Treacher Collins Syndrome

Treacher Collins syndrome, also known as mandibulofacial dysostosis or Franceschetti-Zwahlen-Klein syndrome, is a rare autosomal dominant disorder characterized by congenital abnormalities of the eyes, ears and mandible, and is considered a neonatal emergency because the tongue may obstruct the airway^1,2. Antenatal sonographic diagnosis of Treacher Collins syndrome using conventional 2D ultrasound has been reported^3,4. Three-Dimensional ultrasound can reveal the typical malformations in the late second-third trimester.^5,6

Q75.4

1 in 10,000-50,000 individuals in the general population, with no difference between male or female sex.

TCS is characterized by abnormal or disruptive development of the first and second branchial arches caused by a mutation in genes on chromosome 5. The mutations causing TCS are responsible for excessive neuroepithelial apoptosis during early embryogenesis, affecting the development of neural crest cells involving the first and second branchial arches, which are crucial in the development of facial bones and tissue.
The mal/underdevelopment syndrome affects the zygomatic complex, orbit, eye, palate mandible and ears.

TCS is caused by a mutation in the TCOF1 (78–93%) and POLR1C or POLR1D genes (8%). TCOF1, whose locus is on chromosome 5, encodes a nucleolar phosphoprotein termed Treacle. In approximately 60% of cases, TCS is caused by a new mutation. More than 130 distinct mutations have been identified thus far. 

Infants with TCS show hypoplasia of the facial bones, particularly the mandible (78% of cases) and zygomatic complex (81%), or absent cheekbones (malars), causing a typical flattening of this area of the face. The mandible is incompletely developed (micrognathia).  Hypoplasia of the facial bones may result in dental malocclusion, with anterior open bite and scarce, malpositioned and widely spaced teeth. In a large proportion of cases, the palate is high, arched and occasionally clefted (28%). In severe cases, the zygomatic arches may be completely absent.  Affected infants may also have pharyngeal hypoplasia. These anomalies may contribute to breathing difficulties at birth and feeding problems during early infancy. Ophthalmic abnormalities include downward slanting of the palpebral fissures (89%) with notching of the lower eyelids (69%), colobomas and a scarcity of lid lashes medial to the defect (69%). Other clinical features of TCS include alterations in the shape, size and position of the external ears, which are frequently associated with atresia of the external auditory canals and anomalies of the middle ear ossicles. Affected infants may experience obstructive sleep apnea. Intelligence is usually normal in the majority of affected cases. The specific symptoms and physical characteristics associated with TCS can vary significantly from one individual to another.  

Brain and behavioral anomalies such as microcephaly and psychomotor delay have occasionally been reported in affected individuals.

In the case of TCOF1, the mode of inheritance is autosomal dominant, with a 50% risk of passing the abnormal gene from the affected parent to the offspring in each pregnancy. Some adult individuals can be so mildly affected that it can be challenging to get a clear diagnosis. If this is the case for one of the parents, it is not uncommon that TCS is diagnosed in one of the parents only after the birth of a more severely affected child. New mutations, that account for about 60% of the cases, have an extremely low recurrence risk in the offspring. 

The ultrasound findings that should prompt suspicion of TCS syndrome are micrognathia, low-set and abnormally formed ears, downward (antimongoloid) slanting palpebral fissures and cleft palate. Polyhydramnios is also a common feature.
The most useful diagnostic view with 2D sonography is the mid-sagittal view of the face showing micrognathia. This should be complemented with tangential or slightly obliques coronal views of the face. From the late second-third trimester, 3D surface rendering can provide striking images of the fetal face and clearly show the subtle change in the mandible and the other facial features. Ears anomalies can also be clearly identified.⁷ Amniocentesis with targeted molecular investigation by arrays CGH of the TCOF1, and POLR1 genes can confirm the suspicion in familial cases. However, the wide spectrum of mutations observed in TCS complicates the provision of prenatal molecular diagnosis because it is necessary to identify the mutation in each family before undertaking diagnostic predictions.⁸ Moreover, it has been shown that families with TCS did not show pathogenic mutations in the TCOF1 gene, suggesting that multiple mechanisms or genetic heterogeneity may possibly lead to TCS.⁹
Diagnosis of new mutations is still challenging and not readily available in all centers. Even when the genetic investigation successfully confirms the diagnostic suspicion, it cannot predict how severely affected the fetus is. Therefore, ultrasonography is invaluable in providing information about the severity of the individual TCS case and in evaluating fetal progression.

The differential diagnosis includes: 1) Goldenhar syndrome (oculoauriculovertebral dysplasia), a familial inherited condition, almost always unilateral and involves notching of the upper rather than the lower lid and epibulbar dermoids.⁴ Fetuses affected with Goldenhar syndrome may manifest hemivertebrae or vertebral (usually cervical) hypoplasia and various cardiac defects. 2) Nager acrofacial dysostosis, in which mandibulofacial dysostosis occurs with preaxial reduction defects of the upper limbs⁴, especially radial limb defects ranging from hypoplasia to aplasia of the thumb with or without the involvement of the radius¹. 3) Pierre-Robin sequence, characterized by early mandibular hypoplasia as the primary anomaly and with associated anomalies limited to this area¹ . 4) Miller syndrome, which demonstrates a similar phenotype, with the additional diagnostic feature of ectropion of the lower lids.¹⁰

The reliability of sonography in detecting Treacher Collins syndrome depends on the severity of abnormalities in the affected fetus. Because of the overlap among this and other disorders, prenatal differentiation of less severely affected fetuses may not be possible.

Birth can be a dangerous event for infants affected by a severe form of TCS as intubation or even tracheostomy may be required in cases with life-threatening respiratory difficulties. The birth of a fetus with TCS should always take place in a referral center with experience in managing these emergencies. 
Individuals diagnosed with TCS must frequently undergo multiple reconstructive surgeries, which rarely can achieve satisfactory reconstruction and correction.  

Infants affected by TCS require a multidisciplinary approach both pre-and post-operatively. Management of the hard and soft tissues anomaly usually requires multiple surgeries. Anomalies such as cleft of the palate and eyelid coloboma are corrected first in early life, followed by orbital reconstruction at about 5–7 years of age when orbital growth is about complete. Mandibular distraction or maxillo-mandibular osteotomies may be performed around the same time. Multiple surgeries are needed to correct under-developed or abnormal facial structures with suboptimal results in most cases. Corollary problems can be deafness and speech problems, which in turn can impact learning ability and social interaction of the affected individual.8 Recent research on animal models has suggested a possible avenue for preventing and treating the craniofacial anomalies observed in TCS.⁸ 

2. Cohen J, Ghezzi F, Gongalves L, Fuentes JD, Paulyson KJ, Sherer DM. Prenatal sonographic diagnosis of Treacher Collins syndrome: a case and review of the literature. Am J Perinatol 1995; 12: 416–9 
3. Crane JP, Beaver HA. Midtrimester sonographic diagnosis of mandibulofacial dysostosis. Am J Med General 1986; 25: 251–5
4. Meizner I, Carmi B, Katz M. Prenatal ultrasonic diagnosis of mandibulofacial dysostosis (Treacher Collins syndrome). J Clin Ultrasound 1991; 19: 124–7
5. Hsu TY, Hsu JJ, Chang SY, Chang MS. Prenatal three-dimensional sonographic images associated with Treacher Collins syndrome. Ultrasound Obstet Gynecol. 2002;19(4):413-422. 
6. Tanaka Y, Kanenishi K, Tanaka H, Yanagihara T, Hata T. Antenatal three-dimensional sonographic features of Treacher Collins syndrome. Ultrasound Obstet Gynecol. 2002;19(4):414-415. 
7. Shih JC, Shyu MK, Lee CN, Wu CH, Lin GJ, Hsieh FJ. Antenatal depiction of the fetal ear with three-dimensional ultrasonography. Obstet Gynecol 1998; 91: 500–5
8. Trainor PA, Dixon J, Dixon MJ. Treacher Collins syndrome: etiology, pathogenesis and prevention. Eur J Hum Genet. 2009 Mar;17(3):275-83. 
9. Wei Shin Chou, Jia Shing Chen, Yu Ming Shiao, Ju Chin Tsauer, Yi Fen Chang, Ching Hua Hsiao, Prenatally diagnosed microdeletion in the TCOF1 gene in fetal congenital primary Treacher Collins Syndrome,Taiwanese Journal of Obstetrics and Gynecology. 2022; 61-3: 514-516,
  RJ Gorlin, MM Cohen, RCM Hennekam. Syndromes of the Head and Neck. Oxford University Press, 2001

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