Cuillier F. MD*, Avignon MS, MD**, Avignon A, MD***

* Department of Gynecology, Félix Guyon’Hospital ** Gynecologist *** Radiologist Saint-Denis, Ile de la Réunion, France.

Definition: Holoprosencephaly is a developmental abnormality of the fetal brain, resulting from failure of cleavages of the prosencephalon. There are three different forms: alobar, semilobar and lobar. Holoprosencephaly is frequently associated by midline facial abnormalities such as cyclopia, ethmocephaly, cebocephaly and premaxillary agenesis (Potters).

Case report: A 26-year-old woman, primigravida, was referred to our service at 19 weeks, with a suspicious of a microcephaly. She denied any exposition of to alcohol, teratogenic agents, irradiation of infectious diseases during the pregnancy. The patient did not have a first trimester screening. At 16 weeks, the Down syndrome risk was 1:300 calculated by the seric markers.

The ultrasound examination performed at 19 weeks, revealed an alobar holoprosencephaly, with centrally fused thalami surrounded by a mono ventricle. The microcephaly was confirmed associated with hypertelorism and a frontal encephalocele. The heart was normal. There was no polydactyly.

After extensive counseling, parents decided for the interruption of pregnancy. Amniocentesis and termination were performed at 20 weeks. The karyotype was normal. An autopsy was refused. The female fetus weighted 400g and measured 15 cm. The external autopsy findings were an striking cranial-facial abnormalities and hypertelorism. The nose was present but an anterior encephalocele was confirmed. On X-ray examination of the skull, the frontal defect was confirmed.

View of the fetal brain at 19 weeks revealing microcephaly, fused thalami surround by a monoventricle.

Left image: Note the hypertelorism. Right image: Note the mass above the nose.

View of the fetal face showing the mass upper the nose.

Note the mass and the hole above the nose

3D view showing an anterior hole between the orbits.

Postnatal view of the fetus

History: Cyclopia has been known since antiquity, as described by Homer in the figure of Polyphemos, the giant cyclopic who was blinded by Odysseus (800 year BC). The first suspected prenatal diagnosis of holoprosencephaly has been described by Kurtz et al in 1980 (Blas). The prenatal sonographic diagnosis of alobar holoprosencephaly was first described in 1984. With increasing quality of ultrasound equipment detection of holoprosencephaly is now possible at an earlier gestational age. Achiron et al (1995) described one case at 10 weeks and 4 days as well as Wong (1999), Hong Soo Wong (1999) and Turner (1999). Blass et al (1999) described another case of holoprosencephaly at 9 weeks and other case at 10 weeks and 2 days.

Prevalence: The incidence of holoprosencephaly is about 0,6;1,9:10000 live births. However, since many cases spontaneously abort and milder forms may be unrecognized, a higher incidence is considered possible. In the cases without chromosomal abnormalities, the recurrence risk is estimated to be 6%. Holoprosencephaly occurs in about 70% of the patients with Trisomy 13.

Etiology: The etiology of holoprosencephaly is heterogeneous and not completely known. Most cases are sporadic and environmental, mechanical and genetic factors have all been implicated as possible causes. Several chromosomal disorders have been described in the literature. Trisomy 13 is the most frequently related. Holoprosencephaly in association with extra cephalic malformations suggests aneuploidy. Familial holoprosencephaly is known. Autosomal dominant and autosomal recessive forms have been described as have environmentally includes cases. In experimental animal studies, the condition has been induced by teratogenic agents.

Pathogenesis: In alobar holoprosencephaly, the most severe form, the cerebral hemispheres are fused and enclose a single prosencephalic ventricle. There is a complete failure of cleavage of the forebrain into two hemispheres. It results in a single ventricular cavity with fusion of thalami, absence of corpus callosus, falx cerebri, optic tracts and olfactory bulbs. Partial cleavage results in semilobar holoprosencephaly, with posterior separation of the cerebral hemispheres, variable degrees of fusion of the thalami and absent olfactory bulbs and corpus callosus. In lobar holoprosencephaly, the abnormalities may be confined to absence of the corpus callosus and fusion of the lateral ventricles and cingulate gyrus. The two hemispheres are separated anteriorly and posteriorly.

The more severe forms include:

• Cyclopia: is usually associated with alobar holoprosencephaly. There is median monoophthalmia, synophthalmia or anophthalmia with proboscis.
• Cebocephaly: literally « monkey head », presents with ocular hypotelorism and a blind single nostril nose.
• Ethmocephaly: There is ocular hypotelorism with proboscis.
• Median cleft lip

Sonographic findings: Prenatal diagnosis of holoprosencephaly is usually performed in the second trimester by the demonstration of fused lateral ventricles, no visible midline structures and fusion of the thalami. Nowadays, prenatal sonographic diagnosis is feasible in the first trimester, by the visualization of the cross detection of the fetal brain. In these cases, in fetuses between 11 and 14 weeks, the principal sign (« butterfly sign ») is absent.

Implications for target examinations: Associated anomalies should be looked for. An amniocentesis is indicated.

Differential diagnosis: The differential diagnosis includes hydranencephaly and severe hydrocephaly.

Associated anomalies: Holoprosencephaly is an obligatory or associated feature in a wide range of syndromes. Therefore careful antenatal scanning to detect associated anomalies is essential to enable a correct diagnosis. Commonly associated anomalies are post-axial polydactyly, congenital heart defects (features of both trisomy 13 and pseudo T13), renal dysplasias, and encephalocele (seen in Meckel's syndrome, micro and macrocephaly, exomphalos and polyhydramnios). There is often considerable overlap between many of the individual features of each syndrome.

Prognosis: The management of fetuses with alobar and semi-lobar holoprosencephaly is based on their uniformly poor prognosis. The most infants die shortly after birth and there is a severe mental retardation in the survivors. Termination of the pregnancy is common.

Management: Because of the high risk of associated chromosomal anomalies, karyotype should be offered in all cases. This may not be relevant to the management of the current pregnancy but it helps with counseling for recurrence risk. Cytogenetic analysis should look in particular for the following chromosomal rearrangement:

• Trisomy 13 and
• Tisomy 18,
• del (13q),
• del (18p),
• dup. (3p) and
• del (7q36).

If the karyotype is normal, the presence of other abnormalities, may suggest the presence of a specific syndrome. Genetic counseling is complicated by the malformation heterogeneity. If it is caused by a genetic abnormality, the recurrence risk is approximatively 1%. If the parents are carriers of a balanced translocation, the recurrence risk is higher. Syndromic holoprosencephaly will carry a recurrence risk specific to the syndrome (Potter). A sporadic case of holoprosencephaly, with no evidence of a chromosomal abnormality, has an empirical recurrence risk of 6%.

In our case, unfortunately, the patient did not perform the first sonography at 13 weeks. We could have done the diagnosis by not seeing the « butterfly sign ». The slicing figures from a 3-D reconstruction easily revealed holoprosencephaly with central bony defect and the surface –rendering mode clearly showed the encephalocele with brain exteriorization.

References
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2- Blaas H.G.K.- Picture of the month. Holoprosencephaly at 10 weeks and 2 days (CRL 33 mm). Ultrasound Obstet Gynecol 2000 15 : 86-7.

3- Fu-Nan Cho, Yuen-Yee Kan, San-Nung Chen, te-Ching Lee, Ti-ju Hsu, Pei-Hua Hsu- Prenatal diagnosis of cyclopia and proboscis in a fetus with normal chromosome at 13 WG by three-dimensional transabdominal sonography. Prenatal Diagn 2005 ; 25 : 1059-72.

4- Hong Soo Wong, Mary Hoi Yin Tang, Kin Wing Yan, lauvena Wu Kiu Cheung- Histological findings in a case of alobar holoprosencephaly diagnosed at 10 WG of pregnancy. Prenat Diagn 1999 ; 19 : 859-62.

5- Potters A.E., Schierbeek J.M. Jansen W.- A unique case of holoprosencepgaly. Prenat Diagn1996 ; 16 : 950-3.6- Sepulvada W., Dezerega V., Be C.- First trimester sonographic diagnosis of holoprosencephaly. J Ultrasound Obstet Gynecol 2004 ; 23 : 761-5.

7+ Turner C.D., Silva S., Jeanty P.- Prenatal diagnosis of alobar holoprosencephaly at 10 weeks of egstation. Ultrasound Obstet Gynecol 1999 ; 13 : 360-2.

8- Wong H.S., Lam Y.H., Tang M.H.Y., Cheung L.W.K., Ng L.K.L., Yan K.W.- First-trimester ultrasound diagnosis of holoprosencephaly : Three case reports. Ultrasound Obstet Gynecol 1999 ; 13 :356-9