Holoprosencephaly

Medical quality assurance by Dr. Albrecht Nonnenmacher, MD at October 20, 2016
StartDiseasesHoloprosencephaly

Holoprosencephaly is a rare congenital disorder affecting the fetal forebrain. During embryonic development, the forebrain fails to divide into the cerebral hemispheres. This results in a single-lobed brain and severe facial deformity and skull defects.

Contents

Definition & Facts

Holoprosencephaly is estimated to occur during embryonic development in approximately 1 in 250 pregnancies. In most cases, the malformation is so severe that the fetus does not survive until birth.

The condition occurs in an estimated 1 in 16,000 live births. Among infants born with the condition, the prognosis can vary widely. Those with severe malformations often die within a few days from brain stem dysfunction. Those with less significant deformities may survive beyond infancy.

Holoprosencephaly is divided into three general classifications. Alobar holoprosencephaly is characterized by a complete absence of brain division. This is the most severe classification and is associated with significant facial anomalies. A moderate form of the disorder is called semilobar holoprosencephaly in which there is some discernable brain division. In the lobar form of the disorder, there is considerable division between the hemispheres, and the brain may be almost normal.

Symptoms & Complaints

The symptoms and degree of malformation associated with holoprosencephaly can vary widely. Intellectual disabilities and seizures are common in patients with the disorder. Physical characteristics typically include the following:

In the most extreme cases, affected infants may be born with one eye located in the center of the face where the root of the nose is normally situated. There may also be significant deformities of the nose. The eyes may also be closely-set, incomplete, or underdeveloped.

Holoprosencephaly may also affect other body systems. As a result, children with the condition can experience metabolic disorders such as low blood sugar (hypoglycemia), low sodium levels, and diabetes insipidus.

Children with the condition often have feeding difficulties, which can result in gastroesophageal reflux and failure to thrive. Other problems common in patients with holoprosencephaly include a disturbed wake/sleep cycle, problems regulating body temperature, frequent respiratory infections, and lung disease.

Causes

Holoprosencephaly occurs during the early weeks of pregnancy. For many children, there is not specific cause or intrauterine exposure that can be positively linked to the development of the condition. Women who experience diabetes mellitus during their pregnancy do have a higher incidence of the disorder.

It is believed that many cases of holoprosencephaly are genetic in nature. An estimated one-third of infants born with the disorder have chromosomal abnormalities. The most common abnormality found in cases of holoprosencephaly is called trisomy 13 in which there are three copies of the 13th chromosome.

In other instances, the defect involves a mutation of a specific gene and its associated proteins. The most commonly affected genes include SHH, TGIF, SIX3, and ZIC2. Holoprosencephaly can also occur in conjunction with genetic conditions, such as Smith-Lemli-Opitz syndrome, Hartfield syndrome, and Pallister-Hall syndrome, that can also affect the face, brain, and other organs. Holoprosencephaly appears to affect males and females relatively equally and is seen across various ethnic groups. 

Diagnosis & Tests

Prenatal diagnosis of holoprosencephaly can be made through genetic testing, ultrasound, and magnetic resonance imaging (MRI). Karyotype genetic testing reveals abnormalities in up to 41 percent of holoprosencephaly cases. Molecular genetic testing is available to identify specific genetic mutations. More recently, DNA microarray testing using fetal blood has been used to identify genomic rearrangements associated with the disorder.

Prenatal MRI and ultrasound images can provide visual confirmation of the brain and skeletal malformations; however, these imaging tests are not always reliable in identifying mild forms of the disorder prenatally. Electroencephalography, also known as EEG, may be used in the event of suspected seizures. This procedure uses small electrodes attached to the scalp to measure the electrical impulses in the brain. 

Treatment & Therapy

Since there is no cure, treatment for holoprosencephaly is symptomatic and supportive in nature and based on the child’s specific medical issues. In creating the treatment plan, it is necessary to include a team of specialists, including neurologists, dentists, surgeons, pediatricians, therapists, and others. An endocrinologist can evaluate the child to determine if there are any pituitary or other endocrine abnormalities and recommend appropriate treatments.

A neurologist can provide treatment for seizures. Plastic and reconstructive surgery may be available to help correct a cleft lip and palate and other facial deformities. Children suffering from excessive fluid on the brain, a condition known as hydrocephalus, may require a surgical procedure to implant a ventriculoperitoneal shunt to drain the fluid.

Children with feeding difficulties, gastroesophageal reflux, or poor weight gain may require surgery to insert a gastrostomy tube or to strengthen the esophageal sphincter to prevent reflux. A variety of medications may be used to treat the symptoms associated with holoprosencephaly, including anticonvulsants, muscle relaxants, and acid reflux medications.

Developmental pediatricians, special education teachers, physical therapists, and occupational therapists may be required to address cognitive and physical developmental issues. 

Prevention & Prophylaxis

Since most instances of holoprosencephaly appear to be genetic in nature or of unknown origin, there is little that can be done to prevent the condition. The close family members of children born with the disorder should consider undergoing genetic counseling and testing following the diagnosis. This typically involves gene testing and chromosome analysis. There is evidence that these individuals are at an increased risk for having a child with the condition.

The parents of the child should talk to their doctor or genetic counselor about the risk of having a child with holoprosencephaly in subsequent pregnancies. Certain factors, such as the child having only one central incisor, appear to increase the risk of having another child with the condition.

The National Institute of Neurological Disorders and Stroke is currently conducting and supporting research efforts regarding a variety of brain development disorders, including holoprosencephaly. This research has helped isolate specific genetic mutations that can cause the holoprosencephaly. The hope is that this increased knowledge will provide insight into new treatments and ways to prevent the disorder.