Central Journal of and Clinical Research

Case Report *Corresponding author Daniel D. Mais, Department of Pathology, University of Texas Health, 7703 Floyd Curl Dr, San Antonio, TX 78229, Clinicopathologic Features of USA, Tel: 210-863-2646; Fax: 210-567-6729; Email:

Submitted: 09 September 2017 Hepatic Involvement in Senior- Accepted: 08 October 2017 Published: 10 October 2017 Loken Syndrome: A Case Report ISSN: 2379-0830 Copyright and Review of Literature © 2017 Mais et al. OPEN ACCESS Lian-Qun Qiu and Daniel D. Mais* Department of Pathology, University of Texas Health, USA Keywords • Senior-loken syndrome • Congenital hepatic fibrosis Abstract • Senior-Loken syndrome is an autosomal recessive disorder, characterized by the • combination of nephronophthisis and retinopathy, the hepatic manifestations of which have not been well characterized. We describe here a case of a 14-year-old girl with Senior- Loken syndrome who presented with persistent elevation of liver enzymes. Histological examination of liver biopsy specimen revealed remarkable portal expansion featured by portal fibrosis and minute ductile duplication, consistent with the malformation of interlobular bile ducts. The liver parenchyma and lobular architecture were relatively preserved with minimal inflammation. The clinical and morphologic features for the triad of nephronophthisis, retinopathy, and congenital hepatic fibrosis were reviewed and compared with other cases available in the literature. We presented a case of Senior- Loken syndrome with severe nephronophthisis and mild retinal degeneration in association with congenital hepatic fibrosis. The liver involvement poses a big challenge to the clinical interventions after renal transplantation.

ABBREVIATIONS The retinal lesions in the Senior-Loken syndrome are variable, ranging from Leber’samaurosis to . ALP: Alkaline Phosphatase; ALT: Alanine Aminotransferase; This condition causes vision problems, including an increased AST: Aspartate Aminotransferase sensitivity to light (photophobia), involuntary movements INTRODUCTION of the eyes (nystagmus), and extreme farsightedness (hyperopia). Retinitis pigmentosa is characterized by bone Senior-Løken syndrome is a rare autosome recessive spicule pigmentation of the retina and presents initially with disorder, characterized by the combination of nephronophthisis night blindness which slowly progress to daytime blindness. Leber’samaurosis is a severe form of retinal dystrophy which of life. The estimated prevalence is about 1 in 1 million people leads to blindness nystagmus and a diffuse atypical retinal and retinopathy, which usually presents in the first two decades et al., and Loken et al. [1,2], and has also been referred to as that have been reported in this syndrome include cataract, Coat’s hereditaryworldwide. renal-retinalIt was first described syndrome, in 1961, juvenile separately nephronophthisis by Senior pigmentation and pallor of the optic disc [7]. Other ocular findings with leberamaurosis, and renal dysplasia with retinal aplasia. Hepatic manifestations of Senior-Loken syndrome have been diseaseLiver and involvement keratoconus in[8,9]. Senior-Loken syndrome has been mentioned in a small number of reports. reported rarely, but the clinicopathologic features are not well characterized. The present case reports was aimed at describing Nephronophthisis presents initially with and the clinical and morphologic features in a recent case of and progressing insidiously to end-stage renal disease Senior-Loken syndrome and, in conjunction with prior reports, summarizes the known features of liver involvement in this syndrome. theby the tubular second basement decade. The membrane main histological [3,4]. It is findings the most are common tubular atrophy, interstitial fibrosis, and thickening and lamellation of CASE PRESENTATION presenting alone or in combination with another multisystem A 14-year-old female patient was referred to the pediatric disorder,genetic cause and ofSenior-Loken end stage renal syndrome disease accounts in the first for three about decades, 10-15 hepatology division for the evaluation of persistent elevation of % of cases [5-7]. liver enzymes with intermittent itching in the soles of the feet.

Cite this article: Qiu LQ, Mais DD (2017) Clinicopathologic Features of Hepatic Involvement in Senior-Loken Syndrome: A Case Report and Review of Litera- ture. J Liver Clin Res 4(2): 1037. Mais et al. (2017) Email: Central

She was asymptomatic overall, denying , icterus, disease secondary to nephronophthisis, and decreased night dark urine, fatigue, and malaise. Her family history was non- visionHer past due medical to retinitis history pigmentosa, was significant with a diagnosis for end-stage of Senior- renal contributory. She was progressing normally in school. In early Loken syndrome type 1, with NPHP1 gene mutation, rendered in 2014. She subsequently underwent hemodialysis followed by 12 years of age, an at that time was interpreted peritoneal , and cadaveric renal transplantation in July as2014 , when she and first a liver presented biopsy forwas end-stage performed. renal She disease was then at 2015. noted to have abnormal liver enzymes and alkaline phosphatase (ALP), with alanine aminotransferase (ALT) and aspartate

Table 1: Age at Liver Clinical and morphologicalRetinal features of the triad of nephronophthisis, retinal lesion and congenital hepatic fibrosis. Case Sex diagnosis function Liver biopsy Other Follow-up Reference lesions (years) tests Diffuse Mild peri-lobular Tapetoretinal elevation Mental Died of uremia at 1 M 12 Y degeneration ALP: retardation age 13 normal fibrosis,proliferation small [6] Mental Tapetoretinal Minimal retardation, Died of uremia at 2 M 12 degeneration Y [23] elevation psychomotor (since birth) Portal fibrosis retardation Not able to Growth age 19 follow light retardation, Died of uremia at 3 M 4.5 and blindness Y Normal ductal polydactyly [25] age 5 within 4 years Portalproliferation fibrosis, and cerebral of age abnormalities Not able to Growth follow light AST 54 ductal retardation, Died of uremia at 4 M 5.5 and blindness Y Portalproliferation, fibrosis, [25] thymic atrophy, age 5.75 within 4 years ALP 240 centri-lobular ptosis of age ALT 65 congestion 2 years later after Pigmentary ALT 70 5 F 15 Y (not biopsy- transplantation and [24] retinopathy ALP 300 Liverproven) fibrosis cyclophosphamide therapy Fibrosis, Pigmentary ALT 53 portal A minor increase retinopathy ALP 222 F 13 Y in liver enzymes in [24] (night the rest: proliferation 4-year follow-up blindness) normal 6 ofinfiltration, bile ducts Mental retardation, Retinitis coloboma, 7 F 12.5 Y NA NA [5] pigmentosa skeletal Portal fibrosis anomalies, and cerebellar ataxia Mental retardation, kyphoscoliosis, Retinitis short 8 F 13 NA NA (not biopsy- NA [5] pigmentosa metatarsale IV), Liverproven) fibrosis cerebellar ataxia, pulmonary emphysema ALT:144- Retinitis 770 Ductal pigmentosa Hepato- AST: 37- F 12 proliferation, Current This report (decreased 300 9 night vision) 851 portal fibrosis ALP: 97- Notes: Abbreviations: ALT: Alanine Transaminase; AST: Aspartate Transaminase; ALP: Alkaline Phosphatase Case 2, mother had abnormal ERG; Cases 3 and 4 were monozygotic twins; Cases 5 and 6 were sisters from one family; NA, not available.

J Liver Clin Res 4(2): 1037 (2017) 2/5 Mais et al. (2017) Email: Central aminotransferase (AST) being elevated to 1.5 to 2 times the nephronophthisis and retinopathy. Also reported are several variants, including some with short stature, kyphoscoliosis, small hands (short metacarpals), madarosis, dysmorphic features enzymesupper limit surged, of normal with inALT late of 2014. approximately Her liver enzymes 500 U/L, fluctuated AST 200 U/L,between and normalALP 800 to U/L. slightly Her serum elevated bilirubin until early and albumin 2016 when had Cases in which there is hepatic involvement are rare and the remained normal throughout the course. clinicopathologicof face and hands, features pancreatitis, in such and caseshepatic therefore fibrosis [5,10-13]. not well characterized. On examination, she was found to have short stature and underweight (< 5th percentile for age) before renal transplantation Senior-Loken syndrome, like nephronophthisis disorders in 2015 but had gained weight normally since, achieving normal generally, is considered one of the “,” multisystem developmental disorders stemming from defects in genes encoding ciliary proteins [4,14]. Mutations in NPHP2 and NPHP3 toranges have inhepatomegaly August 2016. and Her splenomegaly. eye examination There showed were no no stigmata icterus genes in particular, although only accounting for 1% of all cases ofor portalnystagmus , and negative and pupillaryupper endoscopy reflexes. showedShe was noalso varices. found of nephronophthisis overall, are prevalent among patients NPHP2-encoded protein Her laboratory studies were remarkable for pancytopenia, inversin interacts with nephrocystin-1, the product of NPHP1, particularly low platelet count, which were largely ascribed withand together liver involvement these co-localize [4,15,16]. to The cilia within the developing to hypersplenism after bone marrow biopsy to rule out NPHP3 encodes nephrocystin-3, which interacts hematological disorders in January 2014. Her transplanted renal with nephrocystin-1 and inversin and can inhibit canonical wnt function was within normal range, with creatinine of 0.54 mg/ signalingnephron [16].[17,18]. anti-nuclear, anti-mitochondrial, anti-liver-kidney microsomal, The nephronophthisis disorders are genetically anti-myeloperoxidase,dl and blood urea nitrogen and of anti-serine 17 mg/dl proteasein July 2016. 3 antibodies Tests for heterogeneous, originating from a variety of mutations in a small were negative; however, anti-smooth muscle antibody was genetic markers, homozygosity mapping with single nucleotide detectable). Serological tests for the viral hepatitis, including number of pleiotropic genes [19]. Molecular diagnosis may utilize hepatitisdetected A,positive hepatitis three B, andtimes hepatitis (31.6, 38.4C, were and negative. 42.4, normal: The liver not microsatellite markers, in addition to the traditional positional cloning.polymorphism A novel microarrays approach [16,17,19], involving the linkage step-wise analysis, Sanger and texture with nodular contour consistent with cirrhosis. sequencing and targeted exome sequencing is recently proposed ultrasonography in July 2016 revealed coarsened hepatic echo for studying patients with nephronophthisis [20]. A liver core needle biopsy was performed (Figures 1-3). The The clinicopathologic features of hepatic dysfunction in the case described above are consistent with congenital hepatic couldportal be tracts seen, wererepresenting enlarged, bile expanded duct reduplication. primarily There by fibrosis. was no Within the fibrous portal stroma numerous bile duct profiles properly mature during embryogenesis. It primarily affects the dilation, bile plugs, cholangitis, or ductular proliferation. The fibrosis, a disorder that results from failure of the ductal plate to lobularsignificant histology inflammation was essentially in the portal unremarkable, tracts. There with was no evidence no duct may arise sporadically or as part of an autosomal recessive of cholestasis, any sinusoidal dilation, and normal reticulin small interlobular bile ducts [5,10]. Congenital hepatic fibrosis framework. PAS and iron stains were negative. Central veins had bileinherited ducts, disease. cystic ductal Pathologically, malformations, it is defined and abnormalities by a variable of degree of periportal fibrosis, irregularly shaped reduplicating DISCUSSIONa normal appearance, no dilation or pericentral fibrosis. minimally symptomatic disease to cirrhosis. The most common In its classical form, Senior-Loken syndrome consists of manifestationportal veins [6,10]. is portal It has a hypertension, variable clinical frequently course, ranging presenting from

Figure 1

Low power magnification (40x) H&E-stained section of liver core biopsy showing nodular hepatic parenchyma with markedly expanded and confluent portal areas surrounding lobules of hepatocytes. J Liver Clin Res 4(2): 1037 (2017) 3/5 Mais et al. (2017) Email: Central

Figure 2

Medium power magnification (200x) H&E-stained section showing portal area containing multiple reduplicated profiles of interlobular bile ducts within a fibrous stroma. Adjacent lobular hepatocytes are seen in the right lower corner.

Figure 3

Medium power magnification (100x) PAS-stained section showing portal area containing multiple reduplicated profiles of interlobular bile ducts within a fibrous stroma. Adjacent lobular hepatocytes are seen to the right and left.

[10,21]. with variceal bleeding or findings attributable to hypersplenism casescongenital were hepatic reported fibrosis so far was according first mentioned to literature in 1975 search [4], using and multiplenamed Senior-Boichis keyword combinations syndrome (Table thereafter 1); several [24]. A other total cases of 9 that were presented in meeting abstract were not included distinguishedThe clinicopathologic from biliary cirrhosis, findings the presented latter demonstrating a challenging a contrastingdifferential picture diagnosis. of regenerative Congenital nodules,hepatic fibrosis periportal must edema, be typical features of severe nephronophthisis leading to dialysis, and ductular reaction not seen in this case. Caroli’s disease is in the comparison [3,24-26]. All these cases presented with the additional features of cholangitis, marked cholestasis, and renal transplantation, or death due to uremia [6,26]. The retinal characterized by the findings of congenital hepatic fibrosis with decade of life (as in the present case) to blindness by the age of 4 years.manifestations All cases variedshowed from mild decreasedelevation of night liver vision enzymes, in the normal first presents with cholestasis and a histologic picture including or slight elevation of alkaline phosphatase, and hepatomegaly ductularportal inflammation. proliferation, Lastly, rather extrahepatic than duct reduplication, biliary obstruction with with or without splenomegaly. The eight biopsy-proven cases periportal edema and inflammation. duplications secondary to either minute ductal proliferation or ductiledemonstrated malformation. portal or In peri-portal contrast tofibrosis typical and congenital multiple hepaticductile then,Congenital it was found hepatic to be associated fibrosis, with with polycystic its varied clinical manifestations, was recognized first by Kerr in 1961 [22]. Since were not observed; likewise, we did not observe this feature in fibrosis, dilatation of bile ducts and portal vein abnormalities and nephronophthisis. Congenital hepatic fibrosis in association [23].with The nephronophthisis triad of nephronophthisis, was first described retinal degeneration, by Boichis and functionour case. after These renal biopsy transplantation findings were and confirmed immunosuppressive subsequently coworkers in 1973 in a family where parents were first cousins in three autopsies [6,26]. Two cases developed worsening liver

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Cite this article Qiu LQ, Mais DD (2017) Clinicopathologic Features of Hepatic Involvement in Senior-Loken Syndrome: A Case Report and Review of Literature. J Liver Clin Res 4(2): 1037.

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