Craniofrontonasal Dysplasia

Disease Overview

Craniofrontonasal dysplasia (CFND) is a rare disorder characterized by facial asymmetry, defects along the midline of the body, skeletal abnormalities, and skin problems.¹  Other common symptoms include widely spaced eyes (hypertelorism), a cleft on the nose tip, and an unusually wide mouth  In addition, the top, bony part of the skull can have an  unusual shape due to premature closure of the joints (sutures) between certain bones in the skull (coronal synostosis) in early development.² These problems are congenital, which means that they are present at birth.

CFND is a dominant X-linked disorder, but females with CFND usually experience a more severe form than males, due to a biological phenomenon called X-inactivation (see Causes below).³ For people with CFND, the majority of the treatments are supportive and aimed at addressing the external manifestations of the condition. More severe symptoms and rare complications are typically addressed with surgery.

Due to the wide variation in the symptoms among people affected by CFND, there is no standardized treatment. However, common forms of therapy are craniofacial (facial) deformity correction, repair of abnormalities of the hands and feet, narrowing of the nose (rhinoplasty), etc.⁴ Each person’s treatment is unique and may involve consultations with multiple specialists. Management is focused on improving quality of life and addressing specific symptoms as they arise.⁵

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Synonyms

• CFND
• craniofrontonasal dysostosis
• CFNS
• craniofrontonasal syndrome

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Signs & Symptoms

People with CFND experience a range of symptoms both in variety and severity. However, women often have more severe symptoms.^{7, 8} Limited research, primarily a few reports, complicates this issue further, making understanding and managing the condition more challenging.^{5, 7, 9-12} Common symptoms associated with CFND can be grouped into two categories, clinical facial features and skeletal abnormalities in the arms, wrists, hands, and shoulders (upper extremities).

Common facial features include: ^{5, 6, 13, 14}

• Short and broad skull (brachycephaly)
• Unusual head shape due to premature joint (suture) closure between certain skull bones (coronal synostosis) that results in facial asymmetry
• Lack of nose prominence (depressed nasal ridge)
• Forehead bulge/protrusion (frontal bossing)
• Widely spaced eyes (orbital hypertelorism)
• One eye that is lower than the other (orbital dystopia)
• Vertical groove (cleft) on the tip of the nose
• Midline nasal defect
• Broad nose and face (wide nasal bridge)
• Cleft on the lip and the roof of the mouth (cleft palate)
• Low-set ears and a webbed neck
• Thick, wiry, and curly hair that appears in females of 2-3 months of age

Skeletal abnormalities include: ^{5, 6, 13, 14}

• Ridged fingernails
• Webbed fingers and toes (syndactyly)
• Curved fifth finger (clinodactyly)
• Splits and grooves in fingernails and toenails
• Broad fingers and big toes

Additional skeletal abnormalities may include narrow sloping shoulders, 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).¹⁵ One arm or leg may be shorter than the other and  some females may have underdevelopment of one breast. 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.¹⁶ Females may have a womb (uterus) anomaly that may result in having more miscarriages than other women in the general population.

Some people with CFND who have skeletal abnormalities may also have diminished muscle tone (hypotonia), a sunken chest (pectus excavatum), and/or protrusion of part of the stomach and/or small intestines into the chest cavity (diaphragmatic hernia). ^{2, 17, 18} Several reports have linked CFND to Poland syndrome, a condition where chest wall muscles are absent on one side of the body and abnormally short, webbed fingers are present on the hand of the same side. Some people have a complete or partial absence of the corpus callosum, the band of nerves connecting the brain’s two hemispheres.^{2, 17, 18}

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). Males may show no symptoms but may be carriers of the EFNB1 gene variation.^{2, 17, 18}

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Causes

CFND is caused by variants in the EFNB1 gene, located on the long arm (q) of the X chromosome at the position 13.1 (Xq13.1)¹  The EFNB1 gene has instructions to produce (encode) a protein known as ephrin B1. EFNB1 gene variants are usually loss-of-function variants, which means that the gene stops working or works less effectively, preventing the full or proper formation of the ephrin B1 protein and, and leading to the clinical features.^{19, 20}

The ephrin B1 protein is  a transmembrane protein that plays an important role in cell signaling and development,²¹ It functions  mainly in the ability of a cell to stick to another cell or an extracellular matrix (cell adhesion), which is important in development because of its involvement in forming tissues and maintaining the structural integrity, essential for proper tissue patterning and organ development before birth. Specifically, the ephrin B1 protein signaling is involved in directing cell movement and positioning, also playing a role in the development of the blood vessels.²¹ The craniofacial features of CFND, such as hypertelorism, broad nasal bridge, and craniosynostosis, can be attributed to the disruption of ephrin B1’s role in tissue patterning and organ development before birth.⁸

The EFNB1 gene variants obstruct proper skull development, leading to single-suture synostosis (SSS) of the coronal suture, which can lead to abnormal skull shape and, in some cases, increased intracranial pressure.  Some affected people experience neurological symptoms, such as learning disabilities or developmental delays. These can be linked to the role of the ephrin B1 in nervous system development, as ephrin B1 helps guide the growth of nerve cells (neurons) and allows connections between neurons to change and adapt over time. ^22-25 Disruption of these processes can affect brain development and function ²⁶. The skin and nail abnormalities observed in CFND affected individuals can be attributed to the role of ephrin B1 in epithelial tissue development and maintenance.⁹ This complex interplay of cellular and molecular factors results in characteristic skull shape abnormalities observed in CFND, highlighting the critical role of the ephrin B1 signaling in normal craniofacial development.

Inheritance

CFND is inherited as a dominant X-linked disorder.¹  X-linked dominant disorders are caused by a disease-causing gene variant located on the X chromosome and mostly affect females. Females are affected when they have an X chromosome with the gene variant. Males with a disease-causing gene variant for an X-linked dominant disorder are more typically severely affected than females and often do not survive. However, unlike most X-linked disorders, women with CFND are more severely affected than men.

Women have two X chromosomes (XX), while men have one X and one Y chromosome (XY). For a woman to have a dominant sex-linked disorder, she usually needs an altered gene in any of her X chromosomes. In contrast, for a man, a single altered gene on his only X chromosome is enough to cause the disorder.^{27, 28}  However, as commented before, females are more commonly affected and typically show more severe features due to a unique phenomenon called X chromosome inactivation in addition to cellular interference.³

During early embryonic development, one of the two X chromosomes of a woman is randomly inactivated, resulting in a mosaic pattern where some cells express the normal EFNB1 gene, while others express the variant version.^{27, 29} Due to this variation in affected individuals, a mixture of cells with functional and non-functional ephrin-B1 leads to a phenomenon called cellular interference, where the expression of an altered  gene can affect the function/expression of a neighboring gene/cell. In CFND, this results in a disrupted tissue pattern that affects the development of the head and face. In contrast, males with CFND have the altered EFNB1 gene only on their lone X chromosome, resulting in a complete absence of functional ephrin-B1 protein. This allows the body to compensate through alternative pathways and mechanisms, with other proteins potentially performing similar functions, resulting in milder signs and symptoms.^{1, 30}

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Affected populations

CFND occurs roughly every 1/100,000 to 1/120,000 newborns.⁵³ To date, there is no evidence that CFND affects certain populations (ethnic or racial groups) more than others. However, females are more severely affected and more often diagnosed than males.^{2, 19}

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to CFND. Comparisons may be useful for a differential diagnosis:

Aarskog syndrome is an extremely rare genetic disorder marked by stunted growth that, unlike CFND which is present at birth, may not become obvious until the child is about three years of age, broad facial abnormalities, musculoskeletal and genital anomalies, and mild intellectual disability. ³¹ It is caused by variants in the FGD1 gene.  Inheritance is X-linked recessive and primarily affects males. ³² Clinical facial feature symptoms in Aarskog syndrome include a rounded face, wide-set eyes, and a small nose with anteverted nostrils, contrasting with CFND’s hypertelorism, coronal craniosynostosis, and bifid nasal tip.^{31, 33} Skeletal abnormalities differ as well, with Aarskog syndrome involving short stature and brachydactyly, while CFND may present asymmetric limbs and clavicle abnormalities. Mild intellectual disability is known to be associated with Aarskog syndrome, while CFND generally doesn’t affect cognitive function.

Frontofacionasal dysplasia (FND) is a very rare 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).^{34, 35} It is widely considered a broader blanket category of congenital malformations affecting the midface, where CFND is a subtype of FND. FND’s are generally inherited as an autosomal recessive genetic condition. While CFND is caused by variations in the EFNB1 gene on the X chromosome, other forms of FND have different genetic origins.^{36, 37, 38} FND more commonly displays distinct limb abnormalities and central nervous system malformations

Frontorhiny is another subtype of FND and is characterized by hypertelorism, a wide nasal bridge, and a split nasal tip. Unlike CFND, frontorhiny has an autosomal recessive inheritance pattern, contrasting CFND’s X-linked dominant pattern.^39,40 Autosomal recessive patterns can cause traits or disorders to skip generations and affect males and females equally.

Greig cephalopolysyndactyly syndrome (GCPS) is a rare genetic disorder characterized by physical abnormalities affecting the fingers and toes (digits) and the head and facial (craniofacial) area. ⁴¹ Characteristic digital features may include extra (supernumerary) fingers and/or toes (polydactyly), webbing and/or fusion of the fingers and/or toes (cutaneous or osseous syndactyly), and/or additional abnormalities. ⁴¹ Craniofacial malformations may include a large and/or unusually shaped skull, a high, prominent forehead (frontal bossing), an abnormally broad nasal bridge, ocular hypertelorism and/or other physical abnormalities. ⁴² GCPS is caused by variants in the GLI3 gene on chromosome 7 and is inherited in an autosomal dominant manner, affecting males and females equally.^{43, 44} A key distinguishing feature of GCPS is polysyndactyly (extra fingers/toes along with webbed limbs), often with preaxial polydactyly of the feet and postaxial polydactyly of the hands^..⁴¹

Frontonasal dysplasia, also known as median cleft face syndrome, is a rare craniofacial disorder characterized by widely spaced eyes due to hypertelorism, 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).⁴⁵ Other symptoms may include a short, broad head (brachycephaly); cleft lip and/or palate; abnormally small eyeballs (microphthalmia); and/or mild intellectual disability. Frontonasal dysplasia is a heterogeneous disorder. ⁴⁵  It may be caused by variants in the ALX1, ALX3, and ALX4 genes but in most people it tend to occur randomly with no apparent cause (sporadic) compared to CFND’s paradoxical X-linked inheritance.^{46, 47}

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 intellectual disability, an abnormally small head (microcephaly), and/or low birth weight. ^{48, 49} Orocraniodigital syndrome is thought to be inherited as an autosomal recessive genetic condition, although other patterns of inheritance may occur.  Additionally, orocraniodigital syndrome involves hypoplasia or agenesis of thumbs, syndactyly of toes, and stiff thumbs. Intellectual disability has occurred in most people  affected by orocraniodigital syndrome.^{48, 49}

Many other rare craniofacial disorders are characterized by facial abnormalities similar to those of CFND.

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Diagnosis

When CFND is suspected, the first step is usually a thorough clinical evaluation based on the identification of the characteristic signs and symptoms of CFND. Common clinical features that are looked for are facial asymmetry, hypertelorism, bifid nasal tip, craniosynostosis, etc. ¹³ Next, diagnostic imaging modalities such as X-rays and CT scans may be used to assess the extent of craniosynostosis and other skeletal abnormalities (fusion of skull sutures and other bone-related features). Finally, molecular testing of the EFNB1 gene, or deletion/duplication analysis if sequence analysis is negative.³

While uncommon, CFND can be detected prenatally through ultrasound imaging, which may reveal features like hypertelorism or bifid nasal tip. These features can be difficult to detect in early pregnancy and aren’t definitive.¹³ Furthermore, genetic testing through amniocentesis or chorionic villus sampling is used as a detection method if there is a known family history and/or parents suspect the possibility of CFND.

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Standard Therapies

Treatment

There is currently no standard treatment for people with CFND because symptoms vary from person to person. Each person is uniquely assessed and treated based on their specific presentation of symptoms and treatment plans are typically carefully staged and may evolve as the person grows and develops. Life-threatening complications are uncommon. Some exceptions include the dangerous buildup of pressure in the skull (elevated intracranial pressure), the diaphragm pushing through a weak spot in the muscle or tissue wall that usually holds it in place (diaphragmatic hernia), and/or airway obstruction, all usually treated with surgery.³⁰

Most treatments to date are aesthetic and performed to improve the appearance.  Surgery for craniosynostosis usually involves moving the forehead forward and reshaping the bone above the eyes, called the supraorbital rim (the upper edge of the eye socket). ⁵⁰ Another common surgery is orbital hypertelorism repair, which is usually done between ages 5-8. It involves carefully cutting and moving the bones around the eye sockets (osteotomies, meaning surgical cuts in bone) so the eyes can be brought closer together. In some cases, the surgeon may reposition the eye sockets (orbital translocation) or split and reshape the middle of the face (facial bipartition) to improve alignment.^{51, 52} This procedure is often delayed to wait for the development of the teeth (dentition) so it doesn’t interfere with how the teeth grow. Nasal deformity correction is often performed together with orbital hypertelorism repair to correct a bifid nose tip. Surgery may also be used to narrow the nose and reduce neck webbing.

Aside from physical treatments, supportive care is often needed. These treatments are symptomatic and supportive, including, physical and occupational therapy, and are based on the specific needs of the affected individuals and their families.⁵ A team approach for infants and children with this disorder may be of benefit and may include special social support and other medical services.⁵ Genetic counseling is often recommended for affected individuals and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/ . All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/for-patients-and-families/information-resources/info-clinical-trials-and-research-studies/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

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30. Bissonnette B, Luginbuehl I, Engelhardt T. Craniofrontonasal Dysplasia. Syndromes: Rapid Recognition and Perioperative Implications, 2e. New York, NY: McGraw-Hill Education 2019.
31. Pavone P, Marino S, Maniaci A, et al. Aarskog-Scott syndrome: clinical and molecular characterisation of a family with the coexistence of a novel FGD1 mutation and 16p13.11-p12.3 microduplication. BMJ Case Rep. 2020;13(6).
32. Zhu Y, Chen Q, Lin H, et al. FGD1 Variant Associated With Aarskog-Scott Syndrome. Front Pediatr. 2022;10:888923.
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51. Haq EU, Qayyum MU, Ilahı MI, et al. Surgical correction of grade III hypertelorism. J Korean Assoc Oral Maxillofac Surg. 2017;43(Suppl 1):S19-s24.
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