**2.1 Goldenhar syndrome**

Hemifacial microsomia (or Goldenahr syndrome or oculo-auricolar-vertebral syndrome) is usually a sporadic disorder even if there is evidence of familial transmission. In some cases autosomal recessive and autosomal dominant inheritance have also been described. The incidence of Goldenhar syndrome is reported to be approximately 1 in 5,000-25,000 live births (Editorial Team Orphanet, 2005). Genetic heterogenity is frequently observed . Kelberman et al performed a genome search for linkage in two families with features of hemifacial microsomia and identified data highly suggestive of linkage to a region of approximately 10.7 cM on chromosome 14q32 for one family (Kelberman et al., 2001).

During embryogenesis the correct development of the 1st or the 2nd branchial arches are hypothesized to be interrupted resulting in Goldenhar Syndrome. Clinical features mainly consist of a hemifacial microsomia. Maxillary, temporal, malar and skull bones can also be involved. Auricular malformations range from mild abnormalities in the external ears (such as preauricular tags or pinnae hypoplasia of various degrees) to anotia. Vertebrae abnormalities (e.g. hemivertebrae and fused vertebrae) as well as facial cleft or ocular abnormalities (epibulbar dermoid, eyelid coloboma, microphtalmia, retinal anomalies) are described. Mouth opening can be modified by mandibular hypoplasia. Congenital heart diseases of various degrees (e.g. ventricular septal defect of Tetralogy of Fallot) or a wide range of CNS malformations can be associated too. Bony involvement can cause weakness of cranial nerves. Mental retardation is described in 5-15% patients. Kidney, pulmonary or gastrointestinal abnormalities can also be associated less frequently. (OMIM 164210; Toriello et al., 2004)

**Hearing loss** in Goldenhar syndrome usually ranges from mild to moderate conductive impairment and severe to profound sensorineural hearing loss (Skarzynski et al., 2009). Deformity of the auricle, external auditory canal atresia and malformation of the tympanic cavity or ossicles may be the main cause of conductive hearing impairment. Abnormalities of the stria vascularis and the semicircular canals have also been reported (Scholtz et al., 2001). Sensorineural hearing loss and facial nerve disfunction is often underestimated. In the study by Carvalho et al (Carvalho et a.l, 1999) 11% of the patients with Hemifacial microsomia had sensorineural hearing loss.

#### **2.2 Charge syndrome**

In 1981 Pagon et al. first introduced the acronym "CHARGE" to define a nonrandom association of the following features: **C**oloboma, **H**eart defect, **A**tresia choanae, **R**etarded growth and development, **G**enital hypoplasia and **E**ar anomalies/deafness.

Charge syndrome (OMIM 214800) is a rare disorder with an incidence of about 1 in every 8500–10000 births (Issekutz et al., 2005). CHARGE syndrome is an autosomal dominant disorder. Mutations in *CHD7* have been detected in more than 75% of CHARGE patients. *CHD7* belongs to the gene family coding for ChromodomainHelicase DNA binding proteins. During early human development, *CHD7* is expressed in the undifferentiated neuroepithelium and in mesenchyme of neural crest origin. It is thought to play a role in regulating the expression of important developmental genes in mesenchymal cells derived from the cephalic neural crest, by chromatin remodeling. The phenotype of CHARGE

Hemifacial microsomia (or Goldenahr syndrome or oculo-auricolar-vertebral syndrome) is usually a sporadic disorder even if there is evidence of familial transmission. In some cases autosomal recessive and autosomal dominant inheritance have also been described. The incidence of Goldenhar syndrome is reported to be approximately 1 in 5,000-25,000 live births (Editorial Team Orphanet, 2005). Genetic heterogenity is frequently observed . Kelberman et al performed a genome search for linkage in two families with features of hemifacial microsomia and identified data highly suggestive of linkage to a region of approximately 10.7 cM on chromosome 14q32 for one family (Kelberman et al., 2001).

During embryogenesis the correct development of the 1st or the 2nd branchial arches are hypothesized to be interrupted resulting in Goldenhar Syndrome. Clinical features mainly consist of a hemifacial microsomia. Maxillary, temporal, malar and skull bones can also be involved. Auricular malformations range from mild abnormalities in the external ears (such as preauricular tags or pinnae hypoplasia of various degrees) to anotia. Vertebrae abnormalities (e.g. hemivertebrae and fused vertebrae) as well as facial cleft or ocular abnormalities (epibulbar dermoid, eyelid coloboma, microphtalmia, retinal anomalies) are described. Mouth opening can be modified by mandibular hypoplasia. Congenital heart diseases of various degrees (e.g. ventricular septal defect of Tetralogy of Fallot) or a wide range of CNS malformations can be associated too. Bony involvement can cause weakness of cranial nerves. Mental retardation is described in 5-15% patients. Kidney, pulmonary or gastrointestinal abnormalities can also be associated less frequently. (OMIM 164210; Toriello

**Hearing loss** in Goldenhar syndrome usually ranges from mild to moderate conductive impairment and severe to profound sensorineural hearing loss (Skarzynski et al., 2009). Deformity of the auricle, external auditory canal atresia and malformation of the tympanic cavity or ossicles may be the main cause of conductive hearing impairment. Abnormalities of the stria vascularis and the semicircular canals have also been reported (Scholtz et al., 2001). Sensorineural hearing loss and facial nerve disfunction is often underestimated. In the study by Carvalho et al (Carvalho et a.l, 1999) 11% of the patients with Hemifacial

In 1981 Pagon et al. first introduced the acronym "CHARGE" to define a nonrandom association of the following features: **C**oloboma, **H**eart defect, **A**tresia choanae, **R**etarded

Charge syndrome (OMIM 214800) is a rare disorder with an incidence of about 1 in every 8500–10000 births (Issekutz et al., 2005). CHARGE syndrome is an autosomal dominant disorder. Mutations in *CHD7* have been detected in more than 75% of CHARGE patients. *CHD7* belongs to the gene family coding for ChromodomainHelicase DNA binding proteins. During early human development, *CHD7* is expressed in the undifferentiated neuroepithelium and in mesenchyme of neural crest origin. It is thought to play a role in regulating the expression of important developmental genes in mesenchymal cells derived from the cephalic neural crest, by chromatin remodeling. The phenotype of CHARGE

growth and development, **G**enital hypoplasia and **E**ar anomalies/deafness.

**2. Clinical syndromes 2.1 Goldenhar syndrome** 

et al., 2004)

microsomia had sensorineural hearing loss.

**2.2 Charge syndrome** 

syndrome can also be caused by mutation in the semaphorin-3E gene. (Michelucci et al., 2010).Patients with Charge syndrome have a typical square-flattened face, usually asymmetric, with a bulbous nasal tip, long philtrum, low-set and dysplastic ears, antimongoloid slant of palpebral fissures, anteverted nares and malar hypoplasia. Ptosis and cleft lip or palate can also be associated findings. (OMIM 214800). Based on Blake et al definition, individuals with all four major characteristics (the classical 4C's: Choanal atresia, Coloboma, Characteristic ears and Cranial nerve anomalies) or three major and three minor characteristics (Cardiovascular malformations, Genital hypoplasia, Cleft lip/palate, Tracheoesophageal fistula, Distinctive CHARGE facies, Growth deficiency, Developmental delay) are highly likely to have CHARGE syndrome. Nevertheless any infant with one or two major criteria and several minor characteristics is highly suspected to have CHARGE. (Blake et al). Based on Verloes criteria the presence of three major findings (Coloboma of the iris or choroid, with or without microphthalmia, Atresia of Choanae, Hypoplastic semicircular Canals) are necessary and sufcient to make a diagnosis of CHARGE, even if no other features are present. Patients with ''borderline phenotypes'' are classied in two groups: partial (or incomplete) CHARGE and atypical CHARGE. Partial CHARGE are those individuals who have two major signs but only one minor sign (minor signs for Verloes are Rhombencephalic dysfunction, Hypothalamo-hypophyseal dysfunction, Abnormal middle or external ear, Malformation of mediastinal organs, Mental retardation), whereas individuals with atypical CHARGE are those who have two major signs and no minor sign, or one major sign and at least three minor signs of CHARGE. (Verloes et al., 2005) Coloboma is uni-lateral or bilateral, involving iris, retina and/or disc.

Heart defects in CHARGE syndrome are mainly conotruncal defects or aortic arch anomalies. Urinary defects range from abnormalities of kidney (or genitourinary tract) size or position to renal agenesis, genital hypoplasia, which is typically recognized only in males (micropenis/cryptorchidism). Almost every part of the audiologic system can be involved in Charge association. External ears are typically low-set and malformed. Unusually shaped and floppy external Pinnae can cause difficulties in placing behind-ear- hearing aids. Ear canals may be stenotic. The most common audiological features are severe-to-profound asymmetric mixed losses. (Edwards et al., 2002). Ossicular anomalies (eg stapes or incus abnormalities), absence of oval window or absence of the stapedium muscle and middle ear effusion (eustachian tube dysfunction from craniofacial malformation is a common finding) cause conductive hearing loss which is often asymmetrical and fluctuating in nature, usually greater on low frequencies. (Dhooge et al., 1998) . Cochlear malformations such as Mondini's Displasia can contribute to hearing loss. Cochlear involvement is greatest for high frequencies (Thelin et al., 1986). Abnormalities of the semicircular canals can be found in most patients (Morimoto et al., 2006). Auditory neural pathway abnormalities (such as hypoplasia or absence of the auditory nerve) may be involved as well.

#### **2.3 Pierre Robin sequence**

This condition is commonly defined Pierre Robin "sequence" instead of "syndrome" because the major clinical features have a common origin. The mandibular hypoplasia starts being evident in the first period of gestation and causes an anomalous position of the tongue. This prevents the correct development of the palate. At birth micrognathia, glossoptosis and cleft palate are the main signs. Consequently, respiratory, feeding and swallowing problems are the major problems in these patients. (Evans et al., 2011)

Genetic Hearing Loss Associated with Craniofacial Abnormalities 279

Branchio-oto-renal syndrome (OMIM 113650) is a genetic condition with a prevalence of 1/40.000 births and has an autosomal dominant mode of inheritance. *EYA1, SIX1*, and *SIX5* are three genes which are known to be mutated in this syndrome. The syndrome is called "Branchio-oto-renal" because malformations of the second branchial arch are associated with ears and renal abnormalities. The face is typically long and narrow with a constricted palate. (Alkis et al., 2002)Kidney and urinary tract show various degree of involvement. Shape or position abnormalities can be isolated or associated with an impaired renal function. Abnormalities in the development of the second branchial arch lead to neck

**Auditory system** involvement ranges from pinnae abnormalities such as microtia, abnormally shaped ears, pre-auricular tags or pits to inner ear or middle ear malformations leading to sensorineural, conductive or mixed hearing loss. Hearing impairment occurs in 75%-93% of patients with BOR syndrome and ranges from mild to profound. Age of onset varies from early childhood to adult age. Younger patients manifest greater threshold fluctuation. Inner and middle ear anomalies ranges from cochlear hypoplasia, semicircular canals hypoplasia, ossicular anomalies, external auditory canal stenosis or atresia, vestibular displasia, enlarged aqueductus or endolymphatic sac (the last seems to predispose to more severe hearing impairment), absence of stapedium muscle or Eustachian tube dilation and cochlear nerve deficiency. (Huang et al., 2011; Kemperman et al., 2004)

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

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

**2.5 Brachio-Oto-renal (BOR) syndrome** 

**2.6 Treacher-Collins syndrome** 

displacement is a typical finding.

malformations such as branchial cleft, cysts or fistulae.

Pierre Robin sequence is usually a sporadic event with an estimated prevalence of about 1/10.000. In about 10% of patients a familial transmission has been described although the involved genes have not been identified.

**Hearing loss** is typically conductive and bilateral patients with Pierre Robin sequence. In Middle ear effusion is a finding in most patients. Therefore the use of tympanostomy (ventilation) tubes is the therapy of choice in patients with Pierre Robin Sequence. In a study by Handzic et al the mean hearing loss at speech frequencies was 24.5 dB (Handzić J et al., 1995, 1996). Pierre Robin Sequence is also a risk factor for sensorineural Hearing Loss: the 30% of the Pierre Robin patients in a study (Medard et al., 1999) had congenital permanent sensorineural evolutive hearing loss.

Another study revealed multiple architectural anomalies involving the entire ear such as abnormal auricles or ossicles, aplasia of the lateral semicircular canals or a large vestibual aqueduct (Gruen et al., 2005).
