Researchers Pinpoint Genetic Pathway of Rare Facial Malformation in Children

Three sculls small2

3D CT scan of child with ACS. Lower jaw is small and malformed (left); same aged child with normal jaw (middle); lower jaw of child with ACS inverted over upper jaw of normal skull (right)

Two Distinct Mutations Cause “Question Mark Ears Syndrome,” Study Finds

Researchers at Seattle Children’s Research Institute and their collaborators have discovered a pair of defective genes that cause a rare congenital malformation syndrome that can make it impossible for the child to breathe or eat properly without reparative surgery. In a study led by Michael L. Cunningham, MD, PhD, medical director of the Seattle Children’s Hospital’s Craniofacial Center, a research team pinpointed two genes known as PLCB4 and GNAI3 in a genetic pathway that affects children with auriculocondylar syndrome (ACS). ACS is a rare disorder in which a child’s bottom jaw develops as an upper jaw and, in some cases, incorrectly fuses to the base of the skull.

As part of the study, the DNA of five children with similar facial features characteristic of ACS was sequenced. Cunningham and his colleague Mark J. Rieder, PhD (University of Washington) used exome sequencing, selectively sequencing those regions of the patients’ DNA believed to constitute the majority of disease-causing mutations. The study, to be published in the May edition of American Journal of Human Genetics, is one of the first genomic studies to identify causative mutations in two genes for the same disorder in the same pathway in a single analysis, Dr. Cunningham said.

While children with ACS have normal cognitive development, severe cases may require an immediate tracheostomy, feeding tubes, and ultimately extensive facial reconstructive surgery to allow them to eat and breathe properly.

"Although ACS is rare, our findings suggest that these genes may also play a role in more common disorders of the jaw and ears,” said Dr. Cunningham, who is also chief of the division of craniofacial medicine and professor of pediatrics in the Department of Pediatrics at the University of Washington School of Medicine. “It’s possible that more common jaw problems, like the lower jaw abnormality known as Robin sequence and other skull and facial abnormalities such as craniofacial microsomia, are also caused by genes in this pathway.”

ACS, a syndrome first described by scientists in 1978, is believed to affect less than one in 50,000 births, though the precise frequency is not known. It is not uncommon for the condition to be misdiagnosed or for diagnosis to be delayed. According to Dr. Cunningham it was the precision of case choice that allowed this discovery.

Of the five cases studied, two of the parents did not have this condition but were carriers for the mutation. “Now that we know the genetic pathway for ACS, we will be able to better identify and counsel people who have normal facial appearances but carry these genes, about the likelihood of passing on this mutation to their children,’’ Dr. Cunningham said.

Dr. Cunningham’s co-authors were: Mark J. Rieder, University of Washington; Anne V. Hing, Seattle Children’s Research Institute; Glenn E. Green, University of Michigan; Sarah S. Park, Seattle Children’s Research Institute; Brendan D. Stamper, Seattle Children’s Research Institute; Christopher T. Gordon, Universite Paris Descartes; Jason M. Johnson, Massachusetts General Hospital/Harvard Medical School; Christopher M. Cunniff, University of Arizona; Joshua D. Smith, University of Washington; Sarah B. Emery, University of Michigan; Stanislas Lyonnet, Universite Paris Descartes; Jeanne Amiel, University Paris Descartes; Muriel Holder, Hôpital Necker-Enfants Malades; Andrew A. Heggie, Royal Children’s Hospital of Melbourne; Michael J. Bamshad, University of Washington, Seattle Children’s Hospital; Deborah A. Nickerson, University of Washington; Timothy C. Cox, University of Washington, Seattle Children's Research Institute; Jeremy A. Horst, University of California, San Francisco.

About Seattle Children’s

Seattle Children’s Hospital, Foundation and Research Institute together deliver superior patient care, advance new discoveries and treatments through pediatric research, and raise funds to create better futures for patients. Consistently ranked as one of the top 10 children’s hospitals in the country by U.S. News & World Report, Seattle Children’s Hospital specializes in meeting the unique physical, emotional and developmental needs of children from infancy through young adulthood. Through the collaboration of physicians in nearly 60 pediatric subspecialties, Seattle Children’s Hospital provides inpatient, outpatient, diagnostic, surgical, rehabilitative, behavioral, and emergency and outreach services to families from around the world.

Located in downtown Seattle’s biotech corridor, Seattle Children’s Research Institute is pushing the boundaries of medical research to find cures for pediatric diseases and improve outcomes for children all over the world. Internationally recognized investigators and staff at the research institute are advancing new discoveries in cancer, genetics, immunology, pathology, infectious disease, injury prevention, bioethics and much more.

Seattle Children’s Hospital and Research Foundation and Seattle Children’s Hospital Guild Association work together to gather community support and raise funds for uncompensated care, clinical care and research. The foundation receives nearly 80,000 gifts each year, from lemonade stand proceeds to corporate sponsorships. Seattle Children’s Hospital Guild Association is the largest all-volunteer fundraising network for any hospital in the country, serving as the umbrella organization for 450 groups of people who turn an activity they love into a fundraiser. Support from the foundation and guild association makes it possible for Seattle Children’s care and research teams to improve the health and well-being of all kids.

For more information, visit or follow us on Twitter, Facebook and Instagram.