Prominent basal emissary foramina in syndromic craniosynostosis: correlation with phenotypic and molecular diagnoses.
(9/135)BACKGROUND AND PURPOSE: Jugular foraminal stenosis (JFS) or atresia (JFA) with collateral emissary veins (EV) has been documented in syndromic craniosynostosis. Disruption of EV during surgery can produce massive hemorrhage. Our purpose was to describe the prevalence of prominent basal emissary foramina (EF), which transmit enlarged EV, in syndromic craniosynostosis. Our findings were correlated with phenotypic and molecular diagnoses. METHODS: We reviewed the medical records and imaging examinations of 33 patients with syndromic craniosynostosis and known fibroblast growth factor receptor (FGFR) mutations. All patients underwent CT and 14 MR imaging. The cranial base was assessed for size of occipitomastoid EF and jugular foramina (JF). Vascular imaging studies were available from 12 patients. A control group (n = 76) was used to establish normal size criteria for JF and EF. RESULTS: Phenotypic classification included Crouzon syndrome (n = 10), crouzonoid features with acanthosis nigricans (n = 3), Apert syndrome (n = 10), Pfeiffer syndrome (n = 4), and clinically unclassifiable bilateral coronal synostosis (n = 6). EF > or = 3 mm in diameter and JFS or JFA were identified in 23 patients with various molecular diagnoses. Vascular imaging in patients with JFS or JFA and enlarged EF revealed atresia or stenosis of the jugular veins and enlarged basal EV. JFA was seen in all patients with the FGFR3 mutation with crouzonoid features and acanthosis nigricans. Four patients had prominent EF without JFS. Six patients had normal JF and lacked enlarged EF. CONCLUSION: Enlarged basal EF are common in syndromic craniosynostosis and are usually associated with JFS or JFA. Bilateral basilar venous atresia is most common in patients with the FGFR3 ala391glu mutation and crouzonoid features with acanthosis nigricans, but may be found in patients with FGFR2 mutations. Skull base vascular imaging should be obtained in patients with syndromic craniosynostosis with enlarged EF. (+info)
Role of the extracellular matrix and growth factors in skull morphogenesis and in the pathogenesis of craniosynostosis.
(10/135)The complex and largely obscure regulatory processes that underlie ossification and fusion of the sutures during skull morphogenesis are dependent on the conditions of the extracellular microenvironment. The concept that growth factors are involved in the pathophysiology of craniosynostosis due to premature fusion of skull bone sutures, is supported by recent genetic data. Crouzon and Apert syndromes, for example, are characterized by point mutations in the extracellular or transmembrane domains of fibroblast growth factor-2 receptor. In primary cultures of periosteal fibroblasts and osteoblasts obtained from Apert and Crouzon patients, we observed that Crouzon and Apert cells behaved differently with respect to normal cells as regards the expression of cytokines and extracellular matrix (ECM) macromolecule accumulation. Further modulation of ECM components observed after the addition of cytokines provides support for an autocrine involvement of these cytokines in Crouzon and Apert phenotype. Changes in ECM composition could explain the altered osteogenic process and account for pathological variations in cranial development. We suggest that a correlation exists between in vitro phenotype, clinical features and genotype in the two craniosynostotic syndromes. New research into signal transduction pathways should establish further connections between the mutated genotype and the molecular biology of the cellular phenotype. (+info)
Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome.
(11/135)Craniosynostosis syndromes are autosomal dominant human skeletal diseases that result from various mutations in fibroblast growth factor receptor genes (Fgfrs). Apert syndrome (AS) is one of the most severe craniosynostosis syndromes and is associated with severe syndactyly of the hands and feet and with central nervous system malformations. AS is caused by specific missense mutations in one of two adjacent amino acid residues (S252W or P253R) in the highly conserved region linking Ig-like domains II and III of FGFR2. Here we demonstrate that these mutations break one of the cardinal rules governing ligand specificity of FGFR2. We show that the S252W mutation allows the mesenchymal splice form of FGFR2 (FGFR2c) to bind and to be activated by the mesenchymally expressed ligands FGF7 or FGF10 and the epithelial splice form of FGFR2 (FGFR2b) to be activated by FGF2, FGF6, and FGF9. These data demonstrate loss of ligand specificity of FGFR2 with retained ligand dependence for receptor activation. These data suggest that the severe phenotypes of AS likely result from ectopic ligand-dependent activation of FGFR2. (+info)
Using three-dimensional ultrasound to detect craniosynostosis in a fetus with Pfeiffer syndrome.
(12/135)A case of fetal Pfeiffer's syndrome is presented, showing the contribution of three dimensional (3D) sonography in the diagnosis of craniosynostosis--a major feature of this syndrome. (+info)
Hunterian Lecture. What can we learn about mechanisms of mutation from a study of craniosynostosis?
(13/135)Mutation may be defined simply as structural change affecting the genetic material. The generation of genetic variety by spontaneous mutational events has been the driving force behind evolution--without such mutation our complex human genome could not have evolved. However, as doctors, we more frequently encounter mutation in the context of human disease, whether in somatic cells as a cause of cancer, or in the germline as a cause of inheritable disease. In these contexts, the processes of mutagenesis are relevant to every field of medicine. Scientific study of mutational mechanisms has logically been founded in the relatively simple genetic systems of the prokaryotes and such lowly eukaryotes as the fruit-fly. The study of human clinical genetics approaches the problem from quite the opposite direction--from that of the most highly evolved genetic system. Whilst this approach may be dependent less on logical progression and more on phenomenology, it nevertheless provides a complementary avenue for the observation and study of mutational mechanisms. The genetic research described in this article is firmly rooted in such phenomenology, based as it is on rare craniosynostosis syndromes. Over the past decade, there has been a deluge of molecular discoveries in the field of craniosynostosis. This promises improvements in classification, prognostication, pre-natal diagnosis, and perhaps ultimately for potential avenues for cure. However, exciting as these clinical prospects are, the research presented here has a different focus: it investigates the mechanistic basis underlying the craniosynostosis mutations, in the hope that such study may lead to insights applicable generally to the field of mutagenesis. (+info)
Mutations in the basic domain and the loop-helix II junction of TWIST abolish DNA binding in Saethre-Chotzen syndrome.
(14/135)Saethre-Chotzen syndrome is an autosomal dominant skull disorder resulting from premature fusion of coronal sutures (craniosynostosis). It is caused by mutations in the TWIST gene encoding a basic Helix-Loop-Helix transcription factor. Here we report on the identification of a novel mutation affecting a highly conserved residue of the basic domain. Unlike nonsense and missense mutations lying within helices, this mutation does not affect protein stability or heterodimerisation of TWIST with its partner E12. However, it does abolish TWIST binding capacity to a target E-box as efficiently as two missense mutations in the loop-helix II junction. By contrast, elongation of the loop through a 7 amino acid insertion appears not to hamper binding to the DNA target. We conclude that loss of TWIST protein function in Saethre-Chotzen patients can occur at three different levels, namely protein stability, dimerisation, and DNA binding and that the loop-helix II junction is essential for effective protein-DNA interaction. (+info)
A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes.
(15/135)Intercellular signaling by fibroblast growth factors plays vital roles during embryogenesis. Mice deficient for fibroblast growth factor receptors (FgfRs) show abnormalities in early gastrulation and implantation, disruptions in epithelial-mesenchymal interactions, as well as profound defects in membranous and endochondrial bone formation. Activating FGFR mutations are the underlying cause of several craniosynostoses and dwarfism syndromes in humans. Here we show that a heterozygotic abrogation of FgfR2-exon 9 (IIIc) in mice causes a splicing switch, resulting in a gain-of-function mutation. The consequences are neonatal growth retardation and death, coronal synostosis, ocular proptosis, precocious sternal fusion, and abnormalities in secondary branching in several organs that undergo branching morphogenesis. This phenotype has strong parallels to some Apert's and Pfeiffer's syndrome patients. (+info)
Surgical treatment of chronic papilloedema in children.
(16/135)A surgical technique for optic nerve decompression in children is described and contrasted with other techniques described in the literature. The operation was effective in relieving long-standing disc oedema in two cases in which the swelling was due to raised intracranial pressure. Photographic evidence is presented. The indications for surgery and how its effect is exerted are discussed. (+info)