Holoprosencephaly
Encyclopedia
Holoprosencephaly is a cephalic disorder
in which the prosencephalon
(the forebrain of the embryo
) fails to develop
into two hemisphere
s. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. Hox genes, which guide placement of embryonic structures
, fail to activate along the midline
of the head, allowing structures that are normally paired on the left and right to merge. The condition also occurs in other species, as with Cy, the Cyclops
kitten
.
The condition can be mild or severe. According to the National Institute of Neurological Disorders and Stroke
(NINDS), "in most cases of holoprosencephaly, the malformations are so severe that babies die before birth.
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.
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.
, or only a single central incisor
) to moderate (cleft lip or cleft palate) to severe (being a cyclops).
There are four classifications of holoprosencephaly.
or stillbirth
. At the other end of the spectrum are individuals with facial defects which may affect the eye
s, nose
, and upper lip
- and normal or near-normal brain development. Seizures and mental retardation
may occur.
The most severe of the facial defects (or anomalies) is cyclopia
, an abnormality characterized by the development of a single eye
, located in the area normally occupied by the root of the nose
, and a missing nose or a nose in the form of a proboscis
(a tubular appendage) located above the eye. The condition is also referred to as cyclocephaly or synophthalmia, and is very rare.
describes the cause of cyclopia
as a genetic malfunctioning during the process by which the embryo
nic brain is divided into two. 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 gene
s 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. Other candidate gene
s have been located, including the SHH
(holoprosencephaly type 3 aka HPE3), TGIF
, ZIC2
and SIX3
genes.
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
) . Features consistent with familial transmission of the disease (e.g., a single central maxillary incisor) should be carefully assessed in parents and family members.
s have been identified, including gestational diabetes
, transplacental infections
(the "TORCH complex
"), first trimester bleeding
, and a history of miscarriage
. As well, the disorder is found twice as often in female
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 mothers. These include insulin
, birth control pills, aspirin
, lithium
, thorazine, retinoic acid
, and the anticonvulsants. 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).
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 holoprosencephaly 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 mental retardation, spastic
quadriparesis, athetoid movements, endocrine disorders, epilepsy
and other serious conditions. Whereas, 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.
Cephalic disorder
Cephalic disorders are congenital conditions that stem from damage to, or abnormal development of, the budding nervous system...
in which the prosencephalon
Prosencephalon
In the anatomy of the brain of vertebrates, the prosencephalon is the rostral-most portion of the brain. The prosencephalon, the mesencephalon , and rhombencephalon are the three primary portions of the brain during early development of the central nervous system...
(the forebrain of the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
) fails to develop
Develop
DEVELOP or Develop may refer to:*NASA DEVELOP , a NASA Applied Sciences student program*Develop India Group, a independent newsletter*Develop , a trade publication for the video game industry...
into two hemisphere
Cerebral hemisphere
A cerebral hemisphere is one of the two regions of the eutherian brain that are delineated by the median plane, . The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres has an outer layer of grey matter called the cerebral cortex that is...
s. Normally, the forebrain is formed and the face begins to develop in the fifth and sixth weeks of human pregnancy. Hox genes, which guide placement of embryonic structures
Ectopic expression
Ectopic expression is the expression of a gene in an abnormal place in an organism. This can be caused by a disease, or it can be artificially produced as a way to help determine what the function of that gene is....
, fail to activate along the midline
Commissure
A commissure is the place where two things are joined. The term is used especially in the fields of anatomy and biology.In anatomy, commissure refers to a bundle of nerve fibers that cross the midline at their level of origin or entry .* The most common usage of the term refers to the brain's...
of the head, allowing structures that are normally paired on the left and right to merge. The condition also occurs in other species, as with Cy, the Cyclops
Cyclopia
Cyclopia is a rare form of holoprosencephaly and is a congenital disorder characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities...
kitten
Kitten
A kitten is a juvenile domesticated cat.The young of big cats are called cubs rather than kittens. Either term may be used for the young of smaller wild felids such as ocelots, caracals, and lynx, but "kitten" is usually more common for these species....
.
The condition can be mild or severe. According to the National Institute of Neurological Disorders and Stroke
National Institute of Neurological Disorders and Stroke
The National Institute of Neurological Disorders and Stroke is a part of the U.S. National Institutes of Health . It conducts and funds research on brain and nervous system disorders and has a budget of just over US$1.5 billion...
(NINDS), "in most cases of holoprosencephaly, the malformations are so severe that babies die before birth.
When the embryo's forebrain does not divide to form bilateral cerebral hemispheres (the left and right halves of the brain), it causes defects
Congenital abnormality
A congenital anomaly is a condition which is present at the time of birth which varies from the standard presentation....
in the development of the face
Face
The face is a central sense organ complex, for those animals that have one, normally on the ventral surface of the head, and can, depending on the definition in the human case, include the hair, forehead, eyebrow, eyelashes, eyes, nose, ears, cheeks, mouth, lips, philtrum, temple, teeth, skin, and...
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.
Symptoms
Symptoms of holoprosencephaly range from mild (no facial/organ defects, anosmiaAnosmia
Anosmia is a lack of functioning olfaction, or in other words, an inability to perceive odors. Anosmia may be either temporary or permanent. A related term, hyposmia, refers to a decreased ability to smell, while hyperosmia refers to an increased ability to smell. Some people may be anosmic for one...
, or only a single central incisor
Incisor
Incisors are the first kind of tooth in heterodont mammals. They are located in the premaxilla above and mandible below.-Function:...
) to moderate (cleft lip or cleft palate) to severe (being a cyclops).
There are four classifications of holoprosencephaly.
- 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 CyclopiaCyclopiaCyclopia is a rare form of holoprosencephaly and is a congenital disorder characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities...
- Semilobar holoprosencephaly, in which the brain's hemispheres have a slight tendency to separate, is an intermediate form of the disease.
- 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.
- Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV), in which the posterior frontal lobeFrontal lobeThe frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
and the parietal lobeParietal lobeThe parietal lobe is a part of the Brain positioned above the occipital lobe and behind the frontal lobe.The parietal lobe integrates sensory information from different modalities, particularly determining spatial sense and navigation. For example, it comprises somatosensory cortex and the...
are not properly separated, but the rostroRostrum (anatomy)The term rostrum is used for a number of unrelated structures in different groups of animals:*In crustaceans, the rostrum is the forward extension of the carapace in front of the eyes....
basalAnatomical terms of locationStandard anatomical terms of location are designations employed in science that deal with the anatomy of animals to avoid ambiguities that might otherwise arise. They are not language-specific, and thus require no translation...
forebrain properly separates; it is possible that this is not a variant of HPE at all, but is currently classified as such
Presentation
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 miscarriageMiscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
or stillbirth
Stillbirth
A stillbirth occurs when a fetus has died in the uterus. The Australian definition specifies that fetal death is termed a stillbirth after 20 weeks gestation or the fetus weighs more than . Once the fetus has died the mother still has contractions and remains undelivered. The term is often used in...
. At the other end of the spectrum are individuals with facial defects which may affect the eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
s, nose
Human nose
The visible part of the human nose is the protruding part of the face that bears the nostrils. The shape of the nose is determined by the ethmoid bone and the nasal septum, which consists mostly of cartilage and which separates the nostrils...
, and upper lip
Lip
Lips are a visible body part at the mouth of humans and many animals. Lips are soft, movable, and serve as the opening for food intake and in the articulation of sound and speech...
- and normal or near-normal brain development. Seizures and mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
may occur.
The most severe of the facial defects (or anomalies) is cyclopia
Cyclopia
Cyclopia is a rare form of holoprosencephaly and is a congenital disorder characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities...
, an abnormality characterized by the development of a single eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
, located in the area normally occupied by the root of the nose
Human nose
The visible part of the human nose is the protruding part of the face that bears the nostrils. The shape of the nose is determined by the ethmoid bone and the nasal septum, which consists mostly of cartilage and which separates the nostrils...
, and a missing nose or a nose in the form of a proboscis
Proboscis
A proboscis is an elongated appendage from the head of an animal, either a vertebrate or an invertebrate. In simpler terms, a proboscis is the straw-like mouth found in several varieties of species.-Etymology:...
(a tubular appendage) located above the eye. The condition is also referred to as cyclocephaly or synophthalmia, and is very rare.
Causes
The exact cause(s) of HPE are yet to be determined, although the presence of toxins may be suspected. However, it often seems that there is no specific cause at all.Genetics
Armand Marie LeroiArmand Marie Leroi
Armand Marie Leroi is an evolutionary developmental biologist at Imperial College in London. A Dutch citizen, his youth was spent in New Zealand, South Africa and Canada. He was awarded a BSc. by Dalhousie University, Halifax, Canada in 1989, and a Ph.D. by the University of California, Irvine in...
describes the cause of cyclopia
Cyclopia
Cyclopia is a rare form of holoprosencephaly and is a congenital disorder characterized by the failure of the embryonic prosencephalon to properly divide the orbits of the eye into two cavities...
as a genetic malfunctioning during the process by which the embryo
Embryo
An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
nic brain is divided into two. Only later does the visual cortex
Visual cortex
The visual cortex of the brain is the part of the cerebral cortex responsible for processing visual information. It is located in the occipital lobe, in the back of the brain....
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
Gene expression
Gene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of such gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s as Pax-2, as well as inhibition of Pax-6, from the notochord
Notochord
The notochord is a flexible, rod-shaped body found in embryos of all chordates. It is composed of cells derived from the mesoderm and defines the primitive axis of the embryo. In some chordates, it persists throughout life as the main axial support of the body, while in most vertebrates it becomes...
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
Candidate gene
A candidate gene is a gene, located in a chromosome region suspected of being involved in the expression of a trait such as a disease, whose protein product suggests that it could be the gene in question...
s have been located, including the SHH
SHH
SHH can refer to:* Summer Heights High, an Australian TV series* Sonic hedgehog, an important protein during vertebrate organogenesis* Students Helping Honduras, an international non-governmental organization operating in the U.S. and Honduras...
(holoprosencephaly type 3 aka HPE3), TGIF
TGIF
TGIF is an initialism for the phrase "Thank God It's Friday", celebrating the last day of the work/school week before the weekend. Its origin dates to the 1960s. It was first popularized by the restaurant T.G.I. Friday's which was founded in 1965. However, it became mainstream by the late 1970s,...
, ZIC2
ZIC2
Zinc finger protein ZIC 2 is a protein that in humans is encoded by the ZIC2 gene.-Further reading:...
and SIX3
SIX3
Homeobox protein SIX3 is a protein that in humans is encoded by the SIX3 gene.-Interactions:SIX3 has been shown to interact with TLE1 and Neuron-derived orphan receptor 1.-External links:*...
genes.
Although many children with holoprosencephaly have normal chromosomes, specific chromosomal abnormalities have been identified in some patients (trisomy
Trisomy
A trisomy is a type of polysomy in which there are three copies, instead of the normal two, of a particular chromosome. A trisomy is a type of aneuploidy .-Description and causes:...
of chromosome 13, also known as Patau syndrome
Patau syndrome
Patau syndrome, also known as trisomy 13 and trisomy D, is a chromosomal abnormality, a syndrome in which a patient has an additional chromosome 13 due to a nondisjunction of chromosomes during meiosis. Some are caused by Robertsonian translocations...
). There is evidence that in some families, HPE is inherited (autosomal dominant as well as autosomal or X-linked recessive
X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
inheritance
Inheritance
Inheritance is the practice of passing on property, titles, debts, rights and obligations upon the death of an individual. It has long played an important role in human societies...
) . 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 factorRisk factor
In epidemiology, a risk factor is a variable associated with an increased risk of disease or infection. Sometimes, determinant is also used, being a variable associated with either increased or decreased risk.-Correlation vs causation:...
s have been identified, including gestational diabetes
Gestational diabetes
Gestational diabetes is a condition in which women without previously diagnosed diabetes exhibit high blood glucose levels during pregnancy . It is widely accepted as a disease only in the United States, there is some question whether the condition is natural during pregnancy...
, transplacental infections
Perinatal infection
A perinatal infection is an infection caused by bacteria, viruses or, in rare cases, parasites transmitted directly from the mother to an embryo, fetus or baby during pregnancy or childbirth. The term congenital infection is also sometimes used...
(the "TORCH complex
TORCH complex
TORCH complex is a medical acronym for a set of perinatal infections . The TORCH infections can lead to severe fetal anomalies or even fetal loss...
"), first trimester bleeding
First trimester bleeding
In obstetrics, first trimester bleeding, is bleeding from the vagina during pregnancy in the first trimester .It is a common occurrence and estimated to occur in approximately 25% of all pregnancies....
, and a history of miscarriage
Miscarriage
Miscarriage or spontaneous abortion is the spontaneous end of a pregnancy at a stage where the embryo or fetus is incapable of surviving independently, generally defined in humans at prior to 20 weeks of gestation...
. As well, the disorder is found twice as often in female
Female
Female is the sex of an organism, or a part of an organism, which produces non-mobile ova .- Defining characteristics :The ova are defined as the larger gametes in a heterogamous reproduction system, while the smaller, usually motile gamete, the spermatozoon, is produced by the male...
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
Drugs in pregnancy
Drugs used during pregnancy can have temporary or permanent effects on the fetus. Any drug that acts during embryonic or fetal development to produce a permanent alteration of form or function is known as a teratogen.-Prescribing for the pregnant woman:...
classified as being potentially unsafe for pregnant and lactating mothers. These include insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, birth control pills, aspirin
Aspirin
Aspirin , also known as acetylsalicylic acid , is a salicylate drug, often used as an analgesic to relieve minor aches and pains, as an antipyretic to reduce fever, and as an anti-inflammatory medication. It was discovered by Arthur Eichengrun, a chemist with the German company Bayer...
, lithium
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
, thorazine, retinoic acid
Retinoic acid
Retinoic acid is a metabolite of vitamin A that mediates the functions of vitamin A required for growth and development. Retinoic acid is required in chordate animals which includes all higher animals from fishes to humans...
, and the anticonvulsants. There is also a correlation between alcohol consumption
Alcohol consumption
Alcohol consumption may refer to:* Alcohol consumption by youth in the United States* Alcoholic beverage* Legal drinking age* List of countries by alcohol consumption* Long-term effects of alcohol* Short-term effects of alcohol...
and HPE, along with nicotine
Nicotine
Nicotine is an alkaloid found in the nightshade family of plants that constitutes approximately 0.6–3.0% of the dry weight of tobacco, with biosynthesis taking place in the roots and accumulation occurring in the leaves...
, 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 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 birthBirth
Birth is the act or process of bearing or bringing forth offspring. The offspring is brought forth from the mother. The time of human birth is defined as the time at which the fetus comes out of the mother's womb into the world...
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 holoprosencephaly are usually fatal. This disorder consists of a spectrum of defects, malformations and associated abnormalities. Disability
Disability
A disability may be physical, cognitive, mental, sensory, emotional, developmental or some combination of these.Many people would rather be referred to as a person with a disability instead of handicapped...
is based upon the degree in which the brain is affected. Moderate to severe defects may cause mental retardation, spastic
Spastic
The word spastic is used differently depending on location which has led to some controversy and misunderstanding. Derived via Latin from the Greek spastikos , the word originally referred to a change in muscles affected by the medical condition spasticity, which is seen in spastic diplegia and...
quadriparesis, athetoid movements, endocrine disorders, epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
and other serious conditions. Whereas, 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
Puberty is the process of physical changes by which a child's body matures into an adult body capable of reproduction, as initiated by hormonal signals from the brain to the gonads; the ovaries in a girl, the testes in a boy...
. Most are managed with one medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
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
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...
levels during moderate-severe illnesses, that alter fluid intake/output, even if they have no previous diagnosis of diabetes insipidus or hypernatremia.
External links
- GeneReview/NIH/UW entry on Holoprosencephaly Overview
- http://www.familiesforhope.org
- http://www.holoprosencephaly.net