Treacher Collins syndrome (TCS) is a rare inherited disorder that impacts the development of bones and soft tissues in the face. It is characterized by distinct physical features involving the ears, eyes, cheekbones, and jaw. Affected individuals often have underdeveloped cheekbones, a small lower jaw, and ears that are small, rotated, or even absent. These differences can lead to challenges with breathing, feeding, and hearing, though intelligence is typically unaffected. The underlying cause is a mutation in a specific gene.
The Genes Behind Treacher Collins Syndrome
The vast majority of Treacher Collins syndrome cases, between 81 and 93 percent, are linked to mutations in a single gene known as TCOF1. This gene provides the instructions for making a protein called Treacle, which is active during the early stages of embryonic development. Treacle plays a part in the creation of ribosomal RNA (rRNA) within the cell nucleus.
Ribosomal RNA is a molecule that helps assemble proteins, a process that is fundamental for cell function and survival. When a mutation occurs in the TCOF1 gene, it usually leads to a reduction in the amount of functional Treacle protein that is produced. This deficiency disrupts the production of rRNA, which is thought to trigger the self-destruction, or apoptosis, of certain cells.
The critical event happens during the formation of the face, specifically in the migratory population of cells called neural crest cells. These cells are the precursors for most of the bone, cartilage, and connective tissue in the head and face. The abnormal cell death caused by the reduced Treacle protein particularly affects the neural crest cells that form the first and second pharyngeal arches, which are responsible for developing the cheekbones, jaws, and ears.
A small percentage of cases are caused by mutations in other genes, primarily POLR1D and POLR1C, which account for about two percent of all diagnoses. Like TCOF1, these genes are involved in the process of making ribosomal components. A change in any of these genes interferes with the biological machinery needed for proper facial development during the prenatal period.
Understanding Inheritance Patterns
Treacher Collins syndrome follows different patterns of inheritance, though the most common mode is autosomal dominant. Autosomal dominant inheritance means that a person only needs one copy of the altered gene in each cell to develop the condition. If a parent has the syndrome, there is a 50 percent chance of passing the gene variant to each child.
Despite the dominant inheritance pattern, many cases occur without any history of the condition in the family. About 55 to 61 percent of autosomal dominant cases result from a de novo, or spontaneous, mutation. A de novo mutation is a new change in the gene that occurs for the first time in the affected individual, meaning it was not inherited from either parent.
The less frequent form of the syndrome is inherited in an autosomal recessive pattern, which is typically associated with mutations in the POLR1C gene. For a recessive condition to occur, the child must inherit two copies of the altered gene, one from each parent. Parents who carry one copy of the recessive gene are generally unaffected themselves, but they have a 25 percent chance of having a child with the syndrome with each pregnancy.
Implications for Families and Genetic Counseling
The knowledge that Treacher Collins syndrome is genetic allows families to seek specialized guidance through genetic counseling. Genetic counselors are trained to interpret the results of genetic testing and explain the likelihood of the syndrome being passed down or appearing again. This is especially helpful for prospective parents who have an affected child or a family history of the condition, as it helps them understand their reproductive options.
Genetic testing can be performed to identify the specific mutation in the TCOF1, POLR1D, or POLR1C genes. For families where a mutation has been identified, testing can be used for carrier screening in unaffected relatives or for prenatal diagnosis during a pregnancy. Prenatal testing allows for early detection, which can help a medical team prepare for the potential needs of the newborn.
An important concept discussed in counseling is variable expressivity, which is common in Treacher Collins syndrome. This term describes how the severity of the symptoms can vary significantly, even among people who have the exact same gene mutation. One parent might have a very mild, undiagnosed form of the syndrome, while their child may have severe symptoms requiring extensive medical intervention.