Treacher Collins Syndrome (TCS) is a genetic disorder caused by DNA changes that affect how the face develops before birth. It is classified as a congenital craniofacial malformation, meaning structural differences of the head and face are present at birth. TCS, also known as mandibulofacial dysostosis, is a rare disease, affecting an estimated one in every 50,000 newborns worldwide.
Core Characteristics of Treacher Collins Syndrome
The physical characteristics of TCS are bilateral and symmetrical, affecting structures derived from the first and second pharyngeal arches during embryonic development. Individuals present with underdeveloped cheekbones (malar hypoplasia), giving the cheeks a sunken appearance. The lower jaw and chin are often very small (micrognathia), which can lead to breathing and feeding difficulties in infants.
Eye anomalies include a downward slant and a notch in the lower eyelids, known as an eyelid coloboma. The ears are frequently affected, often being small, unusually formed, or absent (microtia). Malformations of the middle ear bones often accompany these external differences, resulting in conductive hearing loss in about half of all affected individuals.
The Specific Genes Responsible
The vast majority of TCS cases are linked to a pathogenic variant in the TCOF1 gene, located on chromosome 5. This gene provides instructions to make the treacle protein. Treacle is active in the nucleolus, playing a significant role in producing ribosomal RNA (rRNA), which is necessary for creating ribosomes.
Ribosome biogenesis is a crucial process. When the TCOF1 gene is mutated, it reduces functional treacle protein, disrupting ribosome production. This disruption is a ribosomopathy, triggering the self-destruction of certain cells, primarily neural crest cells that form the craniofacial skeleton.
While TCOF1 accounts for 81 to 93 percent of cases, POLR1C and POLR1D are less common causes. These genes produce proteins that are subunits of RNA polymerases, which are also directly involved in ribosomal RNA synthesis. Variants in POLR1C and POLR1D lead to the same deficiency in ribosome biogenesis, resulting in the characteristic facial development differences seen in TCS.
Mechanisms of Inheritance
The primary inheritance pattern for Treacher Collins Syndrome is autosomal dominant. This means a person only needs to inherit one copy of the altered gene from either parent to develop the condition. An individual with the autosomal dominant form of TCS has a 50 percent chance of passing the pathogenic variant to each child.
Approximately 60 percent of cases result from a de novo mutation, meaning the genetic change occurs spontaneously and is not inherited. The affected individual is the first in their family to have the syndrome in these instances. The severity of the syndrome can vary greatly, even within the same family, due to variable expressivity.
The likelihood that a person with the gene variant will show signs of the condition is high, estimated at around 90 percent penetrance. For less common gene variants, such as those in POLR1C, the inheritance pattern is typically autosomal recessive. This requires a child to inherit two copies of the altered gene, one from each parent, who are usually unaffected carriers.
Genetic Confirmation and Family Planning
The clinical diagnosis of TCS is often based on characteristic physical features, but genetic testing provides confirmation. Molecular testing, specifically DNA sequencing, identifies the pathogenic variant in associated genes (TCOF1, POLR1C, or POLR1D). Identifying the specific gene confirms the diagnosis and clarifies the mode of inheritance.
Genetic counseling plays a central role, providing a detailed risk assessment and explaining the probability of passing the condition on to future children. This information is crucial for family planning, allowing parents to understand reproductive options like prenatal diagnosis or preimplantation genetic testing.