Craniofrontonasal dysplasia (CFND) is a rare genetic disorder affecting the development of the head and face. It is characterized by malformations in the craniofacial region, along with potential abnormalities in other parts of the body, such as the nails, hair, and skeleton.
Understanding Craniofrontonasal Dysplasia
CFND is a genetic condition caused by mutations in the EFNB1 gene, located on the X chromosome. This gene provides instructions for ephrin-B1, a protein involved in cell adhesion and signaling. Over 30 different mutations in the EFNB1 gene have been identified.
The inheritance pattern of CFND is X-linked dominant. Females are typically more severely affected than males due to skewed X-inactivation, a process where one of the two X chromosomes in females is randomly inactivated. In females with a mutated EFNB1 gene, this random X-inactivation leads to a mosaic pattern of cells, where some cells express the normal protein and others express the mutated version. This cellular mosaicism can disrupt normal tissue development, particularly at the boundaries between cells, contributing to the more severe and variable symptoms seen in females. Males, having only one X chromosome, do not experience this mosaicism.
Males with CFND typically have milder symptoms, often presenting only with widely spaced eyes (hypertelorism). Males can occasionally exhibit a more severe phenotype similar to that seen in females. An affected male will pass the condition to all of his daughters, but none of his sons. An affected female has a 50% chance of passing the gene to each child, regardless of sex.
Recognizing the Signs
The physical manifestations of craniofrontonasal dysplasia are varied and can affect different parts of the body, though they primarily involve the head and face. A common feature is craniosynostosis, the premature fusion of one or more skull bones, especially the coronal sutures that run over the top of the head from ear to ear. This early fusion can lead to an abnormally shaped head and facial asymmetry.
Facial features often include widely spaced eyes (hypertelorism) and abnormalities of the nose, such as a broad nasal bridge or a vertical groove or cleft at the tip. Other possible facial signs include downslanting palpebral fissures, a highly arched palate, or a cleft lip and palate. Beyond the face, individuals may have dry, curly, or frizzy hair, a widow’s peak, and longitudinal ridging or splitting of the fingernails and toenails.
Skeletal anomalies can extend to the shoulders, with sloping shoulders and dysplastic clavicles, and to the hands and feet, including broad or duplicated thumbs and big toes, short thumbs, or webbing of fingers and toes (syndactyly). Diagnosis typically begins with a clinical evaluation based on these physical features. Genetic testing confirms the diagnosis by identifying a mutation in the EFNB1 gene. This testing can be performed using DNA isolated from various tissue samples, such as blood, saliva, or hair roots.
Managing the Condition
Surgical interventions are a significant part of treatment, particularly for correcting cranial and facial abnormalities. Craniosynostosis usually requires surgery during the first year of life to decompress the brain and reshape the skull.
Correction of facial anomalies, such as severe hypertelorism or orbital dystopia, is typically delayed until a later age, often around 5 years or older. Surgical procedures may also address issues like strabismus, where the eyes do not align properly. Beyond surgery, individuals with CFND can benefit from various non-surgical therapies.
These therapies may include orthodontic care to address dental and jaw alignment issues, speech therapy for any associated language or speech development difficulties, and occupational therapy to help with daily living activities. A multidisciplinary care team is generally involved in the comprehensive management of CFND, bringing together specialists such as craniofacial surgeons, neurosurgeons, ophthalmologists, orthodontists, and speech therapists. With appropriate and timely interventions, individuals with CFND can often achieve an improved quality of life, though their facial appearance and other congenital anomalies may still influence it.