Alobar holoprosencephaly is a subtype of holoprosencephaly (HPE), and is the most severe of the classical three subtypes, with both semilobar and lobar holoprosencephaly having less severe clinical manifestations. Holoprosencephaly is a congenital Induction disorder of the brain occurring at 3-6 weeks’ gestation, with failed segmentation of the neural tube. This leads to incomplete separation of the prosencephalon (forebrain).
Holoprosencephaly (HPE) is a rare congenital brain malformation resulting from incomplete separation of the two hemispheres.
In the less severe forms, the brain is only partially divided, and the eyes usually are set close together. Other signs and symptoms often include intellectual disability and pituitary gland problems. Holoprosencephaly can be caused by mutations in any of at least 14 different genes; chromosome abnormalities; or agents that can cause birth defects (teratogens). It may also be a feature of several unique genetic syndromes. In many cases, the exact cause is unknown. Life expectancy for people with this condition varies, and treatment depends on the symptoms and severity in each person.
Holoprosencephaly is a rare congenital disorder which results from failure of cleavage or incomplete differentiation of the forebrain structures at various levels or to various degrees. Depending on the degree of involvement, it is classified into 4 types: Alobar, Semilobar, Lobar and Middle interhemispheric fusion variant. A male child was born to 28-year-old female at 34 weeks of gestation. The mother on antenatal follow-up was detected to have a fetus with multiple congenital anomalies on Ultrasonography (USG) done at 34weeks of gestation. The baby died after 12 hours of birth.
A complete autopsy was performed. On external examination, multiple congenital anomalies were seen including cleft lip and palate, absent nasal bridge, proptosis of right eye, micropenis, left undescended testis, bilateral rocker bottom feet, omphalocele and sacral meningomyelocele. Internal examination of the brain revealed hydrocephalus and features of alobar holoprosencephaly.
Holoprosencephaly is a brain malformation where the forebrain does not completely seperate into two different hemispheres. In more severe cases the brain does not seperate at all. Once known as arhinencephaly, HPE is a neural tube defect that occurs sometime between the forth and sixth week of gestation. There are three types of HPE: alobar being the most severe form, semilobar being intermediate and lobar being the least severe form.
Between the fourth to sixth week of gestation, the forebrain (prosencephalon) is divided into the two hemispheres. Absence of this cleavage results in a spectrum of malformations called holoprosencephaly (HPE). Because the olfactory nerves which are part of the rhinencephalon are absent, the term arrhinencephaly has also been applied to this malformation. However, in HPE, there is much more missing than the olfactory brain. In the most severe form, alobar HPE, the brain consists of a single spherical forebrain structure with a single ventricle. A large cyst which communicates with the ventricle is present in the posterior-dorsal part of the brain.
The brain in alobar HPE is small and the gyral pattern and cortical architecture are abnormal. The eyes, which evaginate from the forebrain in the fourth week, are small and malformed or there is only one eye (cyclopia. Milder forms of HPE are semilobar HPE (fusion of frontal and parietal lobes with separation of the occipital lobes), lobar HPE (fusion of the ventral frontal lobes with separation of the rest of the hemispheres), and the middle interhemispheric fusion variant in which the anterior and posterior parts of the hemispheres are separate but the posterior frontal and and parietal lobes along with the basal ganglia and thalamus are fused.
A specrum of midline facial anomalies accompanies the brain malformations. In alobar HPE, these are severe and include a proboscis (a trunk-like structure above the single eye), a single nostril, cleft lip, and cleft palate. Milder brain pathology is accompanied by milder or subtle facial defects such as a central incisor and hypotelorism. The correlation between the facial anomalies and HPE was pointed out by DeMeyer in a paper titled “The face predicts the brain”. Alobar HPE is incompatible with survival. Milder forms are associated with variable psychomotor retardation depending on the pathology. Diabetes insipidus is frequent in these patients.
Holoprosencephaly is the most common forebrain defect and can be as common as 1 in every 250 embroys and 1 in every 10,000 newborns. It is possible to diagnose in utero. One of the most common ways to diagnose HPE is with a catscan (CT) or magnetic resonance imaging (MRI). While there is no cure for HPE, treatment is symptomatic and supportive.
Some symptoms and conditions caused by HPE are as follows: cyclopia, median cleft lip and palate, seizures, missing front teeth, closley set eyes, small head, multiple hormone deficiencies, feeding difficulties, developmental delays and more. We were told two HPE brain scans can be identical and each child can do completly different things and have different symptoms, but the actual cause of holoprocencephaly is unknown.
How is it confirmed?
Diagnosis of HPE is usually made during the 18+0 − 20+6 weeks’ fetal anomaly ultrasound scan but is occasionally
diagnosed as early in pregnancy as week 12. It is unlikely to be seen on a scan before week 12 of pregnancy.
Is there any treatment?
Unfortunately there is no treatment for this condition. HPE is a severe condition and treatment is based on
- improving symptoms and appropriate support to improve all aspects of the baby’s quality of life. However, due
- to the severity of the condition, some women choose to not continue with the pregnancy after discussing their
- options fully with a specialist doctor, midwife and their families.
What is the outlook for the baby?
Sadly, current studies indicate that only 3% of all babies diagnosed with this condition in pregnancy survive to birth.
Those that do survive until birth usually do not survive past the first six months of life. Survival rates depend on how
severe the brain abnormality is, as well as other health complications that may be present.
How common is it?
It is estimated that HPE affects 1 in 7,500 births.
How likely is it to happen in a future pregnancy?
You are much more likely to have a normal, healthy baby in your next pregnancy than to have another baby
affected with HPE. However, there is a small risk of this happening again and you may wish to talk to a genetic
specialist about future pregnancies.
What causes holoprosencephaly?
The cause of HPE is currently unknown. Often, no specific cause can be identified. Suggested risk factors include maternal diabetes, infections during pregnancy (syphilis, toxoplasmosis, rubella, herpes, cytomegalovirus), and various drugs taken during pregnancy (alcohol, aspirin, lithium, thorazine, anticonvulsants, hormones, retinoic acid). Women with previous pregnancy loss and first trimester bleeding are also more likely to have a child diagnosed with HPE.
Although many children with HPE have normal chromosomes, specific chromosomal abnormalities have been identified in some patients. There is evidence that in some families, HPE is inherited (autosomal dominant as well as autosomal or X-linked recessive inheritance).
Holoprosencephaly is a birth defect that arises during the first few weeks of the pregnancy. Diabetes in the mother during the pregnancy can increase the risk of holoprosencephaly in the fetus. However, for most children, there is no known intrauterine exposure that can be related to holoprosencephaly.
Some children will have an identifiable genetic cause of holoprosencephaly. Approximately one-third of children born with holoprosencephaly have an abnormality of the chromosomes, which contain the genetic material (DNA). The most common chromosomal abnormality associated with HPE is when there are 3 copies of chromosome 13 (trisomy 13), although a number of other chromosomal changes can also cause holoprosencephaly.
In other children, holoprosencephaly is due to a change in a specific gene. These changes cause the genes and their proteins to function abnormally, and this affects the development of the brain, resulting in holoprosencephaly. Some of these genes are SHH, SIX3, TGIF, ZIC2, PTCH1, FOXH1, NODAL, CDON, and GLI2. Holoprosencephaly can also occur in certain genetic syndromes in which there are other medical issues besides those mentioned in this report that affect organs in addition to the brain and face (e.g., Smith-Lemli-Opitz syndrome).
How common is this defect?
It is estimated that HPE affects between 1 in 5,000-10,000 live births. Since many pregnancies with a fetus diagnosed with HPE end in miscarriage, the frequency of HPE among all pregnancies may be as high as 1 in 200-250. Current studies indicate that only 3% of all fetuses with HPE survive to delivery and the vast majority of these infants do not survive past the first six months of life. The prognosis for a child diagnosed with HPE depends on the type of HPE and the presence of associated anomalies. The most severely affected children may live several months or years and the least affected may live a normal life span. Almost two-thirds of affected patients have alobar HPE and approximately one quarter are diagnosed with semilobar HPE.
As with all types of holoprosencephaly, it is a rare congenital brain malformation in which there is failure of complete separation of the two hemispheres (which usually occurs around the 4th to 6th gestational weeks) and failure of transverse cleavage into the diencephalon and telencephalon.
As with most cerebral structural congenital abnormalities, alobar holoprosencephaly is visible on all modalities, but in general is identified on antenatal ultrasound (if performed), and best characterised by MRI.
- fused thalami
- absent corpus callosum
- absent interhemispheric fissure
- absent cavum septi pellucidi
- absence of 3rd ventricle
- middle and anterior cerebral arteries may be replaced by tangled branches of internal carotid and basilar vessels.
- severe facial malformations
The basic structure of the cerebral hemispheres is lost, with variable amounts of residual cortex. Features include 1-2:
- single midline monoventricle (or holosphere)
- lateral and third ventricles are absent
- absent midline structures
- absent septum pellucidum
- agenesis or hypoplasia of the corpus callosum
- absent interhemispheric fissure and falx cerebri
- absent olfactory tract
- dorsal cyst of holoprosencephaly
- absent, fused or normal optic nerves
- middle and anterior cerebral arteries may be replaced by tangled branches of internal carotid and basilar vessels
Associated craniofacial features may also be present which include:
The fused cortex can take on one of three basic shapes 2:
pancake: cerebral tissue is confined to the anterior basicranium
cup: cerebral tissue lines variable amounts of the anterior cranium with a dorsal cyst present posteriorly
ball: a complete rim of tissue surrounds the monoventricle without dorsal cyst
Treatment and prognosis
This is the most severe type of the holoprosencephaly spectrum and often tends to be fatal in the neonatal period.
The prognosis depends on the sub-type. The alobar holoprosencephaly is the most severe type of the defect and the affected fetus are usually stillbirth, or die soon after birth, or during the first 6 months of life. However, a significant proportion of more mildly affected children (as well as some severely affected children) survive past age 12 months. More than 50 percent of children with semi-lobar or lobar holoprosencephaly without significant malformations of other organs are alive at age 12 months.The life expectancy for individuals with semi-lobar holoprosencephaly depends on the underlying cause of the condition and the presence of associated anomalies.
- semilobar holoprosencephaly
- partial separation into hemispheres
- rudimentary occipital and temporal horns
- thalami are often visible and are not fused
- falx cerebri usually present
- not associated with midline facial abnormalities
- no cortex present, or sometimes small islands of tissue
- severe hydrocephalus
- falx cerebri usually present, but may be absent due to severe long-standing hydrocephalus
- bilateral choroid plexus
Holoprosencephaly (HPE) may be suspected during a routine ultrasound examination if the unborn baby’s head is smaller than normal.
After birth, severe cases of HPE may be diagnosed based on the child’s signs and symptoms. In severe cases, characteristic features, such as a small head and facial malformations, are apparent.
In less severe cases, such as lobar HPE, a magnetic resonance imaging (MRI) scan or computerized tomography (CT) scan is performed to confirm a diagnosis. During this non-invasive procedure, a machine takes a picture of the child’s brain. This allows the doctor to see if the brain’s hemispheres have divided properly. If the hemispheres have not completely divided, HPE may be diagnosed.
Molecular testing is also available to detect genetic abnormalities associated with HPE.
What are the signs and symptoms of Alobar holoprosencephaly?
Alobar holoprosencephaly results from complete failure of the brain to divide into right and left hemispheres and there is a single “monoventricle” (instead of two). The findings may include a single eye (cyclopia) with a tubular-shaped nose (proboscis); or ethmocephaly (extremely closely spaced eyes but separate orbits with proboscis between the eyes); or absent (anophthalmia) or very small eye (microophthalmia); or cleft lip, closely spaced eyes and a flattened nose; or bilateral cleft lip, and in some cases a relative normal facial appearance (especially in persons with mutations in the ZIC2 gene)
What happens next?
You will be given the chance to talk to specialists about what having a baby with this condition might mean to
you and your family. After having time to think about it, some women choose to continue with their pregnancy
and do all they can to prepare for having a baby with this condition. Others may choose not to continue with the
pregnancy. You will be offered a termination of pregnancy. Whatever you decide, your decision will be respected
and you will be supported by your midwife and doctor.
Where can I get more information and support?
You may feel you only want to talk to your partner, family members or a particular doctor or midwife from the
hospital. However, there are a lot of other people and organisations that can provide information, help you make
your decisions and support you in your pregnancy and after it. Some are listed below. You can also talk things
through with the hospital chaplain or your own faith leader.
Because the cause of holoprosencephaly (HPE) is poorly understood, there is no known method of prevention for the disorder.
Infants born to diabetic mothers may have an increased risk of having HPE. Diabetic mothers can help reduce their risks of having children with birth defects and congenital disorders, such as HPE, by strictly controlling their blood sugar levels. Therefore, expectant mothers with diabetes are encouraged to choose doctors with expertise in diabetes care. This helps ensure that the pregnant mother and the fetus obtain the best possible care before and during pregnancy.
Infants born to mothers who have infections, such as herpes, syphilis, cytomegalovirus, rubella, and toxoplasmosis, may have an increased risk of developing HPE. Therefore, pregnant mothers who have symptoms of infections should seek prompt medical treatment.
Holoprosencephaly can also occur in association with malformations in other organ systems that are not directly related to holoprosencephaly.
Smith-Lemli-Opitz syndrome (SLOS) is a variable genetic disorder that is characterized by slow growth before and after birth, small head (microcephaly), mild to moderate intellectual disability and multiple birth defects including particular facial features, cleft palate, heart defects, fused second and third toes, extra fingers and toes, and underdeveloped external genitals in males. SLOS is caused by a deficiency in the enzyme 7-dehydrocholesterol reductase that results in an abnormality in cholesterol metabolism. SLOS is inherited as an autosomal recessive genetic disorder. (For more information about this condition, choose “SLOS” as your search term in the Rare Disease Database.)
Other genetic syndromes that have been reported in association with holoprosencephaly include Hartfield syndrome (ectrodactyly, cleft lip/palate), agnathia-otocephaly complex (very small chin, ear anomalies), and Pallister-Hall syndrome (extra fingers/toes, hypothalamic hamartoblastomia, anal anomalies).
The diagnosis of holoprosencephaly is usually made by MRI or CT of the brain. Holoprosencephaly can sometimes be detected prenatally through ultrasound or MRI, though mild forms may not be reliably detected prenatally.
Treatment and care for the issues associated with holoprosencephaly are supportive and based on the specific medical issues present for an individual child.
An endocrinology evaluation should be performed to assess for pituitary abnormalities. A neurologist should also be involved in the child’s care and can guide treatment for seizures if they are present. Plastic reconstructive surgery of cleft lip and palate or other facial features may be needed if indicated. A developmental pediatrician can help direct developmental therapies. Other treatments can be instituted as appropriate.
A clinical genetics evaluation and genetic counseling should be obtained for patients and their families once the diagnosis is made. Relatives of a child with holoprosencephaly may have an increased risk of having a child with holoprosencephaly, and this should be assessed and discussed by the child’s physicians, especially the neurologist and/or clinical geneticist. There are specific features that suggest an increased risk for having another child with holoprosencephaly (e.g., a single central upper incisor), and these should be carefully assessed in parents and family members. A chromosome analysis and gene testing is often performed.
Pediatricians, neurologists, dentists, special education teachers, surgeons, therapists, psychologists, developmental pediatricians, and others must systematically and comprehensively plan the child’s treatment for holoprosencephaly.
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