Treacher Collins syndrome

What is Treacher Collins syndrome?

Treacher Collins is a genetic disorder that occurs in around 1 in every 50,000 births., making it a rare disease.

Symptoms may vary considerably between individuals but the condition mainly affects the development of bones and tissue in the face.

This syndrome is also known as:
Franceschetti syndrome Mandibulofacial Dysostosis, Treacher Collins Type, Autosomal Recessive MFD1 TCS

What gene changes cause Treacher Collins syndrome?

Mutations in the TCOF1 gene cause 90-95% of the cases of the syndrome. The remaining cases are caused by mutations to the POLR1C, POLR1B, POLR1D genes. The disease is inherited in 40% of cases, with the majority being the result of a spontaneous mutation.

n some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation which occurs during the reproductive process.

However Treacher Collins in the family may make future babies more susceptible to the condition.

What are the main symptoms of Treacher Collins syndrome?

The main symptoms of the syndrome mainly relate to the face.

These unique facial features include a lazy eye, sparse or absent eyelashes, abnormal or small cheekbones, a smaller lower jaw and chin.
Ears may be smaller, malformed or even absent and hearing loss is an issue in individuals with the syndrome. As is a cleft palate.

Individuals may also have fewer teeth, and misaligned, discolored teeth.

Speech and motor development delay are not uncommon in individuals with the syndrome as well.

Possible clinical traits/features:
Malar flattening, Lower eyelid coloboma, Downslanted palpebral fissures, Abnormality of the outer ear, Cleft palate, Autosomal recessive inheritance, Micrognathia, Mandibulofacial dysostosis

How does someone get tested for Treacher Collins syndrome?

The initial testing for Treacher Collins syndrome can begin with facial analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the need for further testing. A consultation with a genetic counselor and then a geneticist will follow.

Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.

Medical information on Treacher Collins syndrome

Treacher Collins syndrome is a craniofacial development disorder with a variable phenotype that can include hypoplasia of the zygomatic bones and mandible, microtia and other ear abnormalities, conductive hearing loss, and cleft palate. Treacher Collins syndrome 1 is caused by heterozygous mutations in the TCOF1 gene on chromosome 5q32-q33.

The main features are symmetrical facial abnormalities consisting of malformed ears, malar hypoplasia, a coloboma of the lateral part of the lower lid, mandibular hypoplasia, a cleft palate, and sensorineural deafness. The syndrome must be differentiated from Goldenhar syndrome, Nager syndrome and other acrofacial dysostoses.

This well-documented autosomal dominant condition can be very variable (see Dixon et al., 1994).

Autosomal dominant inheritance is well-established, however Richieri-Costa et al., (1993) reported two affected brothers with apparently unaffected parents and one other affected girl with first-cousin parents. They reviewed other possible autosomal recessive cases in the literature. It is difficult to rule out incomplete expression or germinal mosaicism iand namedn these rare families.

Dixon et al., (1996) isolated the gene TCOF1 encoding Treacle. Mutations resulted in premature termination of the protein.
Arn et al., (1993) reported a 21-month-old girl with mild mandibulofacial dysostosis and a deletion of 3p24.1. Deletions at 13q12.2 involving subunits of RNA polymerases I and III can also cause this phenotype (Dauwerse et al., 2011). Most of their cases were deletions of POLR1D, but they also report homozygous mutations of POLR1C as a cause - see also Schaefer et al., (2014) for the recessive type with mutations in POLR1D.

Gladwin et al., (1996) reported further mutations leading to haploinsufficiency. Additional mutations were reported by Splendore et al., (2002).

Hansen et al., (1996) reported a severely affected case with arhinia and uveal colobomas together with almost absent ears. The mother was mildly affected, the sister was a classical case, and the father was apparently unaffected.

Splendore et al., (2003) showed that seven of 10 sporadic mutations were paternal in origin.

Thirteen families were reported by Dixon et al., (2004) illustrating the usefulness of molecular diagnosis, especially in those cases where clinical diagnosis may be equivocal and when prenatal diagnosis is required.

There were similar findings in the report by Teber et al., (2004).

A clinically unaffected mother of a ""sporadic"" case of Treacher Collins was shown by Shoo et al., (2004) to be mosaic for the mutation.

Robb et al., (1991) reported a case with a tracheoesophageal fistula, a rectovaginal fistula, and anal atresia, and the case reported by Horiuchi et al., (2004) had esophageal regurgitation, craniosynostosis, and choanal atresia. This patient had a novel nonsense TCOF1 mutation.

A patient with a micropenis and male pseudohermaphroditism was reported by Writzl et al., (2008).

The patient reported by Li et al., (2009) had a Nt4365 delA mutation and a most unusual phenotype. Facially, there was an aberrant anterior hairline, with bitemporal rectangular extensions of hair into the preauricular region, and a shallow groove that ran from this region to the corner of the mouth. The eyebrows were widely spaced and besides the lid colobomas, there was an iris coloboma. The nose was prominent with poorly formed nares. The external genitalia were hypoplastic; there was an ASD, patent ductus, displacement of the thyroid and thymus; and a small accessory spleen. There was retinal dysplasia and a choroidal coloboma.

Note the two extraordinary severe cases reported by Bauer et al., (2013). One had a TCOF1 mutation (the other could not be tested). Both looked like the result of amniotic bands, and one had an encephalocele.

Vincent et al., (2015) described a series of 146 patients with Treacher Collins syndrome. Sixty-three percent of patients had a mutation in TCOF1, 6% in POLR1D, and none in POLR1C. The most commonly occurring features in patients with mutations in TCOF1 were downward-slanting palpebral fissures, malar hypoplasia, and conductive deafness. Mandibular hypoplasia, lower eyelid coloboma, and facial asymmetry were less frequent. Patients with mutations in POLR1D had mild features and no life-threatening complications. Congenital cardiac defects occurred in 8% of patients with a TCOF1 mutation. Among the patients with intellectual disability and/or microcephaly, four patients carried a mutation in EFTUD2, and two patients had a 5q32 deletion encompassing TCOF1 and CAMK2A.

* This information is courtesy of the L M D.
If you find a mistake or would like to contribute additional information, please email us at: [email protected]

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