**2.7 Apert syndrome**

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 skin with acne.

Vision and auditory problems are usual findings in Apert syndrome.

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

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

#### **2.8 Crouzon syndrome**

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 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, mainly when treatment is delayed.

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

**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. Sensorineural hearing loss may rarely occur.

In the study by De Jong et al. mild or moderate hearing loss (mostly conductive) was found in 28.5% of patients with Crouzon syndrome (De Jong et al., 2011).

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 (Orvidas et al., 1999)

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., 2007)
