1 Department of Gynecology, Felix Guyon Hospital, 97400 Saint-Denis, Réunion, France.
2 Department of Neonatology, Felix Guyon Hospital, 97400 Saint-Denis, Réunion, France.
3 Department of Genetic, Felix Guyon Hospital, 97400 Saint-Denis, Réunion, France.

Synonyms:

Otocephaly, Agnathia with holoprosencephaly.

Definition:

Otocephaly can be an isolated malformation or associated with others anomalies such as holoprosencephaly, neural tube defects, cardiopathy, renal ectopia, vertebral and ribs abnormalities.

The syndrome complex of otocephaly is divided into four types:

• Isolated agnathia.
• Agnathia with holoprosencephaly.
• Agnathia with situs inversus and visceral anomalies
• Agnathia, holoprosencephaly, situs inversus and other visceral anomalies.

Otocephaly, Agnathia with holoprosencephaly is a complex, lethal anomaly characterized by hypoplasia or absence of the mandible with abnormally positioned ears and any form of holoprosencephaly.

We described a case of prenatal detection of otocephaly, agnathia with holoprosencephaly, using 3D sonography at 13 weeks.

Case report:

A 20-year-old (G2P0) patient with the first pregnancy terminated by a voluntary interruption.  Concerning this second pregnancy, nuchal translucency was 3.3 mm (CRL = 60 mm). Hygroma coli was noted. A trophocentesis was proposed. The fetal karyotype was normal (46XY).  

• At 13 weeks, abnormal ultrasound findings were:    
• Holoprosencephaly with thalami fusion and single ventricular.  
• Right club hand, normal left hand, normal feet. 
• Abnormal profile with probable agnathia. Abnormal bilateral low-set ears were present.
• Atrio-ventricular septal defect.  
• The more important finding was extreme form of micrognathia, or in fact, agnathia. The combination of agnathia and abnormal ear, with the presence of holoprosencephaly.

The diagnosis of otocephaly, holoprosencephaly agnathia was confirmed with normal karyotype. To eliminate a particular form of holoprosencephaly, routine laboratory blood tests and G-banded chromosome were done: SHH (Sonic Hedgehog), ZIC2, SIX3 and TGIF, PTCH, GLI2, TMEM1 AND FBXW11 mutational analysis were performed (No mutation).

History:

Agnathia was initially reported by Ahfeld in 1882. The first antenatal diagnosis was made by Scholl on 1977.

Prevalence:

Few cases have been reported. All cases occurred sporadically. We don’t know actually exactly the frequency. According to the literature and Joffe in 1991 (http://www.sonoworld.com/TheFetus/page.aspx?id=191), the prevalence of Otocephaly-Agnathia- Holoprosencephaly is unknown (less than 10 cases were described twenty years ago).

Otocephaly has an estimated prevalence of one in 70.000 births.

Etiology:

Otocephaly-Agnathia-Holoprosencephaly may be autosomal recessive inheritance.

Pathogenesis:

Unknown. Otocephaly has been designed the most extreme of the first and second branchial arch defects. According with different authors, Otocephaly-Agnathia-Holoprosencephaly is probably due to failure of migration of neural crest mesenchyme into the maxillary prominence at the fourth to fifth week of gestation (post-conception).

Diagnosis:

Otocephaly, agnathia with holoprosencephaly should be suspected when it is impossible to visualize the mandible and when the ears seems in a very low and medial position. Other findings include: absent ears, dysplastic ears, low-set ears, hypertelorism, prominent eyes, proboscis, blepharospasm, choanal atresia stenosis, absent mandible, cleft palate, absent or hypoplastic tongue.

Differential diagnosis:

Otocephaly, agnathia with holoprosencephaly is a so unique syndrome, that differential diagnosis is extremely limited:

• Agnathia-microstomia-synotia: also called otocephaly, is a possible differential diagnosis. Agnathia-microstomia-synotia is defined as absence or hypoplasia of the mandible, proximity of the temporal bones, and abnormal position of the ears¹. When complicated by holoprosencephaly, it is referred to as “agnathia- holoprosencephaly”. This is an extremely rare malformation (less than 10 cases reported). When it is not associated with central nervous system malformations, this anomaly is simply referred to as “agnathia-microstomia-synotia”.
  

• Oto-cephaly : or Synotia – agnathia – melotia. This is a craniofacial syndrome with a constellation of findings consistent with symmetrically deficient development of the first branchial arch. Typically, those affected have low-set ears, microstomia, and an atrophic to absent mandible. Secondary to oropharyngeal incompetence, ventilatory difficulties typically lead to the imminent death of these infants shortly after birth. The syndrome can occur alone, or in association with holoprosencephaly (when it is then called agnathia-holoprosencephaly). 
• Fronto-facio-nasal dysplasia: must be eliminated, by the nasal malformation. 
• Acromelic fronto-nasal dysostosis: Nasal and ocular involment are present. Acromelic involment is present.
• Oculo-auriculo-fronto-nasal syndrome: nasal and ocular involment are present. First branchial arch involvment distinguish it from CONS.  
• Treacher – Collins syndrome: present severe micrognathia with abnormal ears. Cleft palate and Mandibular hypoplasia is present without agnathia.  
• Nager syndrome: or acro-facial dysostosis, including radial limb defect, hypoplastic thumbs and hypoplasia of the radius. 
• Robin anomalad: The differential diagnosis includes agnathia-microstomia-synotia (no holoprosencephaly) and the Robin anomalad. This is another disorder of formation of the mandible, which is characterized by mandibular hypoplasia, posterior cleft palate, and posterior displacement of the tongue. The key to distinguish agnathia-microstomia-synotia from Robin anomalad is localization of the ears. The ears remain in the midline over the neck in agnathia-microstomia-Synotia, while some degree of “migration” does occur in the Robin anomalad.  
• Cerebro-costo-mandibular syndrome: is congenital disorder including severe micrognathia, usually as a part of Robin anomalad with glossoptosis and cleft palate, posterior rib defects of variable extent and severity, facultative cerebral disorders and other associated anomalies. 
• Goldenhar syndrome: facio-auriculo-vertebral dysplasia: consist of pre-auricular ear tags, macrostomia, and vertebral anomalies.  
• Melotia:

Associated anomalies:

Holoprosencephaly, cephalocele, dysgenesis of corpus callosus, cerebella hypoplasia, atresia of third ventricle, midline proboscis, hypoplastic tongue, tracheoesophageal fistula, cardiac anomalies, and adrenal hypoplasia¹.

Prognosis:

The prognosis is lethal.

Recurrence risk:

Theorically none.

Management:

Interruption must be proposed.

Figure 1-3: Hygroma coli was noted.

Figure 4-8: 2D sonography showed holoprosencephaly with thalami fusion and single ventricular

Figure 9, 10: 2D and 3D sonography showed right club hand 

Figure 11-14: 3D scan showed facial anomalies with agnathia, microstomia and abnormal ear insertion.

Figure 15: Abdominal and thorax transverse view showing complete atrio-ventricular septal defect.

Figure 16-20:  Postmortem view of the fetus confirms the absence of the mandible and presence of low-set ears.

Reference:

1- Kokitsu-Nakata N.M, Pittoli S.V., Da Costa A.R.- Cerebro-oculo-nasal syndrome: report of a case with a severe phenotype. Am J Med Genet A. 2009 Mar; 149A (3):519-20.

2- Richieri-Costa A, Ribeiro LA. Cerebro-oculo-nasal syndrome, a disorder with some manifestations suggestive of the holoprosencephalic spectrum: new case and imaging review of previous cases. Am J Med Genet A. 2005 Aug 1;136A(4):352-

3- Guion-Almeida ML, Zechi-Ceide RM, Richieri-Costa A. Cerebro-oculo-nasal syndrome: 13 new Brazilian cases. Am J Med Genet A. 2007 Dec 15;143A(24):3252-66.

4- Guion-Almeida ML, Kokitsu-Nakata NM, Richieri-Costa A. Clinical variability in cerebro-oculo-nasal syndrome: report on two additional cases. Clin Dysmorphol. 2000 Oct;9(4):253-7.

4- Rahmani R., Dixon M., Chitayat D., Korb E., Silver M., Barozzino T., Toi A.- J Ultrasound Med 1998 ; 17 : 595-8.