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'''Holoprosencephaly''' ('''HPE''') is a [[cephalic disorder]] in which the [[prosencephalon]] (the [[forebrain]] of the [[embryo]]) fails to [[Prenatal development|develop]] into two [[Cerebral hemisphere|hemisphere]]s. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of [[human pregnancy]]. The condition also occurs in other species.
'''Holoprosencephaly''' ('''HPE''') is a [[cephalic disorder]] in which the [[prosencephalon]] (the [[forebrain]] of the [[embryo]]) fails to [[Prenatal development|develop]] into two [[Cerebral hemisphere|hemisphere]]s, typically occurring between the 18th and 28th day of gestation.<ref name=":0">{{Cite journal |last=Dubourg |first=Christèle |last2=Bendavid |first2=Claude |last3=Pasquier |first3=Laurent |last4=Henry |first4=Catherine |last5=Odent |first5=Sylvie |last6=David |first6=Véronique |date=2007-02-02 |title=Holoprosencephaly |url=https://doi.org/10.1186/1750-1172-2-8 |journal=Orphanet Journal of Rare Diseases |volume=2 |issue=1 |pages=8 |doi=10.1186/1750-1172-2-8 |issn=1750-1172 |pmc=PMC1802747 |pmid=17274816}}</ref> Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of [[human pregnancy]]. The condition also occurs in other species.


The condition can be mild or severe. Most cases are not compatible with life and result in fetal death [[Uterus|in utero]].<ref>{{cite web|url=https://www.ninds.nih.gov/Disorders/All-Disorders/Holoprosencephaly-Information-Page |title=Holoprosencephaly Information Page | work = National Institute of Neurological Disorders and Stroke | publisher = National Institutes of Health, U.S. Department of Health & Human Services }}</ref>
Holoprosencephaly is estimated to occur in approximately 1 in every 250 conceptions<ref name=":0" /> and most cases are not compatible with life and result in fetal death [[Uterus|in utero]].<ref>{{cite web|url=https://www.ninds.nih.gov/Disorders/All-Disorders/Holoprosencephaly-Information-Page |title=Holoprosencephaly Information Page | work = National Institute of Neurological Disorders and Stroke | publisher = National Institutes of Health, U.S. Department of Health & Human Services }}</ref> However, holoprosencephaly is still estimated to occur in approximately 1 in every 8,000 live births.<ref name=":1">{{Cite journal |last=Raam |first=Manu S |last2=Solomon |first2=Benjamin D |last3=Muenke |first3=Maximilian |date=2011-6 |title=Holoprosencephaly: A Guide to Diagnosis and Clinical Management |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131946/ |journal=Indian pediatrics |volume=48 |issue=6 |pages=457–466 |issn=0019-6061 |pmc=4131946 |pmid=21743112}}</ref>


When the embryo's forebrain does not divide to form bilateral [[cerebral hemispheres]] (the left and right halves of the brain), it causes [[Congenital abnormality|defects]] in the development of the [[face]] and in brain structure and function.
When the embryo's forebrain does not divide to form bilateral [[cerebral hemispheres]] (the left and right halves of the brain), it causes [[Congenital abnormality|defects]] in the development of the [[face]] and in brain structure and function.


In less severe cases, babies are born with normal or near-normal [[brain development]] and facial deformities that may affect the eyes, nose, and upper lip.
The severity of Holoprosencephaly is highly variable. In less severe cases, babies are born with normal or near-normal [[brain development]] and facial deformities that may affect the eyes, nose, and upper lip.<ref name=":2" />


== Signs and symptoms ==
== Signs and symptoms ==
Symptoms of holoprosencephaly range from mild (no facial/organ defects, [[anosmia]], or only a single central [[incisor]]) to moderate to severe ([[cyclopia]]).
Symptoms of holoprosencephaly range from mild (no facial/organ defects, [[anosmia]], or only a single central [[incisor]]) to moderate to severe ([[cyclopia]]). The symptoms are dependent upon the classification type.<ref name=":1" />


There are four classifications of holoprosencephaly.
There are four classifications of holoprosencephaly as well as a mild "microform".
[[Image:Alobar holoprosencephaly.jpg|thumb|[[Gross pathology]] specimen from a case of alobar holoprosencephaly.]]
[[Image:Alobar holoprosencephaly.jpg|thumb|[[Gross pathology]] specimen from a case of alobar holoprosencephaly]]
* '''Alobar'''
* Alobar holoprosencephaly, the most serious form, in which the brain fails to separate, is usually associated with severe facial anomalies, including lack of a nose and the eyes merged to a single median structure (see [[cyclopia]]).
** Most severe form includes formation of synophthalmia (a single central eye),proboscis, and severe impairment. <ref name=":1" />
* Semilobar holoprosencephaly, in which the brain's hemispheres have somewhat divided, is an intermediate form of the disease.
* '''Semilobar'''
* Lobar holoprosencephaly, in which there is considerable evidence of separate brain hemispheres, is the least severe form. In some cases of lobar holoprosencephaly, the patient's brain may be nearly normal.
** Can present with severely decreased distance between eyes, a flat nasal bridge, eye defects, cleft lip and palate, and severe impairment. <ref name=":1" />
* Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV), in which the posterior [[frontal lobe]] and the [[parietal lobe]] are not properly separated, but the [[Rostrum (anatomy)|rostro]] [[Anatomical terms of location|basal]] forebrain properly separates; it is possible that this is not a variant of HPE at all, but it is currently classified as such.<ref name="Peds NeuroRad">{{cite book | pages=92–95 | chapter = Brain Malformations | title = Pediatric Neuroradiology: Brain, Head, Neck and Spine | veditors = Totori-Donati P, Rossi A, Raybaud C | year = 2005 | volume = 1 | isbn = 978-3-540-41077-5 | publisher = [[Springer Science+Business Media|Springer]] | vauthors = Totori-Donati P, Rossi A, Biancheri R }}</ref>
* '''Lobar'''
* [[Agenesis of the corpus callosum]], in which there is a complete or partial absence of the corpus callosum. It occurs when the corpus callosum, the band of white matter connecting the two hemispheres in the brain, fails to develop normally, typically during pregnancy. The fibers that would otherwise form the corpus callosum become longitudinally oriented within each hemisphere and form structures called Probst bundles.
** Can present with decreased distance between eyes, a flat nasal bridge, closely spaced nostrils, mental and locomotion delays may be present. <ref name=":1" />
* '''Syntelencephaly or middle interhemispheric variant of holoprosencephaly (MIHV)'''
** Mild phenotypic presentation which can present with flat nasal bridge, metopic prominence, shallow philtrum, and possible mental and locomotion delays.<ref>{{Cite journal |last=Rajalakshmi |first=P. Prathiba |last2=Gadodia |first2=Ankur |last3=Priyatharshini |first3=P. |date=2015 |title=Middle interhemispheric variant of holoprosencephaly: A rare midline malformation |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4611894/ |journal=Journal of Pediatric Neurosciences |volume=10 |issue=3 |pages=244–246 |doi=10.4103/1817-1745.165678 |issn=1817-1745 |pmc=4611894 |pmid=26557166}}</ref>
* '''"Microform"'''
** Mild phenotypic presentation with reduced distance between eyes, sharp nasal bridge, single maxillary central incisor. <ref name=":1" />


== Diagnosis ==
Holoprosencephaly consists of a spectrum of defects or malformations of the brain and face. At the most severe end of this spectrum are cases involving serious malformations of the brain, malformations so severe that they often cause [[miscarriage]] or [[stillbirth]]. At the other end of the spectrum are individuals with facial defects&nbsp;which may affect the [[Human eye|eye]]s, [[human nose|nose]], and upper [[lip]] - and normal or near-normal brain development. [[Seizures]] and [[intellectual disabilities]] may occur.
Holoprosencephaly is typically diagnosed during fetal development when there are abnormalities found on fetal brain imaging, however it can also be diagnosed after birth. The Protocol for diagnosis includes neuroimaging (Ultrasound or fetal MRI prior to birth or Ultrasound, MRI or CT post birth), syndrome evaluation, cytogenetics, molecular testing, and genetic counseling.<ref name=":1" />


There are four classifications of holoprosencephaly as well as a “microform".<ref name=":1" /> These classifications can be distinguished by their anatomical differences.<ref name=":0" />
The most severe of the facial defects (or [[Birth defect|anomalies]]) is [[cyclopia]], an abnormality characterized by the development of a single [[Human eye|eye]], located in the area normally occupied by the root of the [[human nose|nose]], and a missing nose or a nose in the form of a [[Proboscis (anomaly)|proboscis]] (a tubular appendage) located above the eye. The condition is also referred to as cyclocephaly or synophthalmia, and is very rare.

* '''Alobar holoprosencephaly'''
** Small single forebrain ventricle
** No interhemispheric division
** Absence of olfactory bulbs and tracts
** Absence of corpus callosum
** Non separation of deep gray nuclei<ref name=":0" />
* '''Semilobar holoprosencephaly'''
** Rudimentary cerebral lobes
** Incomplete interhemispheric division
** Absence or hypoplasia of olfactory bulbs and tracts
** Absence of corpus callosum
** Varying non separation of deep gray nuclei<ref name=":0" />
* '''Lobar holoprosencephaly'''
** Fully-developed cerebral lobes
** Distinct interhemispheric division
** Midline continuous frontal neocortex
** Absent, hypoplasic or normal  corpus callosum
** Separation of deep gray nuclei<ref name=":0" />
* '''Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV)'''
** Failure of separation of the posterior frontal and parietal lobes
** Callosal genu and splenium normally formed
** Absence of corpus callosum
** Hypothalamus and lentiform nuclei normally separated
** Heterotopic gray matter<ref name=":0" />
* '''Microform'''
** Subtle defects of corpus callosum
** Subtle midline brain defects<ref name=":1" />


== Causes ==
== Causes ==
In Holoprosencephaly, the neural tube fails to segment, resulting in incomplete separation of the prosencephalon at the fifth week of gestation.<ref>{{Cite journal |last=Winter |first=Thomas C. |last2=Kennedy |first2=Anne M. |last3=Woodward |first3=Paula J. |date=2015-01-01 |title=Holoprosencephaly: A Survey of the Entity, with Embryology and Fetal Imaging |url=https://pubs.rsna.org/doi/10.1148/rg.351140040 |journal=RadioGraphics |volume=35 |issue=1 |pages=275–290 |doi=10.1148/rg.351140040 |issn=0271-5333}}</ref>

The exact cause(s) of HPE are yet to be determined. Mutations in the gene encoding the [[Sonic hedgehog|SHH protein]], which is involved in the development of the central nervous system (CNS), can cause holoprosencephaly.<ref>{{cite journal | vauthors = Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA | title = Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function | journal = Nature | volume = 383 | issue = 6599 | pages = 407–413 | date = October 1996 | pmid = 8837770 | doi = 10.1038/383407a0 | s2cid = 4339131 | bibcode = 1996Natur.383..407C }}</ref><ref>{{cite journal | vauthors = Muenke M, Beachy PA | title = Genetics of ventral forebrain development and holoprosencephaly | journal = Current Opinion in Genetics & Development | volume = 10 | issue = 3 | pages = 262–269 | date = June 2000 | pmid = 10826992 | doi = 10.1016/s0959-437x(00)00084-8 | url = https://zenodo.org/record/1260165 }}</ref><ref>{{cite journal | vauthors = Rash BG, Grove EA | title = Patterning the dorsal telencephalon: a role for sonic hedgehog? | journal = The Journal of Neuroscience | volume = 27 | issue = 43 | pages = 11595–11603 | date = October 2007 | pmid = 17959802 | pmc = 6673221 | doi = 10.1523/jneurosci.3204-07.2007 | doi-access = free }}</ref> In other cases, it often seems that there is no specific cause at all.<ref name="Carter">{{cite web | url=http://www.stanford.edu/group/hpe/about/ | title=About Holoprosencephaly | author=The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations | url-status=dead | archive-url=https://web.archive.org/web/20090514043807/http://www.stanford.edu/group/hpe/about/ | archive-date=2009-05-14 }}</ref>
The exact cause(s) of HPE are yet to be determined. Mutations in the gene encoding the [[Sonic hedgehog|SHH protein]], which is involved in the development of the central nervous system (CNS), can cause holoprosencephaly.<ref>{{cite journal | vauthors = Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA | title = Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function | journal = Nature | volume = 383 | issue = 6599 | pages = 407–413 | date = October 1996 | pmid = 8837770 | doi = 10.1038/383407a0 | s2cid = 4339131 | bibcode = 1996Natur.383..407C }}</ref><ref>{{cite journal | vauthors = Muenke M, Beachy PA | title = Genetics of ventral forebrain development and holoprosencephaly | journal = Current Opinion in Genetics & Development | volume = 10 | issue = 3 | pages = 262–269 | date = June 2000 | pmid = 10826992 | doi = 10.1016/s0959-437x(00)00084-8 | url = https://zenodo.org/record/1260165 }}</ref><ref>{{cite journal | vauthors = Rash BG, Grove EA | title = Patterning the dorsal telencephalon: a role for sonic hedgehog? | journal = The Journal of Neuroscience | volume = 27 | issue = 43 | pages = 11595–11603 | date = October 2007 | pmid = 17959802 | pmc = 6673221 | doi = 10.1523/jneurosci.3204-07.2007 | doi-access = free }}</ref> In other cases, it often seems that there is no specific cause at all.<ref name="Carter">{{cite web | url=http://www.stanford.edu/group/hpe/about/ | title=About Holoprosencephaly | author=The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations | url-status=dead | archive-url=https://web.archive.org/web/20090514043807/http://www.stanford.edu/group/hpe/about/ | archive-date=2009-05-14 }}</ref>


Line 62: Line 98:


== Prognosis ==
== Prognosis ==
HPE is not a condition in which the brain deteriorates over time. Although serious seizure disorders, autonomic dysfunction, complicated [[endocrine]] disorders and other life-threatening conditions may sometimes be associated with HPE, the mere presence of HPE does not mean that these serious problems will occur or develop over time without any previous indication or warning. These abnormalities are usually recognized shortly after [[birth]] or early in life and only occur if areas of the brain controlling those functions are fused, malformed or absent.<ref>{{cite journal | vauthors = Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V | title = Holoprosencephaly | journal = Orphanet Journal of Rare Diseases | volume = 2 | issue = 1 | pages = 8 | date = February 2007 | pmid = 17274816 | pmc = 1802747 | doi = 10.1186/1750-1172-2-8 }}</ref>
HPE is not a condition in which the brain deteriorates over time. Although serious seizure disorders, autonomic dysfunction, complicated [[endocrine]] disorders and other life-threatening conditions may sometimes be associated with HPE, the mere presence of HPE does not mean that these serious problems will occur or develop over time without any previous indication or warning. These abnormalities are usually recognized shortly after [[birth]] or early in life and only occur if areas of the brain controlling those functions are fused, malformed or absent.<ref name=":2">{{cite journal | vauthors = Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V | title = Holoprosencephaly | journal = Orphanet Journal of Rare Diseases | volume = 2 | issue = 1 | pages = 8 | date = February 2007 | pmid = 17274816 | pmc = 1802747 | doi = 10.1186/1750-1172-2-8 }}</ref>


Prognosis is dependent upon the degree of fusion and malformation of the brain, as well as other health complications that may be present.
Prognosis is dependent upon the degree of fusion and malformation of the brain, as well as other health complications that may be present.

Revision as of 01:26, 28 February 2022

Holoprosencephaly
Diagram depicting the main subdivisions of the embryonic vertebrate brain.
SpecialtyMedical genetics

Holoprosencephaly (HPE) is a cephalic disorder in which the prosencephalon (the forebrain of the embryo) fails to develop into two hemispheres, typically occurring between the 18th and 28th day of gestation.[1] Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. The condition also occurs in other species.

Holoprosencephaly is estimated to occur in approximately 1 in every 250 conceptions[1] and most cases are not compatible with life and result in fetal death in utero.[2] However, holoprosencephaly is still estimated to occur in approximately 1 in every 8,000 live births.[3]

When the embryo's forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects in the development of the face and in brain structure and function.

The severity of Holoprosencephaly is highly variable. In less severe cases, babies are born with normal or near-normal brain development and facial deformities that may affect the eyes, nose, and upper lip.[4]

Signs and symptoms

Symptoms of holoprosencephaly range from mild (no facial/organ defects, anosmia, or only a single central incisor) to moderate to severe (cyclopia). The symptoms are dependent upon the classification type.[3]

There are four classifications of holoprosencephaly as well as a mild "microform".

Gross pathology specimen from a case of alobar holoprosencephaly
  • Alobar
    • Most severe form includes formation of synophthalmia (a single central eye),proboscis, and severe impairment. [3]
  • Semilobar
    • Can present with severely decreased distance between eyes, a flat nasal bridge, eye defects, cleft lip and palate, and severe impairment. [3]
  • Lobar
    • Can present with decreased distance between eyes, a flat nasal bridge, closely spaced nostrils, mental and locomotion delays may be present. [3]
  • Syntelencephaly or middle interhemispheric variant of holoprosencephaly (MIHV)
    • Mild phenotypic presentation which can present with flat nasal bridge, metopic prominence, shallow philtrum, and possible mental and locomotion delays.[5]
  • "Microform"
    • Mild phenotypic presentation with reduced distance between eyes, sharp nasal bridge, single maxillary central incisor. [3]

Diagnosis

Holoprosencephaly is typically diagnosed during fetal development when there are abnormalities found on fetal brain imaging, however it can also be diagnosed after birth. The Protocol for diagnosis includes neuroimaging (Ultrasound or fetal MRI prior to birth or Ultrasound, MRI or CT post birth), syndrome evaluation, cytogenetics, molecular testing, and genetic counseling.[3]

There are four classifications of holoprosencephaly as well as a “microform".[3] These classifications can be distinguished by their anatomical differences.[1]

  • Alobar holoprosencephaly
    • Small single forebrain ventricle
    • No interhemispheric division
    • Absence of olfactory bulbs and tracts
    • Absence of corpus callosum
    • Non separation of deep gray nuclei[1]
  • Semilobar holoprosencephaly
    • Rudimentary cerebral lobes
    • Incomplete interhemispheric division
    • Absence or hypoplasia of olfactory bulbs and tracts
    • Absence of corpus callosum
    • Varying non separation of deep gray nuclei[1]
  • Lobar holoprosencephaly
    • Fully-developed cerebral lobes
    • Distinct interhemispheric division
    • Midline continuous frontal neocortex
    • Absent, hypoplasic or normal  corpus callosum
    • Separation of deep gray nuclei[1]
  • Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV)
    • Failure of separation of the posterior frontal and parietal lobes
    • Callosal genu and splenium normally formed
    • Absence of corpus callosum
    • Hypothalamus and lentiform nuclei normally separated
    • Heterotopic gray matter[1]
  • Microform
    • Subtle defects of corpus callosum
    • Subtle midline brain defects[3]

Causes

In Holoprosencephaly, the neural tube fails to segment, resulting in incomplete separation of the prosencephalon at the fifth week of gestation.[6]

The exact cause(s) of HPE are yet to be determined. Mutations in the gene encoding the SHH protein, which is involved in the development of the central nervous system (CNS), can cause holoprosencephaly.[7][8][9] In other cases, it often seems that there is no specific cause at all.[10]

Ultrasound scan of a fetal head at 14 weeks of pregnancy with partial absence of the midline

Genetics

Armand Marie Leroi describes the cause of cyclopia as a genetic malfunctioning during the process by which the embryonic brain is divided into two.[11] Only later does the visual cortex take recognizable form, and at this point an individual with a single forebrain region will be likely to have a single, possibly rather large, eye (at such a time, individuals with separate cerebral hemispheres would form two eyes).

Increases in expression of such genes as Pax-2, as well as inhibition of Pax-6, from the notochord have been implicated in normal differentiation of cephalic midline structures. Inappropriate expression of any of these genes may result in mild to severe forms of holoprosencephaly.[citation needed] Other candidate genes have been located, including the SHH (holoprosencephaly type 3 a.k.a. HPE3), TGIF, ZIC2, SIX3[12] and BOC genes.[13]

Although many children with holoprosencephaly have normal chromosomes, specific chromosomal abnormalities have been identified in some patients (trisomy of chromosome 13, also known as Patau syndrome). There is evidence that in some families, HPE is inherited (autosomal dominant as well as autosomal or X-linked recessive inheritance).[14][15][16] Features consistent with familial transmission of the disease (e.g., a single central maxillary incisor) should be carefully assessed in parents and family members.[17]

Non-genetic factors

Numerous possible risk factors have been identified, including gestational diabetes, transplacental infections (the "TORCH complex"), first trimester bleeding, and a history of miscarriage.[10][18] As well, the disorder is found twice as often in female babies.[18] However, there appears to be no correlation between HPE and maternal age.[18]

There is evidence of a correlation between HPE and the use of various drugs classified as being potentially unsafe for pregnant and lactating mothers. These include insulin, birth control pills, aspirin, lithium, thorazine, retinoic acid, and anticonvulsants.[18] There is also a correlation between alcohol consumption and HPE, along with nicotine, the toxins in cigarettes and toxins in cigarette smoke when used during pregnancy.[18]

Prognosis

HPE is not a condition in which the brain deteriorates over time. Although serious seizure disorders, autonomic dysfunction, complicated endocrine disorders and other life-threatening conditions may sometimes be associated with HPE, the mere presence of HPE does not mean that these serious problems will occur or develop over time without any previous indication or warning. These abnormalities are usually recognized shortly after birth or early in life and only occur if areas of the brain controlling those functions are fused, malformed or absent.[4]

Prognosis is dependent upon the degree of fusion and malformation of the brain, as well as other health complications that may be present.

The more severe forms of encephalopathy are usually fatal. This disorder consists of a spectrum of defects, malformations and associated abnormalities. Disability is based upon the degree in which the brain is affected. Moderate to severe defects may cause intellectual disability, spastic quadriparesis, athetoid movements, endocrine disorders, epilepsy and other serious conditions; mild brain defects may only cause learning or behavior problems with few motor impairments.

Seizures may develop over time with the highest risk before 2 years of age and the onset of puberty. Most are managed with one medication or a combination of medications. Typically, seizures that are difficult to control appear soon after birth, requiring more aggressive medication combinations/doses.

Most children with HPE are at risk of having elevated blood sodium levels during moderate-severe illnesses, that alter fluid intake/output, even if they have no previous diagnosis of diabetes insipidus or hypernatremia.

See also

References

  1. ^ a b c d e f g Dubourg, Christèle; Bendavid, Claude; Pasquier, Laurent; Henry, Catherine; Odent, Sylvie; David, Véronique (2007-02-02). "Holoprosencephaly". Orphanet Journal of Rare Diseases. 2 (1): 8. doi:10.1186/1750-1172-2-8. ISSN 1750-1172. PMC 1802747. PMID 17274816.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: unflagged free DOI (link)
  2. ^ "Holoprosencephaly Information Page". National Institute of Neurological Disorders and Stroke. National Institutes of Health, U.S. Department of Health & Human Services.
  3. ^ a b c d e f g h i Raam, Manu S; Solomon, Benjamin D; Muenke, Maximilian (2011-6). "Holoprosencephaly: A Guide to Diagnosis and Clinical Management". Indian pediatrics. 48 (6): 457–466. ISSN 0019-6061. PMC 4131946. PMID 21743112. {{cite journal}}: Check date values in: |date= (help)
  4. ^ a b Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S, David V (February 2007). "Holoprosencephaly". Orphanet Journal of Rare Diseases. 2 (1): 8. doi:10.1186/1750-1172-2-8. PMC 1802747. PMID 17274816.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  5. ^ Rajalakshmi, P. Prathiba; Gadodia, Ankur; Priyatharshini, P. (2015). "Middle interhemispheric variant of holoprosencephaly: A rare midline malformation". Journal of Pediatric Neurosciences. 10 (3): 244–246. doi:10.4103/1817-1745.165678. ISSN 1817-1745. PMC 4611894. PMID 26557166.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Winter, Thomas C.; Kennedy, Anne M.; Woodward, Paula J. (2015-01-01). "Holoprosencephaly: A Survey of the Entity, with Embryology and Fetal Imaging". RadioGraphics. 35 (1): 275–290. doi:10.1148/rg.351140040. ISSN 0271-5333.
  7. ^ Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA (October 1996). "Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function". Nature. 383 (6599): 407–413. Bibcode:1996Natur.383..407C. doi:10.1038/383407a0. PMID 8837770. S2CID 4339131.
  8. ^ Muenke M, Beachy PA (June 2000). "Genetics of ventral forebrain development and holoprosencephaly". Current Opinion in Genetics & Development. 10 (3): 262–269. doi:10.1016/s0959-437x(00)00084-8. PMID 10826992.
  9. ^ Rash BG, Grove EA (October 2007). "Patterning the dorsal telencephalon: a role for sonic hedgehog?". The Journal of Neuroscience. 27 (43): 11595–11603. doi:10.1523/jneurosci.3204-07.2007. PMC 6673221. PMID 17959802.
  10. ^ a b The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations. "About Holoprosencephaly". Archived from the original on 2009-05-14.
  11. ^ Leroi AM (2003). Mutants : on the form, varieties and errors of the human body. London: HarperCollins. ISBN 978-0-00-653164-7.
  12. ^ "The Carter Center for Research in holoprosencephaly". Archived from the original on 2008-11-21.
  13. ^ Hong M, Srivastava K, Kim S, Allen BL, Leahy DJ, Hu P, et al. (November 2017). "BOC is a modifier gene in holoprosencephaly". Human Mutation. 38 (11): 1464–1470. doi:10.1002/humu.23286. PMC 5673120. PMID 28677295.
  14. ^ Singh S, Tokhunts R, Baubet V, Goetz JA, Huang ZJ, Schilling NS, et al. (February 2009). "Sonic hedgehog mutations identified in holoprosencephaly patients can act in a dominant negative manner". Human Genetics. 125 (1): 95–103. doi:10.1007/s00439-008-0599-0. PMC 2692056. PMID 19057928.
  15. ^ Tekendo-Ngongang C, Muenke M, Kruszka P (1993). "Holoprosencephaly Overview". In Adam MP, Ardinger HH, Pagon RA, Wallace SE (eds.). GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID 20301702. Retrieved 2020-09-01.
  16. ^ Nanni L, Ming JE, Bocian M, Steinhaus K, Bianchi DW, Die-Smulders C, et al. (December 1999). "The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly". Human Molecular Genetics. 8 (13): 2479–2488. doi:10.1093/hmg/8.13.2479. PMID 10556296.
  17. ^ Nanni L, Ming JE, Du Y, Hall RK, Aldred M, Bankier A, Muenke M (July 2001). "SHH mutation is associated with solitary median maxillary central incisor: a study of 13 patients and review of the literature". American Journal of Medical Genetics. 102 (1): 1–10. doi:10.1002/1096-8628(20010722)102:1<1::aid-ajmg1336>3.0.co;2-u. PMID 11471164.
  18. ^ a b c d e Croen LA, Shaw GM, Lammer EJ (February 2000). "Risk factors for cytogenetically normal holoprosencephaly in California: a population-based case-control study". American Journal of Medical Genetics. 90 (4): 320–325. doi:10.1002/(SICI)1096-8628(20000214)90:4<320::AID-AJMG11>3.0.CO;2-8. PMID 10710231.

External links

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