Holoprosencephaly
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Holoprosencephaly (HPE) is a cephalic disorder in which the
prosencephalon In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...
(the
forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...
of the
embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...
) fails to develop into two
hemisphere Hemisphere may refer to: In geometry * Hemisphere (geometry), a half of a sphere As half of Earth or any spherical astronomical object * A hemisphere of Earth ** Northern Hemisphere ** Southern Hemisphere ** Eastern Hemisphere ** Western Hemi ...
s, typically occurring between the 18th and 28th day of gestation. 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; most cases are not compatible with life and result in fetal death in utero due to deformities to the skull and brain. However, holoprosencephaly is still estimated to occur in approximately 1 in every 8,000 live births. 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 The face is the front of the head that features the eyes, nose and mouth, and through which animals express many of their emotions. The face is crucial for human identity, and damage such as scarring or developmental deformities may affect th ...
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 The brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It consists of nervous tissue and is typically located in the head ( cephalization), usually near organs for special sens ...
and facial deformities that may affect the eyes, nose, and upper lip.


Signs and symptoms

Symptoms of holoprosencephaly range from mild (no facial/organ defects,
anosmia Anosmia, also known as smell blindness, is the lack of ability to detect one or more smells. Anosmia may be temporary or permanent. It differs from hyposmia, which is a decreased sensitivity to some or all smells. Anosmia can be categorized int ...
, or only a single central
incisor Incisors (from Latin ''incidere'', "to cut") are the front teeth present in most mammals. They are located in the premaxilla above and on the mandible below. Humans have a total of eight (two on each side, top and bottom). Opossums have 18, wher ...
) to severe (
cyclopia Cyclopia (named after the Greek mythology characters cyclopes), also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosen ...
). The symptoms are dependent upon the classification type. There are four classifications of holoprosencephaly, as well as a mild "microform" variant. ; Alobar : The most severe form of holoprosencephaly, this includes formation of synophthalmia (a single central eye),
proboscis A proboscis () is an elongated appendage from the head of an animal, either a vertebrate or an invertebrate. In invertebrates, the term usually refers to tubular arthropod mouthparts, mouthparts used for feeding and sucking. In vertebrates, a pr ...
, and severe impairment. ; Semilobar : Can present with severely decreased distance between eyes, a flat nasal bridge, eye defects, cleft lip and palate, and severe impairment. ; Lobar : Can present with decreased distance between eyes, a flat nasal bridge, and closely spaced nostrils. Mental and locomotion delays may also be present. ; 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. ; Microform : Mild phenotypic presentation with reduced distance between eyes, sharp nasal bridge, single maxillary central incisor.


Diagnosis

Holoprosencephaly is typically diagnosed during fetal development when there are abnormalities found on fetal brain imaging, but it can also be diagnosed after birth. The protocol for diagnosis includes neuroimaging (
Ultrasound Ultrasound is sound with frequency, frequencies greater than 20 Hertz, kilohertz. This frequency is the approximate upper audible hearing range, limit of human hearing in healthy young adults. The physical principles of acoustic waves apply ...
or fetal
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
prior to birth or Ultrasound, MRI or CT post birth), syndrome evaluation,
cytogenetics Cytogenetics is essentially a branch of genetics, but is also a part of cell biology/cytology (a subdivision of human anatomy), that is concerned with how the chromosomes relate to cell behaviour, particularly to their behaviour during mitosis an ...
, molecular testing, and
genetic counseling Genetic counseling is the process of investigating individuals and families affected by or at risk of genetic disorders to help them understand and adapt to the medical, psychological and familial implications of genetic contributions to disease. ...
. There are four classifications of holoprosencephaly as well as a "microform". These classifications can be distinguished by their anatomical differences. * Alobar holoprosencephaly ** Small single
forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...
ventricle ** No interhemispheric division ** Absence of
olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OF ...
s and tracts ** Absence of
corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental ...
** Non separation of deep gray nuclei * Semilobar holoprosencephaly ** Rudimentary cerebral lobes ** Incomplete interhemispheric division ** Absence or hypoplasia of
olfactory bulb The olfactory bulb (Latin: ''bulbus olfactorius'') is a neural structure of the vertebrate forebrain involved in olfaction, the sense of smell. It sends olfactory information to be further processed in the amygdala, the orbitofrontal cortex (OF ...
s and tracts ** Absence of
corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental ...
** Varying non separation of deep gray nuclei * Lobar holoprosencephaly ** Fully-developed cerebral lobes ** Distinct interhemispheric division ** Midline continuous frontal
neocortex The neocortex, also called the neopallium, isocortex, or the six-layered cortex, is a set of layers of the mammalian cerebral cortex involved in higher-order brain functions such as sensory perception, cognition, generation of motor commands, ...
** Absent, hypoplasic or normal
corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental ...
** Separation of deep gray nuclei * Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV) ** Failure of separation of the posterior frontal and
parietal lobe The parietal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The parietal lobe is positioned above the temporal lobe and behind the frontal lobe and central sulcus. The parietal lobe integra ...
s ** Callosal genu and splenium normally formed ** Absence of corpus callosum **
Hypothalamus The hypothalamus (: hypothalami; ) is a small part of the vertebrate brain that contains a number of nucleus (neuroanatomy), nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrin ...
and lentiform nuclei normally separated ** Heterotopic gray matter * Microform ** Subtle defects of
corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental ...
** Subtle midline brain defects


Causes

In holoprosencephaly, the neural tube fails to segment, resulting in incomplete separation of the prosencephalon at the fifth week of gestation. According to one hypothesis, the holoprosencephalic brain is due to an incomplete axial twisting. 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. Accordingly, holoprosencephaly is possibly an extreme form of
Yakovlevian torque Yakovlevian torque (also known as occipital bending (OB) or counterclockwise brain torque) is the tendency of the right side of the human brain to be warped slightly forward relative to the left and the left side of the human brain to be warped sl ...
. 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. In other cases, it often seems that there is no specific cause at all.


Genetics

Armand Marie Leroi describes the cause of
cyclopia Cyclopia (named after the Greek mythology characters cyclopes), also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosen ...
as a genetic malfunctioning during the process by which the
embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...
nic brain is divided into two. Only later does the
visual cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalam ...
take recognizable form, and at this point an individual with a single
forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the rostral (forward-most) portion of the brain. The forebrain controls body temperature, reproductive functions, eating, sleeping, and the display of emotions. Ve ...
region will be likely to have a single, possibly rather large, eye (when fetuses with separate cerebral hemispheres would have two eyes). Increases in expression of such
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
s as Pax-2, as well as inhibition of Pax-6, from the
notochord The notochord is an elastic, rod-like structure found in chordates. In vertebrates the notochord is an embryonic structure that disintegrates, as the vertebrae develop, to become the nucleus pulposus in the intervertebral discs of the verteb ...
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. Other
candidate gene The candidate gene approach to conducting genetic association studies focuses on associations between genetic variation within pre-specified genes of interest, and Phenotype (clinical medicine), phenotypes or disease states. This is in contrast to ...
s have been located, including the SHH (holoprosencephaly type 3 a.k.a. HPE3), TGIF1, ZIC2,
SIX3 Homeobox protein SIX3 is a protein that in humans is encoded by the ''SIX3'' gene. Function The SIX homeobox 3 (SIX3) gene is crucial in embryonic development by providing necessary instructions for the formation of the forebrain and eye dev ...
and BOC genes. Although many children with holoprosencephaly have normal
chromosomes A chromosome is a package of DNA containing part or all of the genetic material of an organism. In most chromosomes, the very long thin DNA fibers are coated with nucleosome-forming packaging proteins; in eukaryotic cells, the most importa ...
, specific chromosomal abnormalities have been identified in some patients ( trisomy of
chromosome 13 Chromosome 13 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 13 spans about 113 million base pairs (the building material of DNA) and represents between 3.5 and 4% of the total DNA i ...
, also known as
Patau syndrome Patau syndrome is a syndrome caused by a chromosomal abnormality, in which some or all of the cells of the body contain extra genetic material from chromosome 13. The extra genetic material disrupts normal development, causing multiple and co ...
). There is evidence that in some families, HPE is inherited (
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
as well as
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...
or
X-linked recessive ''Main Article'': Sex linkage X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...
inheritance Inheritance is the practice of receiving private property, titles, debts, entitlements, privileges, rights, and obligations upon the death of an individual. The rules of inheritance differ among societies and have changed over time. Offi ...
). Features consistent with familial transmission of the disease (e.g., a single central maxillary incisor) should be carefully assessed in parents and family members.


Non-genetic factors

Numerous possible
risk factor In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...
s have been identified, including
gestational diabetes Gestational diabetes is a condition in which a woman without diabetes develops hyperglycemia, high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms. Obesity increases the rate of pre-eclampsia, cesarea ...
, transplacental infections (the " TORCH complex"), first trimester bleeding, and a history of
miscarriage Miscarriage, also known in medical terms as a spontaneous abortion, is an end to pregnancy resulting in the loss and expulsion of an embryo or fetus from the womb before it can fetal viability, survive independently. Miscarriage before 6 weeks ...
. As well, the disorder is found twice as often in
female An organism's sex is female ( symbol: ♀) if it produces the ovum (egg cell), the type of gamete (sex cell) that fuses with the male gamete (sperm cell) during sexual reproduction. A female has larger gametes than a male. Females and ...
babies. However, there appears to be no correlation between HPE and maternal age. There is evidence of a correlation between HPE and the use of various drugs classified as being potentially unsafe for pregnant and
lactating Lactation describes the secretion of milk from the mammary glands and the period of time that a mother lactates to feed her young. The process naturally occurs with all sexually mature female mammals, although it may predate mammals. The proces ...
mothers. These include
insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...
, birth control pills,
aspirin Aspirin () is the genericized trademark for acetylsalicylic acid (ASA), a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and inflammation, and as an antithrombotic. Specific inflammatory conditions that aspirin is ...
,
lithium Lithium (from , , ) is a chemical element; it has chemical symbol, symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard temperature and pressure, standard conditions, it is the least dense metal and the ...
, thorazine,
retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...
, and
anticonvulsants Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatment ...
. There is also a correlation between
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
consumption and HPE, along with
nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...
, the toxins in cigarettes and toxins in cigarette smoke when used during pregnancy.


Prognosis

HPE is not a condition in which the brain deteriorates over time. Although serious seizure disorders, autonomic dysfunction, complicated
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
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 Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...
or early in life and only occur if areas of the brain controlling those functions are fused, malformed or absent. 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 Disability is the experience of any condition that makes it more difficult for a person to do certain activities or have equitable access within a given society. Disabilities may be Cognitive disability, cognitive, Developmental disability, d ...
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 Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
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 Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a female, the testicles i ...
. Most are managed with one
medication Medication (also called medicament, medicine, pharmaceutical drug, medicinal product, medicinal drug or simply drug) is a drug used to medical diagnosis, diagnose, cure, treat, or preventive medicine, prevent disease. Drug therapy (pharmaco ...
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 Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
levels during moderate-severe illnesses that alter fluid intake/output, even if they have no previous diagnosis of diabetes insipidus or
hypernatremia Hypernatremia, also spelled hypernatraemia, is a high concentration of sodium in the blood. Early symptoms may include a strong feeling of thirst, weakness, nausea, and loss of appetite. Severe symptoms include confusion, muscle twitching, and ...
.


See also

* Cephalic disorder *
Cyclopia Cyclopia (named after the Greek mythology characters cyclopes), also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosen ...
*
Prenatal development Prenatal development () involves the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal de ...


References


External links


GeneReview/NIH/UW entry on Holoprosencephaly Overview
* article on Birth Disorders of the Brain and Spinal Cord
What do we know about holoprosencephaly - Genome.gov
{{Congenital malformations and deformations of nervous system Congenital disorders of nervous system