Craniofrontonasal Syndrome

A number sign (#) is used with this entry because of evidence that craniofrontonasal syndrome (CFNS) is caused by mutation in the EFNB1 gene (300035) on chromosome Xq13.

Description

Craniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (Twigg et al., 2004; Wieland et al., 2004).

Clinical Features

Cohen (1979) 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., 2006).

Pruzansky et al. (1982) described an extensively affected family in which 14 females and 1 male had CFNS.

Kwee and Lindhout (1983) 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, with 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. Other family members exhibited one or more minor anomalies, including longitudinally split nails, broad thumbs and first toes, hypertelorism, and/or downslanting palpebral fissures.

Morris et al. (1987) described a 4-generation family in which 6 persons had frontonasal dysplasia with variable extracranial abnormalities. 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. Morris et al. (1987) reviewed reported families, including those of Reynolds et al. (1982), Slover and Sujansky (1979), and Pruzansky et al. (1982). All daughters of affected males were affected, a finding consistent with X-linked dominant inheritance.

Hurst and Baraitser (1988) confirmed the female preponderance in this condition and noted that all of their patients had thick, wiry hair. Smith et al. (1989) described a 3-generation family. In addition to the coronal craniosynostosis and facial changes, syndactyly of fingers and toes and longitudinally grooved nails were present. More mildly affected males did not have craniosynostosis but did show hypertelorism, broad great toes, and grooved nails. Smith et al. (1989) provided follow-up of the family reported by Slover and Sujansky (1979); 5 daughters were all affected, whereas 3 sons were all normal.

Since there is no evidence of tissue dysplasia in CFNS, Michels et al. (1989) suggested that the disorder be designated craniofrontonasal dysostosis. 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. Kapusta et al. (1992) reported a patient who was only the second male in the literature with all the clinical features of classic CFNS.

Devriendt et al. (1995) reported craniofrontal nasal dysplasia in mother and son, further illustrating 2 unexplained observations in this disorder: more severe clinical expression in females and an increased incidence of miscarriages.

In a review of 41 patients with CFNS studied in Mexico City between 1979 and 1993, Saavedra et al. (1996) reported several unusual manifestations in females, including thick, wiry, and curly hair (49%), anterior cranium bifidum (6%), axillary pterygia (9%), unilateral breast hypoplasia, postpubertal (11%), and asymmetric lower limb shortness (14%).

McGaughran et al. (2002) reported a mother and daughter with CFNS; the daughter also had diaphragmatic hernia. McGaughran et al. (2002) stated that this was the first reported female case of CFNS associated with diaphragmatic hernia and suggested that the brothers reported by Morris et al. (1987) with CFNS and diaphragmatic hernia instead had Teebi syndrome (145420).

Wieland et al. (2002, 2004) reported a 5-generation German family in which 6 females had features of CFNS, including hypertelorism, orbital asymmetry, brachycephaly, brachydactyly, and Sprengel deformity (184400). 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.' Wieland et al. (2004) reported 2 more families with CFNS; additional variable features included agenesis of the corpus callosum, syndactyly, and scoliosis.

Vasudevan et al. (2006) reported 2 unrelated families in which a mother and son had CFNS confirmed by molecular analysis. The mothers both had classic features of CFNS. Both sons had no major craniofacial features other than telecanthus, but both had congenital diaphragmatic hernia.

Hogue et al. (2010) reported a father and daughter with CFNS and a truncating mutation in the EFNB1 gene (300035). The father displayed hypertelorism and a widow's peak, and had 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 undergone therapeutic abortion of a female fetus with congenital diaphragmatic hernia. Hogue et al. (2010) suggested that CFNS should be considered in patients presenting with congenital diaphragmatic hernia.

Inheritance

Rollnick et al. (1981) presented a pedigree most plausibly interpreted as indicating X-linked inheritance with 'metabolic interference,' a pattern proposed on theoretic grounds by Johnson (1980). Johnson (1980) 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.

Reynolds et al. (1982) reported a 3-generation family in which 4 females and 1 male were affected. The mode of inheritance was unclear.

Young and Moore (1984) suggested that CFNS may be lethal in the male. From a study of 21 unrelated patients with CFNS and their families, Reich et al. (1985) suggested autosomal dominant inheritance based on 2 instances of apparent male-to-male transmission. An excess of females (19:2) remained unexplained, but the fact that 10 of 12 sibs of family-history-positive probands were male appeared to rule against semilethality in males.

In the family reported by Kumar et al. (1986), the trait may have occurred in 6 females of 5 generations. Sax and Flannery (1986) 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.

Kere et al. (1990) described variable expression of craniofrontonasal dysostosis in a 3-generation family. There were 3 severely affected females, 2 of them daughters of apparently healthy parents. Two male relatives, including the father of the 2 affected daughters, had orbital hypertelorism and other minor anomalies. Kere et al. (1990) concluded that the expression of the gene is modified by the sex of the subject.

In connection with the description of 9 patients with CFNS, Kapusta et al. (1992) commented on the unusual pattern of familial occurrence: while affected females apparently transmit the disorder in equal proportions to sons and daughters, they stated that no male-to-male transmission had been documented (Grutzner and Gorlin, 1988). Two affected fathers in their series had an unaffected son. Added to published information, 8 affected males had reproduced, producing 21 females, all affected, and 8 males, all unaffected.

Of 41 patients with CFNS studied in Mexico City between 1979 and 1993, Saavedra et al. (1996) found that 35 were female and 6 were male. Although most cases were sporadic, 7 familial instances were found. They pointed out that male-to-male transmission had not been observed. They stated the opinion that CFNS is an 'incompletely understood X-linked disorder.'

Mapping

Wieland et al. (2002) described a German family with CFNS in which the locus appeared to map to the pericentromeric region of the X chromosome, at Xq12, rather than to Xp22, as had previously been suggested by Feldman et al. (1997) and Muenke et al. (1997) (see below). Wieland et al. (2002) showed random X inactivation in affected females, and favored X-linked inheritance with metabolic interference as the explanation for the pedigree pattern.

Possible Genetic Heterogeneity

McPherson et al. (1991) reported a female with typical CFNS manifested by hypertelorism, slightly bifid nose, turribrachycephaly, sloping shoulders, minor digital anomalies, short stature, and moderate mental retardation who also had a terminal deletion of Xpter-p22.2. The phenotypically normal mother had normal chromosomes. Studying 2 independent cases of CFNS associated with breaks at Xp22, Muenke (1996) identified YACs that crossed the breakpoints.

By linkage analysis of 12 CFNS families, Feldman et al. (1997) and Muenke et al. (1997) mapped the disorder to a 13-cM interval on Xp22 (maximum 2-point lod score of 3.9 at theta = 0.0 for DXS8022; and a multipoint lod score of 5.08 at DXS1224). 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.

Molecular Genetics

In affected members of 3 unrelated families with CFNS, Wieland et al. (2004) identified mutations in the EFNB1 gene (300035.0001-300035.0003).

In 24 affected females from 20 unrelated families with CFNS, Twigg et al. (2004) identified 17 different mutations in the EFNB1 gene (see, e.g., 300035.0004-300035.0007).

Among 38 unrelated patients with CFNS, Wieland et al. (2005) identified 33 different mutations in the EFNB1 gene, including 26 novel mutations. Nine cases were familial, and 29 cases were sporadic.

Wieland et al. (2007) identified mutations in the EFNB1 gene in 10 of 13 patients with CFNS. The 3 remaining patients had contiguous gene deletions involving EFNB1 and the neighboring genes OPHN1 (300127), PJA1 (300420), and EDA (300451).

Wallis et al. (2008) analyzed the EFNB1 gene in 35 unrelated CFNS patients (16 sporadic cases and 19 familial), and identified mutations in 19 patients. The authors stated that 33 (20%) of 129 CFNS cases published to date have no identifiable mutation in the EFNB1 gene and suggested that those cases might involve misdiagnoses, undetected large deletions or rearrangements, or mutations outside the EFNB1 coding region, mosaicism, or additional CFNS loci.

Wieland et al. (2008) showed that cultured fibroblasts derived from female patients with heterozygous EFNB1 mutations expressed both mutant and wildtype EFNB1 and that upon clonal expansion it was possible to separate wildtype and mutant EFNB1-expressing cells in vitro, indicating that they carry 2 distinct cell populations with respect to EFNB1 gene function. 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.

In 6 severely affected males with a diagnosis of CFNS, 2 of whom had previously been reported (Kwee and Lindhout, 1983; Kapusta et al., 1992), Twigg et al. (2013) analyzed multiple tissue samples and identified mosaic mutations in the EFNB1 gene in all 6 patients (see, e.g., 300035.0010-300035.0012), with levels of mutant cells between 15% and 69%. 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. Twigg et al. (2013) noted that these results demonstrated a more severe outcome in mosaic males than in constitutionally deficient males in an X-linked dominant disorder and provided further support for the cellular interference mechanism, which is normally related to X inactivation in females.