**1. Introduction**

274 Hearing Loss

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Nance, W. E., Kanaan, M., Avraham, K. B., Tekaia, F., Loiselet, J., Lathrop, M., Richardson, G. & Petit, C. (2002). Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. *Proc Natl Acad*  It is estimated that hereditary hearing loss accounts for 60% of deafness in the developed countries. About 30% of hereditary hearing impairment is syndromic which involves other presenting abnormalities along with deafness. There are more than 400 syndromes which include various degrees of hearing impairment with different phenotypes. (Barlow Stewart et al., 2007; Berrettini et al., 2008)*.* Abnormalities of different systems or suggestive clinical findings have been associated with syndromic hearing loss. These include craniofacial malformations, dental abnormalities, ocular abnormalities, renal defects, cardiac abnormalities, endocrine dysfunction, neurologic dysfunction, skeletal abnormalities, integumentary abnormalities, metabolic disease, chromosomal abnormalities.

Treacher Collins, Goldenhar and Charge syndrome, Pierre Robin sequence, Stickler, Apert, Crouzon, Pfeiffer and velocardiofacial syndrome are just few conditions in which hearing loss is associated with craniofacial abnormalities. Most of these conditions are related to first and second branchial arches development abnormalities. The first and second branchial arches contribute to the development of skeletal (e.g. mandibula, maxilla, middle ear ossicules), muscular (facial muscles) and nervous (e.g. facial nerve) structures of the face. That explains why, due to the abnormal development of first and second branchial arches, midface malformations are usually the typical findings in these patients. (Gorlin et al., 1995; Johnson et al., 2011)

We describe some of these disorders underlining the main characteristic impairments and the observed hearing loss. We also report our observations on some clinical cases seen at Neonatology Unity of Santa Chiara University Hospital of Pisa (Table 2).

*<sup>1</sup>Neonatology Unit and NICU, Italy* 

*<sup>2</sup>Section of Neonatal Endocrinology and Dysmorphology, Mother and Child Department, Italy 3Division of ENT, Department of Neuroscience, Italy* 

*<sup>4</sup>Cytogenetics and Molecular Genetics Unit, Mother and Child Department, Italy* 

Genetic Hearing Loss Associated with Craniofacial Abnormalities 277

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.

hypoplasia or absence of the auditory nerve) may be involved as well.

**2.3 Pierre Robin sequence** 

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

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)
