Clinical characteristics.

Treacher Collins syndrome (TCS) is characterized by bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, micrognathia, and external ear abnormalities. Hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. About 40%-50% of individuals have conductive hearing loss attributed most commonly to malformation of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures tend to be normal. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia. Typically intellect is normal.

Diagnosis/testing.

The diagnosis of TCS is established in about 97% of probands by detection of a heterozygous (autosomal dominant) pathogenic variant in TCOF1, POLR1D, or POLR1B or biallelic (autosomal recessive) pathogenic variants in POLR1C or POLR1D using molecular genetic testing and in about 3% of probands by clinical findings when molecular genetic testing has not been performed or does not identify pathogenic variants in one of the known genes.

Management.

Treatment of manifestations: Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team. Neonates with airway issues may require special positioning or tracheostomy to facilitate ventilation. Hearing loss is treated with bone conduction amplification, speech therapy, and educational intervention. Craniofacial reconstruction is often necessary. Cleft palate repair (if needed) occurs at about age one year; zygomatic and orbital reconstruction at about age five to seven years; and bilateral microtia and/or narrow ear canal reconstruction after age six years. The age of maxillomandibular reconstruction varies by severity; orthognathic therapies are typically before age 16 years.

Genetic counseling.

Treacher Collins syndrome (TCS) can be inherited in an autosomal dominant or autosomal recessive manner.

• Autosomal dominant TCS. About 55%-61% of probands have the disorder as the result of a de novo TCOF1, POLR1D, or POLR1B pathogenic variant. Each child of an individual with TCS has a 50% chance of inheriting the pathogenic variant.
• Autosomal recessive TCS. The parents of a child with autosomal recessive TCS are obligate heterozygotes (i.e., carriers of one POLR1C or POLR1D pathogenic variant). At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once the TCS-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

Treacher Collins syndrome (TCS) should be suspected in individuals with the following craniofacial features (see Teber et al [2004], Figure 2; Trainor et al [2009], Figure 2; Dauwerse et al [2011], Figure 1; and Vincent et al [2016], Figure 1), hearing loss, and radiographic findings.

Craniofacial features

• Midface hypoplasia with a bilaterally symmetric convex facial profile, prominent nose, and characteristic downward slant of the eyes secondary to hypoplasia of the zygomatic arch and lateral aspects of the orbits
• Micrognathia and retrognathia with variable effects on the temporomandibular joints and jaw muscles
• External ear abnormalities including absent, small, malformed, and/or rotated ears, and atresia or stenosis of the external auditory canals
• Lower eyelid abnormalities including the following:
  • Coloboma (notching)
  • Sparse, partially absent, or totally absent lashes and tear ducts

Preauricular hair displacement, in which hair growth extends in front of the ear to the lateral cheekbones

Conductive hearing loss is attributed most commonly to ankylosis, hypoplasia, or absence of the ossicles and hypoplasia of the middle ear cavities. Inner ear structures are typically normal.

Radiographic features

• Hypoplasia or aplasia (discontinuity) of the zygomatic arch, detected by occipitomental radiographs (Waters' view) [Posnick & Ruiz 2000]
• Mandibular retrognathia, detected by orthopantogram [Posnick & Ruiz 2000]

Establishing the Diagnosis

The diagnosis of TCS is established in about 97% of probands by detection of a heterozygous (autosomal dominant) pathogenic variant in TCOF1, POLR1D, or POLR1B or biallelic (autosomal recessive) pathogenic variants in POLR1C or POLR1D using molecular genetic testing (Table 1) and in about 3% of probands by clinical findings when molecular genetic testing has not been performed or does not identify pathogenic variants in one of the known genes.

Clinical Description

Treacher Collins syndrome (TCS) is characterized by facial features of bilateral and symmetric downslanting palpebral fissures, malar hypoplasia, and micrognathia. The hypoplasia of the zygomatic bones and mandible can cause significant feeding and respiratory difficulties. Ear abnormalities are associated with conductive hearing loss. Other, less common abnormalities include cleft palate and unilateral or bilateral choanal stenosis or atresia.

Significant inter- and intrafamilial clinical variability is common in TCS [Posnick & Ruiz 2000, Teber et al 2004]. While some individuals may be so mildly affected as to go undiagnosed (Figure 1), others can have severe facial involvement and life-threatening airway compromise [Trainor & Andrews 2013].

Figure 1.

Intrafamilial variation in families with a confirmed TCOF1 pathogenic variant. a. The proband (arrow) has the characteristic facial phenotype with downward-slanting palpebral fissures, hypoplastic zygomatic complex, hypoplasia of mandible, slightly dysplastic (more...)

Classic features of TCS are bilaterally symmetric and evident at birth (Table 2). Table 3 presents a scoring system to rate the severity of clinical findings.