Holoprosencephaly (HPE) is a

cephalic disorder Cephalic disorders () are congenital conditions that stem from damage to, or abnormal development of, the budding nervous system. Cephalic disorders are not necessarily caused by a single factor, but may be influenced by hereditary or genetic ...

in which the

prosencephalon In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the Anatomical terms of location#Directional terms, rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hin ...

(the

forebrain In the anatomy of the brain of vertebrates, the forebrain or prosencephalon is the Anatomical terms of location#Directional terms, rostral (forward-most) portion of the brain. The forebrain (prosencephalon), the midbrain (mesencephalon), and hin ...

of the

embryo An embryo is an initial stage of development of 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 spe ...

) fails to

develop Develop or DEVELOP may refer to: * ''Develop'' (magazine), a trade publication for the video game industry * ''Develop'' (Apple magazine), a technical magazine formerly published by Apple Computer * Develop (chess), moving a piece from its origina ...

into two

hemisphere Hemisphere refers to: * A half of a sphere As half of the Earth * A hemisphere of Earth ** Northern Hemisphere ** Southern Hemisphere ** Eastern Hemisphere ** Western Hemisphere ** Land and water hemispheres * A half of the (geocentric) celes ...

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 and most cases are not compatible with life and result in fetal death

in utero ''In Utero'' is the third and final studio album by American rock band Nirvana. It was released on September 21, 1993, by DGC Records. After breaking into the mainstream with their second album, ''Nevermind'' (1991), Nirvana hired Steve Albin ...

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 vertebrate cerebrum (brain) is formed by two cerebral hemispheres that are separated by a groove, the longitudinal fissure. The brain can thus be described as being divided into left and right cerebral hemispheres. Each of these hemispheres ...

(the left and right halves of the brain), it causes defects in the development of the

face The face is the front of an animal's 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 aff ...

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 development of the nervous system, or neural development (neurodevelopment), refers to the processes that generate, shape, and reshape the nervous system of animals, from the earliest stages of embryonic development to adulthood. The fiel ...

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 loss of the 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 due to a nu ...

, 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, whe ...

) to moderate to severe (

cyclopia Cyclopia (named after the Greek mythology character cyclopes) is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of ...

). The symptoms are dependent upon the classification type. There are four classifications of holoprosencephaly as well as a mild "microform". * Alobar ** Most severe form 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 mouthparts used for feeding and sucking. In vertebrates, a proboscis is an elong ...

, 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, closely spaced nostrils, mental and locomotion delays may 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, however it can also be diagnosed after birth. The Protocol for diagnosis includes neuroimaging (

Ultrasound Ultrasound is sound waves with frequency, frequencies higher than the upper audible limit of human hearing range, hearing. Ultrasound is not different from "normal" (audible) sound in its physical properties, except that humans cannot hea ...

or fetal

MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

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. There are four classifications of holoprosencephaly as well as a “microform". These classifications can be distinguished by their anatomical differences. * Alobar holoprosencephaly ** Small single

ventricle ** No interhemispheric division ** Absence of

olfactory bulbs 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 (O ...

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 mam ...

** Non separation of deep gray nuclei * Semilobar holoprosencephaly ** Rudimentary cerebral lobes ** Incomplete interhemispheric division ** Absence or hypoplasia of

and tracts ** Absence of

** 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, sp ...

** Absent, hypoplasic or normal

** Separation of deep gray nuclei * Syntelencephaly, or middle interhemispheric variant of holoprosencephaly (MIHV) ** Failure of separation of the posterior

frontal Front may refer to: Arts, entertainment, and media Films * ''The Front'' (1943 film), a 1943 Soviet drama film * ''The Front'', 1976 film Music * The Front (band), an American rock band signed to Columbia Records and active in the 1980s and e ...

and

parietal lobes The parietal lobe is one of the four 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 integrates sensory informa ...

** Callosal genu and splenium normally formed ** Absence of corpus callosum **

Hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

and lentiform nuclei normally separated ** Heterotopic gray matter * Microform ** Subtle defects of

** 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. 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. Holoprosencephaly fetus 14 weks US by Dr

Holoprosencephaly fetus 14 weks US by Dr

Genetics

Armand Marie Leroi Armand Marie Leroi (born 16 July 1964) is a New Zealand-born Dutch author, broadcaster, and professor of evolutionary developmental biology at Imperial College in London. He received the Guardian First Book Award in 2004 for his book ''Mutant ...

describes the cause of

as a genetic malfunctioning during the process by which the

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 thalamus and ...

take recognizable form, and at this point an individual with a single

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 Expression may refer to: Linguistics * Expression (linguistics), a word, phrase, or sentence * Fixed expression, a form of words with a specific meaning * Idiom, a type of fixed expression * Metaphorical expression, a particular word, phrase, o ...

of such

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s as Pax-2, as well as inhibition of

Pax-6 Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the ''PAX6'' gene. Function PAX6 is a member of the Pax gene family which is responsible for carrying the geneti ...

, from the

notochord In anatomy, the notochord is a flexible rod which is similar in structure to the stiffer cartilage. If a species has a notochord at any stage of its life cycle (along with 4 other features), it is, by definition, a chordate. The notochord consis ...

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 phenotypes or disease states. This is in contrast to genome-wide association studies ...

s have been located, including the SHH (holoprosencephaly type 3 a.k.a. HPE3), TGIF, 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 deve ...

and BOC genes. Although many children with holoprosencephaly have normal

chromosomes A chromosome is a long DNA molecule with part or all of the genetic material of an organism. In most chromosomes the very long thin DNA fibers are coated with packaging proteins; in eukaryotic cells the most important of these proteins are ...

, specific

chromosomal abnormalities A chromosomal abnormality, chromosomal anomaly, chromosomal aberration, chromosomal mutation, or chromosomal disorder, is a missing, extra, or irregular portion of chromosomal DNA. These can occur in the form of numerical abnormalities, where ther ...

have been identified in some patients (

trisomy A trisomy is a type of polysomy in which there are three instances of a particular chromosome, instead of the normal two. A trisomy is a type of aneuploidy (an abnormal number of chromosomes). Description and causes Most organisms that reprodu ...

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 114 million base pairs (the building material of DNA) and represents between 3.5 and 4% of the total DNA ...

, also known as

Patau syndrome Patau syndrome is a syndrome caused by a chromosome, chromosomal abnormality, in which some or all of the Cell (biology), cells of the body contain Trisomy, extra genetic material from chromosome 13 (human), chromosome 13. The extra genetic mater ...

). 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 effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and t ...

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 allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...

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 always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...

inheritance Inheritance is the practice of receiving private property, Title (property), titles, debts, entitlements, Privilege (law), privileges, rights, and Law of obligations, obligations upon the death of an individual. The rules of inheritance differ ...

). Features consistent with familial transmission of the disease (e.g., a single central

maxillary 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 ...

) 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 high blood sugar levels during pregnancy. Gestational diabetes generally results in few symptoms; however, it increases the risk of pre-eclampsia, depression, and of ...

, transplacental infections (the "

TORCH complex A vertically transmitted infection is an infection caused by pathogenic bacteria or viruses that use mother-to-child transmission, that is, transmission directly from the mother to an embryo, fetus, or baby during pregnancy or childbirth. It ...

"), first trimester bleeding, and a history of

miscarriage Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemical lo ...

. As well, the disorder is found twice as often in

female Female (Venus symbol, symbol: ♀) is the sex of an organism that produces the large non-motile ovum, ova (egg cells), the type of gamete (sex cell) that fuses with the Sperm, male gamete during sexual reproduction. A female has larger gamet ...

babies. However, there appears to be no correlation between HPE and

maternal age Advanced maternal age, in a broad sense, is the instance of a woman being of an older age at a stage of reproduction, although there are various definitions of specific age and stage of reproduction. 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 Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

birth control pills Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control. Female Two types of female oral contraceptive pill, taken once per day, are widely available: * The combin ...

aspirin Aspirin, also known as acetylsalicylic acid (ASA), is a nonsteroidal anti-inflammatory drug (NSAID) used to reduce pain, fever, and/or inflammation, and as an antithrombotic. Specific inflammatory conditions which aspirin is used to treat inc ...

lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...

thorazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar dis ...

retinoic acid Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...

, and

anticonvulsants Anticonvulsants (also known as antiepileptic drugs or recently as antiseizure drugs) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of b ...

. There is also a correlation between

alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...

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 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, dev ...

is based upon the degree in which the brain is affected. Moderate to severe defects may cause intellectual disability, spastic quadriparesis,

athetoid Athetosis is a symptom characterized by slow, involuntary, convoluted, writhing movements of the fingers, hands, toes, and feet and in some cases, arms, legs, neck and tongue. Movements typical of athetosis are sometimes called ''athetoid'' moveme ...

movements, endocrine disorders,

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

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 girl, the testes in a boy. ...

. Most are managed with one

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

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 with the symbol Na (from Latin ''natrium'') and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable iso ...

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 b ...

References

External links

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