Frontonasal dysplasia

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Rare Dermatology News

Disease Profile

Unknown

US Estimated

Europe Estimated

Age of onset

Neonatal

ICD-10

Q75.8

Inheritance

Frontal dysplasia can run in a person’s family, but the way it can be passed down depends on the type. Types 1 and 3 are inherited in an autosomal recessive manner.^[4] This means that both copies of the ALX3 or ALX1 gene must be changed in order to have symptoms of the disorder. We inherit one copy of each gene from our mother and one from our father. Men and women with a mutation in only one copy of the genes are known as carriers of frontonasal dysplasia, meaning they do not have signs or symptoms of the disease, but they can pass the changed gene down to their children. When two carriers of a ALX3 or ALX1 mutation have children together, for each child there is a:

25% chance that the child will have frontonasal dysplasia
50% chance that the child will be a carrier of frontonasal dysplasia like the parents
25% chance that the child will have two working copies of the genes, so the child will not have frontonasal dysplasia and will not be a carrier

If a person has type 1 or 3 frontal dysplasia and they have a child with a person who does not have frontonasal dysplasia and is not a carrier of the same type of the disease (in other words, both copies of the gene work normally), all of the person’s children will be carriers of frontonasal dysplasia, but none will have the disease.

If a person has type 1 or 3 frontal dysplasia and they have a child with a person who is a carrier of the same type, each of their children has a:

50% chance of being a carrier
50% chance of having the same type of frontonasal dysplasia

Type 2 frontonasal dysplasia is inherited in an autosomal dominant manner. This means that only one copy of the ALX4 gene needs to be changed for a person to have signs and symptoms of the disorder.

In some cases, people with type 2 frontonasal dysplasia are the first people in their family who are diagnosed with the disorder. This may occur when the genetic change that causes the disorder is new in the affected person (de novo), and it is not inherited from either parent. In other cases, people with the autosomal dominant form of frontonasal dysplasia have inherited the disorder from an affected parent.^[4]

If a person with type 2 frontonasal dysplasia has children with a person who does not have type 2 frontonasal dysplasia, each of their children will have a:

50% chance of not having type 2
50% chance of having type 2

Many people find talking to a genetic counselor before they decided to get pregnant helpful, so they can better understand the chance they may pass their type of frontonasal dysplasia onto their children.

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

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.

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.

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

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.

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.

Not applicable

Other names (AKA)

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

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

Do you have updated information on this disease? We want to hear from you.

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

Ameriface
PO Box 751112
Las Vegas, NV 89136
Toll-free: 888-486-1209
Telephone: 702-769-9264
E-mail: [email protected]
Website: https://www.ameriface.org
Children's Craniofacial Association
13140 Coit Road Suite 517
Dallas, TX 75240
Toll-free: 1-800-535-3643
Telephone: +1-214-570-9099
Fax: +1-214-570-8811
E-mail: [email protected]
Website: https://ccakids.org/
FACES: The National Craniofacial Association
PO Box 11082
Chattanooga, TN 37401
Toll-free: 800-332-2373
Telephone: 423-266-1632
E-mail: [email protected]
Website: https://www.faces-cranio.org/

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

Frontonasal dysplasia. Genetics Home Reference (GHR). April 2014; https://ghr.nlm.nih.gov/condition/frontonasal-dysplasia.
Frontonasal dysplasia. Orphanet. October 2006; https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=250.
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/.
Nurten Akarsu A. Frontonasal Dysplasia. National Organization for Rare Disorders (NORD). 2017; https://rarediseases.org/rare-diseases/frontonasal-dysplasia/.

Rare Dermatology News

Rare Dermatology News

Rare Dermatology News

Neonatal

Q75.8

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

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.

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.

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

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.

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.

Not applicable

Other names (AKA)

Categories

Summary

Symptoms

Cause

Diagnosis

Testing Resources

Treatment

Organizations

Organizations Supporting this Disease

Learn more

Where to Start

In-Depth Information

References

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.

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