Cerebro-oculo-nasal syndrome

Fabrice Cuillier, MD*, J.L. Alessandri, MD**, F. Cartault, MD***

*   Department of Gynecology, Félix Guyon Hospital, 97400 Saint-Denis, Ile de la Réunion, France.
**  Department of Neonatology, Felix Guyon Hospital, 97400 Saint-Denis, Réunion, France.
*** Department of Genetics, Felix Guyon Hospital, 97400 Saint-Denis, Réunion, France.

Introduction

Cerebro-oculo-nasal syndrome is a rare multiple congenital anomaly with structural anomalies of the central nervous system, ocular and nasal malformations. It was first described in 1993 by Richieri-Costa and Guion-Almeida. Later Guion-Almeida reported 13 more cases and reviewed seven others. Of this 20 reported cases, 18 were from Brazil.

Main manifestations include mental retardation with various structural anomalies of the central nervous system: encephalocele, ventricular dilatation, abnormalities of the corpus callosum, Dandy-Walker malformation, holoprosencephaly. The ocular malformations were mainly microphtalmia or anophthalmia. The nasal malformation resembled proboscis-like nares.

Etiology

The etiology of most of the reported cases remains unknown. Only one of the cases had known PTCH1 mutation (Sonic Hedgehog).

Ultrasound findings

Bilateral anophthalmia
Abnormal nares
Abnormal ears
Central nervous system anomalies

Additional findings:

Brachycephaly
Prominent forehead
Ocular hypertelorism
Malar hypoplasia
Large philtrum
High-arched palate with atypical cleft
Inferior rotated ears with hypoplastic tragus

Holoprosencephaly-like anomalies such as agenesis of the corpus callosum, cystic malformations or frontal encephalocele are present in 50% of the affected pregnancies. Abnormal proboscis-like nose appears to be  unique and diagnostic finding despite the clinical variability among the cases.

Differential diagnosis

  • Fronto-facio-nasal dysplasia
  • Acromelic fronto-nasal dysostosis
  • Oculo-auriculo-fronto-nasal syndrom
  • Amniotic band¬†syndrom

Associated anomalies: Malar hypoplasia; Pedunculated post-axial polydactyly; Genital hypoplasia; Hyperpigmented skin lesions

Prognosis

This syndrome is associated with a severe mental retardation, deafness and blindness and has a very poor prognosis.

Case report

This is a case of a 28-year-old G3 P0. Her first pregnancy was terminated for trisomy 21 and the second pregnancy resulted in a spontaneous abortion.  This pregnancy was uneventful at the beginning. The first trimester scan was negative, NT=1 mm, the triple test was normal and fetal karyotype was normal as well, 46 XX.

The ultrasound exam at 22 weeks of gestation was reported as normal. Patient was referred to our department at 28 weeks of gestation and her ultrasound exam revealed the following findings:

  • Facial dysmorphic features - frontal bossing, anophthalmia on the right, midline cleft lip, single nostril
  • Low set, malformed right ear
  • Fusion of thalami and monoventricle

The follow-up ultrasound at 29 weeks confirmed the previous findings. The intracranial findings suggested some form of holoprosencephaly. Coronal views showed nearly median cleft lip and a single nostril. Both hands, feet and heart did not show any abnormalities.

The couple was counseled and decided for pregnancy termination based on the poor prognosis for the fetus.

The pathology and MRI examination after pregnancy termination confirmed our ultrasound findings.

The final diagnosis was Cerebro-oculo-nasal syndrome. 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 and no mutations were discovered. DNA Microarray revealed a 108 Kb duplication of the region on the chromosome 7p22.1. This duplication involves gene RBAK which is responsible for the tumorigenesis and cell cycle control.

Images 1-4: 28 weeks, images show an extreme frontal bossing, abnormal facial profile, monoventricle.

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Images 5-8: 3D-images showing the dysmorphic facial features, frontal bossing, midline cleft lip, the right eye seemed missing. 

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Images 9,10: 3D-images of the malformed right ear which is small and low-set .

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Images 11,12: 29 weeks, image 11 shows the fused thalami and monoventricle. Image 12 shows the sagittal view of the brain with monoventricle.

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Images 13,14: Axial view of the fetal brain.

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Images 15,16: Image 15 shows the fused thalami. Image 16 shows the median cleft lip.

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Images 17,18: Image 17 shows a 3D-image of the midline cleft lip. Image 18 shows a normal looking hand.

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Images 19,20: Images of the face, note the anophthalmia on the right, single nostril, midline cleft lip and malformed right ear. Fetal cranium is markedly enlarged.

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Images 21,22: Images show the normal looking left ear.

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Images 23-25: X-ray images showing abnormal cranium but no other skeletal malformations,
 
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References:

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.

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