Syndromic Craniosynostosis Can Define New Candidate Genes for Suture Development or Result from the Non-specifc Effects of Pleiotropic Genes: Rasopathies and Chromatinopathies as Examples.

Marcella Zollino,Giuseppe Marangi,Eugenio Mercuri,Serena Lattante,Daniela Orteschi,Silvia Frangella,Paolo N Doronzio,Ilaria Contaldo

doi:10.3389/fnins.2017.00587

Abstract

Craniosynostosis is a heterogeneous condition caused by the premature fusion of cranial sutures, occurring mostly as an isolated anomaly. Pathogenesis of non-syndromic forms of craniosynostosis is largely unknown. In about 15–30% of cases craniosynostosis occurs in association with other physical anomalies and it is referred to as syndromic craniosynostosis. Syndromic forms of craniosynostosis arise from mutations in genes belonging to the Fibroblast Growth Factor Receptor (FGFR) family and the interconnected molecular pathways in most cases. However it can occur in association with other gene variants and with a variety of chromosome abnormalities as well, usually in association with intellectual disability (ID) and additional physical anomalies. Evaluating the molecular properties of the genes undergoing intragenic mutations or copy number variations (CNVs) along with prevalence of craniosynostosis in different conditions and animal models if available, we made an attempt to define two distinct groups of unusual syndromic craniosynostosis, which can reflect direct effects of emerging new candidate genes with roles in suture homeostasis or a non-specific phenotypic manifestation of pleiotropic genes, respectively. RASopathies and 9p23p22.3 deletions are reviewed as examples of conditions in the first group. In particular, we found that craniosynostosis is a relatively common component manifestation of cardio-facio-cutaneous (CFC) syndrome. Chromatinopathies and neurocristopathies are presented as examples of conditions in the second group. We observed that craniosynostosis is uncommon on average in these conditions. It was randomly associated with Kabuki, Koolen-de Vries/KANSL1 haploinsufficiency and Mowat–Wilson syndromes and in KAT6B-related disorders. As an exception, trigonocephaly in Bohring-Opitz syndrome reflects specific molecular properties of the chromatin modifier ASXL1 gene. Surveillance for craniosynostosis in syndromic forms of intellectual disability, as well as ascertainment of genomic CNVs by array-CGH in apparently non-syndromic craniosynostosis is recommended, to allow for improvement of both the clinical outcome of patients and the accurate individual diagnosis.

Highlights

The premature fusion of cranial sutures affects ∼1 in 2,500 newborns in a condition known as craniosynostosis (Cohen and MacLean, 2000; Boulet et al, 2008)
In about 15–30% of cases craniosynostosis occurs in association with other physical anomalies, as a consequence of variable gene variants and different chromosome abnormalities and they are referred to as syndromic craniosynostosis
Most cases arise from disruption of the morphogenic events regulated by the FGFR family proteins and their interconnected signaling pathways

Summary

INTRODUCTION

The premature fusion of cranial sutures affects ∼1 in 2,500 newborns in a condition known as craniosynostosis (Cohen and MacLean, 2000; Boulet et al, 2008). One can speculate that the final phenotype in individual patients can reflect balance disruption of the different compartments of the epigenetic machinery (Paro, 1995), and the molecular constitution of the target genes (Law et al, 2010) All these reasons can likely account for the usually low frequency of craniosynostosis in chromatinopathies and for its association with specific conditions as well. KANSL1 is capable of acetylating nonhistone substrates, namely p53 protein on lysine 120, and KANSL1 is essential for the transcription of p53 target genes (Huang et al, 2012) We recently characterized both clinically and genetically a cohort of 32 patients with KANSL1 haploinsufficiency syndrome, of whom 27 had a 17q21.31 deletion, and 5 an intragenic KANSL1 mutation (Zollino et al, 2015). The heterogeneous basic genomic defect consists in chromosome 2q21-q23 deletions in a few patients, and in variable loss-of-function intragenic

Cardiofaciocutaneous syndrome or Noonan syndrome

Kabuki syndrome

Findings

CONCLUDING REMARKS