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

Am J Med Genet A. 2020 May;182(5):1223-1229. doi: 10.1002/ajmg.a.61506. Epub 2020 Feb 5.


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.

Keywords: EFNB1; uterus didelphys; duplex collecting system; glaucoma; ocular melanocytosis; septate vagina.

Publication types

  • Case Reports

MeSH terms

  • Agenesis of Corpus Callosum / diagnostic imaging
  • Agenesis of Corpus Callosum / genetics*
  • Agenesis of Corpus Callosum / pathology
  • Child
  • Child, Preschool
  • Craniofacial Abnormalities / diagnostic imaging
  • Craniofacial Abnormalities / genetics*
  • Craniofacial Abnormalities / pathology
  • Ephrin-B1 / genetics*
  • Exons / genetics
  • Female
  • Hernias, Diaphragmatic, Congenital / diagnostic imaging
  • Hernias, Diaphragmatic, Congenital / genetics*
  • Hernias, Diaphragmatic, Congenital / pathology
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Mutation / genetics
  • Skull / diagnostic imaging
  • Skull / pathology


  • EFNB1 protein, human
  • Ephrin-B1

Supplementary concepts

  • Craniofrontonasal dysplasia