Craniofacial features resembling frontonasal dysplasia with a tubulonodular interhemispheric lipoma in the adult 3H1 tuft mouse

Abstract

Intracranial lipomas are rare, but 45% of them occur along the midline cisterns between the hemispheres and are often associated with corpus callosum hypoplasia and craniofacial defects. They are difficult to detect, as they are generally asymptomatic and visible by MRI or by postmortem examination. The exact cause of these interhemispheric lipomas is not known, but they arise from a developmental defect resulting in the maldifferentiation of mesenchymal cells into mesodermal derivatives that are not normally present. We have identified a new mouse mutant called tuft, exhibiting a forebrain, intracranial lipoma with midline craniofacial defects resembling frontonasal dysplasia (FND) that arose spontaneously in our wild-type 3H1 colony. The tuft trait appears to be transmitted in recessive fashion, but approximately 80% less frequent than the expected Mendelian 25%, due to either incomplete penetrance or prenatal lethality. MRI and histological analysis revealed that the intracranial lipoma occurred between the hemispheres and often protruded through the sagittal suture. We also observed a lesion at the lamina terminalis that may indicate improper closure of the anterior neuropore. We have mapped the tuft trait to within an 18 cM region on mouse chromosome 10 by microsatellite linkage analysis and identified several candidate genes involved with craniofacial development and cellular differentiation of adipose tissue. tuft is the only known mouse model for midline craniofacial defects with an intracranial lipoma. Identifying the gene(s) and mutation(s) causing this early developmental defect will help us understand the pathogenesis of FND and related craniofacial disorders.

Midline craniofacial malformations with a lipomatous cephalocele are associated with insufficient closure of the neural tube in the tuft mouse

“…The etiology of FND is thought to be a developmental field defect affecting features along the frontonasal midline during morphogenesis of the facial bones and tissues (DeMeyer, ; Sedano, ; Cohen et al, ; Wu et al, ; Guion‐Almeida and Richieri‐Costa, ). Cephaloceles, cranium bifidum, ocular hypertelorism, a bifid nose, and midfacial cleft are features of FND that were observed in the tuft mouse (Fong et al, ). Consistent with the clinical manifestations of FND, each of these traits in tuft mice did not necessarily occur together in the same animal, nor did they occur to the same degree.…”

“…We have identified a candidate region on mouse Chromosome 10 that contain several loci associated with cellular adhesion (Fong et al, ). Most notably is Alx1, which along with Alx3 and Alx4, were found mutated in humans with FND‐like defects (Kayserili et al, ; Twigg et al, ; Uz et al, ).…”

“…All procedures were carried out in accordance with Institutional Animal Care & Use Committee specifications and performed following protocols approved by the University of Hawai'i Laboratory of Animal Services. Mice strains were housed under standard conditions and bred as previously described (Fong et al, ). Timed matings were determined by noting the presence of a vaginal plug as day 0.5 for staging embryo collections and estimating date of births.…”

“…Whole‐mount staining of newborn skulls with Alcian blue and Alizarin red were previously described (Fong et al, ). Each mouse cranium was observed with a Leitz dissection microscope and digitally documented (Olympus Imaging America Inc., Center Valley, PA).…”

“…We recently described the tuft mouse with heritable craniofacial malformations resembling frontonasal dysplasia (FND) featuring an interhemispheric lipoma. Affected adults exhibited one or more craniofacial malformations that included ocular hypertelorism, frontonasal cleft (bifid nose), shortened and sloping nasal ridge, and a lipomatous extracranial mass emanating from the anterior part of the skull (Fong et al, ). Histological and imaging analysis indicated that the lipomatous mass was an extension of the meninges protruding through an opening along the sagittal suture, usually between the paired frontal bones of the mouse.…”