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Disease Profile

Holoprosencephaly

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Neonatal

ICD-10

Q04.2

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

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Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

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X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

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X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

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Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

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Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

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Not applicable

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Other names (AKA)

HPE

Categories

Endocrine Diseases

Summary

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 geneschromosome 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]

Symptoms

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 dysfunctionshort 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.

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.

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

Diagnosis

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.

    Organizations

    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

      Learn more

      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.

          References

          1. Solomon BD, Gropman A & Muenke M. Holoprosencephaly Overview. GeneReviews. August 29, 2013; https://www.ncbi.nlm.nih.gov/books/NBK1530/.
          2. Nonsyndromic holoprosencephaly. Genetics Home Reference. September 2010; https://ghr.nlm.nih.gov/condition/nonsyndromic-holoprosencephaly.
          3. Hollier LH. Facial clefts and holoprosencephaly. UpToDate.. February 18, 2016; https://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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1802747/.

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