NORD gratefully acknowledges Prof. Dr. Peter Wieacker, Director of the Institute of Human Genetics, University Hospital Muenster, Germany,for assistance in the preparation of this report.
Craniofrontonasal dysplasia (CFND) is a very rare inherited disorder characterized by body – especially facial - asymmetry, midline defects, skeletal abnormalities, and dermatological abnormalities. 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). CFND is an X-linked genetic disorder that occurs mostly in females and is caused by a mutation in the EFNB1 gene.
The symptoms of CFND 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 typically has an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis) resulting in facial asymmetry.
Some 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 CFND 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.) Females may have a uterus anomaly that may cause an increased incidence of miscarriages.
Some individuals affected by CFND 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 CFND 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. Some patients have a complete or partial absence of the corpus callosum, the band of nerves that connect the two hemispheres of the brain.
Some affected males 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 CFND.
CFND is an X-linked disorder caused by a mutation in the EFNB1 gene. There have been at least 33 different mutations of the EFNB1 gene identified. All daughters of affected males are affected, consistent with X-linked inheritance.
CFND is a very rare genetic disorder that affects females more often than males. Females have a more severe form of the disorder.
A diagnosis of CFND may be suspected after a thorough clinical evaluation and characteristic physical findings. Molecular genetic testing for mutations in the EFNB1 gene is available to confirm the diagnosis. CFND can sometimes be detected before birth (prenatally) by ultrasound.
Treatment of CFND depends upon the specific malformations and their severity in each individual patient, and the timing of diagnosis. 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. 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.
Genetic counseling is recommended for affected individuals and their families.
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