Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion

Laufer-Cahana, Ayala; Krantz, Ian D.; Bason, Lynn; Lu, Fengmin; Piccoli, David A.; Spinner, Nancy B.

doi:10.1002/ajmg.10616

Cited by 24 publications

(12 citation statements)

References 19 publications

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“…13,21 Our detailed evaluation of the explant liver strongly suggests that a lack of branching and elongation of bile ducts during postnatal liver growth is the mechanism by which peripheral bile duct paucity developed in this AGS patient. Because the Jagged1 mutation was present in both the periphery and the center of the liver, this regional difference is not due to mosaicism, a feature that has been described in peripheral blood cells of parents of some AGS patients.…”

Section: Discussionmentioning

confidence: 88%

Peripheral Bile Duct Paucity and Cholestasis in the Liver of a Patient With Alagille Syndrome

Libbrecht

Spinner²,

Moore³

et al. 2005

American Journal of Surgical Pathology

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Alagille syndrome (AGS) is a developmental, multiorgan disease caused by mutations of the Jagged1 gene. The liver is one of the major organs affected in AGS, and the hallmark of liver pathology in AGS is an age-related increase in the proportion of portal tracts that have no bile duct, but without evidence of prominent bile duct damage. The pathogenesis of this bile duct paucity is currently not well understood. (Immuno)histochemical and molecular analyses were performed on several liver biopsies that were taken during macroscopic examination of the explant liver of a 17-year-old AGS patient. The liver periphery was macroscopically pale and was microscopically characterized by complete absence of bile ducts and presence of severe cholestasis, but there was no ductular reaction. Conversely, the central, hilar portion contained normally developed bile ducts showing no or minimal damage and cholestasis. A missense mutation in the Jagged1 gene was present in both parts of the liver, indicating that mosaicism did not cause this peculiar picture. There was also a hypertrophy of the hepatic arterial branches in the liver periphery. Together with previous indirect findings, the current study of the explant liver of an AGS patient strongly suggests that a lack of branching and elongation of bile ducts during postnatal liver growth is the mechanism by which peripheral bile duct paucity and cholestasis develops in AGS. Our findings also suggest that anomalies of the intrahepatic arterial branches may be part of AGS in some patients.

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Section: Discussionmentioning

confidence: 88%

Peripheral Bile Duct Paucity and Cholestasis in the Liver of a Patient With Alagille Syndrome

Libbrecht

Spinner²,

Moore³

et al. 2005

American Journal of Surgical Pathology

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“…One of these cases is mosaic for a deletion in chromosome 20, and has been previously reported. 20 The other individual with no features also had normal clinical evaluations for the major features of AGS, but carried the identical mutation in JAG1 as their affected child. Studies are underway to determine if he might also be mosaic.…”

Section: Discussionmentioning

confidence: 99%

Consequences of JAG1 mutations

Kamath

Bason²,

Piccoli³

et al. 2003

Journal of Medical Genetics

166

128

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Background: Alagille syndrome (AGS) is a multi-system, autosomal dominant disorder with highly variable expressivity, caused by mutations within the Jagged1 (JAG1) gene. Methods: We studied 53 mutation positive relatives of 34 AGS probands to ascertain the frequency of clinical findings in JAG1 mutation carriers. Results: Eleven of 53 (21%) mutation positive relatives had clinical features that would have led to a diagnosis of AGS. Seventeen of the 53 (32%) relatives had mild features of AGS, revealed only after targeted evaluation following the diagnosis of a proband in their family. Twenty five of the 53 (47%) mutation positive relatives did not meet clinical criteria, and two of these individuals had no features consistent with AGS at all. The frequency of cardiac and liver disease was notably lower in the relatives than in the probands, characterising the milder end of the phenotypic spectrum. The characteristic facies of AGS was the feature with the highest penetrance, occuring almost universally in mutation positive probands and relatives. Conclusions: This study has implications for genetic counselling of families with AGS and JAG1 mutations.

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“…Deletions of 20p are rare. The majority of reported cases involve 20p12 deletions and a diagnosis of AGS, which is characterized by intrahepatic bile duct hypoplasia and cholestasis, peripheral pulmonary artery stenosis, vertebral anomalies, ocular abnormalities (embryotoxin) and characteristic facial features, including deep set eyes, frontal bossing, hypertelorism, elongated nose with bulbous tip, long philtrum and low set ears [Anad et al, 1990; Krantz et al, 1998; Kamath et al, 2002; Laufer‐Cahana et al, 2002]. AGS is transmitted as an autosomal dominant trait caused by mutations of the JAG 1 gene in 94% of cases.…”

Section: Discussionmentioning

confidence: 99%

20p11 deletion in a female child with panhypopituitarism, cleft lip and palate, dysmorphic facial features, global developmental delay and seizure disorder

Williams

Wetherbee

Rosenfeld

et al. 2010

American J of Med Genetics Pt A

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Deletions of 20p are rare with the majority of reported cases involving individuals with 20p12 deletions associated with Alagille syndrome. We report on a child with a de novo mosaic 20p11 deletion who presents with panhypopituitarism; hypoplastic pituitary gland and ectopic posterior pituitary gland on MRI of the brain; cleft lip and palate; kyphosis with anterior beaking of L1 and L2 vertebral bodies; pulmonic stenosis; dysmorphic facial features including flat nasal bridge, hypoplastic premaxilla, hypotelorism, preauricular pit, and cupped ears; seizure disorder; variable muscle tone; and global developmental delay. Array comparative genomic hybridization revealed this deletion to be approximately 5.4 Mb in size, containing 35 genes. Previously, an infant with 20p11.22 deletion who had panhypopituitarism, craniofacial, and genital abnormalities was reported, but the precise parameters of that deletion are unavailable. Several other reported cases of 20p11 deletions also have phenotypic overlap with our case. The similarities in clinical features of these patients suggest that the genes at 20p11 have a critical role in development of midline brain structures.

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Alagille syndrome inherited from a phenotypically normal mother with a mosaic 20p microdeletion

Cited by 24 publications

References 19 publications

Peripheral Bile Duct Paucity and Cholestasis in the Liver of a Patient With Alagille Syndrome

Peripheral Bile Duct Paucity and Cholestasis in the Liver of a Patient With Alagille Syndrome

Consequences of JAG1 mutations

20p11 deletion in a female child with panhypopituitarism, cleft lip and palate, dysmorphic facial features, global developmental delay and seizure disorder

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