Features of Alagille Syndrome in 92 Patients: Frequency and Relation to Prognosis

Emerick, Karan; Rand, Elizabeth B.; Goldmuntz, Elizabeth; Krantz, Ian D.; Spinner, Nancy B.; Piccoli, David A.

doi:10.1002/hep.510290331

Cited by 595 publications

(745 citation statements)

References 50 publications

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“…However there are previous reports indicating that mutations in the FGF pathway can cause clinical manifestations which have overlap with AGS. Ocular manifestations are a consistent finding in AGS [Emerick et al, 1999]. The predominant abnormalities are anterior chamber defects (posterior embryotoxon or Axenfeld anomaly) [Puklin et al, 1981].…”

Section: Discussionmentioning

confidence: 69%

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Craniosynostosis in Alagille syndrome

et al. 2002

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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. © 2002 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 69%

“…Abnormalities of the skeletal system have been well documented in AGS [Rosenfield et al, 1980]. Butterfly vertebrae are the most common bony abnormality described and are seen in approximately 50% of individuals with AGS [Emerick et al, 1999]. This is the first report of craniosynostosis in individuals with AGS.…”

Section: Introductionmentioning

confidence: 76%

Craniosynostosis in Alagille syndrome

et al. 2002

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“…Congenital heart disease is present in a large proportion of patients, and the pulmonary vasculature is most commonly involved. Thus, pulmonary valve or pulmonary artery stenosis, and peripheral pulmonary artery stenosis, are the common lesions, occurring in two thirds of AGS patients (Emerick et al, 1999). However, tetralogy of Fallot is a complex malformation that occurs in up to 10% of patients, and ventricular and atrial septal defects are also seen (Alagille et al, 1975;Kamath et al, 2003).…”

Section: Alagille Syndrome (Arteriohepatic Dysplasia) Jagged1 and Nomentioning

confidence: 99%

“…Interestingly, one family has been reported in which congenital heart disease segregates with a JAGGED1 mutation in the absence of hepatic or other features of AGS (Eldadah et al, 2001). AGS patients with complex congenital heart disease have a poorer prognosis compared with patients with similar congenital heart defects without AGS (Emerick et al, 1999), the reasons for which are not fully understood.…”

Section: Alagille Syndrome (Arteriohepatic Dysplasia) Jagged1 and Nomentioning

confidence: 99%

Abnormal vertebral segmentation and the notch signaling pathway in man

Turnpenny

Alman

Cornier

et al. 2007

Developmental Dynamics

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Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes-DLL3, MESP2, and LNFG-have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing.

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“…Alagille et al [1975] defined clinical criteria for the syndrome as the histological finding of bile duct paucity on liver biopsy in association with three out of the following five major clinical features: cholestasis, butterfly vertebrae, posterior embryotoxon, congenital heart disease, and facial features. Other systems are also involved in AGS and these minor clinical criteria include renal abnormalities and intracranial bleeding [Emerick et al, 1999]. Jagged1 (JAG1) has been identified as the disease gene in AGS [Li et al, 1997].…”

Section: Introductionmentioning

confidence: 99%

Supernumerary digital flexion creases: An additional clinical manifestation of Alagille syndrome

et al. 2002

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Alagille syndrome (AGS; OMIM 118450) is a complex dominantly inherited multisystem disorder involving the liver, heart, eyes, facies, skeleton, and other systems. Criteria for the clinical diagnosis have been established as the presence of bile duct paucity on liver biopsy in association with three of five major clinical findings (cholestasis, butterfly vertebrae, posterior embryotoxon, congenital heart disease, and facial features). Jagged1 has been identified as the AGS disease gene. Jagged1 is a large gene, with no mutational hot spots, making molecular testing difficult at this time. Other clinical features would prove helpful in establishing the diagnosis in the absence of molecular confirmation. Supernumerary digital flexion creases have been identified in 16/46 (35%) of AGS probands examined through the Alagille Syndrome Diagnostic Center at the Children's Hospital of Philadelphia. Although digital abnormalities have been noted in AGS in the past, including short distal phalanges and fifth finger clinodactyly, digital crease abnormalities have never before been reported. Supernumerary digital creases have been reported in less than 1% of the general population. The presence of extra and missing digital creases in individuals with normal joint anatomy, their occurrence in several syndromes, and mouse in situ expression studies indicate that genetic factors contribute to digital crease formation. However, these factors are poorly understood. Hypotheses regarding the origin of flexion creases are discussed. The identification of supernumerary digital creases in one‐third of AGS probands provides another diagnostic aid and allows for speculation of the role of Jagged1 in the molecular development of digital crease patterns. © 2002 Wiley‐Liss, Inc.

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Features of Alagille Syndrome in 92 Patients: Frequency and Relation to Prognosis

Cited by 595 publications

References 50 publications

Craniosynostosis in Alagille syndrome

Craniosynostosis in Alagille syndrome

Abnormal vertebral segmentation and the notch signaling pathway in man

Supernumerary digital flexion creases: An additional clinical manifestation of Alagille syndrome

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