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Craniofrontonasal dysplasia
CFND typically causes distinctive features such as an unusually shaped head, wide-set eyes, and nasal anomalies. It often presents with different severity in females and males, with females generally showing more pronounced symptoms.
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Overview
Craniofrontonasal dysplasia (CFND) is a rare genetic disorder that mainly impacts the development of the head and face. The condition can also affect other body parts, including bones, skin, and nails, though these are less common [PMID:24632007]. CFND is considered an X-linked condition, meaning it is caused by changes in a gene located on the X chromosome.
Remarkably, females with CFND generally experience more significant symptoms than males, which is unusual for X-linked conditions. This difference in presentation helps clinicians distinguish CFND from other similar conditions. While CFND is present from birth, its features can vary widely among affected individuals, even within the same family.
Symptoms & clinical features
The most common features of CFND relate to the head and face. These can include craniosynostosis, where the skull bones fuse prematurely, leading to an abnormal head shape and sometimes impacting brain development [PMID:27878832]. Other facial characteristics often include a wide groove between the nostrils and the upper lip (nasal groove), widely spaced eyes (hypertelorism), and a broad nasal bridge. The hairline may also be unusually high.
Beyond the craniofacial region, CFND can sometimes affect other body systems. Skeletal features might include abnormalities of the collarbones, shoulders, and ribs, and in some cases, finger and toe abnormalities. Skin and hair involvement can include brittle nails or coarse hair. Less commonly, individuals with CFND may experience hearing impairment or mild learning difficulties, although intelligence is typically unaffected [PMID:24632007].
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Affected organs
The primary body systems affected in CFND are the skeletal system, particularly the bones of the skull and face. The premature fusion of skull sutures (craniosynostosis) is a hallmark sign. The eyes are also frequently affected, primarily due to the wide spacing caused by facial bone development.
While less common, other skeletal components such as the clavicles (collarbones), ribs, and extremities (fingers and toes) can also show developmental differences. Hair, skin, and nails may also exhibit minor changes in some individuals.
Risks & severity
The severity of CFND symptoms is highly variable, even within the same family. Females typically present with more pronounced craniofacial features, including craniosynostosis, hypertelorism, and other facial anomalies, compared to males. Males with the genetic change may have no or very mild symptoms, such as subtle eyebrow changes or slight hypertelorism, making diagnosis more challenging [PMID:24632007]. Rarely, males can experience more severe features, including craniosynostosis.
Lifetime risks for specific complications depend on the features present. For example, craniosynostosis, if severe and untreated, can potentially affect brain development. However, once managed, individuals with CFND generally have a typical life expectancy. There is no specific age of onset as the features are congenital (present from birth), but new symptoms related to bone growth or development may appear or become more noticeable over time.
Genetic causes
Craniofrontonasal dysplasia is caused by genetic changes (pathogenic variants) in the EFNB1 gene. This gene provides instructions for making a protein called ephrin B1. Ephrin B1 is a transmembrane protein, meaning it extends through the cell membrane, acting as a crucial component in cell communication pathways.
The ephrin B1 protein is vital for guiding cell movement and organisation during embryonic development, particularly in the formation and patterning of structures in the head and face. When there is a pathogenic variant in EFNB1, the protein's function is disrupted. This disruption interferes with the delicate balance of cell signalling, leading to the characteristic developmental abnormalities seen in people with CFND.
- EFNB1 ephrin B1The EFNB1 gene encodes the ephrin B1 protein, vital for cell-to-cell communication and proper tissue development, with clinical implications in conditions like craniofrontonasal dysplasia.
Inheritance pattern
CFND follows an X-linked dominant inheritance pattern. This means the gene responsible, EFNB1, is located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome.
In typical X-linked dominant conditions, males are usually more severely affected. However, CFND is an exception, where females often show more pronounced features. This is thought to be due to a process called 'cell-autonomous random X-inactivation'. In females, one of the two X chromosomes is randomly inactivated in each cell. If an X chromosome carrying the altered EFNB1 gene is inactivated in some cells, and the normal X chromosome in others, this creates a mosaic pattern of cells that are either affected or unaffected. This cellular mosaicism is believed to be the reason for the more severe clinical presentation in females. Males, having only one X chromosome, either have the condition or do not, and often present with milder or no symptoms if they carry the pathogenic variant.
X-linked dominant: all daughters of an affected father inherit the altered X and are affected. Sons receive the father's Y and are unaffected.
Diagnosis & testing
Diagnosing CFND typically begins with a clinical examination by a specialist, such as a paediatrician or a clinical geneticist, based on the characteristic craniofacial features. Imaging studies, such as X-rays or CT scans of the head, may be used to identify craniosynostosis or other skeletal anomalies. Once CFND is suspected, a definitive diagnosis is confirmed through genetic testing.
Genetic testing identifies pathogenic variants in the EFNB1 gene. This testing is crucial for confirming the diagnosis, understanding the inheritance pattern, and providing accurate genetic counselling to affected individuals and their families. In the UK, genetic testing for suspected CFND may be requested through the NHS Genomic Medicine Service, often initiated following a referral to a clinical genetics department. Relevant R-codes for genetic testing would be applied based on the specific clinical presentation and suspected genetic cause.
Management & lifestyle
Due to the varying symptoms of CFND, management is individualised and multidisciplinary. This typically involves a team of specialists, which may include craniofacial surgeons, neurosurgeons, ophthalmologists, orthodontists, and geneticists. For individuals with craniosynostosis, surgical intervention may be required to reshape the skull and prevent potential complications associated with brain development.
Regular follow-up appointments are important to monitor development and address any emerging concerns. For example, eye examinations may be needed to monitor for visual issues or changes related to hypertelorism. Genetic counselling is a key component of management, offering information about the condition, its inheritance, and implications for family planning. Support groups and patient organisations can also provide valuable resources and a community for those affected by CFND.
UK care pathway
In the UK, individuals suspected of having CFND would typically be referred to a clinical genetics service by their GP or another specialist. The clinical genetics team, which includes genetic counsellors, can arrange diagnostic genetic testing through the NHS Genomic Medicine Service (GMS). This testing will look for pathogenic variants in relevant genes, such as EFNB1, often utilising GMS R-codes for specific test requests. Once a genetic diagnosis is confirmed, further management and specialist referrals would be coordinated through the NHS, ensuring access to appropriate multidisciplinary care.
Frequently asked questions
Why are females often more affected by CFND than males, even though it's an X-linked condition?
This unusual pattern is thought to be due to 'X-inactivation'. Females have two X chromosomes, and in each cell, one is randomly switched off. This creates a mixture of cells, some working normally and others affected by the gene change, leading to more pronounced symptoms in females.
Will my child's intelligence be affected by CFND?
In most cases, intelligence is not affected in individuals with CFND. While some may experience mild learning difficulties, the condition primarily impacts physical development, especially of the head and face.
Is surgery always needed for CFND?
Surgery may be recommended if there is craniosynostosis (premature fusion of skull bones) to correct head shape and allow proper brain growth. However, not all individuals with CFND will require surgery, as the severity of features can vary greatly.
Can CFND be passed down in families?
Yes, CFND is an inherited condition following an X-linked dominant pattern. If a parent has the genetic change, there is a chance their children could inherit it. Genetic counselling can provide specific risk information for your family.
Where can I find support for CFND in the UK?
Your clinical genetics team or genetic counsellor can provide information on patient support organisations in the UK. These groups often offer valuable resources and connect families with similar experiences.
References
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- Kapusta L, Brunner HG, Hamel BC. Craniofrontonasal dysplasia. European journal of pediatrics. 1992. PMID: 1468459
- Ghosh K, Xu H, Roy M. Craniofrontonasal dysplasia: A case report. Pediatric discovery. 2023. PMID: 40625570
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- O'Hara J, Ruggiero F, Wilson L. Syndromic Craniosynostosis: Complexities of Clinical Care. Molecular syndromology. 2019. PMID: 30976282
- Schaefer GB, Olney AH, Kolodziej P. Craniofrontonasal dysplasia. Ear, nose, & throat journal. 1998. PMID: 9509720
- Cohen MM Jr. Craniofrontonasal dysplasia. Birth defects original article series. 1979. PMID: 526593
- Grutzner E, Gorlin RJ. Craniofrontonasal dysplasia: phenotypic expression in females and males and genetic considerations. Oral surgery, oral medicine, and oral pathology. 1988. PMID: 3283635