Holoprosencephaly

Failure of separation of the cerebral hemispheres fequently associated with complex cranio-facial malformations.

Arhinencephaly, holotencephaly, aprosencephaly, atelencephaly, syntelencephaly, otocephaly, cyclopia, ethmocephaly, cebocephaly

ICD-10: Q04.2

The prevalence of holoprosencephaly at birth and in pregnancy terminations has been extensively reviewed recently and is in the range of 1:10,000.^1-4 However, there is probably a high fatality rate in very early gestation, and one study has reported a prevalence of 1:250 early voluntary termination of pregnancy.⁵

Failure of the precordal mesenchyma to induce cleavage of the forebrain and midfacial development is thought to result in a combination of cerebral and facial defects.^6-9

Heteroegenous. Most cases are sporadic and of unknown cause. Genetic causes, (chromosomal aberrations and monogenic transmission) are identified in 15-50% cases. The most common aneuploidies include trisomy 13, triploidy and trisomy 18.^{2, 10, 11} Mutations in the sonic hedgehog gene are the most common cause of sporadic and inherited holoprosencephaly. Several loci for holoprosencephaly have been mapped to specific chromosomal sites and the molecular defects have been identified in some cases^{7, 12, 13}. A number of genetic syndrome include holoprosencephaly among their manifestations.⁷ Hereditary holoprosencephaly has been reported with autosomal dominant inheritance with variable penetrance, autosomal recessive and X‑linked recessive⁷. In some cases, only minor findings can be recognized, such as a single median incisor.^{7, 14} An association between fetal holoprosencephaly and several types of teratogens has been suggested, including maternal diabetes, alcohol and retinoic acid consumption.¹⁵

Holoprosencephaly includes a spectrum of malformations of brain and face. Three major varieties are recognized: alobar, semilobar and lobar type. ^{7, 16} In the alobar variety, the most severe one, the interhemispheric fissure and the falx cerebrii are totally absent, there is a single primitive ventricle, the thalami are fused on the midline and there is absence of the corpus callosum and septum pellucidum, third ventricle, neurohypophysis, olfactory bulbs and tracts. In the semilobar variety, the cerebral hemispheres are partially separated posteriorly but there is still a single ventricular cavity. In both the alobar and semilobar forms, the roof of the ventricular cavity, the thela choroidea, normally enfolded within the brain, may balloon out between the cerebral convexity and the skull to form a cyst of variable size, commonly referred to as the dorsal sac. With lobar holoprosencephaly the anatomical derangement is less extensive. The hemispheres are almost completely divided, and there is fusion only at the level of the cyngulate gyrus and in the lower portion of the frontal horns The septum pellucidum is always absent, the frontal horns and fornices are fused. The corpus callosum is usually absent although fibers crossing in between the two hemispheres may simulate it on diagnostic imaging techniques. This classification is debated and many variations are commonly encountered. Recently two new varieties have been described: the middle interhemispheric variant of holoprosencephaly (intermediate between the lobar and alobar type) and synthelencephaly (minimal degree of fusion of the cerebral hemispheres).^{7, 17, 18}

Facial anomalies are fequently encountered in the holoprosencephalic sequence, and they are almost the rule with the most severe forms. Facial anomalies encompass a spectrum of midfacial hypoplasia. Four main categories are commonly encountered:6, 7

- cyclopia, (single eye or partially divided eyes in a single orbit, absence of the nose usually with a proboscis implanted above the orbit;

- ethmocephaly. (hypothelorism, absence of the nose with a proboscis implanted above the orbits)

- cebocephaly, (hypothelorism and a proboscis-like nose)

- hyptelorism and median cleft lip, (hypothelorism and a very flattened or absent nose. Median cleft lip/palate);

Holoprosencephaly is also frequently associated with otocephaly, a severe cranio-facial malformation characterized by extreme hypoplasia or absence of the mandible and abnormal horizontal displacement of the ears. 19-21

Holoprosencephaly reflects a very early derangement of embryogenesis.^{8, 16} As such, it is very frequently associated with other malformations. Chromosomal aberrations are found roughly in 50% of cases. Trisomy 13 is by far the most frequent one (20% of cases). Conversely, over 60% of infants with trisomy 13 have holoprosencephaly. Other aneuploidies associated with holoprosencephaly include triploidy and trisomy 18.^{2, 7, 10, 11, 17} Syndromes that may be associated with holoprosencephaly include: Di George, Meckel, Kallmann's, campomelic dysplasia, Hall‑Pallister, and Vasadi among other.^{13, 22} Microcephaly is frequently encountered, less frequently hydrocephalus and macrocrania.^{17, 23}

In euploid fetuses the recurrence risk is 20%.²⁴ Genetic consultation is recommended because minor signs of holoprosencephaly in the members of the family may suggest monogenic inheritance with a higher recurrence rate, and may dictate the need for DNA analysis.^{6, 14}

In the severe forms, alobar and semilobar varieties, there are no midline structures in the anterior part of the brain. The boomerang shaped ventricle outlined anteriorly by a rim of cortex and posteriorly by the bulb-shaped thalami is in general the most striking sonographic feature. Severe facial anomalies including cyclopia, hypotelorism, probocis and median cleft lip are usually easily demonstrated.^{17, 23} As the derangement from the normal appearance of the cerebral and facial anatomy is extensive, diagnosis is easy in most cases and is frequently made at the 11-13 weeks scan. By transvaginal sonography, holoprosencephaly with cyclopia has been recognized at 9 weeks’ gestation.^{25, 26} It has been recently demonstrated that holoprosencpehalic fetuses have fusion of the frontal bone with obliteration of the metopic suture as early as 11 weeks.²⁷

There are however many possible anatomic variations that may result in different sonographic appearances. The monoventricular cavity may communicate superiorly and posteriorly with the cystic dorsal sac, usually through an ample opening. At the junction between the ventricle and the dorsal sac the cortex is infolded to form a ridge of tissue, that corrisponds to the hippocampal fornix.²³ Depending upon the degree of infolding of the cortex over the monoventricular cavity and the presence or absence of the dorsal sac three varieties have been described: the pancake, the cup and the ball types.⁷

Alobar and semilobar varieties have similar appearances and are frequently difficult to differentiate. Probably the best sonographic clue is the visualization of the hippocampal fornix.²³ In alobar holoprosencephaly the hippocampal fornix and rudimentary gyrus are separated from the brain stem. In semilobar holoprosencephaly the hippocampus is seen close to the thalami to form the echogenic ambient cistern.

Specific diagnosis of lobar holoprosencephaly may be difficult at times. The face is usually normal and chrosomal aberrations are not frequent. In most cases, sonography will present with some degree of enlargement of lateral ventricles, absence of the septum pellucidum and a wide communication between the frontal horns and the inferior third ventricle.^{17, 18, 28} The major problem resides in the differential diagnosis between lobar holoprosencephaly and other conditions associated with secondary disruption of the septum pellucidum.¹⁸ An important clue is the demonstration of a flat roof of frontal horns in a midcoronal view of the brain. However, this approach does carry some subjectivity, and is certainly hampered in cases with gross ventricular enlargement. In some cases of lobar holoprosencephaly the fornices have an abnormal configuration, and are seen in the midline as a thick fasicle running from the anterior to the posterior commissure.²⁹ Eventually, as in lobar holoprosencephaly the interhemispheric fissure is shallow anteriorly due to the fusion of the frontal lobes, the branches of the anterior cerebral artery run along the surface of the brain giving rise on Colour Doppler to a typical sign that has been referred to as ‘the serpent crawling under the skull’.³⁰

In the middle interhemispheric variant the frontal horns are well formed and there is partial separation of the frontal lobes; posteriorly however the ventricular cavity is fused, similar to alobar holoprosencephaly.^{18, 31}

In the typpical case of alobar or semilobar holoprosencephaly sonographic diagnosis is straightforward since early gestation. Magnetic resonance may be helpful however with the less severe varieties of holoprosencephaly and in particular for the lobar types.^{23, 31}

Alobar holoprosencephaly with a large ventricular cavity and/or dorsal sac has an appearance similar to that of hydranencephaly. From a practical perspective, alobar holoprosencephaly and hydranencephaly share in common a very poor prognosis and a diagnostic error would be uneventful However, demonstration of facial anomalies and/or of the hippocampal fornices is typical of holoprosencephaly.²³ Lobar holoprosencephaly must be distinguished from other types of ventriculomegalty that are at times associated with secondary disruption of the septum pellucidum.¹⁸ This is particularly frequent with spina bifida and severe obstructive hydroephalus. Distinction between agenesis of the septum pellucidum and lobar holoprosencephaly is probably the greatest challenge, as the former may be completely asymptomatic. Demonstration of normal ventricles to mild ventriculomegaly, a well formed corpus callosum, well developed interhemispheric fissure and anterior separation of the frontal horns favors the diagnosis of agenesis of the septum pellucidum.¹⁸

Implications for sonographic screening:

Alobar and semilobar holoprosencephaly are associated with profound distortion of intracranial architecture that should always be detected with a standard sonographic examination performed in the midtrimester. Findings associated with the lobar variety may be subtle. The cavum septi pellucidi is always absent, with central fusion of the frontal horns. This however may be difficult to demonstrate at times.32 In recent reports, holoprosencephaly is detected prenatally in about 90 % of cases,. And in about 70% of cases within 24 weeks. In 5% of cases the condition is not diagnosed in utero, for reasons that are not clear.² The sensitivity of ultrasound may be however overestimated because it is possible that mild presentation of the disease have escaped the surveillance system.

Prognosis:

Although alobar holoprosencephaly is considered a lethal condition, with a high intrauterine fatality rate, long term survival has been reported. Facial anomalies seem to predict survival better than the intracranial findings. With cyclopia, ethmocephaly, and cebocephaly, 50% may survive for 1–2 days. With median cleft lip, 50% survive for 4–5 months. For infants with less severely malformed or normal faces, 50% may survive as long as 12–18 months.⁷ It has also been reported that isolated holoprosencephaly with a normal karyotype has a one-year survival rate of 30% compared with 2% when associated with aneuploidy.²² Semilobar holoprosencephaly is not necesserily lethal, but is consistently associated with extremely severe neurologic compromise The available antenatal series consistently indicate a uniformely poor prognosis with any type of holoprosencephaly diagnosed antenatally.²⁸

Management:

Fetal karyotype is recommended. Genetic consultation is important because examination of the parents or family may disclose mild manifestation of the disease (e.g. single median incisor)^{7, 14} indicating a familial trait with a high recurrence rate. Severe forms of the disease (alobar and semilobra type) are almost invariably associated with a dismal prognosis and in countries where termination of pregnancy is possible, this should be discussed with the couple.

Alobar and semilobar holoprosencephaly are associated with profound distortion of intracranial architecture that should always be detected with a standard sonographic examination performed in the midtrimester. Findings associated with the lobar variety may be subtle. The cavum septi pellucidi is always absent, with central fusion of the frontal horns. This however may be difficult to demonstrate at times.³² In recent reports, holoprosencephaly is detected prenatally in about 90 % of cases,. And in about 70% of cases within 24 weeks. In 5% of cases the condition is not diagnosed in utero, for reasons that are not clear.² The sensitivity of ultrasound may be however overestimated because it is possible that mild presentation of the disease have escaped the surveillance system.

Although alobar holoprosencephaly is considered a lethal condition, with a high intrauterine fatality rate, long term survival has been reported. Facial anomalies seem to predict survival better than the intracranial findings. With cyclopia, ethmocephaly, and cebocephaly, 50% may survive for 1–2 days. With median cleft lip, 50% survive for 4–5 months. For infants with less severely malformed or normal faces, 50% may survive as long as 12–18 months.⁷ It has also been reported that isolated holoprosencephaly with a normal karyotype has a one-year survival rate of 30% compared with 2% when associated with aneuploidy.²²Semilobar holoprosencephaly is not necesserily lethal, but is consistently associated with extremely severe neurologic compromise The available antenatal series consistently indicate a uniformely poor prognosis with any type of holoprosencephaly diagnosed antenatally.²⁸

Fetal karyotype is recommended. Genetic consultation is important because examination of the parents or family may disclose mild manifestation of the disease (e.g. single median incisor)^{7, 14} indicating a familial trait with a high recurrence rate. Severe forms of the disease (alobar and semilobra type) are almost invariably associated with a dismal prognosis and in countries where termination of pregnancy is possible, this should be discussed with the couple.

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