Molecular Genetics of Craniosynostosis

Abstract

Craniosynostosis (CS) is a relatively prevalent congenital malformation, due to the premature ossification of calvarial sutures that articulate skull bones, leading to a variable alteration of craniofacial landmarks and shape. CS is extremely heterogeneous in both clinical and a etiological aspects. It occurs as an isolated defect (i.e. nonsyndromic) in most cases, while it is syndromic in less than one fourth of cases. A genetic aetiology (i.e. mutations in FGFR , TWIST1 , EFNB1 , MSX , and ERF genes, among others) is known for most syndromes. Recent studies helped clarifying the genetic basis of new CS syndromes and nonsyndromic forms. The discovery of new genes (including RUNX2 , ALX4 , TCF12 and ZIC1 ) enabled deciphering the complex signalling network that orchestrates craniofacial development. In this light, the entire CS disease spectrum can be regarded as a nosological continuum, with variable degree of severity, in which a strong genetic component provides the background for environmental factors that contribute to the aetiopathogenesis of the birth defect. Key Concepts Craniosynostosis is a frequent congenital defect with a high degree of clinical and genetic heterogeneity. Nonsyndromic forms are more frequent, although their aetiology is still poorly understood. Many developmental syndromes include craniosynostosis in their phenotype. Different closely interacting genes ( FGFR , TWIST1 , MSX2 , ERF , TCF12 , among others) are involved in the molecular genetics of the best characterised and more frequent syndromic craniosynostoses. Most genes involved in the etiopathogenesis of craniosynostosis interact within a common gene network.

Brivaracetam add-on therapy for drug-resistant epilepsy

“…The findings of our current review are consistent with the observations made in other systematic reviews, which similarly assessed the e icacy and tolerability of brivaracetam (Lattanzi 2016;Ma 2015; Tian 2015). These other systematic reviews likewise reported risk ratios for both the 50% responder rate and the seizure freedom rate.…”

“…As observed here, in two of the reviews, the risk ratio for seizure freedom demonstrated an especially large e ect for brivaracetam compared to placebo (Lattanzi 2016;Ma 2015). One review also completed a subgroup analysis according to dosage, and reported that any dose above 5 mg/d was associated with a significant therapeutic e ect.…”

Genetic advances in craniosynostosis

“…In recent years, converging evidence suggests a stronger influence of genetic factors in the etiopathogenesis of NCS thanks to genome-wide analyses aimed at identifying new mutations and disease-associated loci in large patient cohorts. The complete list of genetic syndromes with a CS phenotype currently includes around 170 entries in the OMIM database (http://www.ncbi.nlm.nih.gov/omim/?term=craniosynostosis) [Heuzé et al, 2014; Twigg and Wilkie, 2015a; Lattanzi, 2016]. …”

Schizophrenia and Human Self-Domestication: An Evolutionary Linguistics Approach

“…GLI3 is implicated in a craniofacial syndrome involving cognitive impairment both in humans (Greig cephalopolisyndactily, OMIM #175700) and in mice [Veis tinen et al, 2012;Tabler et al, 2016;Lattanzi et al, 2017] with cognitive impairment, which entails language delay [McDonald-McGinn et al, 2010;Lattanzi, 2016]. Indeed, it regulates skull development acting on the DLX5/RUNX2 cascade , and hence it is expected to have played a role in the physiological events leading to globularization, in which these genes were seemingly involved [Boeckx and Benítez-Burraco, 2014a]; nearly 98% of Altaic Neanderthals and Denisovans gained a nonsynonymous change in GLI3 that is described as mildly disruptive [Castellano et al, 2014].…”