Natural History of Craniofacial Anomalies and Developmental Growth Variants

Overview

Background: Some head and facial abnormalities are rare and present at birth. Others are more common, and may not show up until puberty. These conditions have different causes and characteristics. Researchers want to learn more about these conditions by comparing people with face, head, and neck abnormalities to family members and to healthy volunteers without such conditions. Objectives: To learn more about abnormal development of the face, head, and neck. To determine their genetic variants. Eligibility: People who have not had surgery for facial trauma: People ages 2 and older with craniofacial abnormalities (may participate offsite) Unaffected relatives ages 2 and older Healthy volunteers ages 6 and older Design: Participants will be screened with medical history and physical exam focusing on head, face, and neck Participants may be followed for several years. Visits may require staying near the clinic for a few days. A visit is required for the following developmental stages, along with follow-up visits: Age 2-6 Age 6-10 Age 11-17 Age 18 and older Visits may include: Medical history Physical exam Questionnaires Oral exam Blood and urine tests Cheek swab: a cotton swab will be wiped across the inside of the cheek several times. Cone beam CT scan (CBCT): x-rays create an image of the head, face, teeth, and neck. Participants will stand still or sit on a chair for about 20 minutes while the scanner rotates around the head. Photos of the head and face Offsite participants will provide: Copies of medical and dental records Leftover tissue samples from previous surgery Blood sample or cheek swab

Detailed description

Study Description:

This is a natural history study that will examine craniofacial anomalies that affect the normal development of the facial skeleton, including birth defects and dentofacial developmental abnormalities that express themselves with the growth of the individual. Craniofacial anomalies may be rare and present at birth, such as hemifacial microsomia (1 in every 7500 live births), or common, such as dentofacial deformities including the Habsburg Jaw or mandibular prognathism (1% of the US population) that becomes apparent as a child enters puberty. These are striking disorders as they involve the face and surrounding structures, which is a focal point of self-identity and are intimately tied to quality of life and daily function.

Objectives:

Primary Objective:

To characterize and determine genetic variants of rare and common craniofacial anomalies

Secondary Objectives:

1. To establish a curated craniofacial phenomic/genomic database 2. To collect data related to clinically indicated procedures and care performed at the NIH

Endpoints:

Primary Endpoint:

Phenotypic and genomic characterization of craniofacial anomalies will be performed. Phenotypes from affected subjects and healthy volunteers will be assessed using extensive clinical evaluations, 3D cone-beam computed tomography-based geometric morphometric, cephalometric analyses, and surface morphology. Genetic variants will be identified through genomic analysis and compared with genetic patterns obtained from healthy volunteers.

Secondary Endpoints:

1. To create a database with phenotypic and genetic data, collected from the long-term follow up of subjects (females and males) with craniofacial disorders and healthy volunteers 2. To link the data with their clinical information to understand the craniofacial disorders.

Primary outcome measures

• Database or registry [Time frame: 17 years]

Eligibility criteria

• INCLUSION CRITERIA:

For Subjects:

• Age > 2 to < 100 with craniofacial anomalies/abnormalities. Affected family member (defined as an individual with a demonstrable relationship, any family relationship no matter how distant, with the above subject in the pedigree) who expresses craniofacial anomalies will be classified as a subject.
• Able to provide consent, or in the case of minors, have a legally authorized representative to provide consent.

For Unaffected Family Members:

• These family members are defined as individuals with a demonstrable relationship (any family relationship, no matter how distant) with a proband subject by pedigree who do not express craniofacial anomalies.
• >= 2 years old to <= 100 years old.
• Able to provide consent, or in the case of minors, have a legally authorized representative to provide consent.

For Healthy Volunteers:

• In good general health.

->= 6 years old to < 100 years old.

• Able to provide consent, or in the case of minors, have a legally authorized representative to provide consent.
• Absence of a craniofacial congenital anomaly or malocclusion.
• No family history of a craniofacial syndrome.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

For All Participants:

• A history of facial trauma requiring surgical treatment and facial reconstruction.
• Refusal for both genetic testing and CBCT imaging. Participants must agree to at least one of the two (one or the other is required to participate).

For Healthy Volunteers:

-Female volunteers who are pregnant or nursing.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Observational model

Case-control

Study locations

United States · 1 center

• National Institutes of Health Clinical Center — Bethesda

Publications

• Proffit WR, Fields HW Jr, Moray LJ. Prevalence of malocclusion and orthodontic treatment need in the United States: estimates from the NHANES III survey. Int J Adult Orthodon Orthognath Surg. 1998;13(2):97-106. PMID 9743642
• Cruz RM, Krieger H, Ferreira R, Mah J, Hartsfield J Jr, Oliveira S. Major gene and multifactorial inheritance of mandibular prognathism. Am J Med Genet A. 2008 Jan 1;146A(1):71-7. doi: 10.1002/ajmg.a.32062. PMID 18074368
• Frazier-Bowers S, Rincon-Rodriguez R, Zhou J, Alexander K, Lange E. Evidence of linkage in a Hispanic cohort with a Class III dentofacial phenotype. J Dent Res. 2009 Jan;88(1):56-60. doi: 10.1177/0022034508327817. PMID 19131318
• Lee E, Crayton M, Lee JS, Almpani K. Quantitative Assessment Protocol for Facial Soft Tissue Volumetric Changes with Stereophotogrammetry. J Vis Exp. 2025 Dec 9;(226). doi: 10.3791/69204. PMID 41460808

Identifiers

NCT: NCT02639312 · 160040 · 16-D-0040

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗