Frontonasal Dysplasia

Disease Overview

Frontonasal dysplasia is a rare disorder characterized by abnormal development of the head and face before birth. Major physical characteristics may include widely spaced eyes (ocular hypertelorism); a flat broad nose; and/or a vertical groove down the middle of the face. The depth and width of the vertical groove may vary greatly. In some cases, the tip of the nose may be missing; in more severe cases, the nose may separate vertically into two parts. In addition, an abnormal skin-covered gap in the front of the head (anterior cranium occultum) may also be present in some cases. There are at least three types of frontonasal dysplasia that can be distinguished by genetic causes and symptoms.

• View Full Report Show Less
• Print / Download as PDF

• Next section >

• < Previous section
• Next section >

Synonyms

• FND
• median cleft face syndrome
• Frontorhiny
• Frontonasal malformation; FNM

• < Previous section
• Next section >

• < Previous section
• Next section >

Subdivisions

• Frontonasal dysplasia-1
• Frontonasal dysplasia-2
• Frontonasal dysplasia-3

• < Previous section
• Next section >

• < Previous section
• Next section >

Signs & Symptoms

Frontonasal dysplasia-1(FND-1)
The physical characteristics associated with frontonasal dysplasia may vary greatly in severity from person to person. Features of this disorder include widely spaced eyes (ocular hypertelorism) and/or a vertical groove down the middle of the face. The depth and width of the groove may vary greatly among affected infants. The nose may be unusually flat and broad, have a “notched” or missing tip, or, in severe cases, may be completely divided in two.

Other physical characteristics associated with frontonasal dysplasia may include a V-shaped hairline that extends down onto the forehead (widow’s peak), unusually small (slit-like) nostrils, an abnormal skin-covered gap in the front of the head (cranium bifidum occultum), and/or, in rare cases, a head that may appear abnormally short and wide (brachycephaly). Some infants with frontonasal dysplasia may also have incomplete closure of the roof of the mouth (cleft palate) and a vertical groove in the upper lip (cleft lip). The most severe clefts involve the lips, gums, and the bony front portion and/or soft back portions of the roof of the mouth (hard and soft palates). Less severe clefts may involve only one of these areas.

Frontonasal dysplasia-2 (FND-2)
This form of fronotonasal dysplasia is characterized by a large skull defect and a premature fusion of the coronal suture (coronal craniosynostosis). Features of this disorder include widely spaced eyes (ocular hypertelorism) and severely depressed nasal bridge and ridge. Affected individuals may experience broad variations in hair development ranging from rapid hair loss and the absence of hair, eyebrows, eyelashes and body hair (total alopecia) to either normal hair or unusual hair growth on the face (facial hipertrichosis). Males with this form often have genital abnormalities, such as absence of one or both testes from the scrotum (cryptorchidism). There is a partial or complete absence of the corpus callosum, which connects the two hemispheres of the brain (agenesis of the corpus callosum). Patients will have varying degrees of intellectual disability.

Frontonasal dysplasia-3 (FND-3)
Features of frontonasal dysplasia-3 include missing eyes (anophthalmia) or very small eyes (microphthalmia), as well as low set ears that are rotated backwards. FND3 is often associated with the most severe abnormalities; however the characteristics and severity vary from person to person.

Rarely, infants with frontonasal dysplasia may also exhibit a form of cyanotic congenital heart disease (tetralogy of Fallot). The symptoms of tetralogy of Fallot include easy fatigability; rapid, shallow breathing; abnormal bluish coloration, especially of the lips and fingers; irregular heartbeats; and/or mild growth delays. (For more information on tetralogy of Fallot, see the Related Disorders section of this report.)

A subtype of frontonasal dysplasia called acromelic frontonasal dysplasia has been described in which central nervous system (CNS) and skeletal anomalies are combined with the craniofacial anomalies. The CNS anomalies include Dandy-Walker malformation. Dandy-Walker Malformation is characterized by absence (agenesis) of part of the brain (cerebellar vermis) and an abnormally large space at the back of the brain (cystic dilatation of the 4th ventricle). Other associated CNS anomalies are absence (agenesis) of the part of the brain that connects the two cerebral hemispheres (corpus callosum); protrusion of part of the brain and membranes that cover the brain (meninges) through an abnormal gap in the skull (encephalocele); abnormally wide ventricles in the brain that inhibit the flow of cerebral spinal fluid (hydrocephalus); protrusion of only the meninges through a defect in the skull (meningocele) and intellectual disability. The associated skeletal anomalies include an underdeveloped or absent tibia bone, extra toes (preaxial polydactyly of the feet), and clubfoot (talipes). Males affected with acromelic frontonasal dysplasia sometimes have undescended testes.

• < Previous section
• Next section >

• < Previous section
• Next section >

Causes

FND-1 is caused by mutations in the ALX3 gene; FND-2 is caused my mutations in the ALX4 gene; and FND-3 is caused by mutations in the ALX1 gene.

The proteins produced from the ALX3, ALX4, and ALX1 genes are transcription factors, which means they bind to DNA and control the activity of certain genes. The proteins control the gene’s activities; regulate the growth and movement of cells. The ALX3 and ALX4 proteins are involved in the development of the nose, while ALX1 is involved in the development of the eyes, nose and mouth. The abnormal development can also interfere with the formation of the skull and other facial structures (e.g. distance between the eyes).

FND-1 and FND-3 are autosomal recessive genetic conditions.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene from the same trait, one from each parent. If an individual inherits one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the altered gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have higher change than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

FND-2 is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent of can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

In some individuals, the disorder is due to a spontaneous (de novo) genetic mutation that occurs in the egg or sperm cell. In such situations, the disorder is not inherited from the parents.

A person who carries a single copy of the ALX4 gene usually has enlarged openings (foramina) in the parietal bones only. Severe cranial defects, facial abnormalities associated with hair and genital malformations summarized above for FND-2 occur when an individual inherits two copies of the abnormal ALX4 gene, one from each parent.

• < Previous section
• Next section >

• < Previous section
• Next section >

Affected populations

Frontonasal dysplasia is a very rare disorder that affects males and females in equal numbers. The number of people affected by this disorder is not known. There are at least 100 cases reported in the scientific literature.

• < Previous section
• Next section >

• < Previous section
• Next section >

Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of frontonasal dysplasia. Comparisons may be useful for a differential diagnosis:

Craniofrontonasal dysplasia is a rare disorder characterized by widely spaced eyes (ocular hypertelorism), a missing or grooved tip of the nose, a broad nasal bridge, and/or malformation of the bone forming the center of the chest (sternum). Other abnormalities associated with this disorder may include an unusually wide mouth, webbed fingers and/or toes (syndactyly), a broad index finger, split nails, malformed ears, and/or a broad, high forehead. Craniofrontonasal dysplasia is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose “craniofrontonasal dysplasia” as your search term in the Rare Disease Database.)

Frontofacionasal dysplasia is a rare genetic disorder that is apparent at birth (congenital). The disorder is primarily characterized by malformations of the head and facial (craniofacial) area and eye (ocular) defects. Craniofacial malformations may include an unusually short, broad head (brachycephaly); incomplete closure of the roof of the mouth (cleft palate); an abnormal groove in the upper lip (cleft lip); and underdevelopment (hypoplasia) of the nose with malformation of the nostrils. Affected infants may also have abnormal narrowing of the folds (palpebral fissures) between the upper and lower eyelids (blepharophimosis) and an unusually increased distance between the eyes (ocular hypertelorism). Additional eye abnormalities may include partial absence of tissue (coloboma) from the upper eyelids or the colored regions of the eyes (irides) and an inability to completely close the eyes (lagophthalmos). The signs and symptoms of frontofacionasal dysplasia are highly variable. Frontofacionasal dysplasia appears to be inherited as an autosomal recessive trait.

(For more information on this disorder, choose “frontofacionasal dysplasia” as your search term in the Rare Disease Database.)

There are many other rare craniofacial disorders that are characterized by facial and cranial abnormalities similar to those of frontonasal dysplasia. (For more information on these disorders, choose “craniofacial” as your search term in the Rare Disease Database.)

The following disorders may occur in association with frontonasal dysplasia as secondary characteristics. They are not necessary for a differential diagnosis:

Tetralogy of Fallot is a rare form of cyanotic congenital heart disease. Cyanosis is the abnormal bluish discoloration of the skin that occurs because of low levels of circulating oxygen in the blood. Tetralogy of Fallot consists of a combination of four different heart defects: a ventricular septal defect; obstructed outflow of blood from the right ventricle to the lungs (pulmonary stenosis); a displaced aorta, which causes blood to flow into the aorta from both the right and left ventricles; and the abnormal enlargement of the wall of the right ventricle. If infants with tetralogy of Fallot are not treated, the symptoms usually become more severe. Blood flow to the lungs may further decrease and severe cyanosis may result in life-threatening complications. The exact cause of Tetralogy of Fallot is not known. (For more information on this disorder, choose “tetralogy of Fallot” as your search term in the Rare Disease Database.)

Cleft lip and palate are malformations of the lip and/or mouth that are noticeable at birth (congenital). A cleft is an incomplete closure or a groove of the roof of the mouth (palate) and/or upper lip. These abnormalities result when the pair of long bones that form the upper jaw (maxillae) do not fuse properly during the development of the embryo. More than 200 syndromes have cleft lip and/or palate as a feature.

Dandy-Walker malformation is a rare malformation of the brain characterized by absence (agenesis) of part of the brain (cerebellar vermis), an abnormally large space at the back of the brain (cystic dilatation of the 4th ventricle. Children with this disorder may develop swelling of the head caused by the accumulation of cerebrospinal fluid in the skull (hydrocephalus). Other symptoms may include vomiting, headaches, weakness, convulsions, irritability, abnormally slow pulse, and/or unusually slow breathing. Some children with this disorder may experience delays in reaching motor (e.g., sitting and walking) and cognitive (e.g., speech and counting) milestones. The exact cause of Dandy-Walker malformation is not known. (For more information on this disorder, choose “Dandy-Walker” as your search term in the Rare Disease Database.)

Agenesis of corpus callosum (ACC) is a rare disorder that is present at birth (congenital). It is characterized by a partial or complete absence (agenesis) of an area of the brain that connects the two cerebral hemispheres. This part of the brain is normally composed of transverse fibers. The cause of agenesis of corpus callosum is usually not known, but it can be inherited as either an autosomal recessive trait or an X-linked dominant trait. It can also be caused by an infection or injury during the twelfth to the twenty-second week of pregnancy (intrauterine) leading to developmental disturbance of the fetal brain. Intrauterine exposure to alcohol (Fetal alcohol syndrome) can also result in ACC. In some cases, intellectual disability may result, but intelligence may be only mildly impaired and subtle psychosocial symptoms may be present.

ACC is frequently diagnosed during the first two years of life. An epileptic seizure can be the first symptom indicating that a child should be tested for a brain dysfunction. The disorder can also be without apparent symptoms in the mildest cases for many years.

(For more information on this disorder, choose “agenesis of corpus callosum” as your search term in the Rare Disease Database.)

• < Previous section
• Next section >

• < Previous section
• Next section >

Diagnosis

Frontonasal dysplasia is usually diagnosed shortly after birth (neonatal period). Confirmation of the diagnosis typically includes a thorough clinical evaluation, specialized tests including x-ray studies, and the identification of characteristic physical features. Genetic testing for frontonasal dysplasia is available on a research basis only.

• < Previous section
• Next section >

• < Previous section
• Next section >

Standard Therapies

Treatment of this disorder depends upon the severity of the physical characteristics in each individual case. Surgery may be performed to correct the craniofacial abnormalities (e.g., divided nose, cleft lip, etc.) associated with this disorder. In some cases, additional surgeries may be necessary when an affected child grows older.

Genetic counseling may be of benefit for affected individuals and their families. A team approach for infants and children with this disorder may be of benefit and may include special social, educational, and medical services. Other treatment is symptomatic and supportive.

• < Previous section
• Next section >

• < Previous section
• Next section >

Clinical Trials and Studies

Research on birth defects and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of birth defects in the future.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

For information about clinical trials sponsored by private sources, contact: www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

• < Previous section
• Next section >

• < Previous section
• Next section >

References

TEXTBOOKS
Buyse ML, ed. Birth Defects Encyclopedica. Blackwell Scientific Publications, 1990:672-73.

Pine JW, et al, ed. Textbook of Child Neurology, 5th Edition. Williams and Wilkins, 1995:294-99.

Jones KL ed. Smith’s Recognizable Patterns of Human Malformaion, 4th Edition. W. B. Saunders, 1988:202.

JOURNAL ARTICLES
DeMoor MMA, Baruch R, and Human DG. Frontonasal dysplasia associated with tetrology of Fallot. J Med Genet 1987;24:107-109.

Fryberg JS, Persing JA and Lin KY. Frontonasal dysplasia in two successive generations. Am J Med Genet 1993;46:712-714.

Nevin NC Leonard AG, and Jones B. Frontonasal dysostosis in two successive generations. Am J Med Genet 1999;87:251-253.

Sedano HO, Cohen MM Jr., Jirasek, J, et al. Frontonasal dysplasia. J Pediat 1970;76:906-913.

Slaney SF, Goodman FR, Eilers-Walsman, et al. Acromelic frontonasal dysostosis. Am J Med Genet 1999;83:109-116.

INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, The Johns Hopkins University, Entry No. 136760; Last Update: 06/23/2016. https://omim.org/entry/136760. Accessed December 8, 2016.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, The Johns Hopkins University, Entry No. 613451; Last Update 05/18/2015. https://omim.org/entry/613451 . Accessed December 8, 2016.

McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, The Johns Hopkins University, Entry No. 603671; Last Update 10/10/2016. https://omim.org/entry/603671. Accessed December 8, 2016.

Frontonasal Dysplasia. Genetics Home Reference. Last Update August 2, 2016. https://ghr.nlm.nih.gov/condition/frontonasal-dysplasia. Accessed December 8, 2016.

Frontonasal Dysplasia. Orphanet Last Update October 2006. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=250. Accessed December, 2016.

• < Previous section
• Next section >

• < Previous section

Programs & Resources

• Assistance Programs
• Patient Organizations
• More Information

RareCare^® Assistance Programs

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Additional Assistance Programs

MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Rare Caregiver Respite Program

This first-of-its-kind assistance program is designed for caregivers of a child or adult diagnosed with a rare disorder.

Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Learn more about Patient Assistance Programs >

---

Patient Organizations

Children’s Craniofacial Association (CCA)

NORD Member

Phone: 214-570-9099 Email: [email protected]

Related Rare Diseases: Melnick Needles Syndrome, Pfeiffer Syndrome, Shprintzen Goldberg Syndrome, ...

https://rarediseases.org/organizations/childrens-craniofacial-association-cca/

View Profile >

FACES: The National Craniofacial Association

NORD Member

Email: [email protected]

Related Rare Diseases: Melnick Needles Syndrome, Adams-Oliver Syndrome, Trismus-Pseudocamptodactyly Syndrome, ...

https://rarediseases.org/organizations/faces-the-national-craniofacial-association/

View Profile >

AmeriFace

Phone: 702-769-9264 Email: [email protected] Fax: 702-341-5351

Related Rare Diseases: Adams-Oliver Syndrome, Trismus-Pseudocamptodactyly Syndrome, Branchio Oculo Facial Syndrome, ...

https://rarediseases.org/organizations/ameriface/

View Profile >

Learn more about Patient Organization & Membership >

---

More Information

The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.

GARD Disease Summary

The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).

View report

---

Orphanet

Orphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.

View report

---

• < Previous section