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Holoprosencephaly- Classification, Causes, Symptoms, Diagnosis, and Management

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Holoprosencephaly is a congenital disorder that affects the development of the brain during the intrauterine stage. This article reviews holoprosencephaly.

Medically reviewed by

Dr. Veerabhadrudu Kuncham

Published At December 13, 2022
Reviewed AtMarch 17, 2023

Introduction:

Holoprosencephaly is a congenital deformation in the brain due to failed division of the forebrain. It occurs during the third and sixth weeks of intrauterine development. So the brain’s frontal portion is not adequately separated into two halves, causing facial abnormalities. The affected children will have a small-sized head with other facial deformities such as cleft palate.

What Is the Incidence of this Condition?

  • They occur during the early days of gestation and are often undetectable as they end in miscarriage.

  • They are seen in 1 in 250 gestations but rare in live births, with an incidence of 1 in 10000 to 16000 live births.

  • They are more common in females than in males.

How Is Holoprosencephaly Classified?

Depending on the separation, they are classified into three types.

  • Alobar holoprosencephaly.

  • Semilobar holoprosencephaly.

  • Lobar holoprosencephaly.

  1. Alobar Holoprosencephaly:

It is the most severe form of holoprosencephaly. In this variant, there is a complete absence of the division of the forehead. Hence, the lack of midline structures of the face, brain, etc., results in severe facial anomalies. These babies die soon after birth, or they are stillborn. They are also referred to as mono ventricles as there is no fusion of the cerebral hemispheres.

  1. Semilobar Holoprosencephaly:

In this variant, there is partial separation of the brain's two hemispheres. This is considered a moderate form of holoprosencephaly. In this type, the fusion is seen in the anterior region, whereas the posterior part remains separated.

  1. Lobar Holoprosencephaly:

It is a mild form of holoprosencephaly. There is a separation between the two hemispheres, but they are partially divided into right and left halves.

What Is the Cause of Holoprosencephaly?

Generally, during embryonic development, the brain divides into two halves, the right and left hemispheres. But in the case of holoprosencephaly, there is an improper division of the two hemispheres, particularly in the anterior region of the forebrain. This forebrain is essential for the development of the adult brain. So any abnormalities in the forebrain may affect the physical and functional abilities.

Three factors are responsible for this condition. They are:

  • Genetic mutation.

  • Chromosomal abnormalities.

  • Genetic syndromes.

Genetic Mutations:

Any defect in the genetic sequence may interfere with the normal functioning of the baby and cause several growth malformations. The genes that are responsible for holoprosencephaly are SHH, SIX3,TGIF1, ZIC2, PTCH, FOXH1, NODAL, CDON, FGF8, GLI2.

Chromosomal Abnormalities:

The most common chromosomal abnormality seen in holoprosencephaly is the presence of an extra copy of chromosome 13 called trisomy 13. It is also reported in a few cases of trisomy 18 and Down’s syndrome.

Genetic:

Some genetic conditions also cause holoprosencephaly. They are:

  • Hartsfield Syndrome: A rare medical condition with holoprosencephaly and malformations of the hands and feet.

  • Kallman Syndrome: A genetic condition that causes the absence of puberty or delayed puberty, or secondary sexual characteristics.

  • Steinfeld Syndrome: It is a congenital disorder that causes malformations of the heart, kidney, gallbladder, and holoprosencephaly.

  • Smith-Lemli- Opitz Syndrome: A congenital disorder affecting many body parts.

  • Stromme Syndrome: It is a genetic disorder that causes abnormalities in the head, eyes, and intestines.

What Are the Signs and Symptoms?

The clinical presentation varies in each case of holoprosencephaly, depending on the severity of the condition. However, the most common manifestations are:

  • Developmental delays that hinder intellectual abilities.

  • Seizure activity is reported in 40 % of the cases.

  • Short stature.

  • Failure to thrive.

  • Small-sized head (microcephaly)

  • Fluid accumulation in the brain (hydrocephalus).

  • Palatal cleft and cleft lips.

  • Feeding difficulties due to the presence of palatal clefts.

  • Dental abnormalities, such as the presence of only one central incisor.

  • Irregular sleep pattern.

  • Aspiration pneumonia.

Clinical Features of Alobar Holoprosencephaly:

  • Presence of only one eye (cyclopia).

  • Eyes are closely spaced.

  • Flattened nasal bridge.

  • The cleft lip is either unilateral or bilateral.

Clinical Features of Semi-Lobar Holoprosencephaly:

  • Closely spaced eyes.

  • Presence of single nostrils.

  • Cleft lip (median or bilateral).

  • Cleft palate.

  • Normal physical appearance.

Clinical Features of Lobar Holoprosencephaly:

  • Bilateral cleft lip.

  • Flattened nose.

  • Closely spaced eyes.

  • Comparatively normal physical appearance.

What Are the Risk Factors for Holoprosencephaly?

  • Maternal diabetes.

  • Alcohol consumption.

  • Use of medications such as Retinoic acid, Aspirin, and Misoprostol.

  • Presence of hereditary conditions such as trisomy 13, 18, and Down syndrome.

  • Genetic syndromes include Smith-Lemi- Optiz syndrome, Meckel-Gruber syndrome, and Pallister-Hall syndrome.

How to Diagnose Holoprosencephaly?

Holoprosencephaly is often diagnosed during prenatal ultrasounds. They may show structural deformities. Mild cases of holoprosencephaly may be undetected in the ultrasound. Other diagnostic tests may be essential.

  1. Magnetic Resonance Imaging and Computed Tomography: They provide detailed information about the brain structures and detect any abnormalities.

  2. Ultrasound of the Brain: It is a non-invasive diagnostic procedure that uses sound waves of high frequency to picture vital organs.

  3. Electroencephalography: These help to detect seizure activity in the brain.

  4. Chromosomal Analysis: They help to detect the exact cause of holoprosencephaly.

Can Holoprosencephaly Be Prevented?

  • Some research shows that folic acid consumption advised at least three months before conception can help prevent any neural defects in the baby.

  • Exposure to specific teratogens such as retinoic acid, alcohol consumption, or other mycotoxins increases the chance of holoprosencephaly.

How Are They Managed?

Only palliative therapy is recommended for holoprosencephaly as there is no definitive treatment. However, supportive treatment may render relief to the affected children.

  • Seizures: Anticonvulsants are used as a prophylactic regimen.

  • Gastrointestinal Problems: H2- receptor antagonists, proton pump inhibitors

  • Neurosurgery: Neurosurgery may be indicated to relieve the fluid accumulation in the brain. A ventriculoperitoneal shunt is placed to prevent fluid build-up in the brain.

  • Gastrotomy: A feeding tube is inserted to aid the swallowing in the baby due to the presence of a palatal cleft.

  • Physical Therapy: This improves muscle activity in case of spasticity and dystonia.

  • Reconstructive Surgeries: Surgical procedure done to correct the opening in the roof of the mouth (palatal cleft) and the groove in the lips (cleft lips).

What Is the Prognosis of Holoprosencephaly?

The prognosis depends on the type of holoprosencephaly. Generally, in the alobar type, the baby is either stillborn or dies soon after birth. The maximum life expectancy is six months. Babies with semi-lobar holoprosencephaly may survive up to one year, and in the lobar variety, many patients may survive to adulthood.

Conclusion:

Holoprosencephaly in children may be challenging in terms of leading a regular life. They require consistent, lifelong follow-ups. Patients may require multiple surgeries to correct physical deformities. Parents and family members are given counseling to help their children with holoprosencephaly.

Frequently Asked Questions

1.

What Is the Life Expectancy of Babies With Holoprosencephaly?

The life expectancy for babies with holoprosencephaly can vary widely depending on the severity of the condition. In some cases, babies may die shortly after birth; they usually do not live beyond the early stages of infancy. Certain children who are less severely affected can survive beyond 12 months, may live for several years, and even reach adulthood.

2.

What Are the Physical Characteristics of Holoprosencephaly?

Holoprosencephaly can have various physical features, including a small head, facial abnormalities, tooth abnormalities, small eyeballs, eyes that are closely spaced, and cleft lip and palate. However, the appearance can vary depending on the severity and type of the condition.

3.

Is There a Cure for Holoprosencephaly?

There is no cure for holoprosencephaly, but treatment may involve managing symptoms, which include:
 - Plastic reconstructive surgery to repair cleft lip or palate, 
 - Antiseizure medications to control and prevent seizures
 - Physical therapy to address issues related to muscle movements.

4.

What Are the Symptoms Associated With Holoprosencephaly?

Common symptoms of holoprosencephaly include:
 - Intellectual disability, 
 - Seizures.
 - Developmental delays.
 - Endocrine abnormalities like defects in pituitary glands.
 - Small head (microcephaly)
 - Excessive fluid in the brain (hydrocephalus), 
 - Facial abnormalities and tooth abnormalities (single central incisor).
 - Cleft lip or palate.

5.

What Are the Causes of Holoprosencephaly in Infants?

A combination of genetic and environmental factors causes holoprosencephaly. It can be inherited in some cases, but most occur sporadically, without any family history. Genetic causes include chromosomal abnormalities and genetic syndromes. A teratogenic substance (causing birth defects) also causes this condition.

6.

At What Stage of Pregnancy Can Holoprosencephaly Be Detected?

Holoprosencephaly screening is best accomplished using ultrasound between 18 to 20 weeks of gestation. However, the alobar type of holoprosencephaly has been detected as early as 10 to 12 weeks gestation using transvaginal ultrasonography (TVS).

7.

How Uncommon Is Holoprosencephaly?

Holoprosencephaly is the prevalent developmental abnormality of the forebrain in humans, which affects approximately 1 in every 250 human embryos. Unfortunately, a large proportion of these embryos do not survive and are lost due to miscarriage. At the time of birth, the occurrence of HPE is estimated to be around 1 in 8,000 to 1 in 10,000 live births and stillbirths.

8.

Can Holoprosencephaly Be Compatible With Life?

Holoprosencephaly can be compatible with life, but the severity of the condition can vary widely, and some babies may not survive beyond infancy. Compatibility varies among different types of holoprosencephaly.  Children with lobar, semi-lobar and middle hemispheric variants have variable survival rates, while an alobar form of holoprosencephaly is incompatible.

9.

Can Holoprosencephaly Be Fatal?

Some individuals with mild forms of holoprosencephaly can survive and live for several years, while severe forms of the disorder can be life-threatening and may result in early death.

10.

What Is the Underlying Mechanism That Leads to Holoprosencephaly?

Holoprosencephaly is a condition that arises when the prosencephalon, which is the forebrain of an embryo, fails to divide adequately into the paired lobes that form the cerebral hemispheres. As a consequence, the brain structure ends up being a single lobe, leading to significant abnormalities in the skull and facial features.

11.

Can Folic Acid Prevent the Occurrence of Holoprosencephaly?

Folic acid has been shown to reduce the risk of some neural tube defects, but it does not significantly affect the incidence of holoprosencephaly.

12.

Which Gene Mutations Are Associated With Holoprosencephaly?

Several genes have been associated with holoprosencephaly, which includes:
 - Sonic Hedgehog (SHH) gene. 
 - ZIC2 gene (Zinc finger proteins).
 - SIX3.
 - TGIF1

13.

Is Holoprosencephaly Visible on Ultrasound?

Holoprosencephaly can sometimes be seen on prenatal ultrasound. It is visible on an ultrasound done at the 18 to 20 weeks gestation period of pregnancy.

14.

What information can be obtained from an MRI of the holoprosencephaly brain?

An MRI of a holoprosencephaly brain would show abnormalities in the structure and development of the brain, including the degree of separation between the two hemispheres.

15.

Which Genetic Disorder Is Frequently Associated With Holoprosencephaly?

Genetic disorders associated with holoprosencephaly include the following.
 - Hartsfield syndrome.
 - Kallman syndrome two.
 - Steinfeld syndrome.
 - Smith-Lemli-Opitz syndrome.
 - Stromme syndrome.

16.

Is Holoprosencephaly Considered a Field Defect?

Holoprosencephaly is a type of field defect. Field defects are abnormalities in the visual field, which is the area of the visual world that can be seen at any given moment without moving the eyes. Holoprosencephaly is a developmental disorder that affects the forebrain and results in incomplete separation of the brain's two hemispheres. This can cause various neurological and physical abnormalities, including field defects in vision.
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Dr. Veerabhadrudu Kuncham
Dr. Veerabhadrudu Kuncham

Pediatrics

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