Year : 2000 | Volume
: 10 | Issue : 2 | Page : 93--98
Prenatal diagnosis of holoprosencephaly: Pictorial essay
Meera Hospital, Shiv Marg, Bani Park, Jaipur, India
S-9, Bhawani Singh Road, C-Scheme, Jaipur 302005
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Agarwal R. Prenatal diagnosis of holoprosencephaly: Pictorial essay.Indian J Radiol Imaging 2000;10:93-98
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Agarwal R. Prenatal diagnosis of holoprosencephaly: Pictorial essay. Indian J Radiol Imaging [serial online] 2000 [cited 2019 Dec 10 ];10:93-98
Available from: http://www.ijri.org/text.asp?2000/10/2/93/30610
Holoprosencephaly (HP) results from failure of the prosencephalon to differentiate into the cerebral hemispheres and lateral ventricles between the fourth and eighth week of gestation ,,. A spectrum of defects of malformations of the brain and face exists, which range from complete to partial failure of cleavage of the prosencephalon. Most cases are associated with severe malformations of the brain and face, which are incompatible with life and often cause spontaneous intrauterine death. At the other end of the spectrum are individuals with facial defects that may affect the eyes, nose and upper lip with normal or near-normal development.
Depending on the degree of disordered prosencephalic cleavage, HP is usually categorized as alobar, semilobar or lobar . In the most devastating lesion, the alobar type, there is no cleavage of the forebrain into right and left hemispheres, into the diencephalon and telencephalon and into the olfactory and optic bulbs. It results in a single, amorphous ventricle, fused thalami and absence of the corpus callosum, falx cerebri, optic tracts and olfactory bulbs ,. Semilobar HP, in which the brain's hemispheres have a slight tendency to separate, is an intermediate form of the disease. It shares many of these same features but demonstrates partial segmentation of the ventricles and incomplete fusion of the thalami ,. Lobar HP, in which there is considerable evidence of separate brain hemispheres, is the least severe form.
The etiology of HP is heterogeneous. Most cases occur sporadically and have a normal karyotype. However, the disorder can be associated with a variety of chromosomal abnormalities such as trisomy 13, ring chromosomes and deletions ,,,. The disorder can be familial, the mode of inheritance having been reported to be both, autosomal recessive and autosomal dominant ,,,. The extreme variation of clinical features associated with HP can also occur within a family ,. In several families, HP correlates with a broken chromosome at position 2p21 and 7q36 ,. Several genes have been implicated in causing this condition and the wild-type alleles at these loci are hypothesized to be crucial for normal forebrain development ,. In addition to the genetic component of HP, environmental factors are also crucial. HP can be associated with maternal diabetes . Several teratogens such as alkaloids of the plant Veratum Californicum and ethanol can cause HP . It is thought that these drugs affect the prechordal mesoderm during gastrulation and/or the neural plate during early neurulation . Other studies have implicated salicylates  and radiation in animals .
The prognosis of affected patients depends on the severity of HP. Alobar and semilobar HP have a very poor prognosis, virtually all infants with the more severe form die in the first postpartum year . Some children with semilobar HP may survive into infancy with amentia . Patients with lobar HP have variable degrees of mental impairment and visual and olfactory abnormalities , but often a normal life expectancy .
Since HP is not compatible with long survival, a specific prenatal diagnosis of the condition may be very influential in the clinical management of a pregnancy.
Craniofacial malformations may be a part of a number of syndromes with multi-system involvement  and their recognition may have important clinical relevance. Ultrasound is feasible and reliable in the prenatal diagnosis of such anomalies. These structural defects can be positively identified as early as the second trimester . However, limitations in the evaluation of the fetal face result from an unfavorable position of the fetus, oligohydramnios and/or maternal obesity. Cranial features are assessed by both axial and coronal sonograms of the fetal head  while the fetal face is evaluated by mid-sagittal, cross-sectional and axial scans . A mid-sagittal scan allows visualization of the fetal face profile; cross sectional images help to assess the integrity of the nose and lips. Axial scans are also used to evaluate the orbital diameters.
Sonographic features of alobar HP, the most severe form, include absence of midline structures (falx cerebri, interhemispheric fissure, absence of corpus callosum), single ventricle with a communicating dorsal sac, fused thalami and facial defects ,,. Instead of a ventricular system with distinct lateral and third ventricles, a mono-ventricular cavity is found occupying the frontal portion of the cerebrum on axial scans [Figure 1]A, [Figure 2]A, [Figure 3], [Figure 4], [Figure 5], [Figure 6]A. The single ventricular cavity displaces the thin rim of cortical mantle rostrally, which is shaped like a horseshoe or boomerang  [Figure 2]b,[Figure 3],[Figure 5]. The thin lining of the ventricular cavity may bulge out to occupy the space between the calvarium and cerebral cortex, forming a cyst known as the dorsal sac, filled with CSF  [Figure 2]b,c,[Figure 4],[Figure 6]A. The sac, if present, can be seen on axial scans at a higher level and by scanning in the coronal plane it may be possible to demonstrate a connection between the ventricular cavity and the dorsal sac  [Figure 2]b,c. However, the junction between the ventricular cavity and the sac is broad and thus relatively inconspicuous though a ridge of cerebral tissue that limits the dorsal sac . The ridge of celebral tissue that limits the dorsal sac from the central ventricle is called 'hippocampal fornix'  [Figure 2]b,c,[Figure 4],[Figure 6]A.
On axial scans, the fused thalami appear to protrude into the mono-ventricular cavity [Figure 1]a,[Figure 2]a,[Figure 3],[Figure 4],[Figure 5], while on coronal scans, the thalami are imaged at the floor of the single ventricular cavity [Figure 2]b,c. Such appearances of the fused thalami remain as one of the characteristic features of alobar HP. Sometimes a central linear echo can be seen in the fused thalami [Figure 2]a. The origin of this echo is unknown . The midbrain, brain stem. and the cerebellum are structurally normal . However, due to significant mass effect of the large mono-ventricular cavity and dorsal sac, the posterior fossa contents may be hypoplastic . These cranial features can be associated with macroceraphy helps in the management of the third trimester pregnancy because macroceraphy due to ventriculomegaly may prevent spontaneous vaginal delivery. To avoid a Cesarean section, cephalocentesis, i.e. decompression of the distended fetal ventricle using transabdominal needle placement under ultrasound guidance, should be considered ,.
Facial anomalities are frequently associated with HP but even in severe alobar HP may not always be present. DeMeyer  reported that 17% of patients with alobar HP had a normal face. Facial anomalities and are caused by incomplete cleavage during embryologic development . The degree of facial dysmorphism tends to parallel the severity of the HP. Facial anomalies in decreasing order of severity, include cyclopia [Figure 6]a,b, ethmocephaly [Figure 7], cebocephaly and a median cleft ,. Cyclopia is characterized by fused (single eye) or nearly fused orbits [Figure 6]a, arhinia [Figure 6]a and a supraorbital proboscis [Figure 6]a. On axial scans through the orbit, the fused single eye is imaged in the area normally occupied by the root of the nose. Absence of fetal nose is extremely rare and is usually associated with severe deformities such as HP. A proboscis is a soft tissue trunk-like appendage that is almost inevitably part of the HP sequence. Ethmocephaly consists of a high midline proboscis, located at the root of the nose, separating narrow-set eyes with an absent nose [Figure 7]. These features can be associated with abnormal smallness of one or both eyes, called as microphthalmia [Figure 8] or anophthalmia [Figure 2]d ,,,.
Cebocephaly is characterized by a small, flattened nose with a single nostril situated below incomplete or underdeveloped closely set eyes. The least severe in he spectrum of facial anomalies is median cleft lip [Figure 9] also called premaxillary agenesis. The median cleft lip is frequently associated with closely set eyes and flat nose.
The lesser grades of HP include various "midline" abnormalities including closely or widely set eyes, unilateral or bilateral cleft lip and others ,. Closely or narrowly set eyes are termed as hypotelorism [Figure 7]. It is defined as a decrease in interorbital distance. Increase in interorbital distance is known as hypertelorism [Figure 5]. Hypotelorism is frequently associated with HP malformation sequence ,,,. Antenatally hypo or hypertelorism can be diagnosed by comparing the outer and interorbital distances to those in established normograms ,.
The facial features described are absolutely specific for HP. Identification of a single orbit, a proboscis, single nostril or hypotelorism, in association with large intracranial fluid collections, confirms the diagnosis of HP with certainty .
In semilobar HP where some cleavage has occurred, the ventricles and the cerebral hemispheres are partially separated posteriorly. There is incomplete separation of the thalami, but anteriorly there is still a single ventricular cavity . The incomplete fusion of the thalami can be best observed on coronal sonograms of the fetal head . Macrocephaly or microcephaly together with facial defects including cyclopia, cebocephaly, ethmocephaly and median cleft can also occur with semilobar HP ,. Therefore, prenatally, it may be difficult to differentiate between the alobar and the semilobar forms but this is not important as the prognosis is similar.
A variety of extra-craniofacial abnormalities can also be seen with HP and include polydactyly, exomphalos [Figure 1]b, renal dysplasia and fetal hydrops [Figure 3] .
Distinguishing the alobar and semilobar HP from other causes of large intracranial fluid collections such as severe ventriculomegaly, hydranencephaly, large porencephalic cyst and large Dandy-Walker cyst, may not help in the fetal outcome because all of these malformations have a poor prognosis. But compared with these anomalies, HP is associated with a higher rate of chromosomal anomalies and has a familial tendency. Therefore, the correct diagnosis of HP is important for patient counseling and for guiding appropriate obstetric management . In case of large intracranial fluid collections other than HP, the midline structures are present and the supratentorial ventricular system can be visualized. Further, with these abnormalities, the characteristic facial features associated with HP are absent.
In lobar holoprosencephaly [Figure 10], there is no evidence of a mono-ventricular cavity and fusion of thalami; considerable evidence of separated brain hemispheres is present. The two hemispheres are separated anteriorly and posteriorly with a certain degree of fusion of structures such as the lateral ventricles and cingulate gyrus and absence of the cavum septum pellucidum . The interhemispheric fissure is well formed and unlike alobar and semilobar HP, the lateral ventricles are only fused anteriorly. Hoffman-Tretin  has reported two cases of lobar HP diagnosed prenatally where fusion of the anterior horns of the ventricular system and a central mass were identified [Figure 9]a. However, the diagnosis of lobar HP is difficult because it relies mainly on the absence of the cavum septum pellucidum, together with variable enlargement of the lateral ventricles. These findings are also associated with agenesis of the corpus callosum and septo-optic dysplasia ,.
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