National Center for Advancing and Translational Sciences Genetic and Rare Diseases Information Center, a program of the National Center for Advancing and Translational Sciences

Holoprosencephaly

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Other Names:
HPE
Categories:
Holoprosencephaly is an abnormality of brain development in which the brain doesn't properly divide into the right and left hemispheres. The condition can also affect development of the head and face. There are 4 types of holoprosencephaly, distinguished by severity. From most to least severe, the 4 types are alobar, semi-lobar, lobar, and middle interhemispheric variant (MIHV).[1] In general, the severity of any facial defects corresponds to the severity of the brain defect. The most severely affected people have one central eye (cyclopia) and a tubular nasal structure (proboscis) located above the eye. 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.[2][1]
Last updated: 3/9/2018
Holoprosencephaly is classified into into 3 main subtypes based upon the severity of the malformation: lobar, semilobar, and alobar, and a fourth subtype, known as the middle interhemispheric (MIH) variant:[3][1]
  • Alobar holoprosencephaly is when there is a complete failure of the brain to divide into right and left hemispheres which results in the loss of midline structures of the brain and face as well as fusion of the cavities of the brain, known as lateral ventricles and the third ventricle (which are normally separated). Facial findings may include a single eye (cyclopia) or very closely spaced eyes  (ethmocephaly) or absent eyes (anophthalmia), or very small eye (microphthalmia) with a tubular-shaped nose (proboscis);  or closely spaced eyes (hypotelorism) and a flattened nose or  cleft lip that occurs in the middle of the lip (median cleft lip) or on both sides (bilateral cleft lip). In some cases the face make look almost normal (especially in persons with variants (mutations) in the ZIC2 gene)
  • Semi-lobar holoprosencephaly occurs when the left side of the brain is fused to the right side in the areas of the brain known as the frontal (front) and parietal lobes (sides of the brain). Also, the dividing line between the right and left hemispheres of the brain (known as the interhemispheric fissure) is only present in the back of the brain. People with semi-lobar holoprosencephaly may have hypotelorism, microphthalmia or anophthalmia. Other features may include a flattened bridge and tip of the nose, one nostril, a median cleft lip or bilateral cleft lip, and a cleft palate.
  • Lobar holoprosencephaly, is when there are two ventricles (right and left) but the cerebral hemispheres are fused in the frontal cortex. Features may include bilateral cleft lip , closely spaced eyes, depressed nose or an almost normal looking face.
  • Middle interhemispheric variant results when the brain is fused in the middle. Signs may include closely spaced eyes, depressed and narrow nose or an almost normal looking face. 
Other signs and symptoms may include seizures, hydrocephalus, neural tube defects, pituitary dysfunction, short stature, feeding difficulties, and instability of temperature, heart rate, and respiration. Most people with holoprosencephaly have developmental delay and intellectual disability, that varies in severity depending on severity of the brain malformation.[1]

Holoprosencephaly may be part of several genetic syndromes which each having unique characteristics.  
Last updated: 3/9/2018

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Showing of 88 |
Medical Terms Other Names
Learn More:
HPO ID
80%-99% of people have these symptoms
Abnormal facial shape
Unusual facial appearance
0001999
Bilateral cleft lip
Both sided cleft lip
Right and left cleft lip
[ more ] 		0100336
Holoprosencephaly 0001360
Median cleft lip and palate
Central cleft lip and palate
Midline cleft lip/palate
[ more ] 		0008501
Single median maxillary incisor
Only one upper front tooth
0006315
30%-79% of people have these symptoms
Anophthalmia
Absence of eyeballs
Failure of development of eyeball
Missing eyeball
No eyeball
[ more ] 		0000528
Anosmia
Lost smell
0000458
Aplasia/Hypoplasia of the corpus callosum 0007370
Choanal atresia
Blockage of the rear opening of the nasal cavity
Obstruction of the rear opening of the nasal cavity
[ more ] 		0000453
Cognitive impairment
Abnormality of cognition
Cognitive abnormality
Cognitive defects
Cognitive deficits
Intellectual impairment
Mental impairment
[ more ] 		0100543
Cyclopia
Cyclops eye
Single central eye
[ more ] 		0009914
Depressed nasal ridge
Flat nose
Recessed nasal ridge
[ more ] 		0000457
Diabetes mellitus 0000819
Dystonia 0001332
Gastroesophageal reflux
Acid reflux
Acid reflux disease
Heartburn
[ more ] 		0002020
Global developmental delay 0001263
Hypoglycemia
Low blood sugar
0001943
Hyposmia 0004409
Hypotelorism
Abnormally close eyes
Closely spaced eyes
[ more ] 		0000601
Iris coloboma
Cat eye
0000612
Microcephaly
Abnormally small skull
Decreased circumference of cranium
Decreased size of skull
Reduced head circumference
Small head circumference
[ more ] 		0000252
Microphthalmia
Abnormally small eyeball
0000568
Muscle weakness
Muscular weakness
0001324
Muscular hypotonia
Low or weak muscle tone
0001252
Reduced number of teeth
Decreased tooth count
0009804
Seizure 0001250
Spasticity
Involuntary muscle stiffness, contraction, or spasm
0001257
5%-29% of people have these symptoms
Abnormal aortic morphology 0001679
Abnormal form of the vertebral bodies 0003312
Abnormal pulmonary valve morphology 0001641
Abnormality of neuronal migration 0002269
Abnormality of the antihelix 0009738
Abnormality of the spleen 0001743
Absent nares
Missing nostrils
0100596
Anteverted nares
Nasal tip, upturned
Upturned nasal tip
Upturned nose
Upturned nostrils
[ more ] 		0000463
Aplasia/Hypoplasia involving the nose
Decreased nasal size
Decreased size of nose
[ more ] 		0009924
Aplasia/Hypoplasia of the cerebellum
Absent/small cerebellum
Absent/underdeveloped cerebellum
[ more ] 		0007360
Aplasia/Hypoplasia of the lungs
Absent/small lungs
Absent/underdeveloped lungs
[ more ] 		0006703
Arrhythmia
Abnormal heart rate
Heart rhythm disorders
Irregular heart beat
Irregular heartbeat
[ more ] 		0011675
Blepharophimosis
Narrow opening between the eyelids
0000581
Brachydactyly
Short fingers or toes
0001156
Branchial anomaly 0009794
Broad philtrum 0000289
Chorea 0002072
Chorioretinal coloboma
Birth defect that causes a hole in the innermost layer at the back of the eye
0000567
Congenital diaphragmatic hernia 0000776
Constipation 0002019
Cryptorchidism
Undescended testes
Undescended testis
[ more ] 		0000028
Dandy-Walker malformation 0001305
Deep philtrum 0002002
Deeply set eye
Deep set eye
Deep-set eyes
Sunken eye
[ more ] 		0000490
Depressed nasal tip
Caved in nasal tip
Depressed tip of nose
Flat nasal tip
Flat tip of nose
Flattened nasal tip
Nasal tip, depressed
[ more ] 		0000437
Diabetes insipidus 0000873
Encephalocele 0002084
Epicanthus
Eye folds
Prominent eye folds
[ more ] 		0000286
External ear malformation 0008572
Failure to thrive in infancy
Faltering weight in infancy
Weight faltering in infancy
[ more ] 		0001531
Feeding difficulties in infancy 0008872
Flat occiput 0005469
Frontal bossing 0002007
Hand polydactyly
Extra finger
0001161
Highly arched eyebrow
Arched eyebrows
Broad, arched eyebrows
High, rounded eyebrows
High-arched eyebrows
Thick, flared eyebrows
[ more ] 		0002553
Hydrocephalus
Too much cerebrospinal fluid in the brain
0000238
Hypertelorism
Wide-set eyes
Widely spaced eyes
[ more ] 		0000316
Hyponatremia
Low blood sodium levels
0002902
Hypoplasia of penis
Underdeveloped penis
0008736
Hypoplasia of the zygomatic bone
Cheekbone underdevelopment
Decreased size of cheekbone
Underdevelopment of cheekbone
[ more ] 		0010669
Intestinal atresia 0011100
Joint hyperflexibility
Joints move beyond expected range of motion
0005692
Macrocephaly
Increased size of skull
Large head
Large head circumference
[ more ] 		0000256
Macrotia
Large ears
0000400
Omphalocele 0001539
Optic atrophy 0000648
Panhypopituitarism 0000871
Proteinuria
High urine protein levels
Protein in urine
[ more ] 		0000093
Ptosis
Drooping upper eyelid
0000508
Respiratory insufficiency
Respiratory impairment
0002093
Retinopathy
Noninflammatory retina disease
0000488
Scoliosis 0002650
Short neck
Decreased length of neck
0000470
Spinal cord tumor
Tumor of the spinal cord
0010302
Spinal dysraphism 0010301
Synophrys
Monobrow
Unibrow
[ more ] 		0000664
Talipes 0001883
Tetralogy of Fallot 0001636
Thick eyebrow
Bushy eyebrows
Dense eyebrow
Heavy eyebrows
Prominent eyebrows
Thick eyebrows
[ more ] 		0000574
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
Ventricular septal defect
Hole in heart wall separating two lower heart chambers
0001629
Showing of 88 |
Last updated: 7/1/2020
Holoprosencephaly (HPE) can be inherited, but it is not always inherited.

Inherited causes of holoprosencephaly may include:[1]
  • certain types of chromosome abnormalities
  • single gene mutations that cause syndromic disorders
  • mutation(s) in a gene associated with isolated (nonsyndromic) HPE
The risk for family members to have HPE depends on the specific cause of HPE in the family, if known.[1] For example, nonsyndromic HPE is usually inherited in an autosomal dominant manner.[2] This means that having a variation (mutation) in only one copy of the responsible gene in each cell is enough to cause the condition. When a person with a mutation that causes an autosomal dominant condition has children, each child has a 50% (1 in 2) chance to inherit that mutation. However, not all people with a gene mutation that causes HPE will have HPE.[2] This is called reduced penetrance.

For people with HPE without a known cause, recurrence risk for family members is likely to be low, but may be as high as 50%.[1] 

People with personal questions about recurrence risks for themselves or family members are encouraged to speak with a genetic counselor or other genetics professional.
Last updated: 3/10/2018

Making a diagnosis for a genetic or rare disease can often be challenging. Healthcare professionals typically look at a person’s medical history, symptoms, physical exam, and laboratory test results in order to make a diagnosis. The following resources provide information relating to diagnosis and testing for this condition. If you have questions about getting a diagnosis, you should contact a healthcare professional.

Testing Resources

  • Orphanet lists international laboratories offering diagnostic testing for this condition.
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.[1] The life expectancy for individuals with semi-lobar holoprosencephaly depends on the underlying cause of the condition and the presence of associated anomalies.[2][4]
Last updated: 2/24/2016

Related diseases are conditions that have similar signs and symptoms. A health care provider may consider these conditions in the table below when making a diagnosis. Please note that the table may not include all the possible conditions related to this disease.

Conditions with similar signs and symptoms from Orphanet
Differential diagnosis includes anencephaly, severe congenital hydrocephalus, Walker-Warburg syndrome (see these terms), large interhemispheric cyst, otocephaly and other midline defects.
Visit the Orphanet disease page for more information.

Research helps us better understand diseases and can lead to advances in diagnosis and treatment. This section provides resources to help you learn about medical research and ways to get involved.

Clinical Research Resources

  • The Centers for Mendelian Genomics program is working to discover the causes of rare genetic disorders. For more information about applying to the research study, please visit their website.
  • ClinicalTrials.gov lists trials that are related to Holoprosencephaly. Click on the link to go to ClinicalTrials.gov to read descriptions of these studies.

    Please note: Studies listed on the ClinicalTrials.gov website are listed for informational purposes only; being listed does not reflect an endorsement by GARD or the NIH. We strongly recommend that you talk with a trusted healthcare provider before choosing to participate in any clinical study.
  • Orphanet lists European clinical trials, research studies, and patient registries enrolling people with this condition. 

Patient Registry

Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

Organizations Supporting this Disease

These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

Where to Start

  • Genetics Home Reference (GHR) contains information on Holoprosencephaly. This website is maintained by the National Library of Medicine.
  • The National Human Genome Research Institute's (NHGRI) website has an information page on this topic. NHGRI is part of the National Institutes of Health and supports research on the structure and function of the human genome and its role in health and disease.
  • The National Institute of Neurological Disorders and Stroke (NINDS) collects and disseminates research information related to neurological disorders. Click on the link to view information on this topic.
  • The National Organization for Rare Disorders (NORD) has a report for patients and families about this condition. NORD is a patient advocacy organization for individuals with rare diseases and the organizations that serve them.

In-Depth Information

  • GeneReviews provides current, expert-authored, peer-reviewed, full-text articles describing the application of genetic testing to the diagnosis, management, and genetic counseling of patients with specific inherited conditions.
  • Medscape Reference provides information on this topic. You may need to register to view the medical textbook, but registration is free.
  • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
  • Online Mendelian Inheritance in Man (OMIM) lists the subtypes and associated genes for Holoprosencephaly in a table called Phenotypic Series. Each entry in OMIM includes a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine.
  • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
  • PubMed is a searchable database of medical literature and lists journal articles that discuss Holoprosencephaly. Click on the link to view a sample search on this topic.

Questions sent to GARD may be posted here if the information could be helpful to others. We remove all identifying information when posting a question to protect your privacy. If you do not want your question posted, please let us know. Submit a new question

  • My mother's brother had holoprosencephaly, as do 3 of his children, 8 of his grandchildren, and now 1 great grandchild. My mother shows no sign of it and it hasn't appeared in her children or grandchildren. But could she still be a carrier of the disorder? If my uncle got it from his mother then does it mean my mother must have it too? Or could it have missed her? See answer

  • What is the life expectancy for a baby with semi-lobar holoprosencephaly? What are the most common defects? See answer


  1. Solomon BD, Gropman A & Muenke M. Holoprosencephaly Overview. GeneReviews. August 29, 2013; http://www.ncbi.nlm.nih.gov/books/NBK1530/.
  2. Nonsyndromic holoprosencephaly. Genetics Home Reference. September 2010; http://ghr.nlm.nih.gov/condition/nonsyndromic-holoprosencephaly.
  3. Hollier LH. Facial clefts and holoprosencephaly. UpToDate.. February 18, 2016; http://www.uptodate.com/contents/facial-clefts-and-holoprosencephaly.
  4. Dubourg C, Bendavid C, Pasquier L, Henry C, Odent S & David V. Holoprosencephaly. Orphanet Journal of Rare Diseases. 2007; 2:8. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1802747/.