Treacher Collins syndrome (TCS) is caused by genetic mutations that disrupt how facial bones and tissues develop during early pregnancy. Specifically, mutations in one of three genes interfere with the production of ribosomes, the tiny cellular machines that build proteins, in the very cells responsible for forming the face. The condition affects roughly 1 in 50,000 live births, and about 60 percent of cases arise spontaneously in families with no prior history of the disorder.
The Three Genes Involved
The most common cause is a mutation in a gene called TCOF1, which produces a protein called Treacle. This protein plays a direct role in building ribosomes inside the cells that eventually form facial structures. When TCOF1 is mutated, those cells can’t produce enough ribosomes to keep up with the rapid growth demands of early embryonic development.
Two other genes, POLR1C and POLR1D, can also cause the syndrome. These genes provide instructions for components of the molecular machinery that reads DNA to begin the ribosome-building process. When either is mutated, the result is the same: not enough ribosomes, not enough protein production, and ultimately, underdeveloped facial bones and tissues.
How a Ribosome Shortage Affects the Face
To understand why a problem with ribosomes leads specifically to facial abnormalities, you need to know about neural crest cells. These are a temporary population of stem cells that form very early in embryonic development, roughly during the first few weeks of pregnancy. They migrate from the developing brain and spinal cord into the face and jaw area, where they multiply rapidly and eventually become the bones, cartilage, and connective tissue of the skull and face.
Neural crest cells are unusually demanding. They divide quickly and need enormous amounts of protein to fuel that growth, which means they depend heavily on ribosomes. When the Treacle protein is missing or deficient, ribosome production drops in exactly these cells at exactly the wrong time. Without enough ribosomes, the neural crest cells can’t keep pace. Many stop dividing. Others undergo programmed cell death, a process called apoptosis. Research published in PNAS showed that in embryos with only one working copy of the TCOF1 gene, there were significantly fewer ribosomes in the neural tissue and a measurable reduction in migrating neural crest cells. The shortage of neural crest cells is then compounded by their reduced ability to multiply once they reach the face.
The end result is hypoplasia, or underdevelopment, of the bones and soft tissues that neural crest cells were supposed to build. This is why TCS affects the cheekbones, jaw, ears, and eye area so specifically. Other parts of the body, which don’t rely on neural crest cells to the same degree or at the same critical moment, develop normally.
Inheritance Patterns
How TCS is passed down depends on which gene is involved. Mutations in TCOF1 or POLR1D follow an autosomal dominant pattern, meaning a child only needs one copy of the mutated gene (from one parent) to develop the condition. A parent with TCS has a 50 percent chance of passing the mutation to each child.
Mutations in POLR1C follow an autosomal recessive pattern. Both parents must carry a copy of the mutated gene, and the child must inherit both copies to be affected. Parents who each carry one copy typically show no symptoms themselves.
The 60 percent figure is important here: the majority of TCS cases involving TCOF1 or POLR1D are caused by new, spontaneous mutations. The child is the first person in the family to have the condition. These new mutations happen randomly during the formation of the egg or sperm, or very early in embryonic development. There is nothing a parent did or didn’t do to cause them.
Severity Varies Widely
One of the more puzzling aspects of TCS is that the same mutation can produce vastly different outcomes, even within the same family. Some people have features so mild they go undiagnosed for years, while a sibling with the identical genetic change may have significant jaw underdevelopment or hearing loss. This variability is not fully understood, but it likely relates to differences in how many neural crest cells survive and successfully migrate during the narrow developmental window when the face is forming. Small differences in timing, cellular environment, or the activity of other genes can tip the balance.
What TCS Looks Like at Birth
The facial features associated with TCS are present at birth and reflect the specific bones and structures that neural crest cells failed to fully build. The most recognizable signs include underdeveloped cheekbones (which can make the face appear flat or sunken), a small or receding lower jaw, downward-slanting eyes, and abnormalities of the outer ears ranging from small size to near-complete absence. The ear canal may be narrowed or missing, which often causes conductive hearing loss since sound can’t travel through to the inner ear normally. Cleft palate occurs in some cases. Intelligence and brain development are not affected.
Detection Before Birth
TCS can sometimes be identified on prenatal ultrasound, particularly in the second trimester when facial structures become visible. Markers that may raise suspicion include an unusually small jaw (micrognathia), underdeveloped or absent outer ears (microtia), a wide mouth (macrostomia), and the characteristic downward slant of the eye openings. Three-dimensional and four-dimensional ultrasound have improved the ability to visualize these features. When TCS is suspected based on imaging, genetic testing through amniocentesis or chorionic villus sampling can confirm the diagnosis by identifying mutations in TCOF1, POLR1C, or POLR1D.
For families with a known history of TCS, preconception genetic counseling and early prenatal testing can identify whether the specific family mutation has been passed on, often before any physical features would be visible on ultrasound.