Address correspondence to Reuwen Achiron, MD, Dept. of Ob-Gyn, The Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel, Ph: 972-3-5302890; Fax: 972-3-5352081, ¶Dept of Neurology, Beilinson Medical Center, Petah-Tiqva. *§Dept of Medical Genetics, The Chaim Sheba Medical Center, Tel-Hashomer, Sackler School of Medicine, Tel Aviv University, Israel.

Synonyms: Arhinencephaly.

Definition: Alobar holoprosencephaly is the most severe form of cleavage failure of the forebrain (prosencephalon) before 6 weeks of gestation.

Prevalence: The reported incidence of holoprosencephaly is between 0.6-1.9:10,000 live births; however, since many cases of holoprosencephaly spontaneously abort, a higher incidence ( 1 in 250 pregnancies) is considered possible.

Etiology: Most cases are sporadic and of unknown cause. There are no environmental teratogens known to cause this malformation in humans, but in animals the condition can be induced by veratrum alkaloids and radiation. Ingestion of salicylates in pregnancy has also been reported in relation to holoprosencephaly. Holoprosencephaly is commonly seen associated with chromosomal abnormalities, especially trisomy 13 but also trisomy 18, 13q-, 18q-, and triploidy. Syndromes that include alobar holoprosencephaly among their manifestations are: Kallmann"s, campomelic dysplasia, Hall-Pallister, and Vasadi among others. Hereditary holoprosencephaly has been reported with autosomal dominant inheritance with variable penetrance (MIM 142945), autosomal recessive (236100) and X-linked recessive (306990).

Pathogenesis: Failure of cleavage of the prosencephalon which gives rise to the cerebral hemispheres and diencephalon during early first trimester (5-6 weeks) results in a single primitive monoventricle, fused basal ganglia, absence of corpus callosum, falx cerebri, optic tracts, and olfactory bulbs.

Associated anomalies: The facial anomalies include a broad spectrum of defects due to median central structure aplasia or hypoplasia: extreme hypotelorism or even cyclopia, cebocephaly (a flat nose or a nasal-like tubular appendix [proboscis] with hypotelorism), ethmocephaly (extreme hypotelorism with arhinia with proboscis and median cleft palate). Extracranial malformations include renal cysts and dysplasia, omphalocele, cardiovascular malformations, clubfoot, myelomeningocele and intestinal abnormalities.

Prognosis: Alobar holoprosencephaly is a lethal condition; infants die perinatally or neonatally.

Recurrence risk: With absence of chromosomal abnormalities, it has been estimated to be 6% (but this includes both truly sporadic events and hereditary conditions with 25-50% risk); with abnormal karyotype such as trisomy, it is associated with about 1% recurrence.

Management: Fetal karyotype is mandatory when holoprosencephaly is discovered by ultrasound; termination of pregnancy should be offered to parents of previable fetuses.

MESH Holoprosencephaly BDE 0473 MIM autosomal dominant 142945, autosomal recessive 236100 and X-linked recessive 306990 ICD9 742.2 CDC 742.260

Introduction

The early detection of fetal brain malformations is now possible^1-3. Although alobar holoprosencephaly has been described during the first trimester⁴, detailed transvaginal sonographic description of the condition has not been shown. The purposes of this communication are to describe the intracranial findings consistent with alobar holoprosencephaly and to emphasize the role of high frequency transvaginal ultrasonography in establishing early diagnosis at 10 weeks of gestation.

Case report

A 26-year-old primigravida with an unremarkable past medical history was referred to our ultrasonographic unit at 10.5 weeks menstrual age, due to a bloody vaginal discharge for two days. An ultrasound examination using a high-frequency transvaginal transducer (7.5 MHz Elscint ESI 3000 Ltd, Haifa, Israel) disclosed an intrauterine pregnancy with fetal heart beat and crown-rump length (CRL) of 35 mm (consistent with 10.4 weeks) (fig. 1).

Figure 1: Longitudinal scan demonstrating 35 mm crown-rump length fetus compatible with 10.4 weeks gestation. The fetal head is on the left.

The fetal cranium could be clearly delineated. High axial scan at the level of the lateral ventricles failed to identify the bilateral prominent intrahemispheric echogenic choroid plexus which normally almost completely fills the lumens of the lateral ventricles at this gestational age1. Instead, a single, wide, fluid-filled monoventricle with no detectable midline echo was observed, displacing the cerebral cortex laterally, and pushing the choroid plexuses against fused thalami when seen in the midcoronal view (fig. 2). A facial anterior coronal view verified hypotelorism (fig. 3). These findings are characteristic of alobar holoprosencephaly. Due to the very poor prognosis, which was explained to the family, the parents requested an immediate termination of pregnancy; this was done by dilatation and evacuation. Chromosomal analysis of the products of conception revealed trisomy 13. No postmortem examination of the brain was possible.

Figure 2: Midcoronal view of a 14 mm wide cranium (between calipers). A single, wide, fluid-filled ventricle is seen. The third ventricle is absent, the thalami (t) are fused at the floor of the monoventricle (m), and there are no detectable midline echoes. The cerebral cortici (c) are displaced laterally and caudally. p, choroid plexus.

Discussion

Holoprosencephaly is a rare central nervous system malformation resulting from absent or incomplete cleavage of the forebrain (prosencephalon) into the two cerebral hemispheres and lateral ventricles.

Etiology and classification

Depending on the degree and the stage at which morphologic development is inhibited, DeMayer categorized holoprosencephaly into alobar, semilobar, and lobar types⁵.

·         Alobar holoprosencephaly is the most severe lesion, in which no cleavage of the prosencephalon has occurred. Instead of a ventricular system with distinct lateral and third ventricles, a monoventricle cavity is present. The thalamus and corpus striatum are fused in the midline, while the midbrain, brainstem, and cerebellum may be structurally normal. Facial abnormalities associated with this type include cleft lip and palate, cyclopia, and chromosomal aberrations, usually trisomy 13, are common in the group.

·         Semilobar holoprosencephaly results from less severe cleavage abnormalities of the prosencephalon. Although a frontal monoventricle is present, posterior partial formation of occipital lobes occurs.

·         In the mildest form, lobar holoprosencephaly, the two hemispheres and lateral ventricles are better separated, the hemispheres may be fused, and the lateral ventricles widely intercommunicated due to absence of the septum pellucidum.

The prognosis of affected infants depends on the severity of holoprosencephaly. Alobar holoprosencephaly is uniformly lethal, while the prognosis of lobar is variable. Infants with the lobar type may have mild, moderate or severe mental retardation. Semilobar holoprosencephaly has an intermediate but generally quite poor, prognosis^6,7.

Associated abnormalities

Aneuploidies

Several chromosomal abnormalities are associated with alobar holoprosencephaly, with the most frequent being trisomy 13; others are trisomy 18 and partial monosomies of 13q and 18q.

Facial anomalies

Severe facial anomalies are typical of alobar holoprosencephaly. The presence of hypotelorism, cyclopia, arhinia with proboscis and median cleft lip/palate help in reaching the diagnosis by ultrasound⁸. In our case, the appearance of hypotelorism supported the specific diagnosis of alobar holoprosencephaly, and trisomy 13 was found on karyotype analysis.

Diagnosis

Due to the poor prognosis, a specific in utero diagnosis of holoprosencephaly is important. Until 1984, the earliest gestational age at the time of diagnosis was 27 weeks^9-10. In utero diagnosis during the early second trimester was then reported¹¹. Bronsthein¹² reported the diagnosis at 14 weeks, and Birnholz¹³ at 12 weeks. Nelson and King⁴ reported first trimester diagnosis of this anomaly but with vague intracranial findings. In the present case, using a high-frequency transvaginal probe (7.5 MHz), identification of earlier fused thalami and a large monoventricular cavity at 10.5 weeks was possible. In addition, absence of midline echo and third ventricle was noted. Although pathologic confirmation of the sonographic features was not possible, the detailed sonographic images were typical of alobar holoprosencephaly^14,15.

Embryologically, holoprosencephaly develops as early as 5-6 weeks of gestation. Therefore, it was not surprising that a high-resolution transvaginal transducer enabled an early in utero diagnosis. In a previous study, we showed that at the beginning of the tenth week the telencephalon, which consists of two lateral outpockets representing the cerebral hemispheres, is clearly identified due to the echogenic choroid plexus which fills the cavities of the lateral ventricles almost completely¹. Caudally, the hypoechoic thalamus, which is the dominant portion of the developing diencephalon, can also be observed at this gestational age. Failure to identify this classical pattern, together with the appearance of facial abnormality, provided an accurate specific prenatal diagnosis so early in pregnancy.

Differential diagnosis

In the differential diagnosis of a fetus with a large intracranial frontal cyst at such a stage of gestation, other abnormalities should be considered. It would be difficult to differentiate alobar holoprosencephaly from hydranencephaly, since absence of the midline echo is found in both conditions. However, midline structures such as falx cerebri, interhemispheric fissure and third ventricle are present in hydranencephaly and absent in alobar holoprosencephaly. In our case, hydranencephaly could be excluded by demonstration of displaced cerebral cortex and hypotelorism that are typical of alobar holoprosencephaly.

Prognosis

From a practical perspective, the prognosis for both hydranencephaly and alobar holoprosencephaly is very poor; therefore, early termination of pregnancy may be requested by the family. Obviously, the main advantage of a first-trimester transvaginal diagnosis of severe brain abnormality is that it allows parents to elect rapid karyotype study and terminate the pregnancy. If termination of pregnancy is requested following the diagnosis, it can be carried out by dilatation and evacuation, which to many pregnant women is a more acceptable procedure and entails lower risk of complications to the mother than does termination later in the second trimester.

References

1. Achiron R, Achiron A. Transvaginal ultrasonic assessment of the early fetal brain. Ultrasound Obstet Gynecol 1991;1:336-44.

2. Kennedy KA, Flick KJ, Thurmond AS. First trimester diagnosis of exencephaly. Am J Obstet Gynecol 1990;162:461-3.

3. Achiron R, Malinger G, Tadmor O, Diamant Y, Zakut H. Exencephaly and anencephaly: A distinct anomaly or an embryologic precursor. In utero study by transvaginal sonography. Israel J Obstet Gynecol 1990;1:60-3.

4. Nelson LH, King M. Early diagnosis of holoprosencephaly. J Ultrasound Med 1992;11:57-59.

5. DeMyer W. Holoprosencephaly. In Vinken PJ, Bruyn GW (eds.) Handbook of Clinical Neurology. Amsterdam: Elsevier, 1977, Vol 30, pp 431-78.

6. Manelfe C, Sevely A. Neuroradiological study of holoprosencephalies. J Neuroradiol 1982;9:15-45.

7. Gorlin RJ, Cohen MM, Levin LS. Syndromes of the Head and Neck, Third Edition. The holoprosencephalic disorders, . New York: Oxford University Press, 1990, pp 573-582.

8. Hunke M. Clinical cytogenetic and molecular approaches to the genetic heterogeneity of holoprosencephaly. Am J Med Genet 1989;34:237-45.

9. Chervenak FA, Isaacson G, Mahoney MJ, Tortora M, Mesologites T, Hobbins JC. The obstetric significance of holoprosencephaly. Obstet Gynecol 1984;63:115-21.

10. Toth Z, Csecsei K, Szeifert G, Torok O, Papp Z. Early prenatal diagnosis of cyclopia associated with holoprosencephaly. JCU 1986;14:550-53.

11. Nyberg DA, Mack LA, Bronstein A, Hirsch J, Pagon RA. Holoprosencephaly: prenatal sonographic diagnosis of fetal anomalies. AJR 1987;149:1051-58.

12. Bronstein M, Weiner Z. Early sonographic diagnosis of alobar holoprosencephaly. Prenat Diagn 1991;11:459-62.

13. Birnholz JC. Smaller parts scanning of the fetus. Radiol Clin North Am 1992;30:977-991.

14. Filly RA, Chinn DH, Callen PW. Alobar holoprosencephaly: ultrasonographic prenatal diagnosis. Radiology 1984;151:455-59.

15. Pilu G, Romero R, Rizzo N, Jeanty P, Bovicelli L, Hobbins JC. Criteria for prenatal diagnosis of holoprosencephaly. Am J Perinatol 1987;4:41-9.