David Chesler1, Richard Bram2, Prince Antwi3, Andrew T Timberlake4, Michael L DiLuna5, Kristopher T Kahle6. 1. Departments of Neurological Surgery and Pediatrics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8122, USA. david.chesler@stonybrookmedicine.edu. 2. Departments of Neurological Surgery and Pediatrics, Stony Brook University School of Medicine, Stony Brook, NY, 11794-8122, USA. 3. Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. 4. Departments of Genetics and Surgery, Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, USA. 5. Department of Neurosurgery and Pediatrics, Yale University School of Medicine, New Haven, CT, USA. 6. Department of Neurosurgery and Pediatrics, Yale University School of Medicine, New Haven, CT, USA. kristopher.kahle@yale.edu.
Abstract
INTRODUCTION: Craniosynostosis is the premature fusion of one or more cranial sutures. The cause of non-syndromic craniosynostosis has been attributed to a complex interaction among genetic, epigenetic, and environmental factors. Increased concordance rates in monozygotic twins support a genetic etiology while a concordance rate less than 100% suggests environmental and/or epigenetic influences. Here, we describe the first reported occurrence of all three children in a triplet set with non-syndromic single-suture craniosynostosis. CASE REPORT: The dichorionic triamniotic triplets were the product of a non-consanguineous marriage delivered at 35 weeks' gestation by a 38-year-old mother and consisted of a monochorionic-diamniotic pair (A and B) and a fraternal triplet (C). Three-dimensional computed tomography scans confirmed sagittal synostosis in A and B and metopic synostosis in C. All patients underwent endoscopic strip craniectomy and were discharged on the second postoperative day with helmet orthoses. Comparative genetic hybridization (CGH) and whole-exome sequencing (WES) failed to identify pathogenic copy number variants or gene mutations, respectively. DISCUSSION AND CONCLUSION: The results of the genetic testing suggest the possibility of a rare variant contributing to the risk of midline craniosynostosis shared among the triplets, with potential modifiers at other genetic loci affecting the phenotype. We speculate mutations at loci within non-coding regions not captured by our genetic analysis may have been involved. Moreover, epigenetic factors as well as environmental factors including, but not limited to, in utero head constraint could have contributed to the observed phenotype.
INTRODUCTION:Craniosynostosis is the premature fusion of one or more cranial sutures. The cause of non-syndromic craniosynostosis has been attributed to a complex interaction among genetic, epigenetic, and environmental factors. Increased concordance rates in monozygotic twins support a genetic etiology while a concordance rate less than 100% suggests environmental and/or epigenetic influences. Here, we describe the first reported occurrence of all three children in a triplet set with non-syndromic single-suture craniosynostosis. CASE REPORT: The dichorionic triamniotic triplets were the product of a non-consanguineous marriage delivered at 35 weeks' gestation by a 38-year-old mother and consisted of a monochorionic-diamniotic pair (A and B) and a fraternal triplet (C). Three-dimensional computed tomography scans confirmed sagittal synostosis in A and B and metopic synostosis in C. All patients underwent endoscopic strip craniectomy and were discharged on the second postoperative day with helmet orthoses. Comparative genetic hybridization (CGH) and whole-exome sequencing (WES) failed to identify pathogenic copy number variants or gene mutations, respectively. DISCUSSION AND CONCLUSION: The results of the genetic testing suggest the possibility of a rare variant contributing to the risk of midline craniosynostosis shared among the triplets, with potential modifiers at other genetic loci affecting the phenotype. We speculate mutations at loci within non-coding regions not captured by our genetic analysis may have been involved. Moreover, epigenetic factors as well as environmental factors including, but not limited to, in utero head constraint could have contributed to the observed phenotype.
Authors: Andrew T Timberlake; Charuta G Furey; Jungmin Choi; Carol Nelson-Williams; Erin Loring; Amy Galm; Kristopher T Kahle; Derek M Steinbacher; Dawid Larysz; John A Persing; Richard P Lifton Journal: Proc Natl Acad Sci U S A Date: 2017-08-14 Impact factor: 11.205
Authors: Cristina M Justice; Jinoh Kim; Sun-Don Kim; Kyunhgho Kim; Garima Yagnik; Araceli Cuellar; Blake Carrington; Chung-Ling Lu; Raman Sood; Simeon A Boyadjiev; Alexander F Wilson Journal: Am J Med Genet A Date: 2017-10-06 Impact factor: 2.802
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