Craniofrontonasal dysplasia in two male sibs

Phenotypes of craniofrontonasal syndrome in patients with a pathogenic mutation in EFNB1

“…Normal boundaries are probably maintained through an alternative mechanism, 25 which could be via an ephrin redundancy 25 and promiscuity of the ephrin ligand/ receptor system. 10 An explanation for the few severely affected males reported in literature [6][7][8]32 could be a mosaicism in these patients, in which the wild type to mutant ratio should be similar to that in heterozygous CFNS females. 23,26,33 Additional mechanisms were recently added to the phenotypic manifestation.…”

“…1 Subsequently, many other studies have focused on the manifestation of this syndrome. Most commonly depicted phenotypic features were coronal synostosis, [1][2][3][4][5][6][7][8][9][10][11] hypertelorism, 1,4-14 bifid nasal tip, 1,4,5,[8][9][10]12,13 frizzy and curly hair [8][9][10][11]15 and longitudinal ridging and splitting of nails. 3,4,6,8,9,[11][12][13] It became clear that the majority of CFNS patients were female.…”

“…A genetic basis was likely, because families with multiple affected members were reported. [2][3][4][6][7][8][9]12 However, there seemed to be a genetic paradox, as all daughters of affected males displayed severe signs of CFNS, but no male-to-male transmission was seen and affected males portrayed only mild or no signs. Therefore, multiple modes for inheritance were proposed; germline mosaicism, autosomal dominant with sex-influenced expression, X-linked dominant and metabolic interference.…”

“…Therefore, multiple modes for inheritance were proposed; germline mosaicism, autosomal dominant with sex-influenced expression, X-linked dominant and metabolic interference. [2][3][4][6][7][8][9] The mystery was unraveled by a combination of results of multiple studies. [16][17][18] The disease locus was finally claimed to be within Xq13.1 and loss of function mutations in EFNB1 were proven to cause CFNS.…”

“…25 Studies following the discovery of the causal gene predominantly describe the location of new mutations, combined with a brief outline of phenotypic features of small families or cohorts. [18][19][20]22,27,29,30 Detailed overviews of phenotypic features of large cohorts of possible CFNS patients do exist, 3,4,[6][7][8][9][10]12,30 but it is not clear what proportion of these patients carry an EFNB1 mutation. The reports in the older literature could therefore cause confusion by reporting patients who might be improperly classified as CFNS patients.…”