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Holoprosencephaly
- 1. Holoprosencephaly ALWALEED ABUSHANAN, BDS PEDIATRIC DENTAL RESIDENT UNIVERSITY OF BRITISH COLUMBIA BC CHILDREN'S HOSPITAL
- 2. Objectives: I. To define holoprosencephaly (HPE) II. Its incidence in the population. III. To illustrate the full spectrum of HPE ranging from the extreme to the most mild manifestation.
- 3. I. Definition Is a common developmental defect of the forbrain and frequently the midface in humans cause: genetic and environmental causes. Involves incomplete development and septation of midline structures in the central nervous system (CNS) It occurs when the prosencephalon fails to cleave sagittally into cerebral hemispheres, transversely into telecephalon and diencephalon, and/or horizontally into olfactory and optic bulbs - Roessler, E., E. Belloni, K. Gaudenz, P. Jay, P. Berta, S. W. Scherer, L. C. Tsui and M. Muenke (1996). "Mutations in the human Sonic Hedgehog gene cause holoprosencephaly." Nat Genet 14(3): 357-360. - DeMyer W, Zeman W. 1963. Alobar holopro- sencephaly (arhinencephaly) with median cleft lip and palate: Clinical, electroence- phalographic and nosologic considerations. Confin Neurol 23:1–36.
- 4. Structural Brain Abnormalities in HPE The primary brain malformations comprise Incomplete cleavage of the forebrain (prosencephalon) into right and left hemispheres, into telencephalon and diencephalon, and into olfactory and optic bulbs and tracts. In the most severe form, a single brain ventricle is present without any evidence of an interhemispheric fissure. - Muenke, M. and P. A. Beachy (2000). "Genetics of ventral forebrain development and holoprosencephaly." Curr Opin Genet Dev 10(3): 262-269.
- 5. The eye fields are in the forebrain and they begin to separate at week 4 Stage 10 human embryo, Week 4, 22-23 days, UNSW
- 6. Formation of the eyes is linked to structural brain defects The eye fields are in the prosencephalon (forebrain). Rapid growth of the prosencephalon carries this region of the brain forward, along with the eye fields. https://syllabus.med.unc.edu/courseware/embryo_images/unit-eye/eye_htms/eye001.htm
- 7. II. Incidence It is considered one of the most common human malformation An estimated prevalence of at least 1/16,000 (1 in10,000- 20,000) live births and in 1/250 conceptuses. - Lacbawan and Muenke, 2002; Ming and Muenke, 2002; Dubourg et al., 2007 - Muenke, M. and P. A. Beachy (2000). "Genetics of ventral forebrain development and holoprosencephaly." Curr Opin Genet Dev 10(3): 262-269.
- 8. III. HPE Spectrum Holoprosencephaly is graded according to the severity of the brain anomaly as: Alobar – (10-40%) Semilobar – (43-45%) Lobar – (17-33%) MIHV (middle interhemispheric variant) Microform (HPE-Like) Cohen MM, Sulik K. Perspectives on holoprosencephaly: Part II. Central nervous system, craniofacial anatomy, syndrome commen- tary, diagnostic approach, and experimental studies. J Craniofac Genet Dev Biol 1992; 12: 196–244
- 9. Alobar Semi lobar Lobar MIHV • Raam MS, Solomon BD and M Muenke. Holoprosencephaly: A Guide to Diagnosis and Clinical Management. Indian Pediatr 2011;48: 457-466.
- 10. DESCRIPTIONS OF TYPICAL BRAIN FINDINGS IN EACH OF THE TYPES OF HOLOPROSENCEPHALY • Raam MS, Solomon BD and M Muenke. Holoprosencephaly: A Guide to Diagnosis and Clinical Management. Indian Pediatr 2011;48: 457-466.
- 11. Alobar most severe in terms of both craniofacial malformations and neurologic impairment Cyclopia proboscis Severe hypotelorism Flat nasal bridge Bilateral colobomas Midline cleft lip and palate • Raam MS, Solomon BD and M Muenke. Holoprosencephaly: A Guide to Diagnosis and Clinical Management. Indian Pediatr 2011;48: 457-466.
- 12. (A) (B) How would you describe these fetuses ? - Blaas et al. (2002) Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases
- 13. Lobar Hypotelorism Flat nasal bridge Closely spaced nostrils - Raam MS, Solomon BD and M Muenke. Holoprosencephaly: A Guide to Diagnosis and Clinical Management. Indian Pediatr 2011;48: 457-466 - Solomon, B. D et al. (2010). "Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals." J Med Genet 47(8): 513-524.
- 14. HPE-Like (Microform) Nanni, L., J. E. Ming, Y. Du, R. K. Hall, M. Aldred, A. Bankier and M. Muenke (2001). "SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature." Am J Med Genet 102(1): 1-10. Richieri-Costa, and A., Ribeiro, L. A.,. Holoprosencephaly and holoprosencephaly-like phenotypes: Review of facial and molecular findings in patients from a craniofacial hospital in Brazil. Am J Med Genet C Semin Med Genet. 2010 ;154C, 149-57.
- 15. References - Roessler, E., E. Belloni, K. Gaudenz, P. Jay, P. Berta, S. W. Scherer, L. C. Tsui and M. Muenke (1996). "Mutations in the human Sonic Hedgehog gene cause holoprosencephaly." Nat Genet 14(3): 357- 360. - DeMyer W, Zeman W. 1963. Alobar holopro- sencephaly (arhinencephaly) with median cleft lip and palate: Clinical, electroence- phalographic and nosologic considerations. Confin Neurol 23:1–36. - Muenke, M. and P. A. Beachy (2000). "Genetics of ventral forebrain development and holoprosencephaly." Curr Opin Genet Dev 10(3): 262-269. - Blaas et al. (2002) Brains and faces in holoprosencephaly: pre- and postnatal description of 30 cases - Lacbawan and Muenke, 2002; Ming and Muenke, 2002; Dubourg et al., 2007 - Cohen MM, Sulik K. Perspectives on holoprosencephaly: Part II. Central nervous system, craniofacial anatomy, syndrome commen- tary, diagnostic approach, and experimental studies. J Craniofac Genet Dev Biol 1992; 12: 196–244 - Raam MS, Solomon BD and M Muenke. Holoprosencephaly: A Guide to Diagnosis and Clinical Management. Indian Pediatr 2011;48: 457-466. - Solomon, B. D et al. (2010). "Mutations in ZIC2 in human holoprosencephaly: description of a novel ZIC2 specific phenotype and comprehensive analysis of 157 individuals." J Med Genet 47(8): 513- 524. - Nanni, L., J. E. Ming, Y. Du, R. K. Hall, M. Aldred, A. Bankier and M. Muenke (2001). "SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature." Am J Med Genet 102(1): 1-10.
Editor's Notes
- Much of what we know about the pathogenesis of HPE is derived from observations in animals. Embryologically, HPE can be traced to varying degrees of loss or disruption in the development of ventral forebrain and midline facial structures. In normal development, the optic vesicles evaginate from the lateral walls of the forebrain, at locations separated by the developing structures of the ventral forebrain. In severe HPE, ventral forebrain structures are absent and the optic primordia consequently develop as a single unpaired evagination from the floor of the forebrain. The resulting cyclopic eye protrudes into the developing face, thus displacing the fused nasal structures superiorly and accounting for the appearance and placement of the eye and proboscis. Muenke, M. and P. A. Beachy (2000). "Genetics of ventral forebrain development and holoprosencephaly." Curr Opin Genet Dev 10(3): 262-269.
- Cleavage of the forebrain (prosencephalon) into right & left hemispheres occurs at week 4 of development & is completed by week 8 Forebrain development occurs simultaneously with facial formation
- Signaling proteins are also important for the formation of the eyes. During early development, the cells that develop into the eyes form a single structure called the eye field. This structure is located in the center of the developing face. The signaling protein produced from the SHH gene causes the eye field to separate into two distinct eyes. The SIX3 gene is involved in the formation of the lens of the eye and the specialized tissue at the back of the eye that detects light and color (the retina).
- Mutations in the genes that cause nonsyndromic holoprosencephaly lead to the production of abnormal or nonfunctional signaling proteins. Without the correct signals, the eyes will not form normally and the brain does not separate into two hemispheres. The development of other parts of the face is affected if the eyes do not move to their proper position http://ghr.nlm.nih.gov/condition/nonsyndromic-holoprosencephaly
- More common in certain countries and ethnicities.
- The distribution of HPE types in both living patients and deceased fetuses with non-chromosomal, non-syndromic HPE has been estimated to be 10e40% alobar, 43e45% semilobar, and 17e33% lobar HPE
- Axial sections through cranial MR images of patients with holoprosencephaly, distinguished by type. MIHV: middle interhemispheric variant. Alobar The basic structure of the cerebral hemispheres is lost, with variable amounts of residual cortex. Features include 1-2: single midline monoventricle (or holosphere) lateral and third ventricles are absent absent midline structures absent septum pellucidum agenesis or hypoplasia of the corpus callosum absent interhemispheric fissure and falx cerebri absent olfactory tract dorsal cyst of holoprosencephaly absent, fused or normal optic nerves middle and anterior cerebral arteries may be replaced by tangled branches of internal carotid and basilar vessels Semi Lobar partial separation into hemispheres rudimentary occipital and temporal horns Lobar fusion of the frontal horns of the lateral ventricles absence of septum pellucidum normal or hypoplasia of the corpus callosum anterior cerebral artery may be displaced anteriorly to lie directly underneath the frontal bones (snake under the skull sign)
- Absence of corpus callosum vision impairments low muscle tone (hypotonia) poor motor coordination delays in motor milestones such as sitting and walking, low perception of pain, delayed toilet training, and chewing and swallowing difficulties falx cerebri is designed to protect and insulate the brain to reduce the risk of injury in response to trauma and infection, while also providing pathways for blood vessels, fluid drainage, and nerves. So absence of Falx Cerebri might cuase diagnostic confusion regarding subdural pathologies. some secondary abnormalities in appearance might be seen such as cerebral gyral interdigitation
- Postabortem images of holoprosencephalic fetuses with Anencephaly (a) single nostril (b) The premaxillary agenesis, absent nose, and rudimentary orbits lying close together.
- Lateral and third ventricles are affected
- plasia or hypoplasia of the anterior nasal spine, diminished or absent nasofrontal angle, hypotelorism, hypoplastic premaxilla, hypoplastic nose, flattened alae and nasal tip poorly developed philtrum single maxillary central incisor (SMCI) The SMMCI is unique in that both crown and root are symmetrical, it develops precisely in the midline, and it is the sole central incisor present (with the crown and root size the same as that of a normal central incisor) NB to differentiate from mesiodens SMMCI can occur in association with other severe facial anomalies in patients with HPE Some individuals with SMMCI, normal intelligence, and normal brain imaging have had children with HPE cleft lip/palate Richieri-Costa, and A., Ribeiro, L. A.,. Holoprosencephaly and holoprosencephaly-like phenotypes: Review of facial and molecular findings in patients from a craniofacial hospital in Brazil. Am J Med Genet C Semin Med Genet. 2010 ;154C, 149-57. Roessler E, and Muenke M. The molecular genetics of holoprosencephaly. Am J Med Genet C Semin Med Genet. 2010; 154C, 52-61.
- Nonsyndromic holoprosencephaly is inherited in an autosomal dominant pattern, which means an alteration in one copy of a gene in each cell is usually sufficient to cause the disorder. However, not all people with a gene mutation will develop signs and symptoms of the condition. In some cases, an affected person inherits the mutation from one parent who may or may not have mild features of the condition. Other cases result from a new gene mutation and occur in people with no history of the disorder in their family. Cognition Vocal communication typically does not develop beyond a few vocalizations or word approximations Social Awareness Visual Attention Auditory Comprehension