Alternative titles; symbols
SNOMEDCT: 82203000; ICD10CM: Q75.4; ORPHA: 861; DO: 0080789;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q32-q33.1 | Treacher Collins syndrome 1 | 154500 | Autosomal dominant | 3 | TCOF1 | 606847 |
A number sign (#) is used with this entry because Treacher Collins syndrome-1 (TCS1) is caused by heterozygous mutation in the 'treacle' gene (TCOF1; 606847) on chromosome 5q32.
Treacher Collins syndrome is a disorder of craniofacial development. The features include downslanting palpebral fissures, coloboma of the eyelid, micrognathia, microtia and other deformity of the ears, hypoplastic zygomatic arches, and macrostomia. Conductive hearing loss and cleft palate are often present (Dixon, 1996).
Genetic Heterogeneity of Treacher Collins Syndrome
Treacher Collins syndrome-2 (TCS2; 613717) is caused by mutation in the POLR1D gene (613715) on chromosome 13q12. Treacher Collins syndrome-3 (TCS3; 248390) is caused by mutation in the POLR1C gene (610060) on chromosome 6p21. Treacher Collins syndrome-4 (TCS4; 618939) is caused by mutation in the POLR1B gene (602000) on chromosome 2q14.
In 2 sisters in an inbred Hutterite kindred, Lowry et al. (1985) described mandibulofacial dysostosis and raised the question of an autosomal recessive form of Treacher Collins syndrome. The palpebral fissures were downward slanting, the outer third of the lower lids showed coloboma, and malar hypoplasia and abnormal pinnae were present. The parents had no signs of mandibulofacial dysostosis. Intraorbital hollowness and prominent ears in the father were considered familial traits. The father and relatives in 3 generations had an apparently isolated dental anomaly characterized by small, widely spaced primary teeth and complete lack of secondary dentition. This appeared to be an independent, autosomal dominant trait.
In a 13-month-old girl who had been diagnosed with Treacher Collins syndrome at 1 month of age, Biebesheimer and Fredrick (2004) reported delayed-onset infantile cataracts.
Teber et al. (2004) identified TCOF1 mutations in 28 of 36 (78%) patients with a clinically unequivocal diagnosis of TCS. The most frequent findings were downward-slanting palpebral fissures, hypoplasia of the zygomatic complex, hypoplasia of the mandible, conductive deafness, any degree of microtia, and atresia of the external ear canal. Although there was inter- and intrafamilial variation ranging from mild to severe, there were no genotype/phenotype correlations. Four clinically unaffected parents were heterozygous for the TCOF1 mutation. Teber et al. (2004) concluded that modifying factors are important for phenotypic expression.
Li et al. (2009) described a patient with Treacher Collins syndrome who had additional features including encephalocele, marked malformation of the eyes, and several extracraniofacial anomalies that involved the thyroid, the thymus, the heart, an accessory spleen, ectopic adrenal gland tissue, and underdeveloped external genitalia.
Vincent et al. (2016) compared the clinical features of their patients with TCS1 with those reported in the literature. In their 70 patients, they reported a frequency of 100% downward-slanting palpebral fissures; 99% malar hypoplasia; 91% conductive deafness; 87% mandibular hypoplasia; 72% had atresia of external ear canal; 71% microtia; 65% coloboma of the lower eyelid; 53% asymmetry; 48% projection of scalp hair onto the lateral cheek; 22% cleft palate; 14% choanal stenosis/atresia; 12% cardiac malformation. Brain, kidney, and limb anomalies were rare.
Treacher Collins syndrome 1 is an autosomal dominant disorder (Dixon, 1996), with variable expression (Edery et al., 1994). Rovin et al. (1964) observed 14 affected persons in 5 generations of a Kentucky family. Intrafamilial variation was wide. Intersib variation was small. There seemed to be a significant increase in affected offspring from affected females and a decrease in affected offspring from affected males. Fazen et al. (1967) described 10 affected persons in 4 generations. (They hyphenated Treacher Collins, which is not proper since Treacher was one of Dr. Collins's given names.) Jones et al. (1975) found evidence of paternal age effect in new mutations for this disorder. Hansen et al. (1996) observed extreme expression of Treacher Collins syndrome in a male infant with arhinia, anotia, absent zygomatic bones, hypoplastic mandibular rami, and bilateral coloboma of iris, choroid plexus, and optic nerve. The Treacher Collins phenotype was mildly expressed in the mother and moderately in a sister. The father had no signs and was not excluded as the father by DNA fingerprinting, thus making homozygosity by descent in the severely affected son very unlikely.
In 10 cases of sporadic Treacher Collins syndrome, Splendore et al. (2003) determined that the pathogenic mutation was of paternal origin in 7 cases and maternal in 3. There was no preferential origin of new mutations in male gametogenesis, and there was no detectable parental age effect.
Based on the finding of Treacher Collins syndrome in 2 Hutterite sisters whose parents were apparently unaffected, Lowry et al. (1985) had suggested either autosomal recessive inheritance or another explanation such as germinal mosaicism, chromosome rearrangement, or delayed mutation. Caluseriu et al. (2013) restudied the 2 Hutterite sisters as well as another Hutterite woman with TCS and found that the patients had classic TCS due to heterozygous mutation in the TCOF1 gene (see MOLECULAR GENETICS). The mutation present in the sisters was also found in their unaffected father, suggesting incomplete penetrance of the disorder.
Differential Diagnosis
Treacher Collins syndrome should not be confused with similar entities such as oculoauriculovertebral dysplasia, or Goldenhar syndrome (164210). Coloboma is present in the lower eyelid in Treacher Collins syndrome and in the upper eyelid in Goldenhar syndrome.
Prenatal Diagnosis
Crane and Beaver (1986) diagnosed this disorder by ultrasonography in a midtrimester fetus. Edwards et al. (1996) used 7 short tandem repeat polymorphic probes closely linked to the TCOF1 locus for prenatal diagnosis of the Treacher Collins syndrome in the fetus of an affected father. A chorionic villus sample was used as a source of fetal DNA. The at-risk fetus, his father, and half sister shared the same haplotype, indicating a very high probability that the fetus inherited the TCOF1 gene. Ultrasound examination at 20 weeks of gestation confirmed the diagnosis.
Arn et al. (1993) suggested that mandibulofacial dysostosis is a heterogeneous entity and that evaluation and counseling of affected persons should be undertaken with caution.
Jabs et al. (1991) studied 8 affected families and concluded that there was no evidence for genetic heterogeneity among the 8 families despite variable expression of the disorder. Edery et al. (1994) provided further evidence of genetic homogeneity using linkage analysis in 8 affected families.
Splendore et al. (2000) found that 2 of 28 families with Treacher Collins did not show apparent pathogenic mutation in the TCOF1 gene (606847). They suggested a possible different mechanism leading to Treacher Collins syndrome or genetic heterogeneity for this condition. The data confirmed the absence of genotype-phenotype correlation and reinforced the conclusion that the apparent anticipation often observed in Treacher Collins syndrome families is due to ascertainment bias.
Wise et al. (1997) postulated that the disorder results from defects in a nucleolar trafficking protein that is critically required during human craniofacial development. Marsh et al. (1998) suggested that the disorder results from aberrant expression of a nucleolar protein. They observed that mutations in the TCOF1 gene (606847) cause truncated proteins to be mislocalized within the cell.
Lungarotti et al. (1987) described changes strikingly similar to those of vitamin A toxicity in both animals and humans in an infant born of a mother who took 2000 IU of vitamin A daily as a supplement during pregnancy. Facial changes resembled those of mandibulofacial dysostosis. Lungarotti et al. (1987) speculated that the mother might have had hypersensitivity to vitamin A.
Calo et al. (2018) demonstrated that genetic perturbations associated with Treacher Collins syndrome lead to relocalization of DDX21 (606357) from the nucleolus to the nucleoplasm, its loss from chromatin targets, and inhibition of ribosomal RNA (rRNA) processing and downregulation of ribosomal protein gene transcription. These effects are cell type-selective, cell autonomous, and involve activation of p53 (191170) tumor suppressor protein. Calo et al. (2018) further showed that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism was not restricted to cranial neural crest cells, as blood formation was also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anemia (105650) disrupted DDX21 localization. At the molecular level, Calo et al. (2018) demonstrated that impaired rRNA synthesis elicits a DNA damage response, and that ribosomal DNA damage results in tissue-selective and dosage-dependent effects on craniofacial development. Calo et al. (2018) concluded that their findings illustrated how disruption in general regulators that compromise nucleolar homeostasis can result in tissue-selective malformations.
Balestrazzi et al. (1983) described Treacher Collins syndrome in a girl with a de novo balanced translocation t(5;13)(q11;p11). The level of hexosaminidase B was decreased; the HEXB locus is thought to be at 5q13. The possibility that the Treacher Collins locus is on 5q was raised by these findings. Arn et al. (1993) described a mild but entirely typical case of Treacher Collins syndrome in association with a small interstitial deletion of 3p: 46,XY,del(3)(p23p24.12). By the time Arn et al. (1993) reported this case, the TCS locus in familial cases had been assigned to 5q31.3.
Because of the report by Balestrazzi et al. (1983) of a de novo balanced translocation involving chromosome 5 in a girl with the Treacher Collins syndrome, Jabs et al. (1991) studied linkage with chromosome 5 markers in 8 families with the disorder. They demonstrated positive lod scores with 4 loci which mapped to 5q31.3-q33.3. The most closely linked locus was D5S210, which is associated with a microsatellite polymorphism; maximum lod score = 8.65 at theta = 0.02. Dixon et al. (1991) demonstrated linkage of the TCS locus to markers in the region 5q31-q34. They concluded that it probably lies in the interval between the GRL locus (138040) and the anonymous marker D5S22. Dixon et al. (1992) refined the localization by linkage studies using hypervariable microsatellite markers and by fluorescence in situ hybridization. They concluded that the gene is in 5q32-q33.2 and described flanking markers. By linkage to 3 microsatellite markers, Dixon et al. (1993) further refined the assignment to 5q32-q33.1. Fluorescence in situ hybridization of a linked clone indicated that TCOF1 is flanked distally by SPARC (182120). Studying 8 independent families and using 12 microsatellite DNA markers at distal 5q, Edery et al. (1994) placed the TCOF1 locus between D5S434 and D5S412, thus corroborating the earlier linkage analyses.
Dixon (1996) reviewed the clinical and molecular features of Treacher Collins syndrome. A total of 20 mutations in the TCOF1 gene (606847) had been identified, of which 2 were nonsense mutations, 5 were insertions, 11 were deletions, and 2 were splicing mutations. All of the mutations observed resulted in introduction of premature termination codons into the reading frame, suggesting haploinsufficiency as the molecular mechanism underlying the disorder.
Edwards et al. (1997) reported 25 previously undescribed mutations throughout the TCOF1 gene in patients with Treacher Collins syndrome. This brought the total reported mutations to 35, which represented a detection rate of 60%. All but one of the mutations resulted in the introduction of a premature termination codon into the predicted protein. The mutational spectrum supported the hypothesis that TCS results from haploinsufficiency.
In a 5-year-old girl with classic findings of Treacher Collins syndrome and craniosynostosis, choanal atresia, and esophageal regurgitation, Horiuchi et al. (2004) identified a de novo truncating mutation in exon 17 of the TCOF1 gene (606847.0007). The authors stated that this was the first case of Treacher Collins syndrome with molecular confirmation and craniosynostosis.
Li et al. (2009) identified a pathogenic mutation in the TCOF1 gene (606847.0009) in a patient with Treacher Collins syndrome who had novel craniofacial and extracranial features.
Bowman et al. (2012) identified pathogenic sequence variants in the TCOF1 gene in 92 (50.5%) of 182 unrelated patients with a clinical diagnosis consistent with Treacher Collins syndrome. Of those with a sequence change, 57% had a frameshift or mutation disrupting the start codon, 23% had a nonsense mutation, 16% had a splice site mutation, and 4% had a missense mutation. In addition, 5.2% of patients had an intragenic deletion of the TCOF1 gene. Thus, the majority of TCOF1 mutations lead to a loss of protein function and haploinsufficiency.
In 2 Hutterite sisters with Treacher Collins syndrome, originally reported by Lowry et al. (1985) and thought to have an autosomal recessive form of the disorder, and in another Hutterite woman with TCS, Caluseriu et al. (2013) identified heterozygosity for 2 mutations in the TCOF1 gene, a previously reported 4-bp deletion (606847.0010) and a novel 1-bp duplication (606847.0011). The deletion mutation, which was found in both sisters, was also present in their unaffected father, supporting incomplete penetrance of the disorder.
Vincent et al. (2016) performed extensive clinical and molecular studies in 146 Treacher Collins patients. They identified a mutation in TCOF1 in 92 of 146 (63%) and a pathogenic variant in POLR1D in 9 of 146 (6%). No patient had a variant in POL1C. Among the atypical negative patients (with intellectual disability or microcephaly), Vincent et al. (2016) identified 4 carrying a mutation in EFTUD2 (603892) and 2 with a 5q32 deletion encompassing TCOF1 and CAMK2A.
Caluseriu et al. (2013) stated that the incidence of Treacher Collins syndrome is thought to be 1 in 50,000 individuals.
Dixon et al. (1991) identified a family in which a mother and 2 children who had the Treacher Collins syndrome also had a balanced translocation t(6;16)(p21.31;p13.11), which suggested the possibility that the mutation might be located at one of the translocation breakpoints. By in situ hybridization, they defined probes located at these breakpoints and then, by linkage analysis using these chromosome 6 and chromosome 16 probes in 12 other families with multiple cases of the Treacher Collins syndrome, excluded the TCS locus from proximity to either translocation breakpoint. The data were confirmed when a third affected child, who did not exhibit the translocation, was born to the mother of their index family.
Jabs et al. (1991) observed a patient with severe manifestations of TCS and a de novo chromosomal deletion in region 4p15.32-p14. Several previously identified anonymous DNA sequences were mapped to the deleted region and several were excluded from the region, on the basis of being deleted or not deleted, respectively. Linkage analysis between 3 of these markers and TCS in 8 multiplex families excluded the TCS gene from this region.
Sulik et al. (1987) suggested that the malformations produced in mice by isotretinoin represent a useful model for the pathogenesis of Treacher Collins syndrome.
Richter et al. (2010) used Tcof1 mutant mice to dissect the developmental mechanisms underlying congenital hearing loss. Effective cavitation of the middle ear was intimately linked to growth of the auditory bulla, the neural crest cell-derived structure that encapsulates all middle ear components, and defects in these processes had a profoundly detrimental effect on hearing.
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