Janica E. Walden, MD Neuroradiology University of North Carolina

1. Janica E. Walden, MD Neuroradiology University of North Carolina

2. Holoprosencephaly (HPE) • Spectrum of congenital structural forebrain anomalies defined by different degrees of frontal lobe fusion • Impaired midline cleavage of the embryonic forebrain • “Face predicts brain”: severe midline anomaly = severe HPE • Clinical severity relates to degree of hemispheric and deep gray nuclei fusion

3. Etiology & Pathology • Normal prosencephalic cleavage occurs at 4-6 weeks • HPE: disruption in dorsoventral axis patterning of secondary prosencephalon, • Result of mutations affecting signaling genes (Sonic hedgehog gene) which regulate neural tube patterning. • Extreme hypoplasia of neocortex • Dorsal cyst (especially in association with non-cleaved thalami) thought to represent expansion of partially blocked posterodorsal 3rd ventricle • Variable degree of fusion of diencephalon & basal ganglia/thalamus with incorporation into upper brainstem

4. Epidemiology • Occurs in 1 to 1.4 per 10,000 live births • More common in early embryogenesis with high spontaneous miscarriage rates • Maternal factors include alcohol use, diabetes, retinoic acid • 1% risk to infants of diabetic mothers (200-fold increased risk than that of general population) • Male: female ratio = 1.4: 1

5. Facial Anomalies • Severe facial anomalies correlate with severity of HPE in 80% • +/- midline clefting • premaxillary agenesis if severe • absent superior frenulum • +/- central incisor • proboscis • single nare; single nasal bone/absent inter-nasal sutures • caudal metopic suture • infants of diabetic mothers may have alobar HPE with near-normal facies

6. Alobar HPE: Note hypotelorism, hypoplastic nose with single nostril, small low set ears.

7. Clinical Features • Most severe (classic alobar HPE) features include: cyclopia, proboscis, midline facial clefting, microcephaly • Severe of pituitary/hypothalamic dysfunction (75% especially diabetes insipidus) & disturbed body temperature regulation • Correlates with degree of hypothalamic non-separation • Seizures (50%) & mental retardation • Most severe with cortical malformations • Dystonia & hypotonia • Severity correlates with degree basal ganglia non-separation

8. Classification • Defined by degree of frontal lobe fusion • Sylvian angle (of Barkovich) = lines drawn tangentially through Sylvian fissures • Anteriorly displaced Sylvian fissures results in increased Sylvian angle • The larger the Sylvian angle is the more severe frontal lobe hypoplasia is too • 3 types of HPE based on criteria (lobar, semilobar, and alobar), as well as a middle interhemispheric variant, septooptic dysplasia, and single central incisor

9. Alobar Holoprosencephaly • “Pancake” or “horseshoe” brain • Monoventricle • Large dorsal cyst • Fused diencephalon • Basal ganglia & thalami may form gray matter fusion mass • No interhemispheric fissure • No olfactory nerves

10. Alobar HPE: note fused thalamic & hemispheres, monoventricle, absent interhemispheric fissure and venous sinsues, & azygous ACA.

11. Fetal MRI shows alobar HPE.

12. MR T1 images in alobar HPE.

13. Diagnosis of HPE by Ultrasound • Diagnosis of HPE by ultrasound can be made as early as 9 weeks gestational age. • Development of forebrain can be delineated in detail with ultrasound from 7 weeks on. • Alobar HPE may be detectable as early as the end of week 7 • Non-visualization of the butterfly sign is very helpful in diagnosis

14. Semilobar Holoprosencephaly • Partial occipital/temporal horns • Moderate sized dorsal cyst • Fused diencephalon • Partial fusion of basal ganglia > thalami • Interhemipheric fissure present posteriorly • Absent of hypoplastic olfactory tracts and bulbs • Corpus callosum is rudimentary

15. CT in semilobar HPE.

16. MRI in semilobar HPE.

17. Lobar Holoprosencephaly • Formed lateral ventricles • Small or no dorsal cyst • Fused diencephalon and/or fornices • +/- partial fusion of basal ganglia > thalami • Interhemispheric fissure nearly normal • Small or normal olfactory nerves

18. MRI in lobar HPE.

19. Middle Interhemispheric Variant • Sylvian fissures connect across midline over vertex (86%) • Interhemispheric fusion of posterior frontal/parietal lobes, with normal separation of anterior frontal/occipital lobes • Non-cleavage of thalami > basal ganglia • Heterotopias and cortical dysplasias common (86%) • Thought to reflect abnormal induction of embryonic roof plate • Classic HPE = abnormal induction of embryonic floor plate • May explain absence of craniofacial malformations • Spasticity, hypotonia, seizures, developmental delay

20. MRI in midline intehemispheris variant of HPE.

21. References • Sepulveda Waldo, Dezerega Victor, Be Cecilia. First-Trimester Sonographic Diagnosis of Holoprosencephaly. Journal of Ultrasound in Medicine 23: 761-765. • Hahn Jin, Barnes Patrick. Neuroimaging Advances in Holoprosencephaly: Refining the Spectrum of the Midline Malformation. American Journal of Medical Genetics 154C: 120-132. • Blaas H., Eriksson A., Salvesen K., et al. Brains and faces in holoprosencephaly: pre- and postnatal description in 30 cases. Ultrasound ObstetGynecol 2002; 19: 24-38. • Takanashi Jun-ichi, Barkovich A. James, Clegg Nancy, Delgado Mauricio. Middle InterhemisphericBariant of Holoprosencephaly Associated with Diffuse Polymicrogyria. AJNR 2003; 24: 394-397. • Simon Erin, Hevner Robert, Pinter Joseph, et al. The Middle Interhemispheric Variant of Holoprosencephaly. AJNR 2002; 23: 151-155.