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European Journal of Case Reports in... 2024Alagille syndrome (ALGS) is a multisystem disorder involving at least three systems among the liver, heart, skeleton, face, and eyes. Common cardiac associations include...
BACKGROUND
Alagille syndrome (ALGS) is a multisystem disorder involving at least three systems among the liver, heart, skeleton, face, and eyes. Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF). Coarctation of aorta (CoA), renal and intracranial arteries are commonly involved vessels in Alagille syndrome. We present two cases with rare cardiovascular manifestations of Alagille syndrome. .
CASE 1
A 25-year-old female with a history of Alagille syndrome presented to the cardiologist office for progressive exertional dyspnoea, orthopnoea, and palpitations. She was tachycardiac on examination and had an apical diastolic rumble. A transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction (LVEF) of 60% and parachute mitral valve (PMV) with severe mitral stenosis. A transoesophageal echocardiogram (TOE) showed insertion of chordae into the anterolateral papillary muscle, severe mitral stenosis with a valve area of 0.7 cm. She was referred to a congenital heart disease specialist and underwent robotic mitral valve replacement with improvement in her symptoms.
CASE 2
A 27-year-old female with known Alagille syndrome and resistant hypertension presented to the cardiologist office due to progressive exertional dyspnoea for a year. She was hypertensive and had a new 2/6 systolic ejection murmur along the left upper sternal border. TTE revealed an LVEF of 60% and pulmonary artery pressure of 19 mmHg. A CoA was suspected distal to the left subclavian artery due to a peak gradient of 38 mmHg. Cardiac magnetic resonance (CMR) imaging ruled out CoA, and diffuse narrowing of the descending thoracic aorta measuring 13-14 mm in diameter was noted. The patient was referred to a congenital heart disease specialist for further management.
CONCLUSION
PMV presenting as mitral stenosis and mid-aortic syndrome are not commonly described anomalies in association with Alagille syndrome. TTE, TOE and CMR played a key role in diagnosis and management of these patients.
LEARNING POINTS
Alagille syndrome (ALGS) is a complex multisystem disorder involving the liver, heart, skeleton, face, and eyes. Cardiovascular involvement occurs in up to 95% of the patients.Common cardiac associations include pulmonary artery stenosis/atresia, atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of fallot (ToF).A parachute mitral valve (PMV) presenting as mitral stenosis and mid-aortic syndrome is not commonly described anomalies in association with ALGS. Here, we present such rare cases.
PubMed: 38846669
DOI: 10.12890/2024_004545 -
Pediatric Gastroenterology, Hepatology... Mar 2016Cholestasis results from impairment in the excretion of bile, which may be due to mechanical obstruction of bile flow or impairment of excretion of bile components into... (Review)
Review
Cholestasis results from impairment in the excretion of bile, which may be due to mechanical obstruction of bile flow or impairment of excretion of bile components into the bile canaliculus. When present, cholestasis warrants prompt diagnosis and treatment. The differential diagnosis of cholestasis beyond the neonatal period is broad and includes congenital and acquired etiologies. It is imperative that the clinician differentiates between intrahepatic and extrahepatic origin of cholestasis. Treatment may be supportive or curative and depends on the etiology. Recent literature shows that optimal nutritional and medical support also plays an integral role in the management of pediatric patients with chronic cholestasis. This review will provide a broad overview of the pathophysiology, diagnostic approach, and management of cholestasis beyond the neonatal and infancy periods.
PubMed: 27066444
DOI: 10.5223/pghn.2016.19.1.1 -
Gene Jan 2016Jagged1 (JAG1) is one of the 5 cell surface ligands that functions primarily in the highly conserved Notch signaling pathway. Notch signaling plays a critical role in... (Review)
Review
Jagged1 (JAG1) is one of the 5 cell surface ligands that functions primarily in the highly conserved Notch signaling pathway. Notch signaling plays a critical role in cellular fate determination and is active throughout development and across many organ systems. The classic JAG1-NOTCH interaction leads to a cascade of proteolytic cleavages resulting in the NOTCH intracellular domain being transported into the nucleus where it functions to activate downstream transcription of target genes. JAG1 mutations have been associated with several disorders including the multi-system dominant disorder Alagille syndrome, and some cases of tetralogy of Fallot (although these may represent variable expressivity of Alagille syndrome). In addition, variations in JAG1 have been found to be associated with multiple types of cancer including breast cancer and adrenocortical carcinoma. Alagille syndrome, which primarily affects the liver, heart, skeleton, eye, face, kidney and vasculature is caused by loss of function mutations in JAG1, demonstrating that haploinsufficiency for JAG1 is disease causing, at least in these tissues. Expression and conditional gene knockout studies of JAG1 (Jag1) have correlated with tissue-specific disease phenotypes and have provided insight into both disease pathogenesis and human development.
Topics: Alagille Syndrome; Calcium-Binding Proteins; Gene Knockdown Techniques; Genetic Predisposition to Disease; Humans; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein; Membrane Proteins; Neoplasms; Pulmonary Valve Stenosis; Serrate-Jagged Proteins; Tetralogy of Fallot
PubMed: 26548814
DOI: 10.1016/j.gene.2015.10.065 -
Journal of Clinical and Translational... Feb 2023Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused by mutations in the and genes. AGS has been rarely reported in adult patients, mainly...
BACKGROUND AND AIMS
Alagille syndrome (AGS) is an autosomal dominant multisystem disorder caused by mutations in the and genes. AGS has been rarely reported in adult patients, mainly because its characteristics in adults are subtle. The study aimed to improve the understanding of adult AGS by a descriptive case series.
METHODS
Eight adults diagnosed with AGS at our hospital between June 2016 and June 2019 were included in the study. Clinical data, biochemical results, imaging results, liver histopathology, and genetic testing were analyzed.
RESULTS
Three female and five male patients with a median age of 24.5 years at the time of diagnosis were included in the analysis. The clinical manifestations were adult-onset (62.5%, 5/8), cholestasis (50%, 4/8), butterfly vertebrae (62.5%, 5/8), systolic murmurs (12.5%, 1/8), typical facies (12.5%, 1/8), posterior embryotoxon, and renal abnormalities (0/8). Genetic sequencing showed that all patients had mutations, with four occurring in the gene and four in the gene. Six were substitution mutations, one was a deletion mutation, and one was a splicing mutation. Five had been previously reported; but the others, one mutation and two mutations were unique and are reported here for the first time.
CONCLUSIONS
The clinical manifestations highlighted by the current diagnostic criteria for most adults with AGS are atypical. Those who do not meet the criteria but are highly suspicious of having AGS need further evaluation, especially genetic testing.
PubMed: 36406308
DOI: 10.14218/JCTH.2021.00313 -
Current Opinion in Cell Biology Feb 2024Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged... (Review)
Review
Notch signaling controls multiple aspects of embryonic development and adult homeostasis. Alagille syndrome is usually caused by a single mutation in the jagged canonical Notch ligand 1 (JAG1), and manifests with liver disease and cardiovascular symptoms that are a direct consequence of JAG1 haploinsufficiency. Recent insights into Jag1/Notch-controlled developmental and homeostatic processes explain how pathology develops in the hepatic and cardiovascular systems and, together with recent elucidation of mechanisms modulating liver regeneration, provide a basis for therapeutic efforts. Importantly, disease presentation can be regulated by genetic modifiers, that may also be therapeutically leverageable. Here, we summarize recent insights into how Jag1 controls processes of relevance to Alagille syndrome, focused on Jag1/Notch functions in hepatic and cardiovascular development and homeostasis.
Topics: Humans; Alagille Syndrome; Serrate-Jagged Proteins; Membrane Proteins; Calcium-Binding Proteins; Intercellular Signaling Peptides and Proteins; Jagged-1 Protein
PubMed: 38194749
DOI: 10.1016/j.ceb.2023.102302 -
Genes Oct 2023Axenfeld-Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. and variants explain the majority of...
Axenfeld-Rieger anomaly (ARA) is a specific ocular disorder that is frequently associated with other systemic abnormalities. and variants explain the majority of individuals with Axenfeld-Rieger syndrome (ARS) but leave ~30% unsolved. Here, we present pathogenic/likely pathogenic variants in nine families with ARA/ARS or similar phenotypes affecting five different genes/regions. and explained three families each. was recently linked with syndromic cognitive impairment that includes hearing loss, dental defects, ventriculomegaly, Dandy-Walker malformation, skeletal anomalies (hip dysplasia), and other features showing a significant overlap with -ARS. Anterior segment anomalies are not currently associated with , yet our cases demonstrate ARA, congenital glaucoma, corneal neovascularization, and cataracts. The identification of variants, linked with Alagille syndrome, in three separate families with a clinical diagnosis of ARA/ARS highlights the overlapping features and high variability of these two phenotypes. Finally, intragenic variants in , , and an X chromosome deletion encompassing and (linked with ocular and dental anomalies, correspondingly) were identified in three additional cases with ARS. Accurate diagnosis has important implications for clinical management. We suggest that broad testing such as exome sequencing be applied as a second-tier test for individuals with ARS with normal results for sequencing and copy number analysis, with attention to the described genes/regions.
Topics: Humans; Transcription Factors; Homeodomain Proteins; Anterior Eye Segment; Eye Abnormalities; Ubiquitin Thiolesterase
PubMed: 37895297
DOI: 10.3390/genes14101948 -
Biology May 2023Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in... (Review)
Review
Pruritus in the setting of cholestatic liver disease is difficult to treat and occurs in patients ranging in age from infancy to adulthood. Likely multifactorial in etiology, this symptom often involves multimodal therapy targeting several pathways and mechanisms proposed in the underlying etiology of cholestatic pruritus. Many patients in both the pediatric and adult populations continue to experience unrelenting pruritus despite maximal conventional therapy. Options are further limited in treating pediatric patients due to sparse data regarding medication safety and efficacy in younger patients. Conventional therapies for the treatment of cholestatic pruritus in children include ursodeoxycholic acid, cholestyramine, hydroxyzine, and rifampin. Certain therapies are more routinely used in the adult populations but with limited data available for use in child and adolescent patients, including opioid antagonists and selective serotonin reuptake inhibitors. Recently, ileal bile acid transport inhibitors have been shown to alleviate pruritus in many children with Alagille syndrome and progressive familial intrahepatic cholestasis and is an additional therapy available for consideration for these patients. Ultimately, surgical options such as biliary diversion or liver transplantation are considered in specific circumstances when medical therapies have been exhausted and pruritus remains debilitating. While further investigation regarding underlying etiologies and effective therapies are needed to better understand itch pathogenesis and treatment in pediatric cholestasis, current considerations beyond conventional management include the use of opioid antagonists, selective serotonin reuptake inhibitors, ileal bile acid transport inhibitors, and surgical intervention.
PubMed: 37237568
DOI: 10.3390/biology12050756 -
Hypertension (Dallas, Tex. : 1979) Sep 2021Renovascular hypertension is one of the most common forms of secondary hypertension. Over 95% of cases of renovascular hypertension are due either to atherosclerosis of... (Review)
Review
Renovascular hypertension is one of the most common forms of secondary hypertension. Over 95% of cases of renovascular hypertension are due either to atherosclerosis of the main renal artery trunks or to fibromuscular dysplasia. These two causes of renal artery stenosis have been extensively discussed in recent reviews and consensus. The aim of the current article is to provide comprehensive and up-to-date information on the remaining causes. While these causes are rare or extremely rare, etiologic and differential diagnosis matters both for prognosis and management. Therefore, the clinician cannot ignore them. For didactic reasons, we have grouped these different entities into stenotic lesions (neurofibromatosis type 1 and other rare syndromes, dissection, arteritis, and segmental arterial mediolysis) often associated with aortic coarctation and other arterial abnormalities, and nonstenotic lesions, where hypertension is secondary to compression of adjacent arteries and changes in arterial pulsatility (aneurysm) or to the formation of a shunt, leading to kidney ischemia (arteriovenous fistula). Finally, thrombotic disorders of the renal artery may also be responsible for renovascular hypertension. Although thrombotic/embolic lesions do not represent primary vessel wall disease, they are characterized by frequent macrovascular involvement. In this review, we illustrate the most characteristic aspects of these different entities responsible for renovascular hypertension and discuss their prevalence, pathophysiology, clinical presentation, management, and prognosis.
Topics: Alagille Syndrome; Aortic Dissection; Atherosclerosis; Fibromuscular Dysplasia; Humans; Hypertension, Renovascular; Neurofibromatosis 1; Renal Artery Obstruction; Takayasu Arteritis
PubMed: 34455817
DOI: 10.1161/HYPERTENSIONAHA.121.17004 -
EMBO Molecular Medicine Dec 2022Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in...
Spontaneous bleeds are a leading cause of death in the pediatric JAG1-related liver disease Alagille syndrome (ALGS). We asked whether there are sex differences in bleeding events in patients, whether Jag1 mice display bleeds or vascular defects, and whether discovered vascular pathology can be confirmed in patients non-invasively. We performed a systematic review of patients with ALGS and vascular events following PRISMA guidelines, in the context of patient sex, and found significantly more girls than boys reported with spontaneous intracranial hemorrhage. We investigated vascular development, homeostasis, and bleeding in Jag1 mice, using retina as a model. Jag1 mice displayed sporadic brain bleeds, a thin skull, tortuous blood vessels, sparse arterial smooth muscle cell coverage in multiple organs, which could be aggravated by hypertension, and sex-specific venous defects. Importantly, we demonstrated that retinographs from patients display similar characteristics with significantly increased vascular tortuosity. In conclusion, there are clinically important sex differences in vascular disease in ALGS, and retinography allows non-invasive vascular analysis in patients. Finally, Jag1 mice represent a new model for vascular compromise in ALGS.
Topics: Female; Male; Animals; Mice; Alagille Syndrome; Sex Characteristics; Retina; Risk Factors
PubMed: 36345711
DOI: 10.15252/emmm.202215809 -
Transgender Health Feb 2023Alagille syndrome is a rare autosomal dominant disorder with variable expression. Liver damage, especially cholestatic, is the most common feature of the syndrome....
Alagille syndrome is a rare autosomal dominant disorder with variable expression. Liver damage, especially cholestatic, is the most common feature of the syndrome. Transgender patients may suffer from a great distress due to the discrepancy between assigned sex at birth and unaffirmed gender identity. Gender affirmation treatment options for these patients include hormone therapy (HT) to induce secondary sexual characteristics and various surgical procedures. Estrogen-based hormonal treatments have been linked to an increased risk of liver enzyme elevation and disruption of bilirubin metabolism, especially in those with a genetic susceptibility. The case presented here is the first described Alagille syndrome transgender patient to undergo gender affirmation treatment, including (HT) and vulvo-vaginoplasty surgery.
PubMed: 36895310
DOI: 10.1089/trgh.2021.0023