Craniofrontonasal dysplasia

Abstract

We report on nine patients with craniofrontonasal dysplasia (CFND). Seven classical cases had facial features suggestive of frontonasal dysplasia and coronal craniosynostosis. Extracranial abnormalities such as brittle nails with prominent longitudinal grooves or syndactyly of fingers and toes were observed in individual patients. In two families the father of classical cases showed a milder pattern of abnormalities, consistent with the diagnosis. We present a 2- to 13-year follow-up on our patients. Hypotonia and laxity of joints are common and may necessitate supportive measures. Mild developmental delay was noted in three out of six classical cases studied in detail. Unlike almost all other X-linked disorders, clinical expression in CFND is generally much more severe in females than in males. In contrast to previous reports of this condition, one of our severely affected cases is a male.

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.…”

“…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. In addition, the female patients appeared to be affected more severely than male carriers, who showed only few mild signs or no clear features at all.…”

“…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.…”