An uncommon cause of early infantile liver disease and raised chitotriosidase.

Our subject presented at 11 months of age, following a varicella zoster infection, with acute on chronic liver disease and was found to have raised serum chitotriosidase. White cell enzyme analysis for Gaucher, Niemann Pick A, B and lysosomal acid lipase deficiency were normal. Niemann Pick type C (NPC) disease was considered as a provisional diagnosis and liver transplantation assessment deferred until recovery from varicella and results of mutational analysis of NPC gene were available. Liver biopsy at a later date showed findings suggestive of glycogen storage disease (GSD) type IV but he was too unstable for an urgent liver transplantation and sadly passed away at the age of 13 months. The classic hepatic subtype of glycogen storage disorder type IV (GSD IV) is a rare metabolic cause of early-onset liver disease and raised chitotriosidase. There are very few reports of raised chito in GSD IV. Liver transplantation has a favourable outcome for the hepatic subtype of GSD IV and early diagnosis in our subject could have potentially altered the outcome.

Successful liver transplantation in short telomere syndromes without bone marrow failure due to DKC1 mutation.

Short telomere syndromes are a heterogenous spectrum of disorders leading to premature cellular aging. These may involve bone marrow failure, adult-onset idiopathic pulmonary fibrosis, and liver disease, and classical entities such as dyskeratosis congenita. We report a patient who presented with common variable immunodeficiency at 3 years of age and autoimmune cytopenias at 8 years of age. He was found to have short telomeres, and genetic testing confirmed a hemizygous mutation NM_001363.4: c.-142C > G in DKC1 gene. He subsequently developed cirrhosis with severe portal hypertension and hepatopulmonary syndrome, prompting liver transplantation at 11 years of age. He remains well 10 years after transplant with no progression of bone marrow failure or progressive lung disease. In conclusion, short telomere syndromes should be considered as a potential cause of pediatric liver disease of unknown etiology, and in severe cases, isolated liver transplantation may be both appropriate and successful.

Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients.

BACKGROUND: Treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC) and dietary phenylalanine and tyrosine restriction improves physical health and life expectancy in Tyrosinemia type 1 (TT1). However, neurocognitive outcome is suboptimal. This study aimed to investigate behavior problems and health-related quality of life (HR-QoL) in NTBC-dietary-treated TT1 and to relate this to phenylalanine and tyrosine concentrations. RESULTS: Thirty-one TT1 patients (19 males; mean age 13.9 ± 5.3 years) were included in this study. Emotional and behavioral problems, as measured by the Achenbach System of Empirically Based Assessment, were present in almost all domains. Attention and thought problems were particularly evident. HR-QoL was assessed by the TNO AZL Children's and Adults QoL questionnaires. Poorer HR-QoL as compared to reference populations was observed for the domains: independent daily functioning, cognitive functioning and school performance, social contacts, motor functioning, and vitality. Both internalizing and externalizing behavior problems were associated with low phenylalanine (and associated lower tyrosine) concentrations during the first year of life. In contrast, high tyrosine (and associated higher phenylalanine) concentrations during life and specifically the last year before testing were associated with more internalizing behavior and/or HR-QoL problems. CONCLUSIONS: TT1 patients showed several behavior problems and a lower HR-QoL. Associations with metabolic control differed for different age periods. This suggests the need for continuous fine-tuning and monitoring of dietary treatment to keep phenylalanine and tyrosine concentrations within target ranges in NTBC-treated TT1 patients.

A novel mutation in VPS33B gene causing a milder ARC syndrome phenotype with prolonged survival.

INTRODUCTION: ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome is an uncommon multisystem disorder that entails a very poor prognosis. It is caused by mutations in either VPS33B or VIPAS39 gene, both playing a key role in intracellular trafficking. We report two siblings born to first cousin parents with a novel mutation in VPS33B who have both shown prolonged survival. CASES PRESENTATION: The index patient presented with bilateral hip dysplasia and arthrogryposis, failure to thrive, undernourishment, developmental delay, and low gamma-glutamyl transferase cholestasis. She at age 2 years underwent external biliary diversion with improvement in pruritus but liver disease continued to progress. She developed stomal bleeding at 7 years of age and liver biopsy displayed cirrhosis. Her 3-year-old sibling showed a similar trajectory as well as he had ichthyotic skin with excoriations. Their renal involvement was mild and stable. Genetic analysis in both patients revealed a novel homozygous mutation in NM_018668.4 (VPS33B):c.1157A > C (p.His386Pro). CONCLUSIONS: ARC syndrome is a severe disorder with few patients reported to survive beyond 12 months of age. This report discloses a novel mutation in the VPS33B gene and describes a phenotype with prolonged survival, mild renal involvement, and progressive liver disease.

Survival of children after liver transplantation for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) in childhood differs from adult HCC because it is often associated with inherited liver disease. It is, however, unclear whether liver transplantation (LT) for HCC in childhood with or without associated inherited disease has a comparable outcome to adult HCC. On the basis of data from the European Liver Transplant Registry (ELTR), we aimed to investigate if there are differences in patient and graft survival after LT for HCC between children and adults and between patients with underlying inherited versus noninherited liver disease, respectively. We included all 175 children who underwent LT for HCC and were enrolled in ELTR between 1985 and 2012. Of these, 38 had an associated inherited liver disease. Adult HCC patients with (n = 79) and without (n = 316, matched by age, sex, and LT date) inherited liver disease served as an adult comparison population. We used multivariable piecewise Cox regression models with shared frailty terms (for LT center) to compare patient and graft survival between the different HCC groups. Survival analyses demonstrated a superior longterm survival of children with inherited liver disease when compared with children with HCC without inherited liver disease (hazard ratio [HR], 0.29; 95% CI, 0.10-0.90; P = 0.03) and adults with HCC with inherited liver disease (HR, 0.27; 95% CI, 0.06-1.25; P = 0.09). There was no survival difference between adults with and without inherited disease (HR, 1.05; 95% CI, 0.66-1.66; P = 0.84). In conclusion, the potential survival advantage of children with an HCC based on inherited disease should be acknowledged when considering transplantation and prioritization for these patients. Further prospective studies accounting for tumor size and extension at LT are necessary to fully interpret our findings. Liver Transplantation 24 246-255 2018 AASLD.

Daily variation of NTBC and its relation to succinylacetone in tyrosinemia type 1 patients comparing a single dose to two doses a day.

INTRODUCTION: In hereditary tyrosinemia type 1 (HT1) patients, the dose of NTBC that leads to the absence of toxic metabolites such as succinylacetone (SA) is still unknown. Therefore, the aims of this study were to investigate the variation and concentrations of 2-(2-nitro-4-trifluormethyl-benzyl)-1,3-cyclohexanedione (NTBC) during the day in relation to the detection of SA, while comparing different dosing regimens. METHODS: All patients were treated with NTBC (mean 1.08 ± 0.34 mg/kg/day) and a low phenylalanine-tyrosine diet. Thirteen patients received a single dose of NTBC and five patients twice daily. Home bloodspots were collected four times daily for three consecutive days measuring NTBC and SA concentrations. Statistical analyses were performed by using mixed model analyses and generalized linear mixed model analyses to study variation and differences in NTBC concentrations and the correlation with SA, respectively. RESULTS: NTBC concentrations varied significantly during the day especially if NTBC was taken at breakfast only (p = 0.026), although no significant difference in NTBC concentrations between different dosing regimens could be found (p = 0.289). Momentary NTBC concentrations were negatively correlated with SA (p < 0.001). Quantitatively detectable SA was only found in subjects with once daily administration of NTBC and associated with momentary NTBC concentrations <44.3 µmol/l. DISCUSSION: NTBC could be less stable than previously considered, thus dosing NTBC once daily and lower concentrations may be less adequate. Further research including more data is necessary to establish the optimal dosing of NTBC.

Neurocognitive outcome in tyrosinemia type 1 patients compared to healthy controls.

BACKGROUND: Hereditary Tyrosinemia type 1 (HT1) is a rare metabolic disorder caused by a defect in the enzyme Fumarylacetoacetate Hydrolase. Due to this defect, toxic products accumulate which, in turn, cause liver and kidney dysfunction. Treatment with 2-(2-nitro-4-trifluoromethylbenoyl)-1,3-cyclohexanedione (NTBC) and diet has diminished these problems, but recent data indicate that HT1 patients have neurocognitive problems. However, the neuropsychological profile of these patients is unknown. Therefore, this study aimed to investigate this neuropsychological profile by comparing HT1 patients with healthy controls. METHODS: Neurocognitive testing was performed in a heterogeneous group of 19 NTBC and dietary treated HT1 patients (five female, fourteen male; mean age 12.9 ± 4.8 years; range 7.9-23.6 years) and 19 age and gender matched controls (five female, fourteen male; mean age 13.2 ± 4.6 years; range 8.1-24.8 years). IQ scores were estimated and all participants performed the Amsterdam Neuropsychological Tasks, measuring executive functions (inhibition, cognitive flexibility and working memory) and social cognition (face recognition and identification of facial emotions). RESULTS: HT1 patients showed poorer estimated IQ, executive functioning (working memory and cognitive flexibility), and social cognition compared to healthy controls. Lower IQ scores in HT1 patients were mostly unrelated to scores on executive function- and social cognition tasks and therefore did not account for group differences in these domains. Further analyses within the HT1 patient group (comparing different groups of patients based on the age at diagnosis and the clinical symptoms at diagnosis) did not reveal any significant results. The duration of NTBC treatment was negatively correlated with IQ. CONCLUSIONS: Despite the heterogeneity of the patient group, these data clearly show that IQ, executive functioning and social cognition are affected in HT1 patients, and that IQ screening is not sufficient for cognitive monitoring of these patients. Further research should focus on the underlying pathophysiological mechanisms of these impairments to consequently try to improve treatment strategies.

Glycogen storage disease type III: diagnosis, genotype, management, clinical course and outcome.

Glycogen storage disease type III (GSDIII) is a rare disorder of glycogenolysis due to AGL gene mutations, causing glycogen debranching enzyme deficiency and storage of limited dextrin. Patients with GSDIIIa show involvement of liver and cardiac/skeletal muscle, whereas GSDIIIb patients display only liver symptoms and signs. The International Study on Glycogen Storage Disease (ISGSDIII) is a descriptive retrospective, international, multi-centre cohort study of diagnosis, genotype, management, clinical course and outcome of 175 patients from 147 families (86 % GSDIIIa; 14 % GSDIIIb), with follow-up into adulthood in 91 patients. In total 58 AGL mutations (non-missense mutations were overrepresented and 21 novel mutations were observed) were identified in 76 families. GSDIII patients first presented before the age of 1.5 years, hepatomegaly was the most common presenting clinical sign. Dietary management was very diverse and included frequent meals, uncooked cornstarch and continuous gastric drip feeding. Chronic complications involved the liver (hepatic cirrhosis, adenoma(s), and/or hepatocellular carcinoma in 11 %), heart (cardiac involvement and cardiomyopathy, in 58 % and 15 %, respectively, generally presenting in early childhood), and muscle (pain in 34 %). Type 2 diabetes mellitus was diagnosed in eight out of 91 adult patients (9 %). In adult patients no significant correlation was detected between (non-) missense AGL genotypes and hepatic, cardiac or muscular complications. This study demonstrates heterogeneity in a large cohort of ageing GSDIII patients. An international GSD patient registry is warranted to prospectively define the clinical course, heterogeneity and the effect of different dietary interventions in patients with GSDIII.

Recurrent acute liver failure due to NBAS deficiency: phenotypic spectrum, disease mechanisms, and therapeutic concepts.

BACKGROUND: Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency and in about 50% the etiology remains unknown. Recently biallelic mutations in NBAS were identified as a new molecular cause of ALF with onset in infancy, leading to recurrent acute liver failure (RALF). METHODS: The phenotype and medical history of 14 individuals with NBAS deficiency was studied in detail and functional studies were performed on patients' fibroblasts. RESULTS: The phenotypic spectrum of NBAS deficiency ranges from isolated RALF to a multisystemic disease with short stature, skeletal dysplasia, immunological abnormalities, optic atrophy, and normal motor and cognitive development resembling SOPH syndrome. Liver crises are triggered by febrile infections; they become less frequent with age but are not restricted to childhood. Complete recovery is typical, but ALF crises can be fatal. Antipyretic therapy and induction of anabolism including glucose and parenteral lipids effectively ameliorates the course of liver crises. Patients' fibroblasts showed an increased sensitivity to high temperature at protein and functional level and a disturbed tethering of vesicles, pointing at a defect of intracellular transport between the endoplasmic reticulum and Golgi. CONCLUSIONS: Mutations in NBAS cause a complex disease with a wide clinical spectrum ranging from isolated RALF to a multisystemic phenotype. Thermal susceptibility of the syntaxin 18 complex is the basis of fever dependency of ALF episodes. NBAS deficiency is the first disease related to a primary defect of retrograde transport. Identification of NBAS deficiency allows optimized therapy of liver crises and even prevention of further episodes.

Biallelic Mutations in NBAS Cause Recurrent Acute Liver Failure with Onset in Infancy.

Acute liver failure (ALF) in infancy and childhood is a life-threatening emergency. Few conditions are known to cause recurrent acute liver failure (RALF), and in about 50% of cases, the underlying molecular cause remains unresolved. Exome sequencing in five unrelated individuals with fever-dependent RALF revealed biallelic mutations in NBAS. Subsequent Sanger sequencing of NBAS in 15 additional unrelated individuals with RALF or ALF identified compound heterozygous mutations in an additional six individuals from five families. Immunoblot analysis of mutant fibroblasts showed reduced protein levels of NBAS and its proposed interaction partner p31, both involved in retrograde transport between endoplasmic reticulum and Golgi. We recommend NBAS analysis in individuals with acute infantile liver failure, especially if triggered by fever.

Early nitisinone treatment reduces the need for liver transplantation in children with tyrosinaemia type 1 and improves post-transplant renal function.

BACKGROUND: Tyrosinaemia type 1 (HT1) is a rare disorder of tyrosine metabolism leading to liver failure and hepatocellular carcinoma. Treatment previously consisted of dietary restriction and orthotopic liver transplantation (OLT) but was transformed by the introduction of nitisinone in 1992. We describe the impact of nitisinone on the outcome and need for OLT in a single centre. METHODS: A retrospective analysis was performed of patients treated for HT1 at Birmingham Children's Hospital from 1989-2009. RESULTS: Thirty eight patients were treated during the study period. Prior to 1992 6/7 (85.7 %) underwent OLT compared to 7/31 (22.6 %) after 1992 (p = 0.004) when nitisinone treatment was available. Furthermore, nitisinone-treated patients proceeding to OLT started treatment at a median age of 428 (86-821) days compared to 52 (2-990) days in those who did not (p = 0.004). Pre-OLT calculated glomerular filtration rate (cGFR) was similar in both groups but nitisinone prevented early decline after OLT (pre-nitisinone median 99.8 to 45.8 ml/min/1.73 m2, p = 0.02 versus nitisinone-treated group median 104.3 to 89.9 ml/min/1.73 m2, p = 0.5). Urinary protein:creatinine ratio (PCR) fell post-OLT to within the normal range for those treated with nitisinone but remained elevated in those not treated with nitisinone. Tubular reabsorption of phosphate (TRP) was normal or near normal in both groups pre-OLT and post-OLT. Hypertension was commoner and more severe in those not treated with nitisinone. CONCLUSIONS: Nitisinone reduces the need for OLT particularly when started early. For those progressing to OLT the use of prior nitisinone therapy results in a preservation of their subsequent renal function.

Phenotypic variation and long-term outcome in children with congenital hepatic fibrosis.

BACKGROUND AND OBJECTIVE: Congenital hepatic fibrosis (CHF) and Caroli syndrome are frequently associated with renal cystic diseases. They have a variable clinical course, and the natural history is not well defined despite molecular advances. Our study describes the clinical manifestations and long-term outcome in children with this disorder. METHODS: A retrospective case review of children with CHF at a single centre diagnosed on the basis of clinical features, radiological and endoscopic evidence of portal hypertension (PHT), and compatible histopathological findings. Children were categorised based on hepatic phenotype-group 1 (Caroli syndrome) and group 2 (CHF). Hepatobiliary as well as renal manifestations were recorded at presentation, and their evolution followed up until transplant or last follow-up. RESULTS: There were 40 children (22 boys) with a median age of 1.3 years at clinical presentation. Fourteen of 40 (35%) children presented in the neonatal period with primarily renal disease, of whom 11 (78%) had Caroli syndrome (P = 0.02). Significant PHT with oesophageal varices was seen in 86%, with no difference in the incidence of gastrointestinal bleeding and varices between Caroli syndrome and CHF. Cholangitis developed in 10 of 40 (25%) and was more common in the Caroli syndrome group (P = 0.009). A higher proportion of children with Caroli syndrome developed chronic kidney disease (CKD) stage 3 and above as compared with CHF (85% vs 42%; P = 0.007). Twelve of 21 (57%) and 8 of 19 (42%) children in the Caroli syndrome and CHF groups required either combined liver-kidney or isolated liver transplant, with the most common indication for renal transplantation being end-stage renal disease (CKD5d) with or without advanced PHT or cholangitis. All 14 (100%) children with neonatal presentation developed CKD5d and required combined liver-kidney transplant before 14 years of age, whereas 77% of children presenting beyond the neonatal period survived without liver-kidney transplant (P < 0.001). Neonatal presentation was the best predictor of the need for transplant. CONCLUSIONS: Caroli syndrome is more likely to present in the neonatal period and these patients are more likely to develop CKD5d. CKD stage 3 or above with recurrent cholangitis is more common in Caroli syndrome presenting beyond the neonatal period and adds to the significant morbidity in these patients. Children presenting in the neonatal period have a more severe phenotype and should be considered early for combined liver-kidney transplant.

Plasma succinylacetone is persistently raised after liver transplantation in tyrosinaemia type 1.

BACKGROUND: Tyrosinaemia type 1 (HT1) is a rare disorder leading to accumulation of toxic metabolites such as succinylacetone (SA) and a high risk of hepatocellular carcinoma. Children with HT1 traditionally required liver transplantation (OLT) and while the need for this has been reduced by the introduction of nitisinone some still require OLT. SA inhibits the enzyme porphobilinogen (PBG) synthase and its activity can be used as a marker of active SA. Elevated urinary SA post OLT has been reported previously. This study describes a novel finding of elevated plasma SA following OLT for HT1. METHODS: A retrospective analysis was performed of patients treated for HT1 at our institution from 1989-2010. RESULTS: Thirteen patients had an OLT for HT1. In patients who received nitisinone prior to OLT, mean urinary and plasma SA were elevated prior to treatment but normalised by the time of OLT (p ≤ 0.01). Mean PBG synthase activity increased from 0.032 to 0.99 nkat/gHb (ref range 0.58-1.25) at the time of OLT (p < 0.01). Mean urinary SA in patients not treated with nitisinone was also elevated prior to OLT; plasma levels and PBG synthase activity were not available prior to OLT for this group. Following OLT, mean urinary and plasma SA were elevated in all for the duration of follow-up and associated with low-normal PBG synthase activity. CONCLUSION: Urinary and plasma SA levels are elevated following OLT for HT1. Low-normal PBG synthase activity suggests the plasma SA may be active. The clinical significance of this is unclear.

Long-term follow-up of children with 6-thioguanine-related chronic hepatoxicity following treatment for acute lymphoblastic leukaemia.

6-Thioguanine (6-TG) therapy in childhood acute lymphoblastic leukaemia results in chronic hepatotoxicity and portal hypertension. We report follow-up data in a cohort of 10 children with acute lymphoblastic leukaemia and 6-TG-related hepatotoxicity described initially in 2006. Clinically significant portal hypertension was present in the majority of patients several years after cessation of 6-TG treatment. These data reflect the natural history of noncirrhotic portal hypertension and emphasises the need to incorporate ongoing surveillance in the transition arrangement to adult services in this select group of patients.

Renal function recovery in children undergoing combined liver kidney transplants.

BACKGROUND AND METHOD: Combined liver kidney transplant (CLKT) is a recognized treatment option for end-stage renal disease due to primary hyperoxaluria (PH-I) and cystic disorders, yet there is only limited data on posttransplant renal function recovery. The objective of this study was to assess postoperative renal function of children with PH-I (group A) undergoing CLKT and to compare this with a cohort of children (group B) who received CLKT for other indications. RESULTS: Twenty-three patients underwent CLKT between 1994 and 2008 (group A: 9 patients; median age 8.6 [1.6-16.7] years; group B: 14 patients; median age 8.5 [1.9-14.6] years). The median follow-up was 88 (14-112) and 22 (4-109) months. Both groups were transplanted with comparable organs. Eight (8/9) and six (6/14) patients received preoperative renal support in each group, respectively, whereas an equal proportion of them required early postoperative renal support (4/8; 50% and 3/6; 50%, respectively). Glomerular function was significantly different between groups until first year posttransplant (median estimated glomerular filtration rate: groups A vs. B; at pretransplant, 3 mo, 6 mo, and 12 mo posttransplant, respectively; 11.06 vs. 12.61 [P=0.4], 40.78 vs. 75.83 [P=0.03], 42.59 vs. 80.56 [P=0.04] and 53.57 vs. 76.75 [P=0.005]). Overall 1-year survival is 89% versus 90% and 5-year survival is 89% versus 62%, respectively. SUMMARY: Children with PH-I receiving CLKT seem to have delayed recovery of renal function compared with polycystic disease, possibly due to mobilization of systemic oxalate. Consideration should be given to earlier or preemptive transplantation for children with PH-I.

Embryonal rhabdomyosarcoma of the ampulla of Vater in early childhood: report of a case and review of literature.

Embryonal rhabdomyosarcoma of the ampullary region is a very rare childhood tumor (2 reported cases), and herein we describe a child presenting with obstructive jaundice at early age owing to such tumor in the ampullary region. Successful management with multidisciplinary approach is discussed with reference to the literature.

The role of endoscopic ultrasound for evaluating portal hypertension in children being assessed for intestinal transplantation.

Intestinal transplant is an established treatment of irreversible intestinal failure, unless complicated by advanced intestinal failure-associated liver disease, when liver-bowel transplant may be necessary. Finding at least moderate hepatic fibrosis or gastroesophageal varices (GOV) at oesophago-gastroduodenoscopy (OGD) has been an indication for combined transplantation. Endoscopic ultrasound (EUS) is a sensitive method for detection of GOV. We hypothesized that EUS would detect early GOV and decrease the need for liver biopsy. Sixteen children, median age 13 months (range, 7-88), being assessed for intestinal transplant underwent simultaneous OGD and EUS. In 9 of 16 patients the results of OGD and EUS were concordant, that is, both positive (2) or both negative (7) for GOV. In seven patients, GOV were only identified by EUS. Liver biopsy was avoided in four of these cases. EUS is superior to OGD for detecting GOV in children with intestinal failure-associated liver disease and results in fewer liver biopsies being necessary.

Visual loss and idiopathic intracranial hypertension in children with Alagille syndrome.

BACKGROUND: Alagille syndrome (AGS) is an autosomal dominant, multisystem disorder defined by developmental abnormalities of the liver, heart, eye and skeleton. Although visual problems are recognised, the severity of visual loss and its link with idiopathic intracranial hypertension (IIH) has not been reported. AIM: To review the incidence of visual loss and IIH in children with AGS managed at a National Paediatric Liver Unit between 1989 and 2004. SUBJECTS AND METHODS: Retrospective case note review of children who fulfilled criteria for diagnosis of AGS and had an ophthalmic examination by a paediatric ophthalmologist. RESULTS: Fifty-five children with AGS were evaluated. Of these, 41 children fulfilled diagnostic criteria and had a documented ophthalmic examination. Six children had undergone liver transplantation. Three children had a definite diagnosis of IIH, 2 of whom developed postliver transplant. All 3 were treated medically, but 1 child with IIH required lumboperitoneal shunting. All 3 children with definite IIH have normal vision after treatment. Another child with probable undiagnosed IIH has bilateral optic atrophy and is registered blind. Two children with AGS are registered partially sighted, one with rod cone dystrophy and the other with pigmentary retinopathy and right disc atrophy. SUMMARY: Although visual abnormalities are well described in children with AGS, a minority of children have significant progressive visual loss. Idiopathic intracranial hypertension has been identified as a potentially treatable precipitating factor. CONCLUSIONS: We recommend annual fundoscopy in the follow-up of children with AGS to facilitate early detection and appropriate management of IIH to prevent visual loss.