Rare Pulmonology News

Disease Profile

Frontonasal dysplasia

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

Q75.8

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)

Median facial cleft syndrome; Median cleft syndrome; Median cleft face syndrome

Categories

Congenital and Genetic Diseases; Mouth Diseases; Musculoskeletal Diseases

Summary

Frontonasal dysplasia is a rare disease that results from abnormal development of the head and face before birth. Symptoms often vary, however more common symptoms include wide spaced eyes, a widow's peak, and a broad nose. Less common features include eye abnormalities, missing the connection between the two halves of the brain (agenesis of the corpus callosum), hearing loss, and undescended testicles in males (cryptorchidism).[1][2] Most people with the dysplasia have normal intelligence.[2] There are three main types of frontonasal dysplasia that are distinguished by their genetic causes and symptoms.[1] Other frontonasal dysplasia syndromes have also been described.[3] Frontonasal dysplasia is very rare, with around 100 cases reported in the literature.[4]

Type 1 frontonasal dysplasia is caused by mutations (changes) in the ALX3 gene, type 2 is caused by mutations in the ALX4 gene, and type 3 is caused by mutations in the ALX1 gene. Type 1 and type 3 frontonasal dysplasia are inherited in an autosomal recessive manner, whereas frontonasal dysplasia type 2 is inherited in an autosomal dominant manner.[1] Diagnosis is often first suspected when a baby has features consistent with frontonasal dysplasia. X-rays and genetic testing may be used to confirm the diagnosis. Treatment of the disease may include one or more surgeries to correct certain birth defects, as well as early intervention and special education services, if needed.[4]

Symptoms

The different types of frontonasal dysplasia can have different signs and symptoms. However, all types of frontonasal dysplasia involve the abnormal development of the head and face, which changes the physical features of the face. People with frontonasal dysplasia are usually born with wide spaced eyes (hypertelorism), a flat broad nose, and a vertical groove (cleft) affecting the middle of the face. Some may be born with a skin-covered gap in the front of the skull where bone should be (anterior cranium bifidum occultum). Other features of the disease include hearing loss and eye defects such as missing tissue in the eye (coloboma).[4]

Other features of type 1 frontonasal dysplasia include a widow’s peak, small nostrils, cleft lip and/or palate, and having a short and small head (brachycephaly). People born with type 2 frontonasal dysplasia may have large differences in the way the skull is formed such as the premature closure of bones that form the skull (craniosynostosis). Other features of type 2 include rapid hair loss, absence of hair (alopecia), or having more facial hair than expected (facial hypertrichosis).[4] 

People with type 3 frontonasal dysplasia may be born without eyes (anophthalmia) or have very small eyes (microphthalmia). Other differences may include having low-set, posteriorly rotated ears, a heart defect known as tetralogy of Fallot, and abnormalities of the brain such as having too much liquid in the brain (hydrocephalus). People with type 3 frontonasal dysplasia also may have skeletal abnormalities such as absent tibia, having an extra toe (polydactyly), or clubfeet (talipes).[4]

Some people with frontonasal dysplasia types 2 and 3 may have intellectual disability. Males with frontonasal dysplasia types 2 and 3 may have undescended testes (cryptorchidism).[4]

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
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Wide nasal bridge
Broad nasal bridge
Broad nasal root
Broadened nasal bridge
Increased breadth of bridge of nose
Increased breadth of nasal bridge
Increased width of bridge of nose
Increased width of nasal bridge
Nasal bridge broad
Wide bridge of nose
Widened nasal bridge

[ more ]

0000431
Widow's peak
Hairline peak
Hairline point
Pointed hairline at front of head
V-shaped frontal hairline

[ more ]

0000349
30%-79% of people have these symptoms
Bifid nasal tip
Cleft nasal tip
0000456
Median cleft lip
Central cleft upper lip
0000161
5%-29% of people have these symptoms
Abnormality of cardiovascular system morphology
0030680
Aplasia/Hypoplasia of the corpus callosum
0007370
Basal encephalocele
0011817
Bilateral single transverse palmar creases
0007598
Camptodactyly of finger
Permanent flexion of the finger
0100490
Choanal atresia
Blockage of the rear opening of the nasal cavity
Obstruction of the rear opening of the nasal cavity

[ more ]

0000453
Cleft palate
Cleft roof of mouth
0000175
Clinodactyly of the 5th finger
Permanent curving of the pinkie finger
0004209
Conductive hearing impairment
Conductive deafness
Conductive hearing loss

[ more ]

0000405
Craniosynostosis
0001363
Cryptorchidism
Undescended testes
Undescended testis

[ more ]

0000028
Flat occiput
0005469
Holoprosencephaly
0001360
Hydrocephalus
Too much cerebrospinal fluid in the brain
0000238
Intellectual disability
Mental deficiency
Mental retardation
Mental retardation, nonspecific
Mental-retardation

[ more ]

0001249
Low-set, posteriorly rotated ears
0000368
Preauricular skin tag
0000384
Short stature
Decreased body height
Small stature

[ more ]

0004322
Webbed neck
Neck webbing
0000465

Cause

Frontonasal dysplasia is caused by changes (mutations) in different genes. Frontonasal dysplasia type 1 is caused by changes in the ALX3 gene. Type 2 is caused by changes in the ALX4 gene. And type 3 is caused by changes in the ALX1 gene. These three genes all provide instructions to the body to make a type of protein called transcription factors, which are responsible for controlling other genes. Specifically, these three genes code proteins that control other genes that affect how the eyes, nose, and mouth develop. When there are changes in one of these three genes, they are not able to properly control the way the face forms. This causes the features associated with frontonasal dysplasia.[4]

Diagnosis

Frontonasal dysplasia is often first suspected when a doctor sees the features of the disorder in a newborn or baby. To be diagnosed with frontonasal dysplasia, a person must be born with at least two of the following physical features: [4][1]

  • Widely spaced eyes (hypertelorism)
  • A flat, broad nose
  • A groove (cleft) in one or both sides of the nose, which can cause it to separate into two parts
  • Missing tip of the nose
  • Cleft involving the nose, upper lip, or roof of the mouth (cleft lip and/or palate)
  • A skin-covered gap in the front of the skull where bone should be (anterior cranium bifidum occultum)
  • Widow’s peak hairline

A doctor may also order other tests such as an X-ray of all of the bones in the body (skeletal survey) in order to determine exactly how the disease is affecting the person and to rule out other possible diseases.[4] Genetic testing may be used to confirm the diagnosis and type.[3]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Treatment

    The treatment for frontonasal dysplasia depends on the changes the disease caused in the person. Surgical procedures to correct facial clefts or other physical differences may be an option. In general, these surgeries are multi-stage procedures that take place when the child is around 6-8 years old.[2] If the facial clefts are impacting the ability to breathe or swallow food, the procedures may occur at a younger age.[4] 

    If a person with frontonasal dysplasia has intellectual disability or developmental delay, early intervention may be offered. When the child gets older, special education may be helpful. A team of specialists may be required for proper treatment and evaluation of possible associated birth defects, for example, a pediatric cardiologist may check for a heart defect, a pediatric ophthalmologist may check for eye problems, and a pediatric audiologist may screen for hearing loss.[4]

    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 Frontonasal dysplasia. This website is maintained by the National Library of Medicine.
      • 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

        • 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.
        • 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 Frontonasal dysplasia. Click on the link to view a sample search on this topic.

          References

          1. Frontonasal dysplasia. Genetics Home Reference (GHR). April 2014; https://ghr.nlm.nih.gov/condition/frontonasal-dysplasia.
          2. Frontonasal dysplasia. Orphanet. October 2006; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=250.
          3. Farlie PG, Baker NL, Yap P, and Tan TY. Frontonasal Dysplasia: Towards an Understanding of Molecular and Developmental Aetiology. Molecular Syndromology. November 2016; 7(6):312-321. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131330/.
          4. Nurten Akarsu A. Frontonasal Dysplasia. National Organization for Rare Disorders (NORD). 2017; https://rarediseases.org/rare-diseases/frontonasal-dysplasia/.

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