**2.6 Treacher-Collins syndrome**

Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development with an incidence of 1 in 50.000 live births. It shows genetic heterogeneity: Treacher Collins syndrome-1 (TCS-1) (OMIM 154500) is caused by a heterozygous mutation in *TCOF-1* located on chromosome 5q32 (Wise et al., 1997). Treacher Collins syndrome-2 (OMIM 613717) is caused by an heterozygous mutation in *POLR1D* on chromosome 5q3213q12.2, while TCS-3 (OMIM 248390) is caused by an heterozygous mutation in the *POLR1C* gene on chromosome 6. However, about 60% of TCS patients have *de novo* gene mutations. Some authors hypothesize that these genetic mutations lead to an aberrant expression of a nuclear protein critically required during human craniofacial development.

Facial abnormalities are usually bilateral in TCS. They involve facial bones showing zygomatic arches hypoplasia, hypoplasia of supraorbital rims and micrognathia. The face is narrow with an antimongoloid slant of the eyes and hypertelorism. Coloboma of the lower lid can be present with deficiency of cilia medial to the coloboma. Ophthalmologic defects such as vision loss or refractive errors require specialistic evaluation: Preauricular hair displacement is a typical finding.

External ear show abnormalities ranging from various degree of pinnae malformations to microtia. About 40-50% of the patients with Treacher Collins have conductive **hearing loss** (often compounded by a high-frequency sensory component) mainly caused by hypoplasia of the middle ear or malformations of the ossicles. Inner ear is usually normal. Pron et al. reported on the hearing loss and computerized tomography (CT) assessments of ear malformations in a large pediatric series of patients with Treacher Collins. Of the 23 subjects assessed the external ear abnormalities were largely symmetric, with a stenotic

Genetic Hearing Loss Associated with Craniofacial Abnormalities 281

by 2-3 years from birth. Different patterns of skull growth depend on which suture is mainly involved (Harroop et al., 2006; Kirman et al., 2005).Increased intracranial pressure can occur,

The face is typically huge with a high forehead, proptosis which causes external strabismus, hypertelorism, prognathism and hypoplastic upper jaw which leads to dental problems. The

**Hearing loss** is mainly conductive and is due to auditory canal abnormalities such as middle ear effusions, intratympanic bony masses, ossicular or oval window malformations.

In the study by De Jong et al. mild or moderate hearing loss (mostly conductive) was found

In the study by Orvidas et al 8 of the 19 patients with Crouzon syndrome had ear anomalies ranging from pinna malformations to auditory canal atresia while 10 had proper hearing impairment: in 4 of them conductive hearing loss was found (mainly due to ossicular fixation and otitis media) in 4 of them hearing loss was sensorineural while in 2 was mixed

A particular variant of Crouzon syndrome caused by a mutation in *FGFR3* has been described in association to Acanthosis Nigrigans. In these patients hydrocephalus, coanal stenosis or atresia and Chiari malformation have been described. (Arnaud-López et al.,

Crouzon syndrome and Pfeiffer syndrome (OMIM 101600) are allelic disorders with overlapping features. Pfeiffer syndrome is an autosomal dominant condition which occurs in 1 every 100.000 live births. It is caused by mutations in *FGFR1* or *FGFR2* which cause prolonged signaling which over stimulates premature cells in the developing embryo. This causes the premature fusion of skull bones. Early fusion of the coronal and lambdoid

The face is usually broad with midface hypoplasia, prognatism, high forehead, flat occiput, hypertelorism and swallowing orbits which cause proptosis. Upperways obstruction can

Skull malformation is associated to limb abnormalities such as short and broad deviating

Three different subtypes of this condition have been described. In type 1 patients, mild skull and facial abnormalities such as brachycephaly and midface hypoplasia are associated with fingers and toes malformations while neurological development is usually normal. In type 2 patients trilobated skull deformity is associated with neurological problems such as underdeveloped brain or increased intracranial pressure. Proptosis is evident and causes visual problems. Other limb defects such as elbow ankylosis are associated to fingers and toes abnormalities. Kidney malformations can also occur. Type 3 patients are similar to type

sutures and occasionally of the sagittal sutures leads to an abnormal skull shape.

follow midface hypoplasia and nasal obstruction (Vogels et al., 2006).

thumbs, big toes and syndactyly of the second and third fingers.

nose is usually beak shaped. Cleft lips or palate have sometimes been observed.

in 28.5% of patients with Crouzon syndrome (De Jong et al., 2011).

mainly when treatment is delayed.

(Orvidas et al., 1999)

**2.9 Pfeiffer syndrome** 

2 patients without cloverleaf skull.

2007)

Sensorineural hearing loss may rarely occur.

atresic canal. In most cases, the middle ear cavity was hypoplastic and dysmorphic with aberrants ossicles while inner ear structures were normal. The majority of patients had asymmetric conductive hearing loss of various degrees. Hearing loss was bilateral and mixed in three patients. (Pron et al., 1993; Jahrsdoerfer et al., 1995).
