# 618939

TREACHER COLLINS SYNDROME 4; TCS4


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
2q14.1 Treacher-Collins syndrome 4 618939 AD 3 POLR1B 602000
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal dominant
HEAD & NECK
Face
- Malar hypoplasia
- Mandibular hypoplasia
- Facial asymmetry
- Projection of scalp hair onto lateral cheek (uncommon)
Ears
- Conductive deafness, bilateral
- Atresia of external ear canal, unilateral or bilateral
- Microtia
Eyes
- Downslanting palpebral fissures
- Coloboma of lower lid
Nose
- Choanal atresia
- Choanal stenosis
Mouth
- Cleft palate
MISCELLANEOUS
- Intubation or tracheostoma in neonatal period
- Nasogastric or gastrostomy tube feedings in neonatal period
- Clinical variability
MOLECULAR BASIS
- Caused by mutation in the RNA polymerase I, subunit-B gene (POLR1B, 602000.0001)

TEXT

A number sign (#) is used with this entry because of evidence that Treacher Collins syndrome-4 (TCS4) is caused by heterozygous mutation in the POLR1B gene (602000) on chromosome 2q14.


Description

Treacher Collins syndrome-4 (TCS4) is characterized by craniofacial dysmorphisms including downslanting palpebral fissures, malar and mandibular hypoplasia, and microtia. Most patients have conductive deafness with atretic external ear canals. Choanal atresia and cleft palate have also been observed (Sanchez et al., 2020).


Clinical Features

Sanchez et al. (2020) reported 6 patients from 5 families with Treacher Collins syndrome and mutations in the POLR1B gene. The patients all exhibited downslanting palpebral fissures and malar hypoplasia, and most also had mandibular hypoplasia as well as microtia, atresia of the external ear canal, and conductive deafness. Facial asymmetry was present in 3 patients, 3 had cleft palate, and 2 had choanal atresia. In the neonatal period, 5 of the 6 patients required nasogastric or gastrostomy tube feedings, and 3 underwent intubation or tracheostoma.


Inheritance

The transmission pattern of TCS4 in 2 families reported by Sanchez et al. (2020) was consistent with autosomal dominant inheritance; in 1 family the proband inherited the mutation from her mosaic father. The heterozygous mutations in 3 other patients occurred de novo.


Molecular Genetics

By trio exome sequencing in 6 patients from a previously described TCS cohort (Vincent et al., 2016) who were negative for mutation in known mandibulofacial dysostosis-associated genes, Sanchez et al. (2020) identified 2 probands with heterozygous missense mutations in the POLR1B gene: a de novo R1003C substitution (602000.0001) in patient 1, and an S682R substitution (602000.0003) in patient 2 and her mother (patient 3). By international collaboration, including GeneMatcher in 1 case, the authors ascertained 3 more patients with TCS and mutations in the POLR1B gene, including 2 more patients (patients 4 and 6) with the R1003C variant. The remaining patient (patient 5) was heterozygous for an R1003S substitution (602000.0002) that was also found to be present in mosaicism in her mildly affected father.


REFERENCES

  1. Sanchez, E., Laplace-Builhe, B., Mau-Them, F. T., Richard, E., Goldenberg, A., Toler, T. L., Guignard, T., Gatinois, V., Vincent, M., Blanchet, C., Boland, A., Bihoreau, M. T., and 16 others. POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Genet. Med. 22: 547-556, 2020. [PubMed: 31649276, related citations] [Full Text]

  2. Vincent, M., Genevieve, D., Ostertag, A., Marlin, S., Lacombe, D., Martin-Coignard, D., Coubes, C., David, A., Lyonnet, S., Vilain, C., Dieux-Coeslier, A., Manouvrier, S., and 44 others. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet. Med. 18: 49-56, 2016. Note: Erratum: Genet. Med. 17: 686 only, 2015. [PubMed: 25790162, related citations] [Full Text]


Creation Date:
Marla J. F. O'Neill : 07/06/2020
carol : 07/08/2020
carol : 07/07/2020
alopez : 07/06/2020

# 618939

TREACHER COLLINS SYNDROME 4; TCS4


ORPHA: 861;   DO: 0080792;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
2q14.1 Treacher-Collins syndrome 4 618939 Autosomal dominant 3 POLR1B 602000

TEXT

A number sign (#) is used with this entry because of evidence that Treacher Collins syndrome-4 (TCS4) is caused by heterozygous mutation in the POLR1B gene (602000) on chromosome 2q14.


Description

Treacher Collins syndrome-4 (TCS4) is characterized by craniofacial dysmorphisms including downslanting palpebral fissures, malar and mandibular hypoplasia, and microtia. Most patients have conductive deafness with atretic external ear canals. Choanal atresia and cleft palate have also been observed (Sanchez et al., 2020).


Clinical Features

Sanchez et al. (2020) reported 6 patients from 5 families with Treacher Collins syndrome and mutations in the POLR1B gene. The patients all exhibited downslanting palpebral fissures and malar hypoplasia, and most also had mandibular hypoplasia as well as microtia, atresia of the external ear canal, and conductive deafness. Facial asymmetry was present in 3 patients, 3 had cleft palate, and 2 had choanal atresia. In the neonatal period, 5 of the 6 patients required nasogastric or gastrostomy tube feedings, and 3 underwent intubation or tracheostoma.


Inheritance

The transmission pattern of TCS4 in 2 families reported by Sanchez et al. (2020) was consistent with autosomal dominant inheritance; in 1 family the proband inherited the mutation from her mosaic father. The heterozygous mutations in 3 other patients occurred de novo.


Molecular Genetics

By trio exome sequencing in 6 patients from a previously described TCS cohort (Vincent et al., 2016) who were negative for mutation in known mandibulofacial dysostosis-associated genes, Sanchez et al. (2020) identified 2 probands with heterozygous missense mutations in the POLR1B gene: a de novo R1003C substitution (602000.0001) in patient 1, and an S682R substitution (602000.0003) in patient 2 and her mother (patient 3). By international collaboration, including GeneMatcher in 1 case, the authors ascertained 3 more patients with TCS and mutations in the POLR1B gene, including 2 more patients (patients 4 and 6) with the R1003C variant. The remaining patient (patient 5) was heterozygous for an R1003S substitution (602000.0002) that was also found to be present in mosaicism in her mildly affected father.


REFERENCES

  1. Sanchez, E., Laplace-Builhe, B., Mau-Them, F. T., Richard, E., Goldenberg, A., Toler, T. L., Guignard, T., Gatinois, V., Vincent, M., Blanchet, C., Boland, A., Bihoreau, M. T., and 16 others. POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. Genet. Med. 22: 547-556, 2020. [PubMed: 31649276] [Full Text: https://doi.org/10.1038/s41436-019-0669-9]

  2. Vincent, M., Genevieve, D., Ostertag, A., Marlin, S., Lacombe, D., Martin-Coignard, D., Coubes, C., David, A., Lyonnet, S., Vilain, C., Dieux-Coeslier, A., Manouvrier, S., and 44 others. Treacher Collins syndrome: a clinical and molecular study based on a large series of patients. Genet. Med. 18: 49-56, 2016. Note: Erratum: Genet. Med. 17: 686 only, 2015. [PubMed: 25790162] [Full Text: https://doi.org/10.1038/gim.2015.29]


Creation Date:
Marla J. F. O'Neill : 07/06/2020

Edit History:
carol : 07/08/2020
carol : 07/07/2020
alopez : 07/06/2020