Holoprosencephaly

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

Holoprosencephaly (HPE) is a

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 due to deformities to the skull and brain.[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

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.[1]

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.[4]
  • "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
  • 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
  • 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

Causes

In holoprosencephaly, the neural tube fails to segment, resulting in incomplete separation of the prosencephalon at the fifth week of gestation.

axial twisting.[6] According to the axial twist theory, each side of the brain represents its opposite body side because the anterior part of the head, including the forebrain, is turned around by a twisting along the body axis during early development.[6][7] Accordingly, holoprosencephaly is possibly an extreme form of Yakovlevian torque
.

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.[8][9][10] In other cases, it often seems that there is no specific cause at all.[11]

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.[12] 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

TGIF, ZIC2, SIX3[13] and BOC genes.[14]

Although many children with holoprosencephaly have normal

maxillary incisor) should be carefully assessed in parents and family members.[18]

Non-genetic factors

Numerous possible

maternal age.[19]

There is evidence of a correlation between HPE and the use of

during pregnancy.[19]

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.[1]

Prognosis is dependent upon the degree of fusion and malformation of the brain, as well as other health complications that may be present.[1]

The more severe forms of encephalopathy are usually fatal. This disorder consists of a spectrum of defects, malformations and associated abnormalities.

athetoid movements, endocrine disorders, epilepsy and other serious conditions; mild brain defects may only cause learning or behavior problems with few motor impairments.[1]

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.[1]

See also

References

  1. ^
    PMID 17274816
    .
  2. ^ "Holoprosencephaly Information Page". National Institute of Neurological Disorders and Stroke. National Institutes of Health, U.S. Department of Health & Human Services.
  3. ^
    PMID 21743112
    .
  4. PMID 26557166
    .
  5. PMID 25590404
    .
  6. ^
    S2CID 7399128
    .
  7. PMID 31211022
    .
  8. S2CID 4339131
    .
  9. PMID 10826992
    .
  10. PMID 17959802
    .
  11. ^ a b The Carter Centers for Brain Research in Holoprosencephaly and Related Malformations. "About Holoprosencephaly". Archived from the original on 2009-05-14.
  12. ISBN 978-0-00-653164-7
    .
  13. ^ "The Carter Center for Research in holoprosencephaly". Archived from the original on 2008-11-21.
  14. PMID 28677295
    .
  15. PMID 19057928
    .
  16. PMID 20301702
    . Retrieved 2020-09-01.
  17. PMID 10556296
    .
  18. PMID 11471164
    .
  19. ^
    PMID 10710231
    .

External links
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