Craniofrontonasal dysplasia is a very rare inherited disorder characterized by abnormalities of the head and face (craniofacial area), hands and feet, and certain skeletal bones. Major symptoms of this disorder may include widely spaced eyes (ocular hypertelorism), a groove (cleft) on the tip of the nose, an unusually wide mouth, malformations of the fingers and toes, and/or underdevelopment of portions of the face (midface hypoplasia), such as the forehead, nose, and chin. In addition, the head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis). Craniofrontonasal dysplasia follows X-linked inheritance in most families, but females are more severely affected than males. An autosomal dominant form of the disorder has also been discussed in the medical literature.
The symptoms of craniofrontonasal dysplasia vary greatly in number and severity among affected individuals. The most common symptoms of this disorder include widely spaced eyes (ocular hypertelorism), a vertical groove (cleft) on the tip of the nose, shoulder and limb abnormalities and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). The head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis).
In some cases, affected individuals may have additional abnormalities of the head and facial (craniofacial) area. These may include a broad nose and face; a broad and high forehead; cleft lip and palate; low-set ears and a webbed neck. Females usually have thick, wiry and curly hair that appears at 2-3 months of age.
Affected individuals may also have webbing of the fingers and toes (syndactyly); a curved fifth finger (clinodactyly); unusually broad fingers and/or toes, especially the first “big” toe; and/or nails that are grooved, split, concave, and/or brittle.
Other physical characteristics sometimes associated with craniofrontonasal dysplasia may include narrow sloping shoulders. Several skeletal abnormalities may be present such as malformation of a long, flat, vertical bone in the center of the chest (sternum); malformation of the collarbone (clavicle); backward curvature of the spine (lordosis); and/or sideways curvature of the spine (scoliosis). One limb may be shorter than the other.
Underdevelopment of one breast is sometimes seen in females. In addition, one shoulder may be unusually high due to the failure of the major bone of the shoulder (scapula) to move into the appropriate position during fetal development (Sprengel Deformity). (For more information on Sprengel Deformity, see the Related Disorders section of this report.)
Some individuals affected by craniofrontonasal dysplasia may also have diminished muscle tone (hypotonia), developmental delays, hearing impairment (sensorineural deafness), a sunken chest (pectus excavatum), and/or protrusion of part of the stomach and/or small intestines into the chest cavity (diaphragmatic hernia). Several reports have linked craniofrontonasal syndrome to Poland syndrome which is a condition in which there is an absence of chest wall muscles on one side of the body and abnormally short, webbed fingers on the hand on the same side.
In some cases, males affected by this disorder may have an abnormal fold of skin extending around the base of the penis (shawl scrotum) and/or improper development of the tube leading from the bladder that discharges urine (urethra). In addition, the urinary opening may be misplaced, such as on the underside of the penis (hypospadias). It is possible that a male may show no symptoms but be a carrier of the gene mutation for craniofrontonasal dysplasia.
The exact cause of craniofrontonasal dysplasia is not fully understood. X-linked and autosomal dominant forms of the disorder have been noted in the medical literature. This condition follows X-linked inheritance in most families but females are more severely affected than males which is unusual for an X-linked disorder. The interaction of different genes and certain metabolic factors may play a role in the number and severity of symptoms that appear in specific cases of craniofrontonasal dysplasia (variable expression). Affected individuals in some families have been found to have a gene mutation on the X chromosome that has been mapped to Xp22.
Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome Xp22” refers to band 22 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.
X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Craniofrontonasal dysplasia is a very rare genetic disorder that affects females more often than males. Females seem to have a more severe form of the disorder.
Craniofrontonasal dysplasia may be detected before birth (prenatally) by ultrasonography (ultrasound), a test that creates an image of the fetus by measuring the reflection of sound waves. A diagnosis of craniofrontonasal dysplasia may be confirmed after birth by a thorough clinical evaluation and characteristic physical findings.
Treatment of craniofrontonasal dysplasia depends upon the specific malformations and their severity in each individual case. Surgery may be performed to correct craniofacial deformities and malformations of the hands and feet. Surgery may also be used to narrow the nose and reduce neck webbing.
Genetic counseling will 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 support and other medical services. Other treatment is symptomatic and supportive.
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
For information about clinical trials sponsored by private sources, contact:
Reichenberger E and Mulliken JB. Craniofrontonasal Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:183-4.
Cohen MM, MacLean RE, eds. Craniosynostosis: diagnosis, evaluation, and management, 2nd ed. New York: Oxford University Press, 2000:380-384.
Buyse ML, ed. The Birth Defects Encyclopedia. Blackwell Scientific Publications, 1990, 459-460, 1308-09.
Pulleyn LJ, Winter RM, Reardon W, et al. Further evidence from two families that craniofrontonasal dysplasia maps to Xp22. Clin Genet 1999;55:473-477.
Feldman GJ, Ward DE, Lajeunie-Renier E, et al. A novel phenotypic pattern in X-linked inheritance: craniofrontonasal syndrome maps to Xp22. Hum Mol Genet 1997;6:1937-1941.
Saavedra D, Richieri-Costa A, Guion-Almeida ML, et al. Craniofrontonasal syndrome: study of 41 patients. Am J Med Genet 1996:61:147-151.
Grutzner E, et al. Craniofrontonasal dysplasia: phenotypic expression in females and males and genetic considerations. Oral Surg Med Oral Pathol 1988:65(4):436-44.
FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore, MD: The Johns Hopkins University; Entry No. 304110; Last Update: 1/26/2010 Accessed 10/28/2010.