A novel mutation in theMSX2 gene in a family with foramina parietalia permagna (FPP)

Department of Clinical Genetics, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands.
American Journal of Medical Genetics Part A (Impact Factor: 2.16). 11/2005; 139(1):45-7. DOI: 10.1002/ajmg.a.30923
Source: PubMed
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    • "Given the rarity of this gain of function mutation it is likely that gain of function is only possible through a very limited mutations repertoire within the DNA binding homeodomain. Most described MSX2 mutations are loss of function mutations and the haploinsuffiency phenotype is different, causing parietal foramina [OMIM:168500] [Wilkie et al., 2000; Wuyts et al., 2000; Garcia-Miñaur et al., 2003; Spruijt et al., 2005; Mavrogiannis et al., 2006]. Osteopoikilosis, which is described as a loss of function mutation of the LEMD3 protein, was found only in two members in this family and considered as a coincidental separate anomaly with an apparently de novo mutation in Patient II-1 [Hellemans et al., 2006; Mumm et al., 2007]. "
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    ABSTRACT: We describe a family that segregated an autosomal dominant form of craniosynostosis characterized by variable expression and limited extra-cranial features. Linkage analysis and genome sequencing were performed to identify the underlying genetic mutation. A c.443C>T missense mutation in MSX2, which predicts p.Pro148Leu was identified and segregated with the disease in all affected family members. One other family with autosomal dominant craniosynostosis (Boston type) has been reported to have a missense mutation in MSX2. These data confirm that missense mutations altering the proline at codon 148 of MSX2 cause dominantly inherited craniosynostosis. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 08/2013; 161(10). DOI:10.1002/ajmg.a.36126 · 2.16 Impact Factor
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    ABSTRACT: Enlarged parietal foramina are characteristic symmetric, paired radiolucencies of the parietal bones, located close to the intersection of the sagittal and lambdoid sutures, caused by deficient ossification around the parietal notch that is normally obliterated by the fifth month of fetal development. Enlarged parietal foramina are usually asymptomatic. Meningeal, cortical, and vascular malformations of the posterior fossa occasionally accompany the bone defects and may predispose to epilepsy. In a minority of individuals, headaches, vomiting, or intense local pain are sometimes associated with the defects, especially on application of mild pressure to the unprotected cerebral cortex. Typically oval or round, enlarged parietal foramina resemble a "pair of spectacles" on postero-anterior skull radiographs. They may be less apparent on lateral skull radiographs because the lucencies are projected obliquely through normal bone. In young children, the disorder may present as a persistently enlarged posterior fontanelle caused by a single large central parietal bone defect (cranium bifidum). 3D CT scanning using bone windows clearly reveals the defect. MRI is useful in defining associated intracranial anatomic changes. Molecular genetic testing for MSX2 and ALX4, the two genes known to be associated with enlarged parietal foramina/cranium bifidum, is available clinically. Treatment of manifestations: Treatment is generally conservative. Persistent cranium bifidum may warrant operative closure. Associated headaches or seizures should be treated appropriately. The risk of penetrating injury to the brain is small but may cause anxiety; education of parents, teachers and the affected child to avoid risky behaviors that could result in injury suffices in most circumstances. Agents/circumstances to avoid: Contact sports should be avoided if a midline bony defect persists. Enlarged parietal foramina/cranium bifidum is inherited in an autosomal dominant manner with high, but not complete, penetrance. Most individuals diagnosed with enlarged parietal foramina/cranium bifidum have an affected parent. The proportion of cases caused by de novo mutations appears to be small. Each child of an individual with enlarged parietal foramina/cranium bifidum has a 50% chance of inheriting the mutation. Careful fetal ultrasound examination at 18 to 20 weeks' gestation can usually detect the defects in a fetus at risk. Fetal MRI is also an option. Prenatal diagnosis using molecular genetic testing is possible for families in which the disease-causing mutation has been identified in an affected family member.
    GeneReviews™, Edited by Roberta A Pagon, Thomas D Bird, Cynthia R Dolan, Karen Stephens, Margaret P Adam; University of Washington, Seattle.
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    ABSTRACT: The findings in a newborn male with agenesis of parietal bones, gracile long bones, and hypoplasia of the spleen are presented. Although parietal agenesis is unique, the findings are compatible with 18 previously reported cases characterized by cranial hypomineralization, Kleeblatschädel, gracile bones, and splenic aplasia/hypoplasia, the nomenclature for which has been descriptive: gracile bone disorders, "osteocraniostenosis," "osteocraniosplenic syndrome." The term "osteocraniostenosis" may be inappropriate in that craniostenosis has been infrequently reported, a feature also of importance with respect to the pathogenesis of the Kleeblatschädel. The group likely reflects heterogeneous etiology and pathogenesis. Precedent, however, including animal models, justifies consideration of genetic aberrations, in particular, mutations in homeobox genes. (c) 2006 Wiley-Liss, Inc.
    American Journal of Medical Genetics Part A 11/2006; 140(21):2341-8. DOI:10.1002/ajmg.a.31473 · 2.16 Impact Factor
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