Extracranial midline defects in a patient with craniofrontonasal syndrome with a novel EFNB1 mutation

Abstract

We report a female patient with craniofrontonasal syndrome (CFNS) who in addition showed other cranial and extracranial midline defects including partial corpus callosum agenesis, ocular melanocytosis, pigmentary glaucoma, duplex collecting system, uterus didelphys, and septate vagina. She was found to have a novel pathogenic variant in exon 5 of EFNB1, c.646G>T (p.Glu216*) predicted to cause premature protein truncation. From our review, we found at least 39 published CFNS patients with extracranial midline defects, comprising congenital diaphragmatic hernia, congenital heart defects, umbilical hernia, hypospadias, and less frequently, sacrococcygeal teratomas, and internal genital anomalies in females. These findings support that the EFNB1 mutations have systemic consequences disrupting morphogenetic events at the extracranial midline. Though these are not rigorously included as midline defects, we found at least 10 CFNS patients with congenital anomalies of the kidney and urinary tract, all females. Additionally, uterus didelphys and ocular melanocytosis observed in our patient are proposed also as a previously unreported EFNB1-related midline defects. In addition, this case may be useful for considering the intentional search for genitourinary anomalies in future patients with CFNS, which will be helpful to define their frequency in this entity. K E Y W O R D S duplex collecting system, EFNB1, glaucoma, ocular melanocytosis, septate vagina, uterus didelphys

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

“…Additionally, extracranial midline defects such as internal genitalial abnormalities, including duplication of the uterus, bicornuate uterus, uterus arcuatus, uterus didelphys, and septate uterus, have been previously reported in females with CFNS. These abnormalities are usually detected in patients with mensturation problems and may be associated with an increased incidence of miscarriages [Acosta-Fernández et al, 2020]. In the present report, patient 4 also had bicornuate uterus which arises when there is partial nonfusion of the müllerian ducts at the level of the fundus [Narang et al, 2019].…”

“…The main characteristic features of CFNS include severe, often asymmetric hypertelorism, a short and wide upper face, a central nasal groove, craniofacial asymmetry, uni-or bicoronal craniosynostosis, sloping shoulders, ridging and longitudinal splitting of the nails, mild cutaneous syndactyly, duplication of the first digit, and wiry curly hair. Additionally, corpus callosum agenesis or dysgenesis, cleft lip and palate, umbilical and diaphragmatic hernia have been noted [Fischer et al, 2016;Acosta-Fernández et al, 2020]. Interestingly, CFNS presents paradoxically with heterozygous females more severely affected than hemizygous males.…”

Trio-Based Whole-Exome Sequencing Identifies a De novo EFNB1 Mutation as a Genetic Cause in Female Infant With Brain Anomaly and Developmental Delay

“…Craniosynostosis comprises a heterogeneous group of disorders correspondingly, in addition to monogenic causes, with reduced transduction of stretch forces from the growing brain due to poor intrinsic growth, intrauterine fetal head constraint, and polygenic background all likely to play substantial roles ( 7 ). Occasionally, extracranial manifestations include asymmetry of the pectoralis, breast, limbs, or thoracic skeleton; clinodactyly of the fifth finger, polydactylism, and diaphragmatic hernia are seen ( 8 – 12 ). Developmental delay or intellectual disability is not usually present ( 13 – 15 ).…”

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

“…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).…”