NeoQuest June 2025: Term Neonate with Absent Cerebral Hemispheres Free

A term male infant was born via an uneventful spontaneous vaginal delivery.  Serial antenatal sonograms were obtained due to concern for progressive fetal ventriculomegaly.  The neonate’s initial examination revealed wide anterior and posterior fontanelles, splayed sutures, macrocephaly, and an unremarkable neurologic examination.  Cranial sonograms revealed absent bilateral frontal, parietal, and temporal lobes, with remnant posterior parietal and occipital lobes. The posterior fossa structures were normal.  Magnetic resonance imaging (MRI) findings are shown below (Figure 1).

Figure 1. Brain magnetic resonance imaging of a neonate with antenatal ultrasonogram findings concerning for progressive ventriculomegaly. A and B: Arrows demonstrate bilateral fronto-parietal. C: Lateral temporal. D: cortices of the brain replaced by fluid without any remnant parenchyma. The bilateral occipital lobes are spared. Image from: Goyal M, Mascarenhas D, Nanavati R. A term neonate with severe fetal brain ventriculomegaly. Neoreviews. 2025;26(6):e419–e423.¹

Which of the following is the most likely diagnosis in this infant?

1. Alobar holoprosencephaly
2. Hydranencephaly
3. Hydrocephaly
4. Large open lip schizencephaly
5. Large porencephalic cyst

Answer: B. Hydranencephaly

Explanation:

The MRI findings of the neonate in the vignette are most consistent with hydranencephaly (Option B) due to the extensive loss of cerebral tissue with replacement by cerebrospinal fluid (CSF) while the basal ganglia and posterior fossa structures are preserved.^1,2

Hydranencephaly is a rare neurological disorder distinguished by the near or complete absence of the cerebral cortex, likely resulting from the destruction of a previously normal brain with replacement with a leptomeningeal sac-like, CSF-filled structure (Figure 1 and Figure 2).^1,2,3  The basal ganglia, cerebellar structures, and falx cerebri remain intact.^1,2,3  Hydranencephaly occurs in approximately one in 10,000 births.²  It likely results from the spontaneous interruption of normal embryonic brain development after the third or fourth month of gestation.^2,4 

Figure 2. Axial head computed tomography images demonstrating hydranencephaly with the absence of supratentorial brain tissue and a prominent CSF space.  Image from: Chinsky JM. Hydranencephaly: transillumination may not illuminate diagnosis. Neoreviews. 2012;13(4):e233–e240.²

Etiologies of hydranencephaly include genetic conditions, such as Fowler syndrome; infectious mechanisms, such as congenital cytomegalovirus or toxoplasmosis; or ischemic mechanisms, such as internal carotid artery occlusion.^1,2,4  Internal carotid artery occlusion, which leads to the blockage of arterial blood supply to the cerebral hemispheres, is the most widely accepted explanation for this condition.³  Diffuse hypoxic-ischemic damage, intrauterine stroke, and cocaine use during pregnancy can also cause significant insult to the fetal cerebral tissue, resulting in hydranencephaly.²

The clinical manifestations of hydranencephaly can vary.  In the immediate neonatal period, some infants are asymptomatic because of an intact brainstem.^1,5  However, because of the lack of cerebral tissue, patients with hydranencephaly may develop severe neurodevelopmental delays, visual impairment, and seizures.^1,5,6  Due to the broad array of etiologies for hydranencephaly, affected infants should undergo genetic testing, advanced imaging, and evaluation for an intrauterine infection.²  Genetic evaluation should include karyotype and microarray analysis to detect potential chromosomal abnormalities or gene mutations, such as mutations in the FLVCR2 gene for Fowler syndrome or mutations in the ARX gene, which has also been linked to hydranencephaly.²  Also referred to as proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), Fowler syndrome is characterized by severe brain abnormalities, including hydranencephaly and ischemic lesions with calcifications affecting the brainstem, basal ganglia, and spinal cord.⁷  It also includes glomeruloid vasculopathy in the retinal blood vessels and central nervous system, along with fetal akinesia deformation sequence with muscular neurogenic atrophy.⁷  Advanced imaging with fetal MRI or computed tomography (CT) to delineate intracranial structures can confirm the diagnosis of hydranencephaly and distinguish it from hydrocephalus and holoprosencephaly.^2,3  An evaluation for intrauterine infections should include testing for cytomegalovirus, toxoplasmosis, rubella, herpes simplex virus, and adenovirus.²  

Management options for hydranencephaly include supportive care and palliative measures, with ventriculoperitoneal (VP) shunt placement considered in select cases of progressive macrocephaly or symptomatic increased intracranial pressure (ICP).^2,6  However, it is important to note and counsel caregivers that VP shunt placement may only be palliative, as it can provide improvement of symptoms caused by ICP but is not associated with an improvement in overall neurodevelopmental outcomes.^6,8  Therefore, caregiver goals of care for individuals with hydranencephaly should be ascertained.  Long-term outcome data for hydranencephaly are limited due to its rarity.^6,8  Historically, it has been reported that the majority of patients with hydranencephaly do not survive beyond the first two years of age.^2,6   However, emerging evidence suggests that with appropriate supportive care and interventions in alignment with caregiver goals, long-term survival is possible, with one reported case of an individual living to 33 years of age.^6,8  Although individuals with hydranencephaly have typically been described as having minimal conscious awareness, caregivers have reported meaningful emotional interactions even in the absence of a functional cerebral cortex.⁸  This underscores the importance of individualized care discussions and aligning medical decisions with caregiver priorities.⁸ 

Holoprosencephaly is due to the failure of the forebrain to divide into two distinct lobes between the third and fourth week of gestation, resulting in the lack of separation of the cerebral hemispheres.⁹  It is classified as alobar, semilobar, or lobar holoprosencephaly based on the degree of residual cerebral hemispheric brain tissue and the degree of the absence of other brain structures.^2,9  Alobar holoprosencephaly (Option A) is the most severe form of holoprosencephaly, presenting on prenatal ultrasound with a single ventricular cavity and with no midline structures; on clinical examination, there are features of cyclopia and proboscis.^2,9 The presence of the falx cerebri in hydranencephaly, whether partial or complete, is helpful in distinguishing it from holoprosencephaly on imaging (Figure 3), as is the presence of partially or totally fused thalami and cerebral tissue in holoprosencephaly.²  Holoprosencephaly is often associated with genetic abnormalities, including trisomy 13 and 18.^2,9  Other clinical manifestations of holoprosencephaly include craniofacial abnormalities such as eye fusion, such as cyclopia or synopthalmia, an absent nose or presence of a proboscis, microcephaly, cleft lip and palate, and a single maxillary central incisor.⁹ 

Figure 3. MRI brain of infant with alobar holoprosencephaly with absent midline structures.  Image from: Image from: Goyal M, Mascarenhas D, Nanavati R. A term neonate with severe fetal brain ventriculomegaly. Neoreviews. 2025;26(6):e419–e423.¹

Hydrocephalus (Option C) is a disorder of the abnormal accumulation of CSF from the overproduction or abnormal flow of CSF, leading to expansion of the cerebral ventricles.^2,10  Infants typically present with signs of increased ICP.¹⁰  The most common causes of hydrocephalus include post-hemorrhagic hydrocephalus related to intraventricular hemorrhage, myelomeningocele, aqueduct stenosis, and brain neoplasms.¹⁰  Ventriculomegaly can be identified with prenatal ultrasonography and further evaluated by neonatal cranial ultrasonography and brain MRI (Figure 4).¹⁰  Imaging of infants with hydrocephalus typically demonstrates symmetric cortical remnants, whereas infants with hydranencephaly have an asymmetric appearance of cerebral tissue.²  Often, patients with hydrocephalus can be treated with CSF shunting, most commonly with a VP shunt.^2,10  Long-term outcomes of infants and children with hydrocephalus are dependent on the causal mechanism of hydrocephalus and associated injury or brain dysmorphology, including vascular insults, genetic mutations, or intrauterine infections.^2,10

Figure 4.  Axial (left panel) and sagittal (right panel) views of a neonatal head ultrasound showing hydrocephalus with ventriculomegaly as a result of suspected perinatal stroke.  Image from: Jorge Martin Lopez Da Re; Newborn with a sudden increase in head circumference, wide sutures, and open fontanelles. Neoreviews. 2023;24(5):e310–e313.¹⁴

Schizencephaly is a congenital malformation of the brain defined by an abnormal cleft lined with gray matter in the cerebral hemisphere (Figure 5).¹¹  The sides of the cleft are referred to as the lips of the schizencephaly and may be narrow and fused (closed lip schizencephaly) or wide and separated (open lip schizencephaly, Option D).¹¹  Fetal and postnatal imaging with ultrasonography and MRI can also show ventriculomegaly, abnormal corpus callosum, and absent cavum septum pellucidum.¹¹  Schizencephaly can be associated with other anomalies, including omphalocele, gastroschisis, cleft lip and palate, atresia of the bowel, and amniotic band syndrome.¹¹  Schizencephaly can be a result of a sporadic genetic variant or an acquired vascular insult.¹¹  Clinical manifestations include epilepsy, neurodevelopmental delays such as cerebral palsy, feeding delays, and hydrocephalus.¹¹ 

Figure 5. MRI head of infant with large open lip schizencephaly with gray matter lining cleft. Image from: Goyal M, Mascarenhas D, Nanavati R. A term neonate with severe fetal brain ventriculomegaly. Neoreviews. 2025;26(6):e419–e423.¹

A porencephalic cyst (Option E) is an intracranial cystic lesion that can communicate with the ventricular system (internal porencephalic cyst) or subarachnoid space (external porencephalic cyst) and is lined with white matter (Figure 6).¹²  This cyst results from a perinatal vascular event such as ischemia, infection, or hemorrhage.¹²  Postnatal imaging with head ultrasound or MRI of a porencephalic cyst typically demonstrates a single, large, often asymmetrical cyst that communicates with the ventricular system or subarachnoid space.¹²  The size of a porencephalic cyst influences the severity of clinical manifestations, which may include neurodevelopmental impairments such as language and motor deficits.¹² 

Figure 6. MRI head of right sided unilateral large porencephalic cyst with communication with right lateral ventricle. Image from: Goyal M, Mascarenhas D, Nanavati R. A term neonate with severe fetal brain ventriculomegaly. Neoreviews. 2025;26(6):e419–e423.¹

Did you know?
Skull diaphanoscopy is the transillumination of an infant’s head using a high-intensity light source placed over open fontanelles (Figure 7).² This technique can be used as an initial bedside screening tool in infants with macrocephaly if there is suspicion for neurologic disease, including hydranencephaly, hydrocephalus, holoprosencephaly, or large subdural hematoma.^2,13

Figure 7. Transillumination of the neonatal head with extensive frontal and occipital prominences. Left panel shows infant’s head with ambient lighting.  Right panel shows extensive transillumination of frontal and occipital prominences. Image from: Chinsky JM. Hydranencephaly: transillumination may not illuminate diagnosis. Neoreviews. 2012;13(4):e233–e240.²

What syndrome that is characterized by numerous hemangiomas, posterior fossa abnormalities, and cardiac defects can be associated with internal carotid artery agenesis or hypoplasia, resulting in hydranencephaly?
For further information, refer to Chinsky JM. Hydranencephaly: transillumination may not illuminate diagnosis. Neoreviews. 2012;13(4):e233–e240.²

NeoQuest June 2025 Authors:
Jeanette Van Steyn, MD, Department of Pediatrics, University of North Carolina
Angelina June, MD, Fairfax Neonatal Associates, Fairfax, VA

References:

1. Goyal M, Mascarenhas D, Nanavati R. A term neonate with severe fetal brain ventriculomegaly. Neoreviews. 2025;26(6):e419–e423
2. Chinsky JM. Hydranencephaly; transillumination may not illuminate diagnosis. Neoreviews. 2012;13(4):e233–e240
3. Rosette TH, Towbin RB, Schaefer CM, Towbin AJ, Aria D J. Hydranencephaly. Applied Radiol. 2022;51(1):46-47
4. Chaudhari BP, Ho ML. Congenital brain malformations: an integrated diagnostic approach. Semin Pediatr Neurol. Jul 2022;42:100973
5. Jeng-Dau Tsai H-TK, I-Ching Chou. Hydranencephaly in neonates. Pediatr Neonatol. 2008;49(4):154-157
6. Omar AT, 2nd, Manalo MKA, Zuniega RRA, Reyes JCB, Brillante EMB, Khu KJO. Hydranencephaly: clinical features and survivorship in a retrospective cohort. World Neurosurg. Dec 2020;144:e589-e596
7. Meyer E, Ricketts C, Morgan N, et al. Mutations in FLVCR2 are associated with proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (Fowler Syndrome). Am J Hum Genet. 2010;(3):471-478.
8. Aleman B, Merker B. Consciousness without cortex: a hydranencephaly family survey. Acta Paediatr. Oct 2014;103(10):1057-65
9. Society for Maternal-Fetal M, Monteagudo A. Holoprosencephaly. Am J Obstet Gynecol. Dec 2020;223(6):B13-B16
10. Kahle KT, Kulkarni AV, Limbrick DD, Jr., Warf BC. Hydrocephalus in children. Lancet. Feb 20 2016;387(10020):788-99
11. Elizabeth George RV, Yolanda Yu, Mary E. Norton, Dawn Gano, Orit A. Glenn. Fetal MRI findings, etiology, and outcome in prenatally diagnosed schizencephaly. Am J Neuroradiol. 2024;doi:10.3174/ajnr.A8523
12. Sood A, Khandelwal S, Singhania S, Mishra GV. Internal porencephalic cyst. BMJ Case Rep. 2024;17(8)
13. Barozzino T, Sgro M. Transillumination of the neonatal skull- Seeing the light. Can Med Assoc J. 2002;167(11):1271-2
14. Re JMLD. Newborn with a sudden increase in head circumference, wide sutures, and open fontanels. Neoreviews. 203;4(5):e310–e313