Craniofrontonasal dysplasia is a very rare X-linked malformation syndrome caused by mutations in the ephrin-B1 gene (EFNB1). Phenotypic expression varies. Disease definition. Craniofrontonasal dysplasia is an X-linked malformation syndrome characterized by facial asymmetry (particularly orbital), body asymmetry. Learn in-depth information on Craniofrontonasal Dysplasia, its causes, symptoms , diagnosis, complications, treatment, prevention, and.

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CC HPO: Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males.

Craniofrontonasal Dysplasia – NORD (National Organization for Rare Disorders)

Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, craniofrononasal males typically show only hypertelorism Twigg et al. Cohen identified CFNS as a subgroup of frontonasal dysplasia.

CFNS is characterized in females by hypertelorism, coronal craniosynostosis, craniofacial asymmetry, frontal bossing, downslanting palpebral fissures, clefting of the nasal tip, longitudinally grooved fingernails, and other digital anomalies Vasudevan et al. Kwee and Lindhout reported a 2-year-old boy, born of nonconsanguineous Dutch parents, who exhibited brachycephaly with a broad, prominent forehead, retracted supraorbital ridges, severe ocular hypertelorism, downslanting palpebral fissures, broad nasal bridge, and broad bifid tip of the nose.

The mouth was tent-shaped, craniofrontomasal a pseudocleft-like philtrum of the upper lip and high-arched palate. Ears were thick and low set, and the neck was short without webbing. The right thumb was broad and partially bifid at the tip, with a broad, concave, and longitudinally split fingernail; x-ray revealed duplication of the distal phalanx of the thumb.

A rudimentary postaxial finger on this hand was surgically removed in infancy, and the nails of several other fingers and toes also showed a median longitudinal split.

In addition, there was bilateral cryptorchidism. Skull x-rays showed synostosis of the coronal suture, and CT scan showed an enlarged ventricular system without apparent structural malformation.

A second cousin of the proband also had unilateral duplication of the distal phalanx with concave fingernails and hypoplastic toenails, but no other anomalies. All affected persons had hypertelorism, bifid or broad nose, and highly arched palate. Cleft lip and palate were present in 1, Sprengel anomaly in 2, pseudarthrosis of the clavicle in 2, pectus excavatum in 3, diaphragmatic hernia in 2, broad first toe in 4, longitudinal grooves of the nails in 5, shawl scrotum in 2 of 3 males, 1 of whom had first-degree hypospadias, and mild retardation in 1.

All daughters of affected males were affected, a finding craniofrojtonasal with X-linked dominant inheritance.

Hurst and Baraitser confirmed the female preponderance in this condition and noted that all of their patients had thick, wiry hair. In addition to the coronal craniosynostosis and facial changes, syndactyly of fingers and toes and longitudinally grooved nails were present. Xysplasia mildly affected males did not have craniosynostosis but did show hypertelorism, broad great toes, and grooved nails. They reported an affected mother and daughter who also had limited hip and shoulder abduction.


In addition, the mother had axillary pterygia, congenital footplate fixation of the left ear, right sensorineural hearing loss, and limited forearm pronation.

One affected member, who had 4 miscarriages, had an arcuate uterus; she also had curly hair, grooved fingernails, and unilateral breast hypoplasia. One son of an affected female was considered to be affected because of hypertelorism with an inner canthal distance greater than the 97th centile at 9 years of age.

One male with 2 affected daughters and no other children was judged to be unaffected or to have at the most ‘microsymptoms.

The mothers both had classic features of CFNS. Both sons had no major craniofacial features other than telecanthus, but both had congenital diaphragmatic hernia.

The father displayed hypertelorism and a widow’s peak, and dysppasia pectus carinatum that had been surgically corrected, whereas the daughter had hypertelorism, bifid nasal tip, widow’s peak, frontal bossing, and a widened metopic suture. The paternal grandmother did not have hypertelorism, but had a dysplastic left fifth toe and a reported ‘chest deformity’ that was not examined.

In addition, the mother had also previously craniofrontonaasal therapeutic abortion of a female fetus with congenital diaphragmatic hernia. Johnson suggested that some disorders may show up only in heterozygotes as a result of adverse interaction of 2 alleles, neither of which occasions abnormality when homozygous or hemizygous. The mode of inheritance was unclear. An excess of females In the family reported by Kumar et al.

Craniofrontonasal dysplasia

Sax and Flannery reviewed 8 published pedigrees and added a ninth. They concluded that the segregation does not fit autosomal dominant, autosomal recessive, X-linked dominant, or X-linked recessive inheritance. There were 3 severely affected females, 2 of them daughters of apparently dyspalsia parents. Two male relatives, including the father of the 2 affected daughters, had orbital hypertelorism and other minor anomalies.

Two affected fathers in their series had an unaffected son. Added to published information, 8 affected cdaniofrontonasal had reproduced, producing 21 females, all affected, and 8 males, all unaffected.

Although most cases were sporadic, 7 familial instances were found. They pointed out that male-to-male transmission had not been observed.

Rare Disease Database

The phenotypically normal mother had normal chromosomes. Detailed phenotypic analysis in these families showed that females were more severely affected than males; affected males showed hypertelorism as the only sign, and none had coronal synostosis in contrast to the findings in their female relatives.


In females, findings included severe hypertelorism with extremely broad nasal root and severe craniofacial asymmetry, including orbital asymmetry probably caused by unicoronal synostosis. Nine cases were familial, and 29 cases were sporadic. These results supported cellular interference as being the cause of the more severe phenotype in CFNS females. Such a situation does not occur in hemizygous carrier males, who are mildly affected.

All 6 patients had documented coronal craniosynostosis and exhibited severe hypertelorism; other features included agenesis of the corpus callosum, bifid nasal tip, longitudinally split nails, cryptorchidism, and mild learning disability. A novel phenotypic pattern in X-linked inheritance: A novel EFNB1 mutation c. A family with craniofrontonasal dysplasia, and fragile site 12q13 segregating independently.

Frontonasal dysplasia, coronal craniosynostosis, pre- and postaxial polydactyly and split nails: Craniofrontonasal syndrome and diaphragmatic hernia. Craniofrontonasal dysplasia in a girl with del X p Craniofrontonasal dysostosis with craniofrontoonasal and axillary ceaniofrontonasal. Delineation of the male phenotype in craniofrontonasal syndrome. Radiocephalometric ceaniofrontonasal in a family with craniofrontonasal dysplasia.

Craniofrontonasal dysplasia in a three-generation kindred. Frontonasal dysplasia with coronal craniosynostosis in three sibs. Cellular interference in craniofrontonasal syndrome: Mutations of ephrin-B1 EFNB1a marker of tissue boundary formation, cause craniofrontonasal syndrome. Expanding the phenotype of craniofrontonasal syndrome: Additional EFNB1 mutations in craniofrontonasal syndrome. Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome.

Mapping of a further locus for Dyslpasia craniofrontonasal syndrome. Dissecting the molecular mechanisms in craniofrontonasal syndrome: Craniofrontonasal dysplasia–a distinct entity with lethality in the male? A bonus to all MIMmatch users is the option to sign up craniofrntonasal updates on new gene-phenotype relationships. Clinical Synopsis Toggle Dropdown. CCC ]. CC ]. Possible Genetic Heterogeneity McPherson et al. OMIM is intended for use primarily by physicians and other professionals concerned with genetic disorders, by genetics researchers, and by advanced students in science and medicine.

While the OMIM database is open to the public, users seeking information about a personal medical or craniofrnotonasal condition are urged to consult with a qualified physician for diagnosis and for answers to personal questions.

Craniofrontonasal Syndrome | Headlines – The Craniofacial Support Group

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