Evaluation of Sporadic and Familial Cases with Craniofrontonasal Syndrome: A Wide Clinical Spectrum and Identification of a Novel <b><i>EFNB1</i></b> Gene Mutation

Abstract

Craniofrontonasal syndrome (CFNS) is a rare X-linked genetic disorder which is characterized by coronal synostosis, widely spaced eyes, a central nasal groove, and various skeletal anomalies. Mutations in the &lt;i&gt;EFNB1&lt;/i&gt; gene in Xq13.1 are responsible for familial and sporadic cases. In the present study, we aimed to evaluate the clinical characteristics and molecular results of 4 patients with CFNS. Genomic DNA was extracted from the peripheral blood lymphocytes of all patients and their parents, and Sanger sequencing of the &lt;i&gt;EFNB1&lt;/i&gt; gene was performed. A novel &lt;i&gt;EFNB1&lt;/i&gt; gene mutation (c.65delG; p.Cys22SerfsTer24) was detected in a newborn who had only dysmorphic facial features and bicornuate uterus. The other 3 patients (2 familial cases and 1 sporadic case) shared the same mutation (c.196C&amp;#x3e;T; p.R66X). However, the clinical features of these patients were highly variable. Additionally, central (meso-axial) polydactyly and deep palmar creases were detected, which have not been previously reported. CFNS has a wide clinical spectrum, but there is no clear genotype-phenotype correlation. However, central (meso-axial) polydactyly and deep palmar creases may be part of the clinical spectrum seen in CFNS. In addition, our findings expand the mutational spectrum in patients with CFNS.

Case report: Craniofrontonasal syndrome caused by a novel variant in the EFNB1 gene in a Colombian woman

“…About 123 variants in the EFNB1 gene, almost all missense, non-sense, and frameshift, have been reported in patients with CFNS ( Bukowska-Olech et al, 2021 ), with the majority of them located at exons 2 and 3 (of the five exons this gene has) that code for the extracellular ephrin domain and thus, affecting the interaction between the ephrin-B1 protein and the Eph receptors ( Darling and Lamb, 2019 ; Gürsoy et al, 2021 ). Accordingly, the variant c.374A>C (p.Glu125Ala) reported in our patient is located at exon 2, changing a polar (glutamic acid) for a non-polar aminoacid (alanine) and probably affecting the receptor-binding domain of the protein, leading to the clinical manifestations described in this proband.…”

“…Typical clinical manifestations in females include coronal synostosis, leading to the characteristic facial asymmetry, wide-set eyes (hypertelorism), bifid nasal tip, longitudinal ridging and splitting of nails, and wiry curly hair ( Van Den Elzen et al, 2014 ). Other reported manifestations are clinodactyly, cutaneous syndactyly, unilateral breast hypoplasia, bilateral cleft lip and palate, depressed nasal bridge, short and wide upper face, skeletal abnormalities, visual complications, umbilical and diaphragmatic hernia, and corpus callosum agenesis or dysgenesis, among others ( Van Den Elzen et al, 2014 ; Inoue et al, 2018 ; Acosta-Fernández et al, 2020 ; Gürsoy et al, 2021 ). Male carriers commonly present only a few mild signs, such as hypertelorism, or no signs at all ( Van Den Elzen et al, 2014 ).…”

“…corpus callosum agenesis or dysgenesis, among others (Van Den Elzen et al, 2014;Inoue et al, 2018;Acosta-Fernández et al, 2020;Gürsoy et al, 2021). Male carriers commonly present only a few mild signs, such as hypertelorism, or no signs at all (Van Den Elzen et al, 2014).…”

No, it is not mutually exclusive! A case report of a girl with two genetic diagnoses: Craniofrontonasal dysplasia and pontocerebellar hypoplasia type 1B

“…Craniofrontonasal dysplasia (CFND) (MIM: 304110) is an X‐linked dominant disorder that shows paradoxically greater severity in heterozygous females compared to hemizygous males. 1 , 2 …”

“…Craniofrontonasal dysplasia (CFND) (MIM: 304110) is an X-linked dominant disorder that shows paradoxically greater severity in heterozygous females compared to hemizygous males. 1,2 Although X-linked disorders typically affect males only or are present in a more severe form in males than females, CFND exclusively affects females. CFNS is identified as a subgroup of frontonasal dysplasia.…”