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Received for publication: 12.6.09; Accepted in revised form: 6.11.09

Nephrol Dial Transplant (2010) 25: 1501–1506doi: 10.1093/ndt/gfp692Advance Access publication 29 December 2009

An unusual cause of hypertension and renal failure: a case series of afamily with Alagille syndrome

Rajesh Shrivastava1, Andrew Williams1, Ashraf Mikhail1, David Roberts3, Martyn Richards2

and Vandse Aithal1

1Morriston Hospital, Renal Medicine, Swansea, United Kingdom, 2Morriston Hospital, Cardiology, Swansea, United Kingdom and3Morriston Hospital, Radiology, Swansea, United Kingdom

Correspondence and offprint requests to: Rajesh Shrivastava; E-mail: [email protected]

AbstractAlagille Syndrome (OMIM 118450) is a multisystem de-velopmental disorder inherited in an autosomal dominantpattern with variable expression. It commonly manifestsin children with early cholestatic jaundice due to paucityof interlobular biliary ducts. Renal involvement is less

common but can take various forms including renovascu-lar disease, renal agenesis or hypoplasia, cystic renal dis-ease, mesangiolipidosis, tubulointerstitial nephritis andrenal tubular acidosis. We describe a family of Alagillesyndrome with JAG 1 mutation running through at leasttwo generations, affecting four members with variable

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phenotypic expressions and disease severity. Alagille syn-drome should be considered in the differential diagnosisof adults with renovascular disease and children withagenesis/dysgenesis of kidney and reflux nephropathyeven in the absence of hepatic disease. Renal transplantcan be successful in these patients although living relateddonation may not be appropriate given the high pene-trance and variable expression of this condition. This syn-drome may cause symptomatic bradyarrhythmias asdescribed in our series.

Keywords: Alagille syndrome; renal failure; hypertension; renaltransplant; haemodialysis

Introduction

Alagille Syndrome (OMIM 118450) is a multisystem de-velopmental disorder inherited in an autosomal dominantpattern with variable expression. It commonly manifestsin children with early cholestatic jaundice due to paucityof interlobular biliary ducts [1]. Renal involvement is lesscommon. Genetic studies have identified mutations (in60–75%) or deletions (in 3–7%) in the JAG 1 gene locat-ed on chromosome 20p12 in typical cases of Alagillesyndrome [2–5]. Recently, NOTCH 2 and HEY 2 muta-tions have also been implicated [6,7]. However, geno-type–phenotype correlations have not been clarified yet[4,8].

We describe a family of Alagille syndrome with JAG 1mutation running through at least two generations, affect-ing four members with variable phenotypic expressionsand disease severity (Figure 1).

Case 1

A 62-year-old male was referred with refractory hyper-tension and chronic kidney disease. He was noted tohave an asymptomatic murmur in childhood. He was di-agnosed with hypertension at the age of 42 years. Fol-lowing the diagnosis of Alagille syndrome in his son,he underwent genetic studies which confirmed that hetoo had the same mutation in the JAG 1 gene ((hetero-zygous for a frameshift mutation—2874_2875delTG inexon 23 of JAG1 gene) consistent with a diagnosis ofAlagille syndrome.

He had dysmorphic facies (Figure 2) and posterior em-bryotoxon. His blood pressure at presentation was 200/90mmHg. He had a pulmonary ejection systolic murmur.There was no evidence of peripheral vascular disease.

Creatinine at presentation was 154 μmol/l [estimatedglomerular filtration rate (eGFR) 42 ml/min/1.72 m2]with urea of 9.8 mmol/l. His liver functions were normal.Urine dipstick showed no haematuria or proteinuria. Ul-trasound scan revealed small asymmetric kidneys (rightkidney 9.4 cm and left kidney 8.3 cm) and a hepatic an-gioma. Computed tomography (CT) angiogram showedsignificant arterial stenosis involving left renal, right sub-clavian and coeliac arteries (Figures 3 and 4). Echocar-

diogram did not show any valvular lesion. His bloodpressure is currently 130/80 mmHg on four anti-hyper-tensive agents. His renal function has remained stableover the last 6 years, and his creatinine is currently 130

1 2

4 35

6 7

Fig. 1. Family tree showing three generations.

Fig. 2. Case 1. Dysmorphic facial features of Alagille syndrome.

1502 R. Shrivastava et al.


μmol/L (eGFR 51 ml/min/1.72 m²). His liver functiontests have remained normal.

Two years after his initial presentation, he required apermanent pacemaker for symptomatic sinus pauses.

Case 2 (case 1's brother)

He was diagnosed with an asymptomatic heart murmur inchildhood. He was referred at 50 years of age with severesystolic hypertension and renal impairment. He had dys-morphic facies, right-sided cataract and left retinal pig-mentary changes. There was no clinical evidence of

peripheral vascular disease. He had a loud ejection systolicmurmur in the pulmonary area.

Creatinine at presentation was 144 μmol/L (eGFR 48ml/min/1.72 m2). He had normal liver functions. He hada 24-hour protein excretion of 900 mg with no haematuria.Ultrasound of the renal tract showed small kidneys, withthin cortices suggestive of parenchymal renal disease.CT renal angiogram revealed 50% ostial stenosis in theright renal artery. He had significant stenoses of externalcarotid arteries, coeliac axis and superior mesenteric artery.Echocardiogram showed left ventricular hypertrophy withmild mitral regurgitation. He has had two separate admis-sions for symptomatic bradycardia and a 24-hour tapeshowed sinus bradycardia with first-degree atrioventricularblock and several sinus pauses, the longest being 2.6 sec-

Fig. 3. Case 1. CT angiogram showing left renal artery stenosis.

Fig. 4. Case 1. CT angiogram showing coeliac artery stenosis.

Algorithm for diagnosis of Alagille syndrome

Clinical features Renovascular disease with no evidence of PVD

Widespread arterial stenosis Absence of conventional risk factors for atherosclerosis

Agenesis/dysgenesis of kidney or reflux nephropathy in children

Dysmorphic facial features

Family h/o cholestatic liver disease / renal disease/ heart murmurs

Radiological evidence of carotid, subclavian, coeliac, superior mesenteric and renal arterial stenoses

Ocular changes – posterior embryotoxon

Skeletal changes – butterfly vertebrae

Pulmonary ejection systolic murmur with a normal echocardiogram

Genetic studies: Mutation in JAG1, Notch2 or HEY2 genes

Fig. 5. Proposed algorithm for diagnosis of Alagille syndrome in renalpatients.



onds. He was unfortunately lost to follow-up until hisbrother (case 1) presented to us 9 years later. The diagnosisof Alagille syndrome was made in retrospect.

His systolic hypertension has been difficult to controldespite introduction of six antihypertensive medicationsincluding an angiotensin-converting enzyme inhibitor.His renal function has gradually deteriorated with a creat-inine of 265 μmol/L (eGFR 23 ml/min/1.72 m2) 14 yearslater. His liver function tests remain normal.

Case 3 (case 2's daughter)

The diagnosis in this case was made in retrospect followingthe clinical presentation of her paternal uncle.

She was separated in childhood from her father. She de-veloped neonatal urinary tract infections, and a micturatingcystogram showed right-sided reflux while the left kidneywas not visualized.

She appears to have been lost to follow-up until the age of12 years when she presented with hypertension, breathless-ness, renal impairment (creatinine 200 μmol/L—eGFR 30ml/min/1.72 m2) and a loud systolic murmur over the pre-cordium. She had dysmorphic facies, and her weight re-mained below the third centile for her age. She hadnormal liver function tests. An echocardiogram and cardiaccatheterization study ruled out valvular stenosis and hermurmur was thought to be secondary to a peripheral pulmo-nary stenosis.

Her renal function progressively deteriorated, and shecommenced haemodialysis at the age of 16 when her creat-inine was 640 μmol/L (eGFR 8 ml/min/1.72 m2).

She had three renal transplants between the ages of 17 and20 years. The first two transplants failed due to acute cellu-lar rejection after nine and thirteen months, respectively.The third renal transplant failed after 7 years due to chronicallograft nephropathy, and she subsequently went back onhaemodialysis. The acute rejection in the first two trans-plants was thought to be secondary to non-compliance withmedication. There was no documentation of any difficultywith vascular anastamoses during the three renal transplantprocedures.

She however was subsequently found to have had mul-tiple arterial stenoses including an 80% stenosis of distalleft common iliac and proximal external iliac arteries. Herleft subclavian artery was stented for symptomatic steno-sis. She had recurrent problems with vascular access forhaemodialysis on account of widespread arterial stenoses.She died at the age of 32 from metastatic gynaecologicalmalignancy. Diagnosis of Alagille syndrome was notmade in her case until her paternal uncle (case 1) pre-sented to us 6 years later.

Case 4

Case 1's son. He presented with cholestatic jaundice inchildhood. He subsequently developed hepatic cirrhosiswith portal hypertension. There was no evidence of signif-icant renal involvement. Genetic studies confirmed a muta-tion in the JAG 1 gene in keeping with a diagnosis ofAlagille syndrome. He died at the age of 20 years from avariceal bleed.

Case 5

Case 1's daughter. Phenotypically normal and geneticstudies did not reveal any mutation.

Case 6

Case 1 and 2's father. We do not have much informationon him as he lived separately and died in his 40s in a roadtraffic accident.

Case 7

Case 1 and 2's mother. We do not know much about hermedical history apart from the fact that she died at 65 yearsfrom carcinoma of the breast.

Discussion

Alagille syndrome is a developmental disorder due tomutation in the genes involved in notch signalling path-way. JAG 1, NOTCH 2 and HEY 2 mutations have beendescribed with JAG 1 mutations accounting for most ofthese [2–7]. JAG 1 gene encodes for a ligand (jagged 1)that interacts with Notch group of transmembrane pro-teins on neighbouring cells to generate notch signallingpathways that are crucial in cell differentiation in embry-onic life [9,10]. Frameshift, missense, nonsense mutations(60–70%) and deletions (3–7%) have been described inalmost all of the 26 exons of JAG 1 gene resulting inhaploinsufficiency for Jagged 1 protein [11].

Notch is a signalling pathway between membrane-bound receptors and ligands expressed on adjacent cells.Binding of ligands induces a proteolytic cleavage of theNotch receptor, releasing its intracellular domain (ICD).This truncated form of Notch then translocates to the nu-cleus where it forms an active transcriptional complex withthe DNA-binding protein CSL [also known as CBF1, Su(H), Lag-1 and RBP-J] and the co-activator Mastermind-like (MAML) [12]. Mammals express four Notch receptors(Notch 1–4) and five ligands [Jagged (JAG) 1 and JAG 2and Dll (Delta-like) 1, Dll3, and Dll4]. Two Notch ligands,Jag1 and Dll4, are prominently expressed in the vascula-ture. Disruption of each of these genes in mice results inembryonic lethality associated with cardiovascular defects,suggesting that both play essential, non-redundant func-tions [12–15].

Endothelial-specific deletion of JAG 1 results in em-bryonic lethality and cardiovascular defects, similar tothe gross defects reported for the complete Jag1 knockout.Expression of vascular smooth muscle markers is severelydiminished in the endothelial-specific JAG 1 mutant em-bryos [16].

Diminished JAG 1 expression on endothelial cells re-sults in abnormal smooth muscle development, whichmay be responsible for the pulmonary artery stenosis thatis a frequent finding in Alagille syndrome patients. It hasbeen shown that inhibition of Notch in neural crest cells(which act as smooth muscle precursors in the pulmonaryartery) results in pulmonary artery stenosis and other con-



genital heart defects similar to those seen in Alagille syn-drome [17].

The clinical correlation of JAG1 mutation is best illus-trated in a study of 200 subjects who fulfilled the diagnos-tic criteria for Alagille syndrome [18]. Seventy-sevenpercent of the study group had mutation in the JAG1 gene.Individuals with JAG1 mutation had a significantly higherfrequency of branch pulmonary arterial anomalies, bilater-al branch pulmonary arterial anomalies and diffuse steno-sis/hypoplasia of the pulmonary arteries than those withAlagille syndrome without the mutation. Within the cohortof subjects with a JAG1 mutation, there was no correlationbetween the type and location of the JAG1 mutation andthe presence or type of cardiovascular anomaly. The var-iable phenotypic expression of a JAG1 mutation in thecardiovascular system suggests that additional epigeneticfactors influence the final cardiac phenotype.

The diagnosis of Alagille syndrome in adults who pres-ent with chronic kidney disease can be difficult as illustrat-ed in our case series. A high degree of clinical suspicionand a good family history is helpful (see Algorithm).

Prevalence of Alagille syndrome has been reported as 1in 100 000 live births when probands were ascertainedbased on finding of neonatal liver disease [19].

In a summary of various studies looking in to clinicalfeatures of Alagille syndrome, the frequency of involve-ment of various organs was as follows: liver (95%), cardio-vascular (92%), facies (91%), eye (78%), vertebra (70%)and renal (38%) [20].

Organ-specific manifestations of Alagille syndrome in-clude the following:

(1) Hepatic: Majority of symptomatic patients present withhepatic disease of varying severity in their infancy.Many progress to cirrhosis and liver failure with 15%requiring liver transplantation [21].

(2) Cardiac: More than 90% of patients with Alagille syn-drome have cardiac malformations, the commonest be-ing peripheral pulmonary stenosis. Tetralogy of Fallotoccurs in 7–10% but ventricular septal defects, atrialseptal defects, patent ductus arteriosus, aortic stenosisand coarctation of aorta are also seen less frequently[1,18,22,23].

(3) Ocular: Most of the ocular anomalies in patients withAlagille syndrome are related to the anterior chamber(posterior embryotoxon being the commonest) or reti-nal pigmentary changes [1,22].

(4) Vascular: Stenoses of aortic, coeliac, superior mesen-teric, subclavian and cerebral arteries are common al-though any artery may be involved. Sixteen percent ofpatients with Alagille syndrome have documented in-tracranial haemorrhage and strokes [25,26].

(5) Skeletal involvement: Butterfly vertebra is the com-monest skeletal abnormality in patients with Alagillesyndrome (70%). Other skeletal anomalies include nar-rowing of interpeduncular spaces in the lumbar spine(50%), pointed anterior process of C1, spina bifida oc-culta, vertebral fusion, hemivertebrae, fused ribs andshort fingers [20].

(6) Facies: Characteristic facies of Alagille syndrome is atriangular face composed of broad forehead, deep seteyes with hypertelorism, straight or saddle nose withbulbous tip [1,20,27].

(7) Renal: Renal anomalies have been reported in 23–74%of patients in studieswhere this was examined [1,20,28].Renal involvement can take various forms including re-novascular disease, renal agenesis or hypoplasia, cysticrenal disease, mesangiolipidosis, tubulointerstitial ne-phritis and renal tubular acidosis [27,29–35].

Being primarily a paediatric disease affecting the liver,adult case reports of renal failure requiring renal replace-ment therapy including renal transplantation are limited[34]. Although renovascular disease and hypertension arethe more likely mechanisms for renal injury, abnormal ne-phrogenesis due to JAG1 haploinsufficiency is also impli-cated. JAG1 expression has been seen in ureteric budsalong with glomerular and tubular structures during allphases of renal embryogenesis [10].

Despite the association of various cardiac abnormalitieswith this syndrome, to the best of our knowledge, conduc-tion abnormality in the form of symptomatic bradyarrhyth-mia has not been described.

We report a family of Alagille syndrome with four affect-ed members through two successive generations. Despitesharing the same mutation in the JAG 1 gene (heterozygousfor a frameshift mutation—2874_2875delTG in exon 23of JAG1 gene) liver and renal disease seemed to manifestindependent of each other. Only one of them had clinicallysignificant hepatic disease. The other three had varyingseverity of renal disease with one requiring long-termrenal replacement therapy. The aetiology of renal failurewas renovascular disease in two patients and agenesis ofone kidney with reflux nephropathy affecting the remnantkidney in the third patient. All three cases with renal dis-ease had vascular abnormalities at more than one site andmurmurs consistent with pulmonary artery stenosis.

The two adults with renovascular disease suffered fromsymptomatic sinus bradyarrhythmias, of whom one re-quired a permanent pacemaker.

The patient who required renal replacement had threesuccessful renal transplants. The first two failed within ayear due to rejection possibly due to poor compliance.The third transplant lasted for >7 years and failed as a re-sult of chronic allograft nephropathy.

Conclusions

Alagille syndrome should be considered in the differentialdiagnosis of adults with renovascular disease and childrenwith agenesis/dysgenesis of kidney and reflux nephropathyeven in the absence of hepatic disease. A family history ofcardiovascular abnormalities, dysmorphic facies, liver andrenal disease helps with the diagnosis.

Vascular access for haemodialysis may be difficult inthese patients on account of vascular stenoses. Renal trans-plant can be successful in these patients although livingrelated donation may not be appropriate given the highpenetrance and variable expression of this condition. This



syndrome may cause symptomatic bradyarrhythmias asdescribed in our series.

Conflict of interest statement. None declared.

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Received for publication: 28.5.09; Accepted in revised form: 23.11.09



Documents

a case series of a family with Alagille syndrome