Holoprosencephaly

Holoprosencephaly

Holoprosencephaly (HPE) is a rare congenital brain malformation, resulting from incomplete separation of the two hemispheres.

Classically three sub types have been recognised, however additional entities are now included in the spectrum of the disease. The three main sub types, in order of decreasing severity are:

1. alobar holoprosencephaly
2. semilobar holoprosencephaly
3. lobar holoprosencephaly

Other entities:

• syntelecephaly(or middle interhemispheric variant (MIH))
• septo optic dysplasia
• other:
  • central incisor syndrome
  • non-specific midline dysplasia
  • frontonasal dysplasia
  • agnathia-otocephaly

This article is a general discussion of holoprosencephaly, with a more detailed discussion of individual radiographic features relegated to individual articles.

Epidemiology

Although rare in absolute terms, holoprosencephaly is the most common forebrain abnormality and is seen in 1 per 10,000-16,000 live births 3. The early embryonic occurrence may be even higher but may not be detected due to most fetuses aborting in early gestation.

Clinical presentation

It is usually obvious at birth even if antenatal diagnosis has not been made, due to associated midline facial anomalies including 3:

• proboscis
• cyclopia
• cleft lip and/or palate
• ocular hypotelorism
• solitary median maxillary central incisor

Additionally these children also have systemic problems, with poor feeding, hypothalamic/pituitary dysfunction and developmental delay 3.

Pathology

The fundamental problem is a failure of the developing brain to divide into left and right halves (which normally occurring at the end of the 5th week of gestation). This results in variable loss of midline structures of the brain and face as well as fusion of lateral ventricles and the 3rd ventricle.

Environmental factors such as maternal diabetes mellitus, alcohol use, and retinoic acid have been implicated in the pathogenesis, as has mutation of a number of genes including Sonic hedgehog and ZIC2, on chromosome 13q32, (the latter also implicated in syntelencephaly) 5-6.

Associations

Recognised associations include:

• aneuploidic/chromosomal:
  • trisomy 13: most common genetic abnormality associated with holoprosencephaly 4
  • trisomy 18
  • chromosome 7q deletion8
  • chromosome 2q deletion8
• non-aneuploidic:
  • congenital renal anomalies
  • congenital cardiac anomalies
  • diabetic embryopathy
  • facial anomalies
  • Shprintzen syndrome

Radiographic features

As with most cerebral structural congenital abnormalities, holoprosencephaly is visible on all modalities, but in general is identified on antenatal ultrasound (if performed), and best characterised by MRI. On antenatal ultrasound there may be also evidence ofpolyhydramnios an secondary feature due to impaired fetal swallowing.

Below are brief descriptions of the three main types. Note should be made that these are along a spectrum and as such some patients can be on the border between two types.

Alobar holoprosencephaly

In alobar holoprosencephaly, the thalami are fused and there is a single large posteriorly located ventricle. Most commonly associated with facial abnormalities such as cyclopia,ethmocephaly, cebocephaly, and median cleft lip.

For more details see the article on alobar holoprosencephaly

Semi-lobar holoprosencephaly

Here the basic structure of the cerebral lobes are present, but are fused most commonly anteriorly and at the thalami. The olfactory tracts and bulbs are usually not present, and there is agenesis or hypoplasia of the corpus callosum.

For more details see the article on semi-lobar holoprosencephaly

Lobar holoprosencephaly

This is the least affected sub type. Patients demonstrate more subtle areas of midline abnormalities such as fusion of the cingulate gyrus and thalami. The olfactory tracts are absent or hypoplastic. There may be hypoplasia or absence of the corpus callosum.

For more details see the article on lobar holoprosencephaly

Treatment and prognosis

The prognosis is dependent on the type of holoprosencephaly with almost all alobar and semilobar forms incompatible with extra-uterine life. There may be recurrence risk for ~6% with non chromosomal sporadic holoproseccephaly.

Differential diagnosis

The differential diagnosis largely depends on the type, and as such please refer to the individual articles above.

Holoprosencephaly: alobar

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 anomaliesinclude 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 malformationsinclude 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 306990ICD9 742.2 CDC 742.260

The early detection of fetal brain malformations is now possible1-3. 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 .disclosed an intrauterine pregnancy with fetal heart beat and crown-rump length (CRL) of 35 mm (consistent with 10.4 weeks)

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 .. A facial anterior coronal view verified hypotelorism . 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.

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, prognosis6,7.

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 weeks9-10. In utero diagnosis during the early second trimester was then reported11. Bronsthein12reported 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 holoprosencephaly14,15.

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.

 

STEVE RAMSEY, PHD- Calgary – Alberta