**2.9 Pfeiffer syndrome**

280 Hearing Loss

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

Apert syndrome (or Acrocephalosyndactyly) (OMIM 101200) occurs in about 1 every 65.000- 88.000 newborns. It is usually sporadic but some familial cases with an autosomal dominant way of inheritance have been observed. Mutations in *FGFR2* (fibroblast growth factor receptor-2) increase the number of precursor cells involved in the osteogenic process leading to increased subperiosteal bone matrix and premature ossification. Consequent premature skull bone ossification leads to craniosynostosis (especially affecting the coronal sutures) which is the main clinical pattern in Apert syndrome (Rice et al., 2008). Patients with this condition have a typical back to front flat skull with frontal bossing which is longer than usual. Eyes are wide set and the midface is typically hypoplastic with a retrusion of supraorbital wings which make proptosis evident, eyebrows interruption, a beaked nose and a small upper jaw causing crowded upper teeth projecting back to the lower teeth.

Cranial abnormalities are quite directly related to brain development: mental status ranges from normal intelligence to various degree of mental retardation. Hydrocephalus and malformations of corpum callosum or septum pellucidum are common findings. Craniofacial abnormalities are associated to finger or toes webbing: syndactyly of at least three finger or three toes typically involves bones structure. When vertebral abnormalities occur, C5-C6 fusion is typically observed. Hyperhidrosis is frequently reported as is also

**Hearing loss** is a common diagnosis in these patients. The conductive hearing loss, usually bilateral, may be due to ossicular chain fixation or otitis media with effusion. Hearing loss is rarely present at birth. In about 50% of the cases hearing loss is acquired by the age of 20. It ranges from mild to moderate, predominantly affecting the lower frequencies. The incidence

In a study by Zhou et al. hearing loss was found in 90% of the 20 pediatric patients with Apert syndrome and 80% of them had conductive hearing loss. Air-bone gaps were found at all frequencies, maximum at the low ones. Inner ear anomalies were found in all patients at CT scans of the temporal bones. The most frequent anomalies were dilated vestibule,

Crouzon syndrome (OMIM 123500) was first described in 1912 by Crouzon. It is a condition which is inherited in an autosomal dominant way. In Europe it occurs in 1 child every 50.000 live births. The syndrome is caused by mutation in the fibroblast growth factor receptor 2. Mutations in this gene lead to the production of an abnormal protein which overstimulates immature cells to form mature bone cells. The premature fusion of skull sutures causes the typical synostosis which begins in the first year of life and is completed

mixed in three patients. (Pron et al., 1993; Jahrsdoerfer et al., 1995).

Vision and auditory problems are usual findings in Apert syndrome.

of congenital hearing loss is low (3–6%) (Rajenderkumar et al., 2005).

malformed lateral semicircular canal and cochlear dysplasia (Zhou et al., 2009)

**2.7 Apert syndrome** 

skin with acne.

**2.8 Crouzon syndrome** 

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

The face is usually broad with midface hypoplasia, prognatism, high forehead, flat occiput, hypertelorism and swallowing orbits which cause proptosis. Upperways obstruction can follow midface hypoplasia and nasal obstruction (Vogels et al., 2006).

Skull malformation is associated to limb abnormalities such as short and broad deviating thumbs, big toes and syndactyly of the second and third fingers.

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 2 patients without cloverleaf skull.

Genetic Hearing Loss Associated with Craniofacial Abnormalities 283

Miller syndrome or postaxial acrofacial dysostosis (OMIM 263750) is a rare condition which affects fewer than 1 in 1 million of newborns. It has an autosomal recessive mode of inheritance. Mutations in *DHODH* cause this syndrome disrupting the development of the first and second pharyngeal arch. Patients with this syndrome typically show craniofacial abnormalities such as malar hypoplasia, micrognathia, down-slanting eyes with drooping of the lower eyelids (which becomes more evident with age) and coloboma, cleft palate, long

Craniofacial abnormalities are associated with limb defects such as syndactyly, hypoplasia or absence of fingers or toes (eg the fifth digits), hypoplasia of forearms or lower legs.

Extra nipples, vertebrae or ribs deformities have been described while abnormalities of the

**Hearing loss** is usually caused by defects in the middle ear (various degree conductive

Nager syndrome (OMIM 154400) is a rare condition (about 70 cases have been described) and the involved genes are unknown. Both autosomal and recessive cases have been described. Facial malformation is associated with limbs abnormalities. The face shows maxillar hypoplasia and micrognatia. The eyes have typical downslanting fissures with ptosis of the upper lids, lack or absence of the lower eyelashes and occasionally coloboma of

Ears can show various degree of malformations which range from abnormal positioning to microtia. Auditory canal or middle ear can be involved leading to conductive **hearing loss**. Otitis media is a common problem. In a study by Herrmann et al. 8 over 10 patients with Nager syndrome had pure conductive hearing loss (> 30 db HL in 90% of cases, between 55 and 70 dB HL in 40% of patients) while in 2 cases hearing impairment was mixed. In the last two cases the sensorineural deficit was progressive and developed later in childhood. A

Limb malformations consist of hypoplasia or absence of radius, radioulnar synostosis, and hypoplasia or absence of the thumbs. Phocomelia is rare. Renal and genital abnormalities

**Syndrome Main Clinical Features Genetics Hearing loss** 

Genetic heterogeneity Ranges from mild to moderate conductive impairment and severe to profound sensorineural hearing loss

**2.12 Miller syndrome** 

philtrum and small, protruding "cup-shaped" ears.

Choleasteatoma has been described in some cases.

• Facial cleft

• Hemifacial microsomia • Auricular malformations • Vertebrae abnormalities

• Ocular abnormalities • Congenital heart diseases

occasionally occur. (Opitz et al., 2003)

hearing loss). (Toriello et al., 2004)

**2.13 Nager acrofacial dysostosis** 

the lower lids.

**Goldenhar syndrome** 

heart, kidneys, genitalia, or gastrointestinal tract are less common.

Otologic malformations and **hearing loss** are common features in Pfeiffer syndrome. They are mainly due to external auditory canal or middle ear malformation. For example atresic or stenotic auditory canal, hypoplasic ossicules or fixed ossicular chain, hypoplasic or enlarged middle ear cavity can be common findings. The inner ear is usually normal though an enlarged internal acoustic meatus may be present. (Cremers et al., 1981)

In a study by Vallino et al. hearing loss, mostly moderate to severe, was present in eight of the nine patients with Pfeiffer syndrome. Seven patients had conductive hearing loss and one had mixed loss (Vallino-Napoli et al., 1996).

Sensorineural hearing loss is less common and may be related to the effect of *FGFR* mutations on cranial nerve or inner-ear development. (Desai et al., 2010)
