**2.13 Nager acrofacial dysostosis**

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 the lower lids.

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 Choleasteatoma has been described in some cases.

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 occasionally occur. (Opitz et al., 2003)


Genetic Hearing Loss Associated with Craniofacial Abnormalities 285

**Syndrome Main Clinical Features Genetics Hearing loss** 

*FGFR2* Conductive

*TWIST1* Conductive or

*FGFR1* & *FGFR2* Conductive

*DHODH* Conductive

Not known Conductive or

loss

It is caused by mutations in *SALL1* 

mixed

Sensorineural or conductive hearing loss

hearing lossmainly due to anomalies of middle ear

mixed hearing

hearing loss

• Proptosis • Small upper jaw • Syndactyly

• Synostosis • High forehead • Proptosis

• External strabismus • Hypertelorism • Prognathism

• Hypoplastic upper jaw

• Widely spaced eyes

• Facial asymmetry • Syndactyly

• Broad face is midface hypoplasia • Prognatism

hypertelorism • Swallowing orbits which cause proptosis • Skull malformation • Limb abnormalities

• Anus imperforatus • Rectovaginal

• Rectoperineal fistula • External ear anomalies • Thumbs malformation

• Malar hypoplasia • Micrognathia • Down-slanting eyes

• Limbs abnormalities • Maxillar hypoplasia

Table 1. Main craniofacial syndromes associated with hearing loss

• Coloboma • Cleft palate • Limb defects

• Micrognatia

• Broad or duplicated thumb or

• High forehead, flat occiput,

• Brachycephaly • Low frontal hair line • Flattened nasofrontal angle

• Ptosis

hallux

**Crouzon syndrome** 

**Saethre-Chotzen syndrome** 

**Pfeiffer syndrome** 

**Townes-Brock syndrome** 

**Miller syndrome** 

**Nager syndrome** 


**Syndrome Main Clinical Features Genetics Hearing loss** 

Mutations in *CHD7* are detected in more than 75% of CHARGE patients

Genetic heterogeneity

Mutations in *COL2A1, COL9A1*, *COL11A1*, and *COL11A2* genes

*EYA1, SIX1*, and *SIX5* mutations

Genetic heterogeneity: TCS-1, TCS-2 and TCS- 3 have been

related to mutations in *TCOF-1*, *POLR1D* and *POLR1C* respectively

Severe-toprofound asymmetrical mixed losses.

Typically conductive and bilateral

sensorineural and conductive

Sensorineural, conductive or mixed hearing

About 40-50% of patients with Treacher Collins have conductive hearing loss. Few cases of mixed hearing loss have been described.

Both

loss

*FGFR2* mutations Mild to moderate

conductive hearing loss

• Choanal atresia • Coloboma

• Characteristic ears • Cranial nerve anomalie • Cardiovascular malformations

• Genital hypoplasia • Cleft lip/palate

• Growth deficiency • Developmental delay

• Long and flat face • Malar and mandibular hypoplasia

• Micrognathia • Glossoptosis • Cleft palate

nares • Altered vision • Joint problems

fistulae • Ear abnormalities • Kidney abnormalities

rims • Micrognathia • Narrow face

alae

• Cleft palate

• Craniosynostosis • Frontal bossing • Wide set eyes • Hypoplastic midface

• Tracheoesophageal fistula

• Small nose with a depressed nasal bridge and anteverted

• Branchial cleft, cysts or

• Zygomatic arches hypoplasia • Hypoplasia of supraorbital

• Antimongoloid slant of the eyes and hypertelorism • Coloboma of the lower lid

to the coloboma

• Down-turning mouth

• External ear abnormalities

with deficiency of cilia medial

• Large nose is with hypoplastic

**Charge syndrome** 

**Pierre Robin Sequence** 

**Stickler syndrome** 

**BOR syndrome** 

**Treacher-Collins syndrome** 

**Apert syndrome** 


Table 1. Main craniofacial syndromes associated with hearing loss

Genetic Hearing Loss Associated with Craniofacial Abnormalities 287

**Gender** M M F F

coloboma, atresia of the right choana, characteristic external ears and hypoplasia of the

Transposition of the great arteries surgically corrected during the first week of life. At 21 months growth deficiency was apparent. He showed delayed

motor milestones, hypotonia, and delayed development of social and emotional skills. He was fed via percutaneous endoscopic

cochlea. Characteristic facial features with squareshaped facies, narrow bifrontal diameter, broad nasal bridge, small mouth and inverted Vshaped upper lip. He had bilateral cryptorchidism, hypoplastic genitalia and orofacial cleft

and head circumference was 29.5 cm (3 th percentile). He had microcephaly

and

trigonocephaly, prominent forehead, flat occiput, narrow palpebral fissures, big and rounded nose with hypoplasic alae, small mouth, with the inferior dental arch lying behind the superior one, low-set ears, micropenis, talipes and metatarsus varus.

A single umbical artery was found.

laryngomalacia was found. Feeding difficulties (poor sucking, gastric stagnation, regurgitation, vomiting) with subsequent failure to thrive due to gastrooesophageal reflux and hypertrophic pyloric stenosis surgically

Breathing problems and chronic tirage due to

**Main problems**  **Case 1 Case 2 Case 3 Case 4** 

upper limbs, neck, head, axillae and inguinal region. She showed mild hypotonia and characteristic facial features: plagiocephaly, with flat occiput, frontal bossing, head bent to the left, left eyelid ptosis; thin upper lip with long filtrum and short

edematous eyelids and atresia of the left choana, Characteristic facial features: hypertelorism, bilateral frontal bossing, large anterior fontanel, bilateral hypoplasic elix and low-set ears, right eye ptosis, rounded nose with flat origin, hypoplasic alae

and micrognatia. The fifth finger was bilateral curved with nails

abnormalities.

Growth deficiency with delayed motor milestones and delayed development of social and emotional skills were apparent

tongue frenulum. Clinodactily of the fifth fingers. Bilteral shortness of ulna and radius with carpal bones relatively longer than fore-arm. Mild enlargement

of cardiac profile.

Low platelets count (16.000/mmc). Cranial USS showed mild dilation of lateral ventricles,

basal ganglia and candelabrum-like

secundum).

hyperechogenic areas in the

appearance of the thalamus. Echocardiography showed mild increasing pulmonary transvalvular gradient and atrial septum defect (ostium

Growth deficiency with delayed motor milestones and delayed development of social and emotional skills
