Information on the following diseases can be found in the Related Disorders section of this report:

• Aarskog syndrome
• Frontofacionasal dysplasia
• Greig cephalopolysyndactyly syndrome
• Frontonasal dysplasia
• Orocraniodigital syndrome
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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.
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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.
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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.
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Symptoms of the following disorders can be similar to those of craniofrontonasal dysplasia. Comparisons may be useful for a differential diagnosis:

Aarskog syndrome is a very rare inherited disorder characterized by short stature, widely spaced eyes (hypertelorism) with drooping eyelids (ptosis), and/or a short, broad nose. Other symptoms may include low-set, floppy ears; short, broad hands with stubby fingers and very extendible joints; wide, flat feet with bulbous toes; and/or a sunken chest (pectus excavatum). Genital malformations may occur, such as an abnormal fold of skin extending around the base of the penis (shawl scrotum) and/or failure of the testes to descend into the scrotum (cryptorchidism). Cleft lip and dental abnormalities as well as mild mental retardation may also be present. Aarskog syndrome is inherited as an X-linked dominant disorder. (For more information on this disorder, choose "Aarskog" as your search term in the Rare Disease Database.)

Frontofacionasal dysplasia is a very rare inherited disorder characterized by cleft lip and/or palate, an unusually wide space between the eyes, an abnormally large distance between the upper and lower eyelids (telecanthus), a short broad head (brachycephaly), and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). Additional abnormalities may include an abnormal opening in the skull (cranium bifidum occultum), through which part of the brain and the membranes that cover the brain may protrude (encephalocele), and/or a fatty tumor (lipomata) on the frontal lobe of the brain. Frontofacionasal dysplasia is inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "frontofacionasal dysplasia" as your search term in the Rare Disease Database.)

Greig cephalopolysyndactyly syndrome (GCPS) is a very rare inherited disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (syndactyly), and/or additional abnormalities. Craniofacial malformations associated with this disorder may include a large and/or unusually shaped skull; a high, prominent forehead (frontal bossing); an abnormally broad nasal bridge; widely spaced eyes (ocular hypertelorism); and/or other physical abnormalities. The range and severity of symptoms may vary greatly from case to case. In most cases, GCPS is thought to be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Greig" as your search term in the Rare Disease Database).

Frontonasal dysplasia, also known as median cleft face syndrome, is a rare craniofacial disorder characterized by widely spaced eyes, a broad nose, a vertical groove down the tip of the nose, a nose that may be split in two, and/or an abnormal, covered gap in the skull (cranium bifidum occultum). Other symptoms may include a short, broad head (brachycephaly); cleft lip and/or palate; abnormally small eyeballs (microphthalmia); and/or mild mental retardation. The cause of frontonasal dysplasia is not known; most cases tend to occur randomly with no apparent cause (sporadic). (For more information, choose "frontonasal" as your search term in the Rare Disease Database.)

Orocraniodigital syndrome is a rare inherited disorder characterized by cleft lip and/or palate, webbing and malformation of the toes, and/or incomplete development (hypoplasia) of the thumbs. Other symptoms may include mental retardation, an abnormally small head (microcephaly), and/or low birthweight. Orocraniodigital syndrome is thought to be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose "orocraniodigital syndrome" as your search terms in the Rare Disease Database.)

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

The following disorders may be associated with craniofrontonasal dysplasia as secondary characteristics. They are not necessary for a differential diagnosis:

Sprengel deformity is a rare birth defect characterized by elevation and/or underdevelopment of the shoulder blade (scapula), limited movement of the arm on the affected side, and development of a lump at the base of the neck due to the scapular elevation. In most cases, affected individuals also have additional abnormalities, such as underdevelopment (hypoplasia) of shoulder muscles, sideways curvature of the spine (scoliosis), fused vertebrae, underdevelopment of one side of vertebrae (hemivertebrae), missing and/or fused ribs, and/or incomplete closure of bones in the spinal column surrounding the spinal cord (spina bifida occulta). In most cases, Sprengel deformity appears to occur randomly with no apparent cause (sporadic). However, in rare cases, the disorder may be inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Sprengel deformity" as your search term in the Rare Disease Database.)

Cleft lip and palate are malformations of the mouth and/or lip that are noticeable at birth (congenital). A cleft is an incomplete closure of or a groove on the palate or lips, or both. 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. Clefts may occur on or both sides of the lip and/or palate. (For more information on this disorder, choose "cleft lip and palate" as your search term in the Rare Disease Database.)
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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.
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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.