Craniosynostosis in Alagille syndrome

Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
American Journal of Medical Genetics (Impact Factor: 3.23). 10/2002; 112(2):176-80. DOI: 10.1002/ajmg.10608
Source: PubMed


Alagille syndrome is a multisystem developmental disorder with primary involvement of the liver, heart, skeleton, eyes and facial structures, and demonstrates highly variable expressivity with respect to all of the involved systems. Alagille syndrome is caused by mutations in the Jagged1 gene. Jagged1 is a ligand in the Notch signaling pathway that has been shown to regulate early cell fate determination. Mutations in Jagged1 have been identified in approximately 80% of patients with Alagille syndrome. We have recently identified two patients with mutation proven Alagille syndrome who also had unilateral coronal craniosynostosis. Both individuals were screened for mutations in fibroblast growth factor receptor 1, 2, 3 and TWIST genes, all associated with various types of craniosynostosis and no mutations were identified. The finding of a conserved form of craniosynostosis in two unrelated patients with Alagille syndrome and mutations in Jagged1 may indicate that Jagged1 plays a role in cranial suture formation.

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Available from: Catherine A Stolle, Oct 30, 2014
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    • "Mutation of these genes has been demonstrated in animal models to cause a condition resembling Alagille syndrome that includes abnormal cranial suture formation 29. Mutations of JAG1 have also been reported in Alagille syndrome patients, who have symptoms that are associated with craniosynostosis 30, 31, implicating the Notch signaling pathway in premature cranial suture formation. "
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    ABSTRACT: Craniosynostosis, the premature fusion of one or more skull sutures, occurs in approximately 1 in 2500 infants, with the majority of cases non-syndromic and of unknown etiology. Two common reasons proposed for premature suture fusion are abnormal compression forces on the skull and rare genetic abnormalities. Our goal was to evaluate whether different sub-classes of disease can be identified based on total gene expression profiles. RNA-Seq data were obtained from 31 human osteoblast cultures derived from bone biopsy samples collected between 2009 and 2011, representing 23 craniosynostosis fusions and 8 normal cranial bones or long bones. No differentiation between regions of the skull was detected, but variance component analysis of gene expression patterns nevertheless supports transcriptome-based classification of craniosynostosis. Cluster analysis showed 4 distinct groups of samples; 1 predominantly normal and 3 craniosynostosis subtypes. Similar constellations of sub-types were also observed upon re-analysis of a similar dataset of 199 calvarial osteoblast cultures. Annotation of gene function of differentially expressed transcripts strongly implicates physiological differences with respect to cell cycle and cell death, stromal cell differentiation, extracellular matrix (ECM) components, and ribosomal activity. Based on these results, we propose non-syndromic craniosynostosis cases can be classified by differences in their gene expression patterns and that these may provide targets for future clinical intervention.
    06/2014; 2:121-130. DOI:10.7150/jgen.8833
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    • "Cephalometric evaluation shows a decreased mandibular ramus and a wide gonion. Macrocephaly and craniosynostosis are rarely found [6,17,23]. "
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    ABSTRACT: Alagille syndrome is a rare, autosomal, complex, dominant disorder associated with dysfunction of the liver, heart, skeleton, and eyes, as well as characteristic facial appearance. It is associated with the defect in component of the Notch signalling pathway. Here, we review the main features of Alagille syndrome with special focus on oro-facial manifestations like prominent forehead, moderate hypertelorism with deep-set eyes, a saddle or straight nose with a flattened, bulbous tip, and large ears. The article is based on the most recent and significant literature available from the Medline database. Contrary to healthy children, patients with Alagille syndrome have many problems, depending on several factors like the severity of cholestasis and scarring in the liver, heart or lung problems, presence of infections, or other problems related to poor nutrition that can manifest in their oral cavity in the dental and periodontal tissues, as well as oral mucosa. From the dentist’s view, the most important elements are careful observation, accurate diagnosis, and planned management of such patients, especially during the patient’s formative years, to prevent complications. Aggressive preventive oral care and consultations with medical specialists before any invasive procedure are obligatory. All this can improve quality of life in patients with Alagille syndrome.
    Medical science monitor: international medical journal of experimental and clinical research 03/2014; 20:476-80. DOI:10.12659/MSM.890577 · 1.43 Impact Factor
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    • "Abnormalities were reported in different systemic organs: In the eye, posterior embryotoxon and retinal pigmentary changes were observed; in the heart, pulmonic valvular stenosis as well as peripheral arterial stenosis; in the bones, abnormal vertebrae (“butterfly” vertebrae) and decrease in interpediculate distance in the lumbar spine; in the nervous system, absence of deep tendon reflexes and difficulty learning; in the faces, characteristic traits such as broad forehead, deep-set eyes, prominent nose, pointed mandible and chin, bulbous tip of the nose, and varying degrees of fingers foreshortening.[3] Unilateral coronal craniosynostosis was also reported in two patients with mutation-proven ALGS.[4] No gene mutations associated with craniosynostosis was found, therefore, JAG1gene was suggested to play a possible role in cranial suture formation. "
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    ABSTRACT: This case report describes the surgical-orthodontic guided-eruption of a deeply impacted macrodontic maxillary central incisor in a 10-year-old patient with Alagille syndrome (ALGS). In the first stage, orthodontic treatment with fixed appliance on deciduous teeth allowed to create enough space for the eruption of the maxillary right central incisor. The second stage included closed surgical exposure and vertical traction. After impacted tooth erupted in the proper position, accessory periodontal treatment and dental reshaping procedures may be indicated to camouflage macrodontic incisor with the adjacent teeth. This is the first report that presents a patient with ALGS undergoing orthodontic and surgical treatment.
    Dental research journal 12/2012; 9(Suppl 2):S251-4. DOI:10.4103/1735-3327.109784
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