232 Archives ofDisease in Childhood 1996; 74: 232-235 Alagille's syndrome associated with cystic renal

disease Arch Dis Child: first published as 10.1136/adc.74.3.232 on 1 March 1996. Downloaded from

S R Martin, L Garel, F Alvarez

Abstract importance for the significance of multicystic Although renal abnormalities have been kidneys detected prenatally and extends the described in children with Alagille's differential diagnosis of hepatic disorders syndrome, cystic disease has not associated with cystic kidney disease. often been documented, and then usually only at necropsy. Three children with Alagille's syndrome are described, in two Case 1 of whom a unilateral multicystic dysplas- A 21 month male was admitted to hospital at 4 tic kidney was detected by prenatal ultra- months of age for associated with sound; in the other, a solitary cortical cyst acholic stools. Previously, he had been investi- was found later in childhood. All have gated for renal disease that presented with a normal renal function, growth, and multicystic right kidney detected by fetal ultra- synthetic function but continue to have sound at 16 and 24 weeks' gestation and con- clinical and biochemical signs ofcholesta- firmed postnatally (fig 1). Evaluation in the sis. These cases show that unilateral cystic neonatal period revealed a urinary tract infec- kidney disease with or without renal dys- tion with Escherichia coli that was treated. He plasia may be associated with Alagille's was jaundiced in the first week of life but the syndrome, that the clinical course is jaundice resolved spontaneously. Results of not necessarily unfavourable, and that investigations of his kidney disease are shown Alagille's syndrome should be included in in table 1. At 4 months of age investigations the differential diagnosis of cystic kidney for cholestasis revealed a total bilirubin of disorders associated with cholestatic liver 139 mmol/l (normal <23 mmol/l) and direct disease. Patients with Alagille's syndrome bilirubin of 105 mmol/l (normal <19 mmoYl). should be evaluated by renal ultrasound. The -y glutamyltranspeptidase (-yGT) was 40 x (Arch Dis Child 1996; 74: 232-235) normal and there was evidence of fat soluble vitamin deficiency. The diagnosis of Alagille's Keywords: Alagille's syndrome, multicystic dysplastic kidney, ultrasound. syndrome was suggested by the presence of four of the five major clinical features - cholestasis associated with the typical facies, http://adc.bmj.com/ peripheral pulmonary stenosis, and posterior Alagille's syndrome, one of the most common embryotoxon. In addition, the patient's cry causes of intrahepatic cholestasis of infancy, is was high pitched, as previously described in a familial disorder characterised by five major this syndrome.2 revealed diffuse features: abnormal facies, chronic cholestasis, cholestasis, enlargement of the portal tracts butterfly vertebrae, peripheral pulmonary with mild fibrosis, paucity of interlobular artery stenosis, and posterior embryotoxon of ducts, and a degeneration ofthe bile ducts with on October 2, 2021 by guest. Protected copyright. the eye. Renal involvement, which is included vacuolisation of the epithelium. among a number of other less common mani- At 23 months of age, his course has been festations, has recently been reported more marked by normal growth (height 5th centile often.2-12 Renal abnormalities comprise three for age, weight 10th centile), variable choles- main types: non-specific mild alterations in tasis (currently: total bilirubin 136 mmol/l; renal function,8 10 12 those possibly related to direct bilirubin 74 mmol/1; -yGT 15X normal, the hypercholesterolaemia that is associated and normal liver synthetic function). He with cholestasis, such as mesangiolipidosis,2-4 receives supplemental fat soluble vitamins. and those resulting from abnormalities in renal were first observed at 14 months of morphogenesis.2 4-12 We present three French age; serum peaked at 17 months of Canadian children with Alagille's syndrome age at 41 mmol/l (normal <4 3 mmol/l) and associated with cystic kidney disease, in two has since gradually declined to 15-9 mmol/l. of whom the diagnosis was initially made by Pruritus became clinically significant at 10 Division of fetal ultrasound. These observations have months of age and was treated with variable and Nutrition, H6pital Sainte-Justine, 3175 Table 1 Investigations ofrenal disease in the three patients Cote Ste Catherine, Montreal, Quebec Patient 1 Patient 2 Patient 3 H3T Canada 1C5, BUN N N N S R Martin Creatinine N N N L Garel DMSA scan* Non-functioning right kidney Non-functioning left kidney ND F Alvarez Ultrasound Multicystic, dysplastic right kidney Multicystic, dysplastic left kidney Right renal cortical cyst CT scan N Atrophic left kidney ND Correspondence to: VCUG** Thick bladder wall, diverticulum Vesicoureteral reflux, grade I ND Dr Martin. Accepted 4 December 1995 *Dimercaptosuccinic acid, **voiding cystourethrogram. ND= not done; N=normal. Alagille 's syndrome and cystic renal disease 233 Arch Dis Child: first published as 10.1136/adc.74.3.232 on 1 March 1996. Downloaded from

Figure 1 Patient 1 at 4 months ofage. (A) Longitudinal scan ofthe right kidney. Macrocystic changes are obvious in a 76 mm kidney. The left kidney (not shown) was normal (66 mm in length in compensatory hypertrophy). (B) Transverse scan.

success with hydroxyzine, phenobarbitone, 19 mmol/l; -yGT 29 x normal, cholesterol , or . 6-9 mmol/l) without xanthomas, for which he has received supplemental fat soluble vitamins, and a mild pruritus that was successfully Case 2 treated with ursodeoxycholic acid. His growth A left multicystic dysplastic kidney was is normal (weight 10th centile for age, height detected by prenatal ultrasound in this patient 50th centile). at 19 weeks (fig 2) and confirmed at 21 and 27 weeks' gestation. He was born at term with a birth weight of 3750 g. Jaundice was noted on Case 3 the third day of life; the serum bilirubin con- This 14 year old patient was initially dis- centration peaked on the fifth day (total bili- covered to have a solitary cortical cyst of the rubin 208 mmoll; direct 111 mmol/l ). At six right kidney on routine follow up ultrasound at weeks of age he was admitted to hospital for 1 1 years of age (table 1). He was first admitted investigation of his kidney disorder and persis- to hospital at Hopital Sainte Justine at 21 http://adc.bmj.com/ tent cholestasis. The renal findings are sum- months of age for pruritus and biochemical marised in table 1. The diagnosis of Alagille's changes consistent with cholestasis. He had syndrome was established from the presence presented elsewhere with cholestasis on the of chronic cholestasis, peripheral pulmonary fourth day of life that had not subsequently stenosis, posterior embryotoxon, butterfly been extensively investigated. The presence vertebrae, and typical facies. Follow up was of cholestasis, typical facies, peripheral pul- notable only for biochemical signs of choles- monary stenosis, and posterior embryotoxon on October 2, 2021 by guest. Protected copyright. tasis (total bilirubin 23 mmol/l; direct bilirubin suggested the diagnosis ofAlagille's syndrome;

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Figure 2 Antenatal ultrasound ofpatient 2 at 19 weeks'gestation. (A) Longitudinal scan. Normal right kidney (in between calipers); multicystic dysplasia ofleft kidney (LK). (B) Transverse scan. 234 Martin, Garel, Alvarez

his mother was also observed to have the Hyams and colleagues, in observing that typical facies of Alagille's syndrome, pruritus, their patient did not have dysplastic changes in

and characteristic voice, but she refused either kidney, suggested that the findings in Arch Dis Child: first published as 10.1136/adc.74.3.232 on 1 March 1996. Downloaded from further investigation. A liver biopsy at 21 Alagille's syndrome differed from other condi- months of age revealed a paucity of bile ducts tions with cystic renal lesions associated with without fibrosis or histological signs of biliary tract abnormalities such as Meckel's cholestasis. The evolution of this patient's ill- syndrome, Jeune's syndrome, and Zellweger's ness was characterised by almost complete syndrome.9 Two of our patients presented pre- remission of the cholestasis (total bilirubin natally with a unilateral multicystic dysplastic 5 mmol/l, direct bilirubin 0 mmol/l, yGT 3 X kidney, suggesting that dysplastic kidneys may normal, cholesterol 4'1 mmol/1). He receives also occur in this syndrome. Indeed, concen- rifampicin for mild pruritus and fat soluble tric layering of mesenchymal cells around bile vitamin supplementation, and is growing nor- ducts in early Alagille's syndrome was sug- mally (weight 75th centile for age, height 50th gested to be superficially reminiscent of centile). changes observed in dysplastic kidneys. 13 Desmet hypothesised that a defect in epithe- lial-mesenchymal inductive interactions in Discussion early gestation may explain the coexistence of Renal involvement was not a prominent feature biliary and renal cystic abnormalities in a of early reports of Alagille's syndrome.' Since variety of inherited malformation syndromes then, a variety of non-specific findings has been associated with fibrocystic cholangiopathy and described, including azotaemia, urine concen- abnormal remodelling of the primitive ductal tration defects, and nephrolithiasis. Mesangio- plate.'4 In some, progression of the disease lipidosis is common and while it most probably leads to ductal degeneration and involution. relates to the hypercholesterolaemia that is He suggested that because intrahepatic paucity associated with chronic cholestasis,2-4 Alagille of interlobular bile ducts is not associated with and coworkers did not find a correlation with renal lesions, the cause and mechanism of bile the serum lipid levels.2 In addition, a variety of duct destruction is probably different from abnormalities in renal morphogenesis has been those disorders associated with congenital described, which include small kidneys,6 10 12 hepatic fibrosis. Our observations, together congenital single kidney,5 '0 microcystic tubular with other reports of abnormalities in renal dilatation with interstitial fibrosis,4 9-l1 and morphogenesis with Alagille's syndrome, renal Cysts.2 4 5 7 9 11 The association of cystic suggest that a defect in epithelial-mesenchymal kidney disease with Alagille's syndrome has induction may also be responsible for the con- been reported infrequently (table 2), possibly stellation of abnormalities in this disorder. The because of the poor definition of cysts using lack of reports of ductal plate malformation older ultrasound equipment and the difficulty does not necessarily exclude Alagille's syn- in lesions by ultrasound. drome from Desmet's Rather this identifying early hypothesis. http://adc.bmj.com/ Medullary cystic kidney disease was found at may merely reflect a slower, less aggressive necropsy in two patients with a partial form of hepatic disease process that allows more com- Alagille's syndrome,5 in one dying of sepsis plete ductal plate remodelling to occur, while following at three years of in other organs more severe disturbances arise age,4 and in another who died at two months of in early development, giving the typical post- age in renal failure.I1 All other documented natal pattern of malformations of Alagille's cases of cystic kidney disease have been syndrome. The cause of such failures of induc- described at necropsy, prompting some investi- tion is likely to be multifactorial and may on October 2, 2021 by guest. Protected copyright. gators to question whether this finding may include differences in the expression of genes suggest a poor prognosis in Alagille's syn- regulating inductive interactions. Such differ- drome.5 6 However, none of our three patients ences may account for the variability of clinical has shown signs of deteriorating renal function, expression of inherited disorders with biliary while showing the full spectrum of possible and renal manifestations. evolution of their cholestasis. This implies that In conclusion, Alagille's syndrome belongs cystic kidney disease may not of itself indicate a in the spectrum of disorders associated with poor prognosis, but rather the type (simple cyst cystic renal disease and thus expands the dif- versus ) and extent (unilateral ferential diagnosis of multicystic kidney versus bilateral) of renal involvement that detected by prenatal ultrasound. Cystic governs the patient's prognosis. dysplastic kidneys may be included in the

Table 2 Review ofpublished cases ofcystic renal abnormalities in Alagille's syndrome Reference Features* Renalfindings Status 2 5/5 'Polycystic kidneys' Died 4 5/5 1-5 mm Corticomedullary cysts; microcystic tubular dilatation; interstitial fibrosis Died 4/5 Single 2 cm subcapsular cyst Died 5 1/5 Medullary cystic disease (nephronophthisis) Died 1/5 Medullary cystic disease (nephronophthisis) 7 3/5 'Cystic kidney disease' Died 3/5 'Cystic kidney disease' Died 9 3/5 Severe tubulointerstitial nephropathy with microcystic tubular dilatation Died 10 3/5 Bilateral focal tubular dilatation; interstitial fibrosis Alive 11 3/5 Subcortical cysts; interstitial fibrosis; nephronophthisis) Died *Number of major characteristics of Alagille's syndrome. Alagille's syndrome and cystic renal disease 235

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