Holoprosencephaly

What Causes Holoprosencephaly?

In many cases, the cause of HPE isn’t apparent, but abnormal changes (mutations) in several genes have been associated with the condition. The associated genes include:

• SHH
• SIX3
• TGIF1
• ZIC2
• PTCH1
• FOXH1
• NODAL
• CDON
• FGF8
• GLI2

In about a third of cases, HPE is associated with abnormalities in chromosomes, the structures inside cells containing genetic material. The most common abnormality is trisomy 13, a condition in which three copies of chromosome 13 are present instead of the usual two.

HPE is also sometimes associated with genetic syndromes such as Smith-Lemli-Opitz syndrome and Hartsfield syndrome.

Is Holoprosencephaly Hereditary?

HPE is sometimes inherited. In some cases, the genetic mutations or chromosomal abnormalities that cause the condition are passed from parent to child. In other cases, the mutation may occur spontaneously during the development of the sperm or egg cell or in the early development of the embryo.

When inherited, HPE is usually passed down in an autosomal dominant pattern. This means a child may develop the condition if they inherit even one copy of the disorder-causing gene mutation from either parent.

Syndromes associated with HPE, such as Smith-Lemli-Opitz syndrome and Hartsfield syndrome, may be inherited by a child from their parents.

How Is Holoprosencephaly Detected?

Imaging exams such as ultrasound or magnetic resonance imaging (MRI) may detect HPE malformations during pregnancy. However, if the malformations are not severe, they may not be apparent before birth.

How Is Holoprosencephaly Diagnosed?

HPE may be suspected when a baby shows facial malformations characteristic of the condition. Imaging exams of the brain such as MRI or computerized tomography (CT) scans will show the distinctive malformation of the cerebral hemispheres.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Holoprosencephaly Treated?

There is no way to correct the brain malformation of HPE, and no treatment will reverse the condition’s neurological symptoms. Treatments and therapies focus on managing symptoms, preventing complications, and improving the child’s quality of life.

Common treatments and therapies include:

• Surgery to correct facial malformations
• Correction of dental malformations
• Physical therapy
• Psychotherapy
• Special education

How Does Holoprosencephaly Progress?

Children with alobar holoprosencephaly typically do not survive past the first few months of life. Many of those with semi-lobar or lobar holoprosencephaly survive beyond 12 months, depending on the severity of the HPE malformations and whether there are problems with any other organs. In cases of lobar HPE in which brain malformation is mild, survival into adulthood is not uncommon.

How Is Holoprosencephaly Prevented?

Diabetes in the mother during pregnancy has been identified as a risk factor for HPE, but no other avoidable prenatal risk factors are known. People with a family history of HPE or other genetic disorders associated with HPE should consult with a genetic counselor to assess their risks before becoming pregnant. Parents who have had a child with HPE should also seek genetic counseling before having more children.

Holoprosencephaly Caregiver Tips

• Living with HPE can be exhausting, but you will also experience moments of joy with your child. Remember to slow down and cherish each of them.
• Watch out for your own health. Parents and caregivers are at risk of mental and physical health problems when they neglect their needs in favor of their caregiving duties. Don’t feel guilty about taking time away from caregiving when you can, and don’t be afraid to ask for help when you need it.
• Get help from the HPE community. Families for HoPE sponsors online support groups for families living with HPE, and the organization also maintains links to educational and other resources.

Some children with HPE may also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with HPE:

• HPE sometimes causes hydrocephalus.
• At least one study has suggested a genetic association between HPE and bipolar disorder.

Holoprosencephaly Brain Science

Scientists have identified mutations in at least 11 different genes that are associated with HPE. Some of these genes contain instructions for making compounds called signaling proteins. These proteins are responsible for directing newly formed brain cells to differentiate into distinct hemispheres during embryonic development. Some signaling proteins are also vital in the development of the eyes. The SHH gene, for example, is responsible for the production of a protein that causes a specific group of cells to divide into two separate eyes.

Mutations in these genes likely cause abnormal protein production, which, in turn, interferes with the normal development of the cerebral hemispheres, the eyes, and other features of the skull and face.

Holoprosencephaly Research

Title:  Study of the Experiences and Needs of Parents Continuing a Pregnancy Following a Prenatal Diagnosis of Holoprosencephaly

Stage: Completed

National Human Genome Research Institute

Bethesda, MD

Holoprosencephaly (HPE) is a condition that, when found prenatally, offers parents a poor but often uncertain prognosis for their baby. Parents that continue the pregnancy given this diagnosis are left to endure the remainder of the pregnancy and the ambiguity involved in this highly variable condition. Previous studies have examined the psychological and social impact of prenatal diagnosis on parents and the outcomes of the pregnancy in cases such as Down syndrome and sex chromosome abnormalities. Because the majority of parents receiving abnormal prenatal information terminate their pregnancies, most studies have focused on these parents’ experiences, specifically the mothers’. However, little is known about the experiences of parents (both fathers and mothers) continuing a pregnancy given abnormal prenatal information, especially in highly variable conditions such as HPE.

In this study, the experiences and needs of parents who received the diagnosis of HPE prenatally will be explored. Study participants will be drawn from several sites that include an existing molecular diagnostic protocol for HPE at the University of Pennsylvania, clinical patients seen at the University of Michigan, HPE family resources, and an upcoming conference on HPE to be held in April of 2000. Through semi-structured interviews, fathers and mothers of children with HPE who were diagnosed prenatally will be asked to talk individually about their experiences of receiving the diagnosis and continuing with the pregnancy. Their perceived informational, emotional, and supportive needs at that time will be explored. In addition, their thoughts on the health care professionals’ role in meeting these needs will be discussed. A brief questionnaire following the interview will gather quantitative data to serve as descriptors of the population and to help interpret the qualitative findings. The questionnaire includes demographic questions as well as a scale measuring tolerance for ambiguity and questions regarding the parent’s perceived severity of their child’s diagnosis of HPE.

Interviews will be analyzed qualitatively through thematic analysis. Specifically, recurring themes that emerge from interview transcripts will be analyzed for content and patterns. In addition, descriptive statistics will be applied to the questionnaire data and will be used to aid in the interpretation of the qualitative findings. Finally, an exploration of the experiences and needs of fathers and mothers who receive the diagnosis of HPE prenatally will offer a better understanding for health care professionals, specifically genetic counselors, regarding their role in working with parents continuing a pregnancy given prenatal information about a fetal anomaly.

Title: Clinical and Genetic Studies on Holoprosencephaly

Stage: Completed

Principal investigator: Paul S. Kruszka, MD

National Institutes of Health Clinical Center

Bethesda, MD

This study will examine how holoprosencephaly (HPE) affects people, how they change over time, and what genes may be involved in the cause of the disorder. HPE is a defect of brain development in utero. The forebrain fails to sufficiently divide into two hemispheres, resulting in a single-lobed brain and skull and facial malformations. In most cases, the defects are so severe that babies die before birth. There are three classifications of HPE. In alobar HPE, the brain does not divide at all; this form is usually associated with severe facial deformities. In semi-lobar HPE, the hemispheres divide somewhat, causing an intermediate form of the disorder. In lobar HPE, the mildest form, separation of hemispheres is nearly normal.

The purpose of this study is to increase our understanding of the genetic and clinical manifestations of HPE through detailed physical, psychological, developmental, neurologic, endocrinologic, and radiologic studies. In addition, we will examine the spectrum of clinical characteristics of HPE to facilitate early diagnosis and clinical management, including genetic counseling. Finally, we plan to assess the psychosocial impact of HPE on the family as a unit. Most patients and their families will be seen at the NIH Clinical Center. A subset may be examined outside the NIH, and a further subset, for the psychosocial studies, may be interviewed by phone.

Title: Retrospective Study Using Next-Generation Sequencing (NGS) on Biological Samples to Improve Genetic Counseling for Patients With Previously Explored Craniofacial Midline Defects. (EXOMEDIANE)

Stage: Recruiting

Principal investigator: Alinoë Lavillaureix, MD

CHU Rennes

Rennes, France

Holoprosencephaly, or HPE, is the most common congenital cerebral malformation in humans and the most severe of a group of pathologies related to a deficiency of the SHH signaling pathway (Sonic Hedgehog SHH-D). It is characterized by severe cerebral and craniofacial abnormalities.

The regulation of SHH concentration is therefore crucial for correct craniofacial development.

Despite the recent identification of about 20 genes, 70% of cases of EHPE and craniofacial midline abnormalities of genetic origin do not have a molecular diagnosis. It is therefore important to continue the search for new candidate genes to improve the understanding of brain and facial development and to improve genetic counseling for these families.

The development of Next-Generation Sequencing (NGS) technologies opens up the possibility of studying the exome or even the genome in a single manipulation. The latter type of analysis is particularly well suited to the discovery of new genes and will therefore improve the care of patients and their families.