Craniofrontonasal syndrome

What it is, symptoms and effects

From: MedlinePlus Genetics, National Library of Medicine

Craniofrontonasal syndrome is a rare condition characterized by the premature closure of certain bones of the skull (craniosynostosis) during development, which affects the shape of the head and face. The condition is named for the areas of the body that are typically affected: the skull (cranio-), face (fronto-), and nose (nasal).

In people with craniofrontonasal syndrome, the skull bones along the coronal suture, which is the growth line that goes over the head from ear to ear, closes early. These changes can result in an abnormally shaped head and distinctive facial features. The size and shape of facial structures may differ between the right and left sides of the face (facial asymmetry) in individuals with craniofrontonasal syndrome. Affected individuals may also have wide-set eyes (ocular hypertelorism), eyes that do not point in the same direction (strabismus), involuntary eye movements (nystagmus), a slit (cleft) in the tip of the nose, a wide nasal bridge, an upper lip that points outward (called a tented lip), or a cleft in the upper lip with or without a cleft in roof of the mouth (palate). Some affected individuals have brain abnormalities, such as absent or underdeveloped tissue connecting the left and right halves of the brain (agenesis or dysgenesis of the corpus callosum). However, intelligence is usually unaffected in people with this condition. Females with craniofrontonasal syndrome typically have more severe signs and symptoms than affected males, who often have hypertelorism and rarely, cleft lip.

Other common features of craniofrontonasal syndrome include extra folds of skin on the neck (webbed neck), ridged nails, unusual curving of the fingers or toes (clinodactyly), extra fingers (polydactyly) or fingers that are fused together (syndactyly), low-set breasts, a sunken chest (pectus excavatum), a spine that curves to the side (scoliosis), or narrow and sloped shoulders with reduced range of motion. People with this condition may also have eyebrows that grow together in the middle (synophrys), a widow's peak hairline with a low hairline in the back, or wiry hair.

Causes and biological mechanisms

From: MedlinePlus Genetics, National Library of Medicine

Craniofrontonasal syndrome is caused by mutations in a gene known as EFNB1. This gene provides instructions for making a protein called ephrin B1. This protein spans the cell membrane where it can attach (bind) to other proteins on the surface of neighboring cells. Protein binding between nearby cells helps cells stick to one another (cell adhesion) and communicate, which are important for the normal shaping (patterning) of many tissues and organs before birth.

Mutations in the EFNB1 gene result in a shortage (deficiency) of ephrin B1 protein. Most of these mutations lead to an abnormally short version of the molecule that acts as the genetic blueprint for the ephrin B1 protein. The shortened molecules are quickly broken down before protein can be made. A deficiency of ephrin B1 protein prevents cell adhesion, which disrupts normal patterning in tissues before birth, leading to the signs and symptoms of craniofrontonasal syndrome.

Inheritance and family implications

From: MedlinePlus Genetics, National Library of Medicine

Craniofrontonasal syndrome is inherited in an X-linked pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes in each cell. Males have only one X chromosome and females have two copies of the X chromosome. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

Researchers suspect that the signs and symptoms of craniofrontonasal syndrome vary in severity between males and females in part because of a normal process called X-inactivation. Early in embryonic development in females, one of the two X chromosomes is permanently turned off (inactivated) in somatic cells (cells other than egg and sperm cells). X-inactivation ensures that females, like males, have only one active copy of the X chromosome in each body cell. Usually X-inactivation occurs randomly, so that each X chromosome is active in about half the body's cells. This means that in affected females with craniofrontonasal syndrome, the X chromosome with an EFNB1 gene mutation is active in about half of cells, and the X chromosome with the normal EFNB1 gene is active in about half. Because X-inactivation leads to some cells that produce functional ephrin B1 protein and some cells that do not, patterning of tissues becomes patchy, which can alter development of the head and face.

In affected males, all cells have a single X chromosome with an EFNB1 gene mutation. Because ephrin B1 activity is completely missing in all cells, normal tissue patterning cannot occur and it is thought that other proteins perform similar functions to compensate.

How common is it?

From: MedlinePlus Genetics, National Library of Medicine

Craniofrontonasal syndrome is a very rare condition, although its prevalence is unknown. More than 115 cases have been described in the scientific literature.

Reported clinical features and what the terms mean

The following findings are associated with this condition in Orphanet. They are not a checklist for diagnosing yourself, and they do not all occur in every affected person. Some are examination, imaging or laboratory findings that cannot be recognised at home.

The frequency labels describe how often a finding was reported among people with the condition in the source. They do not give the chance that a person with that symptom has the condition. Definitions below reproduce HPO terminology; they explain the term, not the likely severity in an individual.

Brachycephaly · Very frequent (99-80%)

An abnormality of skull shape characterized by a decreased anterior-posterior diameter. That is, a cephalic index greater than 81%. Alternatively, an apparently shortened anteroposterior dimension (length) of the head compared to width.

Craniosynostosis · Very frequent (99-80%)

Craniosynostosis refers to the premature closure of the cranial sutures. Primary craniosynostosis refers to the closure of one or more sutures due to abnormalities in skull development, and secondary craniosynostosis results from failure of brain growth.

Depressed nasal ridge · Very frequent (99-80%)

Lack of prominence of the nose resulting from a posteriorly-placed nasal ridge.

Frontal bossing · Very frequent (99-80%)

Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.

Hypertelorism · Very frequent (99-80%)

Interpupillary distance more than 2 SD above the mean (alternatively, the appearance of an increased interpupillary distance or widely spaced eyes).

Midline defect of the nose · Very frequent (99-80%)

This term groups together three conditions that presumably represent different degrees of severity of a midline defect of the nose or nasal tip.

Ridged fingernail · Very frequent (99-80%)

Longitudinal, linear prominences in the fingernail plate.

Wide nasal bridge · Very frequent (99-80%)

Increased breadth of the nasal bridge (and with it, the nasal root).

Other findings in the same source

From: Orphanet

Additional reported features include Abnormality of hair texture (Frequent (79-30%)); Abnormality of the clavicle (Frequent (79-30%)); Abnormality of the dentition (Frequent (79-30%)); Brachydactyly (Frequent (79-30%)); Broad hallux phalanx (Frequent (79-30%)); Camptodactyly of finger (Frequent (79-30%)); Clinodactyly of the 5th finger (Frequent (79-30%)); Congenital pseudoarthrosis of the clavicle (Frequent (79-30%)); Down-sloping shoulders (Frequent (79-30%)); Downslanted palpebral fissures (Frequent (79-30%)). This is a selected summary, not a complete description of the condition.

Which doctor should you see?

The suggested department for discussing Craniofrontonasal syndrome is Clinical Genetics, with a clinical geneticist as the relevant type of clinician. Paediatrician (children) or physician (adults), with clinical geneticist referral.

This is an editorial referral starting point. The appropriate clinic depends on the person’s age, symptoms, previous diagnosis and local services. The first clinician can decide whether another specialty or a team is needed; a department label does not confirm the diagnosis.

How to prepare for an assessment

Bring a short timeline of the main symptoms: when they first appeared, whether they are constant or episodic, what seems to change them, and how they affect daily activities. Include previous reports, discharge summaries, current medicines and supplements, allergies, and any relevant family history. A dated record is more useful than trying to match every feature in an online article.

Ask the clinician what is already established and what remains uncertain. If a test is suggested, ask what question it answers, what its limitations are and how the result would change the next step. The information here is not an instruction to arrange every possible test. In children, bring growth, developmental and school information if it is relevant to the concern.

• Does the exact genetic or chromosome finding explain the observed features?
• Would a genetic counsellor help the family understand the result?
• Which organ-specific assessments are appropriate for this particular diagnosis?

Treatment discussions and follow-up

The material gathered for this draft does not provide a complete condition-specific treatment pathway for Craniofrontonasal syndrome. That gap does not mean that treatment is unavailable. A clinician needs to establish the diagnosis and review current guidance before recommending medicines, procedures, rehabilitation or other support.

Before leaving the appointment, clarify the next review date, who will communicate results, and whom to contact if the situation changes. Discuss difficulties with sleep, work, school, mobility, eating or emotional wellbeing when these are relevant. Practical support may require coordination between the treating clinician and other services.

The collected references do not establish a complete prevention or long-term outlook section for this entry. Missing information should not be interpreted as proof that prevention is impossible or that a particular outcome is inevitable. Ask what is known for the exact subtype, stage and personal circumstances, and which uncertainties remain.

When to seek emergency help

Severe breathing difficulty, collapse, new stroke-like symptoms, a seizure that is prolonged or repeated without recovery, uncontrolled major bleeding, or an immediate risk of self-harm require emergency help. In India, call 112 or reach the nearest emergency department. This is a general, non-exhaustive warning list; it is not a condition-specific triage tool.