NORD gratefully acknowledges A. Nurten Akarsu, MD, PhD, Professor of Genetics, Hacettepe University Medical Faculty, Department of Medical Genetics, Gene Mapping Laboratory, Ankara, Turkey, for assistance in the preparation of this report.
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.
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.
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.
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.
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.
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.
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
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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/
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