Holoprosencephaly – semi lobar

Holoprosencephaly – semi lobar


By the fourth week of intrauterine life the normal brain, developed from the closed neural tube, has segmented into three primary vesicles: the prosencephalon (forebrain), mesencephalon (midbrain) and rhombencephalon (hindbrain). The prosencephalon subdivides into the telencephalon and the diencephalon. The telencephalon gives rise to the cerebral cortex, the olfactory tract (rhinencephalon), part of the hypothalamus, the corpora striata, the lateral ventricles and a small portion of the third ventricle. The diencephalon develops into the thalamus, hypothalamus and the remainder of the third ventricle. The lamina terminalis, which stretches from the optic stalk to the interventricular foramen, gives rise to the corpus callosum. Holoprosencephaly is a failure of embryologic development where the prosencephalon remains a single, undifferentiated structure. There is a spectrum of abnormality resulting from this in which the common findings are of hemispheric fusion, cerebral hypoplasia, olfactory bulb hypoplasia, absence of the corpus callosum and of the cavum septi pellucidi. In some cases, facial development will also affected by the failed cleavage of the prosencephalon, and again there will be a spectrum of disorder observed; in general, where the intracranial defects are minimal there are no facial anomalies, but with increasing failure of differentiation of the prosencephalon the facial defects become worse. According to the degree of incomplete division of the prosencephalic derivatives three types of holoprosencephaly are recognised. Alobar, the most severe, in which there is complete absence of the interhemispheric fissure leading to a single primitive ventricle, fused thalami, and absence of the third ventricle, neurohypophysis and olfactory bulbs. Cyclopia and proboscis formation may be observed. Semi-lobar, in which the two cerebral hemispheres are partially separated posteriorly, but there remains a single ventricular cavity. Lobar, where the interhemispheric fissure may be well developed anteriorly and posteriorly, but there still exists a degree of fusion of some structures, such as the lateral ventricles. In addition the cavum septi pellucidi will be absent together with variable hypogenesis of the corpus callosum, which may manifest itself in disproportionate enlargement of the occipital horns (colpocephaly). Antenatal differentiation of the lobar form of holoprosencephaly may be extremely difficult. Further classification of the above may be made depending on the degree of failure of rotation of the prosencephalon; both alobar and semi-lobar varieties are thus further subdivided into three types: pancake, cup and ball, referring to the distribution of cerebral cortex relative to the monoventricle. Reported associations have been proposed linking holoprosencephaly to ionising radiation, alkaloids, phenytoin, salicylates, toxoplasmosis and diabetes mellitus.


The single most valuable finding is a sickle-shaped single ventricle seen in the transverse plane with a crescent-shaped cortex anteriorly and bulb-like thalami posteriorly undivided by the third ventricle. Both alobar and semi-lobar holoprosencephaly may be associated with microcephaly or macrocephaly. There is absence of the cavum septi pellucidi, the falx cerebri, and the corpus callosum. The thalami are fused. As mentioned, facial abnormalities reflect the severity of the intracranial process, cyclopia (fused orbits with supraorbital proboscis) representing the worst end of the spectrum. In general, fetal facial dysmorphism is characterised by hypotelorism, which may be found in association with a high midline proboscis (ethmocephaly), a single nostril (cebocephaly), or a defective premaxilla (median facial cleft). If any of these facial features are seen the intracranial anatomy should be carefully examined, although holoprosencephaly can occur with a normal face. It may be possible to diagnose holoprosencephaly within the first trimester using endovaginal sonography. Holoprosencephaly is associated with aneuploidy in up to one third of cases, in particular trisomy 13. It may also be found with other congenital anomalies such as anencephaly, encephalocele, Di George syndrome, Meckel-Gruber syndrome, and campomelic dysplasia. The finding of holoprosencephaly is therefore an indication for karyotyping and a detailed search for other cranial and systemic abnormalities. The prognosis in the severe forms of holoprosencephaly is hopeless; infants with isolated lobar holoprosencephaly are usually intellectually impaired.

Differential Diagnosis

Distinction needs to be made from other conditions where there may be profound ventriculomegaly or cystic dilatation. In ventriculomegaly there are always two separate lateral ventricles and even in the severest form the cortex is thinned out evenly, in contrast to the asymmetric displacement of the cerebral cortex in alobar holoprosencephaly. Midline intracranial structures (falx cerebri, interhemispheric fissure, corpus callosum, third ventricle) will usually be present in ventriculomegaly, distinguishing it from semilobar holoprosencephaly. Distinction from hydranencephaly may be more difficult as destruction of the frontal lobes may lead to disappearance of the midline and to the presence of an extensive fluid collection anterior to the thalami. The finding of a crescent-shaped rim of cortex will indicate holoprosencephaly. Facial abnormalities are not characteristic of hydranencephaly. The cyst seen in the Dandy-Walker malformation can displace the cortex rostrally and simulate alobar holoprosencephaly; however, a normal supratentorial ventricular system can usually be identified. The posterior fossa cyst will also demonstrate angular margins as it herniates through the tentorial notch, in contrast with the rounder monoventricular cavity of alobar holoprosencephaly.

Sonographic Features

Monoventricle with no frontal, temporal, or occipital horns

Fused thalami

No midline brain structures (falx cerebri, cavum septi pellucidi, corpus callosum)

Associated facial anomalies (midline cleft, cyclopia)

Three subdivisions are recognized:

‘Pancake’ – residual brain at skull base only

‘Cup’ – residual brain anteriorly, not covering whole ventricle

‘Ball’ – brain does not cover monoventricle, dorsal sac present

Associated Syndromes

  • Acalvaria-holoprosencephaly-facial dysmorphism
  • Agnathia-holoprosencephaly-tetramelia
  • Aicardi
  • Alcohol
  • Aqueductal stenosis
  • Brachial amelia-cleft lip/palate
  • CHARGE association
  • Chromosomal
  • Craniosynostosis-holoprosencephaly
  • Diabetes insipidus-coloboma-alobar holoprosencephaly
  • Ectopia cordis-embryonal neoplasms
  • Familial, isolated
  • Goldenhar
  • Grote: octodactyly-cardiac anomalies
  • Hartsfield: ectrodactyly-cleft face
  • Holoprosencephaly-fetal hypokinesia
  • Holoprosencephaly-NTD-nerve palsy-deafness
  • Hydantoin
  • Lambotte: microcephaly-facial anomalies
  • Lip synechia-imperforate anus
  • Majewski variant chondrodysplasia
  • Martin: midline clefting-skeletal anomalies
  • Maternal diabetes
  • Meckel-Gruber
  • Meckel-like (Fried)
  • Median cleft face-other anomalies
  • Pallister-Hall
  • Pseudotrisomy 13
  • Steinfeld: absent thumb-short forearm
  • Thomas: brachial amelia-facial clefts
  • Velo-cardio-facial


  1. Oba H, Barkovich AJ Holoprosencephly: an analysis of callosal formation and its relation to development of the interhemispheric fissure AJNR 16: 453-460
  2. Lehman CD, Nyberg DA, Winter TC, Kapur RP, Resta RG, Luthy DA Trisomy 13 syndrome: prenatal US findings in a review of 33 cases Radiology 194: 217-222
  3. Paidas MJ, Cohen A Disorders of the central nervous system Semin Perinatol 18: 266-282
  4. Achiron R, Achiron A, Lipitz S, Mashiach S, Goldman B Holoprosencephaly: alobar Fetus 4(2): 7422.9
  5. Sills IN, Rapaport R, Desposito F, Lieber C Familial Pallister-Hall syndrome: three affected offspring Am J Med Genet 52: 251
  6. Sakala EP, Gaio KL Fundal uterine leiomyoma obscuring first-trimester transabdominal sonographic diagnosis of fetal holoprosencephaly: a case report J Reprod Med 38: 400-402
  7. Santolaya J, McCorquodale MM, Torres W, Meyer WJ, Gauthier D, Lemery D Ultrasonographic prenatal diagnosis of the 13q- syndrome Fetal Diagn Ther 8: 261-267
  8. Seller MJ, Chitty LS, Dunbar H Pseudotrisomy 13 and autosomal recesive holoprosencephaly J Med Genet 30: 970-971
  9. Gonzalez-Gomez F, Salamanca A, Padilla MC, Camara M, Sabatel RM Alobar holoprosencephalic embryo detected via transvaginal sonography Europ J Obstet Gynecol Reprod Biol 47: 266-270
  10. Nelson LH, King M Early diagnosis of holoprosencephaly J Ultrasound Med 11: 57-59
  11. Hamada H, Oki A, Tsunoda H, Kubo T Prenatal diagnosis of holoprosencephaly by transvaginal ultrasonography in the first trimester Asia-Oceania J Obstet Gynaecol 18: 125-129
  12. Bronshtein M, Wiener Z Early transvaginal sonographic diagnosis of alobar holoprosencephaly Prenat Diagn 11: 459-462
  13. Rolland M, Sarramon MF, Bloom MC Astomia-agnathia-holoprosencephaly association. Prenatal diagnosis of a new case Prenat Diagn 11: 199-203
  14. Petit P, Moerman P, Fryns JP Lobar holoprosencephaly and Xq22 deletion Genet Couns 2: 119-121
  15. Hsieh F-J, Lee C-N, Wu C-C, Ko T-M, Kao M-L, Wong A-H, Chen M-L, Chen H-Y Antenatal ultrasonic findings of craniofacial malformations J Formosan Med Assoc 90: 551-554
  16. McGahan JP, Nyberg DA, Mack LA Sonography of facial features of alobar and semilobar holoprosencephaly AJR 154: 143-148
  17. Persutte WH, Yeasting RA, Kurczynski TW, Lenke RR, Robinson H Agnathia malformation complex associated with a cystic distention of the oral cavity and hydranencephaly J Craniofac Genet Dev Biol 10: 391-397
  18. Berry SM, Gosden C, Snijders RJM, Nicolaides KH Fetal holoprosencephaly: associated malformations and chromosomal defects Fetal Diagn Ther 5: 92-99
  19. Persutte WH, Lenke RR, DeRosa RT Prenatal ultrasonographic appearance of the agnathia malformation complex J Ultrasound Med 9: 725-728
  20. Kuo H-C, Chang F-M, Wu C-H, Yao B-L, Liu C-H Antenatal ultrasonographic diagnosis of hypotelorism J Formosan Med Assoc 89: 803-805
  21. Funk KC, Siegel MJ Sonography of congenital midline brain malformations Radiographics 8: 11-25
  22. Nyberg DA, Mack LA, Bronstein A, Hirsch J, Pagon RA Holoprosencephaly: prenatal sonographic diagnosis AJR 149: 1051-1058
  23. Pilu G, Romero R, Rizzo N, Jeanty P, Bovicelli L, Hobbins JC Criteria for the prenatal diagnosis of holoprosencephaly Am J Perinatol 4: 41-43
  24. Hoffman-Tretin JC, Horoupian DS, Koenigsberg M, Schnur MJ, Llena JF Lobar holoprosencephaly with hydrocephalus: antenatal demonstration and differential diagnosis J Ultrasound Med 5: 691-697
  25. Chervenak FA, Isaacson G, Hobbins JC, Chitkara U, Tortora M, Berkowitz RL Diagnosis and management of fetal holoprosencephaly Obstet Gynecol 66: 322-326
  26. Filly RA, Chinn DH, Callen PW Alobar holoprosencephaly: ultrasonographic prenatal diagnosis Radiology 151: 455-459
  27. Cayea PD, Balcar I, Alberti O, Jones TB Prenatal diagnosis of semilobar holoprosencephaly AJR 142: 401-402
  28. Hill LM, Breckle R, Bonebrake CR Ultrasonic findings with holoprosencephaly J Reprod Med 27: 172-175
  29. Blackwell DE, Spinnato JA, Hirsch G, Giles HR, Sackler J Antenatal ultrasound diagnosis of holoprosencephaly: a case report Am J Obstet Gynecol 143: 848-849
  30. Stagiannis KD, Sepulveda W, Bower S Early prenatal diagnosis of holoprosencephaly: the value of transvaginal ultrasonography Euro J Obstet Gynecol Repro Bio 61:175-176