P-05

Craniofrontonasal syndrome: case report

Gabriela Soares^I; Natália Tkachenko^I; Ana Maria Fortuna^I,II

^IUnidade de Genética Médica, Centro Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto E.P.E., Porto, Portugal
^IIUnidade Multidisciplinar de Investigação Biomédica, ICBAS-UP

gabriela.soares@chporto.min-saude.pt

Background: Craniofrontonasal syndrome (CFNS, MIM #304110) is a very rare X-linked developmental malformation, caused by mutations in the EFNB1 gene, located at Xq13.1.It was first identified as a subgroup of frontonasal dysplasia by Cohen in 1979. The incidence values that were reported ranged from 1:100.000 to 1:120.000. Heterozygous females have craniofrontonasal dysplasia (CFND) and occasionally extracranial manifestations including midline defects and skeletal abnormalities, whereas hemizygous males show no or only mild features such as hypertelorism and rarely show cleft lip or palate.

Methods: Following first description of the syndrome, approximately 180 additional cases have been published in medical literature. We report here on an additional case of a Portuguese girl with CFNS. We compared the clinical features of the previously published cases of craniofrontonasal syndrome with our case.

Results: Common findings in all reports, including our case, are coronal craniosynostosis, craniofacial asymmetry, hypertelorism, downslanting palpebral fissures, broad bifid nose, malocclusion and longitudinally grooved fingernails. Craniofrontonasal syndrome was confirmed in this patient by molecular analysis of EFBN1 gene which was excluded in her father.

Discussion: CFNS shows a phenotypic pattern not usually seen in X-linked disorders, as heterozygous females are more severely affected than hemizygous males. Mutations in EFNB1 are the cause of CFNS in the majority of patients, with a mutation detection rate of 92%. CNFS ’s clinical manifestations are sex dependent, with multiple skeletal malformations in affected females and mild or no malformations in male carriers. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EFNB1, generating abnormal tissue boundaries — a process that cannot occur in hemizygous males. Our report discusses a patient with clinical characteristics consistent with CNFS and in whom a de novo EFNB1 mutation was demonstrated. Postzygotic mutation leading to somatic/germline mosaicism in the first generation is a relatively common feature of this condition and could not be excluded in the father, who had mild hypertelorism. This issue and its implications in recurrence risk were discussed with the couple.