline
Cranial base morphology (N-S-Ar and S-Ar-Go angles)	N-S-Ar and S-Ar-Go angles will be measured to evaluate cranial base flexure and posterior cranial base-mandibular ramus relationship.	Baseline
Mandibular morphology (Ar-Go-N angle)	Ar-Go-N angle will be measured to assess mandibular morphology and angular configuration.	Baseline
Facial vertical pattern (N-Go-Gn angle)	N-Go-Gn angle will be measured to assess facial vertical growth pattern.	Baseline
Maxillary incisor inclination (11-Occ and 11-PP)	11-Occ and 11-PP measurements will be used to assess maxillary central incisor inclination relative to the occlusal and palatal planes.	Baseline
Mandibular incisor inclination (41-Occ and 41-MP)	41-Occ and 41-MP measurements will be used to assess mandibular central incisor inclination relative to the occlusal and mandibular planes.	Baseline
Nasolabial angle (NLA)	The nasolabial angle will be measured to assess soft tissue profile characteristics.	Baseline
Facial angle (FA)	The facial angle will be measured to evaluate overall facial profile morphology.	Baseline

Collaborators and Investigators

• Sponsor: Andrea Scribante
• Investigators: Principal Investigator: Andrea Scribante, DDS, PhD, Associate Professor, Principal Investigator

Study record dates

Study Major Dates

• Study Start (Actual): July 7, 2012
• Primary Completion (Actual): July 1, 2021
• Study Completion (Actual): July 5, 2021

Study Registration Dates

• First Submitted: January 13, 2026
• First Submitted That Met QC Criteria: January 13, 2026
• First Posted (Actual): January 22, 2026

Study Record Updates

• Last Update Posted (Actual): January 22, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Vascular Diseases; Cardiovascular Diseases; Heart Diseases; Genetic Diseases, Inborn; Connective Tissue Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Abnormalities, Multiple; Aortic Diseases; Bone Diseases, Developmental; Aneurysm; Aortic Aneurysm; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Loeys-Dietz Syndrome; Marfan Syndrome
• Other Study ID Numbers: 2026-MARFANLDS

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data will be available upon motivated request to the Principal Investigator.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No