A Novel De Novo EFNB1 Gene Mutation in a Mexican Patient with Craniofrontonasal Syndrome

Craniofrontonasal syndrome (CNFS) is an X-linked disorder caused by mutations in the EFNB1 gene in which, paradoxically, heterozygous females are more severely affected than hemizygous males. In this paper, the clinical and molecular studies of a female subject with CFNS are described. A novel de novo c.473T>C (p.M158T) mutation in exon 3 of EFNB1 was demonstrated in this patient. The M158 residue of the Ephrin-B1 protein is highly conserved between species. Our results expand the mutational spectrum exposed by CNFS. 1. Introduction Craniofrontonasal syndrome (CFNS; OMIM # 304110) [1] is an X-linked syndrome involving developmental malformation with variable clinical expression characterized by severe hypertelorism, depressed nasal bridge and bifid nasal tip, frontal bossing, coronal suture synostosis, corpus callosum agenesis, and occasionally cleft lip or palate [2–4]. This disorder is caused by mutations in the EFNB1 gene, located at Xq13.1, and encoding a ligand of the Ephrin family of receptor protein tyrosine kinases [3]. The most common types of EFNB1 mutations (up to 55%) in CFNS patients are frameshift, nonsense, and splice site mutations that lead to premature termination codons (PTCs). Missense mutations constitute approximately 42% of all EFNB1 mutations, and most of them occur in exons 2 and 3, leading to the substitutions of amino acid residues involved in receptor-ligand interaction and cell signaling, which are critical for cell sorting, migration and adhesion, midline fusion, axon guidance, neural plasticity, and synaptogenesis [5–8]. Here, we describe a sporadic case of CFNS due to a novel EFNB1 mutation occurring in a female Mexican patient. 2. Case Presentation A 3-month-old girl was referred to the Genetics Department after a frontoorbital advancement surgery due to right unicoronal synostosis and facial dysmorphism. She is the only child of healthy, nonconsanguineous parents. There was no prenatal exposure to teratogenic agents. A structural ultrasound at 24 weeks revealed a nonspecific cranial malformation. The patient was delivered by caesarean section at 38 weeks of pregnancy and had a birth weight of 2,700？g, birth length of 48.5？cm, and an Apgar score of . Birth examination disclosed plagiocephaly (left frontal bossing and right coronal synostosis), hypertelorism, downslanting palpebral fissures, facial asymmetry, a broad and flattened nasal bridge, a bifid nasal tip, and broad thumbs and halluces with longitudinally split nails (Figure 1). No abnormalities were found in the transfontanellar ultrasound and echocardiogram