Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System

BACKGROUND: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far. PROCEDURE: Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria. RESULTS: After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence. CONCLUSION: Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment.     

Expanding phenotype of mitochondrial depletion syndrome in association with TWNK mutations

Mitochondrial DNA depletion syndromes (MDS) are a group of clinically and genetically heterogeneous autosomal recessive disorders characterized by a reduction of mtDNA. We report two siblings of Armenian origin with early onset neurodegenerative disease characterized by encephalopathy, severe hypotonia, facial dyskinetic movements, abnormal eye movements, severe failure to thrive, and abnormal renal and hepatic function. Sanger sequencing confirmed two variants in the C10orf2 gene (TWNK) and indicated a diagnosis of MDS. Our recent observation confirms that nephrocalcinosis and proximal tubulopathy can be a part of a clinical picture of MDS associated with TWNK mutations and document peculiar ocular and orobuccolingual dyskinesias. Wrist myoclonia and tongue tremor were new clinical features in our patients. We suggest that the above-mentioned clinical constellation could potentially provide the basis for the diagnosis of MDS.     

Growth impairment after ifosfamide-induced nephrotoxicity in children

BACKGROUND: The goal of this study was to analyze long-term consequences of ifosfamide-induced nephrotoxicity on growth and renal function in children treated for cancer. PROCEDURE: In a retrospective study, departments for pediatric oncology and nephrology in Germany, Austria, and Switzerland were asked to report patients with serious long-term nephrotoxicity after ifosfamide-treatment. Data at first appearance of renal dysfunction and at the last renal examination were collected using a standardized questionnaire. RESULTS: Fifty-nine patients with tubulopathy (35 severe, 24 moderate) following ifosfamide therapy were eligible for analysis of long-term outcome (median follow-up 4 years, range 1.1 to 12.9). Median height standard deviation score was significantly reduced at renal diagnosis, and at last renal examination (-1.7 and -2.1 respectively, P < 0.01 at each point in time). Patients with tubulopathy also had stunted growth in comparison with a control group of cancer patients without renal disease (mean difference at last examination: 7.3 cm (95% confidence interval: 2.5 to 12.1 cm). In patients with severe tubulopathy, glomerular filtration rate deteriorated significantly over time. End-stage renal disease was reported in one patient only, not solely caused by ifosfamide. CONCLUSION: Depending on the extent of tubular dysfunction, patients with ifosfamide-induced nephrotoxicity experienced significant growth impairment and a slow decline in glomerular filtration rate.     

Imaging features of type 1 hereditary tyrosinemia: a review of 30 patients

Hereditary tyrosinemia type 1, a common genetic disorder in the province of Quebec, is characterized by a deficiency of fumarylacetoacetate hydrolase. In this autosomal recessive disorder of tyrosine metabolism, the accumulation of succinyiacetone leads to neurologic crises, acute and chronic liver failure, complex renal tubulopathy, rickets and a hemorrhagic syndrome. Liver transplantation has dramatically modified the spontaneous course of this lethal disease. The present paper describes the imaging features of tyrosinemia in 30 patients followed from 1980 to 1995 at Hôpital Sainte-Justine, Montreal, Canada.     

Inherited salt‐losing tubulopathy: An old condition but a new category of tubulopathy

Bartter syndrome (BS) and Gitelman syndrome (GS) are syndromes associated with congenital tubular dysfunction, characterized by hypokalemia and metabolic alkalosis. Clinically, BS is classified into two types: the severe antenatal/neonatal type, which develops during the fetal period with polyhydramnios and preterm delivery; and the relatively mild classic type, which is usually found during infancy with failure to thrive. GS can be clinically differentiated from BS by its age at onset, usually after school age, or laboratory findings of hypomagnesemia and hypocalciuria. Recent advances in molecular biology have shown that these diseases can be genetically classified into type 1 to 5 BS and GS. As a result, it has become clear that the clinical classification of antenatal/neonatal BS, classic BS, and GS does not always correspond to the clinical symptoms associated with the genotypes in a one‐to‐one manner; and there is clinically no clear differential border between type 3 BS and GS. This has caused confusion among clinicians in the diagnosis of these diseases. It has been proposed that the disease name “inherited salt‐losing tubulopathy” can be used for cases of tubulopathies accompanied by hypokalemia and metabolic alkalosis. It is reasonable to use this term prior to genetic typing into type 1–5 BS or GS, to avoid confusion in a clinical setting. In this article, we review causative genes and phenotypic correlations, diagnosis, and treatment strategies for salt‐losing tubulopathy as well as the clinical characteristics of pseudo‐BS/GS, which can also be called a “salt‐losing disorder”.     

Neonatal hemochromatosis: a case report with unique presentation

Acute liver failure (ALF) is a relatively rare condition in neonates, and early diagnosis and treatment are crucial for the treatable conditions. Neonatal hemochromatosis (NH) is a rare clinical condition that is clinically defined as severe neonatal liver disease associated with hepatic and extrahepatic iron deposition in a distribution similar to that seen in hereditary hemochromatosis. Although a few cases have been reported with spontaneous remission, early and aggressive medical treatment is essential for improving the outcome. Despite aggressive treatment, some patients may require liver transplantation. We report a five-day-old male infant with NH and associated Duarte variant galactosemia, renal tubulopathy and hypertyrosinemia, who was successfully treated with combination medical treatment. Combination therapy may reduce the need for liver transplantation in infants with NH. Early diagnosis and aggressive treatment are important as in galactosemia or tyrosinemia for the outcome. Thus, NH may be listed as a treatable cause of ALF in neonates.     

Tyrosinämie Typ I Klinische und biochemische Symptome bei 3 Säuglingen

Background. Tyrosinemia type I is an autosomal recessively inherited deficiency of fumarylacetoacetate hydrolase resulting in accumulation of tyrosin and its degradation products (succinylacetoacetone mainly). Typical clinical features include liver and kidney failure as well as central nervous system involvement. There are three main forms of the disease: the acute form with manifestation in newborn infants and the subacute and the chronic form in children older than one year of age. Case reports. We report on three infants with acute tyrosinemia type 1. In two patients impaired liver function with coagulopathy, hypalbuminemia and low cholinesterase as well as renal tubulopathy with urinary phosphate loss led to the diagnosis. In one patient high galactose and phenylalanine levels at routine neonatal screening gave the hint for further investigations. All patients had anemia and thrombocytopenia. Diagnosis was established by measurement of urinary succinylacetoacetone at mean age of 54.6 days. Treatment. Treatment with 2-(nitro-4-trifluoromethylbenzoyl)-1–3-cyclohexanedione (NTBC) and a diet low in tyrosine, and phenylalanine was started. Clinical improvement and normalization of laboratory findings were noted in all patients. Discussion. Tyrosinemia type I must be considered in newborns and infants with impaired hepatic synthesis of coagulation parameters, albumin and cholinesterase and with additional signs of renal tubulopathy (hypophosphatemia and rickets mainly). For diagnosis measurements of urinary succinylacetoaceton is essential.     

Diagnosis of X-linked hypophosphatemia vitamin D resistant rickets

Recent advances in the pathophysiology and diagnosis of X-linked hypophosphatemic rickets (XLH) are reviewed. The recent discovery of the gene that is responsible for XLH especially enables us to understand the mechanism of hypophosphatemia in XLH. Laboratory and radiological findings are important for the diagnosis. However, dental abnormalities such as spontaneous dental abscess and a defect of dentin maturation are also notable findings.     

Persistently high urine glucose levels caused by familial renal glycosuria

Glycosuria generally occurs when the threshold for glucose reabsorption by the proximal renal tubule is exceeded or when reabsorption of filtered glucose is impaired. Although the discovery of glycosuria in a child will prompt screening for diabetes mellitus, it is also a sign of a rare tubulopathy called “familial renal glycosuria” (OMIM #233100). This tubulopathy is linked to a defect in the sodium–glucose co-transporter 2, encoded by the SLC5A2 gene. Here, we describe and discuss two pediatric cases in whom familial renal glycosuria was discovered fortuitously after the observation of persistently high urine glucose levels in the absence of hyperglycemia.     

X-linked hypophosphatemia: The medical expert's challenges and the patient's concerns on their journey with the disease

X-linked hypophosphatemia (XLH) is a rare inheritable disorder of phosphate handling due to loss of function mutations of the PHEX gene, associated with increased production of FGF23 and impaired bone mineralization. In children, the disease's most common manifestations are bowing deformities of the lower limbs, short stature, and spontaneous dental abscesses. In adults, these are osteomalacia, insufficiency fractures, and enthesopathies associated with bone and joint pain. The XLH patient's journey with the disease may be difficult, reflecting concerns and experiences globally common to all patients with rare genetic diseases. Delays in diagnosis often preclude an optimal treatment outcome. Under-treatment is common as treating physicians, particularly those not familiar with the disease, tend to err on the side of caution, often choosing safety over efficacy. Physical abnormalities, pain, diminished function, and impaired mobility tend not only to isolate the XLH patient from his peers but also to have a significant psychological effect, eventually leading to significant impairment in quality of life. Significant advances in understanding the pathophysiology of XLH, the availability of a very comprehensive Evidence-based Guideline for the diagnosis and management of XLH, and the successful development of an effective and safe disease-specific novel therapy for XLH, have paved the way for a significant improvement in the management of this rare disorder of phosphate metabolism, heralding a significant improvement in the disease's outcome measures. Additional data from long-term observational studies and randomized controlled trials are eagerly awaited to consolidate these promising developments in the field of this rare disease.     

Genetic advances, biochemical and clinical features and critical approach to treatment of patients with X-linked hypophosphatemic rickets

X-linked hypophosphatemic rickets (XLH) is an hereditary form of rickets due to isolated renal tubular phosphate wasting and impaired production of 1,25-dihydroxyvitamin D [1,25(OH)2D]. XLH is caused by mutations in the PHEX (phosphate regulating gene with homology to endopeptidases) gene, which is located on Xp22.1. The pathogenetic mechanisms by which mutations in the PHEX gene cause XLH are not completely known. Hypophosphatemia associated with disproportionate short stature and bone deformities of the lower limbs are the main findings in XLH patients. Some studies have shown that conventional treatment with vitamin D metabolites, such as 1,25(OH)2D3 or 1 alpha-hydroxyvitamin D3, combined with inorganic phosphate salts is able to improve serum phosphate concentrations and linear growth, as well as healing rickets. However, some patients may have poor beneficial effects by this therapy. On the other hand, some important treatment complications, such as hypervitaminosis D, nephrocalcinosis and secondary/tertiary hyperparathyroidism may occur during the current therapy. Despite conventional treatment, some patients may require surgical correction of bone deformities. In the light of the recent genetic advances the mechanisms that could be involved in the pathogenesis of XLH are discussed. Furthermore, the article reviews the effects of the medical treatment providing current recommendations for the management of XLH patients.     

Diagnostic Problems of Disorders of Tyrosine Metabolism

Abnormalities of tyrosine metabolism have been reported in infants and children with a variety of liver diseases. Especially infants with hereditary fructose intolerance show often the very similar picture of clinical symptoms with congenital tyrosinemia. The livers of the patients, two cases of congenital tyrosinemia type 1 and three cases of hereditary fructose intolerance, were studied biochemically and compared to normal control livers. Kinetic studies of p-hydroxyphenylpyruvate oxidase revealed that crude extract of livers from patients with congenital tyrosinemia were distinctively inhibited by substrate in low concentration. It is suggested that this kinetic abnormality is closely related to the fundamental defect of congenital tyrosinemia. Activity of p-hydroxyphenylpyruvate oxidase was noted in peripheral leucocytes. The patient showed a reduced activity as low as 20% of normal. Enzyme assay in leucocytes might be useful in making the definite diagnosis prior to starting correct diagnosis for tyrosinemic state.     

Die Überlebenden einer Krebserkrankung im Kindesalter Nachsorge und Spätfolgen nach erfolgreicher Therapie

With increasing success of cancer therapy in childhood detection, treatment and possibly avoidance of long term sequelae after antineoplastic therapy and the aftercare of these patients are of great importance today. The “Late Effects Surveillance System (LESS)” of the GPOH, established in 1995, collects systematically data on major late effects of patients treated according to the therapy optimising studies to answer the questions about incidence and latency after first line treatment as well as prognosis. The most significant late effects known today are cardiotoxicity mainly after therapy with anthracyclines, oto- and nephrotoxicity after platinum derivatives, tubulopathy after ifosfamide and endocrine dysfunctions causing deficiencies in growth, pubertal development and fertility. Furthermore the risk of secondary neoplasia is an important issue in the management of these patients. This is investigated by the German Childhood Cancer Registry. Knowledge of a structured aftercare in the frame work of a vertical network provides the basis of efficient care and counselling of cancer survivors in childhood and adolescence.     

Experience and Problems of Newborn Mass Screening for Inborn Errors of Metabolism in Japan

A program of newborn mass screening for inborn errors of metabolism has since 1977 been conducted by The Ministry of Health and Welfare in Japan with great success in preventing mental and physical handicaps in children and estimating the incidence of these diseases in our country as follows: phenylketonuria (PKU) 1/78,100 maple syrup urine disease (MSUD) 1/281,200 histidinemia 1/10,600 galactosemia 1/156,200 There are some genetic variants of each of these diseases, PKU, MSUD and others. Circumspection is therefore required in making a diagnosis or selecting a particular method of treatment. When MSUD is suspected, it is necessary to make a definite diagnosis promptly and take therapeutic measures including peritoneal dialysis. The efficacy of low histidine diet in histidinemia is not yet ascertained. Close inquiries should be made about the benefit of such a dietary regimen and the long term prognosis therewith. A screening test for homocystinuria by the detection of blood methionine level is difficult. In cases with high blood methionine level during the neonatal period, it is necessary to differentiate the condition from other disease with high blood methionine. Hepatorenal tyrosinemia appears to be unsuitable for mass screening because of the the unefficacy of low phenylalanine tyrosine diet in some of the patient and the difficulty to differentiate from transient tyrosinemia in normal newborn infants. However, mass-screening is recommendable for Richner-Hanhalt type tyrosinemia which responds well to dietary therapy and which is easy to differentiate from the transient tyrosinemia because of the marked elevation of blood tyrosine.     

The efficacy of liver transplantation in malignant liver tumors associated with tyrosinemia: clinical and laboratory findings of five cases

To evaluate clinical and laboratory findings of these patients and the efficacy of liver transplantation in children with hepatocellular carcinoma (HCC) and hepatoblastoma (HB) associated with tyrosinemia. Among 113 children with liver tumors diagnosed between 1972 and 2004 five patients had HCC or HB associated with tyrosinemia. The age at diagnosis of the HCC or HB ranged from 9.5 to 17 yr and male:female ratio was 1:4. During regular clinic visits for tyrosinemia, elevated alpha-fetoprotein (AFP) was detected in all patients. AFP levels ranged between 13.7 and 29 340 IU/mL. Radiological studies including ultrasound, computed tomography and magnetic resonance imaging showed heterogeneous parenchyma and nodules in the liver. The patients did not have any metastatic disease. The time from diagnosis of tyrosinemia to HCC or HB ranged from 9.25 to 15.25 yr. Histopathologically, four patients have been diagnosed as HCC and one patient had HB. All patients were given chemotherapy including cisplatin and adriamycin. In three patients, living-related liver transplantation was performed. They had no treatment after transplantation. All of them are disease free. One patient was treated with chemotherapy and right hepatectomy. She had no suitable donor for living-related liver transplantation. Three months after completing chemotherapy, she had recurrent tumor in the left lobe of the liver and she died with progressive disease. The last patient whose parents were not suitable as donors for living-related liver transplantation is waiting for a deceased donor graft. All patients had limited disease to liver due to close clinical and radiological follow up for tyrosinemia. In these patients liver transplantation is curative both for liver tumor and tyrosinemia.     

儿童脓毒性休克诊治专家共识--我们需要关注哪些变化

《儿童脓毒性休克（感染性休克）诊治专家共识（2015版）》已发表,是在国际指南的引领下,并结合国内外大量研究文献,在2006年制定的《儿科感染性休克（脓毒性休克）诊断治疗推荐方案》基础上,主要就儿童脓毒性休克定义、诊断和早期集束化治疗方案进行了部分修订。《儿童脓毒性休克（感染性休克）诊治专家共识（2015版）》的制定旨在指导临床一线医师对儿童脓毒性休克早期识别和早期积极干预,并进一步降低病死率和改善预后。     

3例低血磷性抗维生素D佝偻病的基因诊断及文献复习

对3例临床疑似X连锁低血磷抗维生素D佝偻病（XLH）患儿进行磷酸盐调节基因（PHEX）分析并确诊的临床资料进行回顾性分析及相关文献复习,探讨中国人存在的突变热点和突变类型。3例患儿均检测到PHEX基因突变,1例为无义突变（c.58C>T）,2例为剪接突变（c.1645+1G>A,c.436+1G>A）,其中c.436+1G>A为新突变。至2014年1月,世界上已报道的PHEX基因突变共有329个,错义突变占数量最多（24%）,突变热点区域有3个。不同地区的病例总数和突变类型存在差异。中国人群中,89例XLH病人进行了PHEX基因检测,发现28种突变,其中在22外显子上发现的突变数量最多（18%）,突变类型最多的为错义突变（61%）。总之,在中国人群中,XLH病人PHEX基因最常见的突变位置为第22外显子,最常见的突变类型为错义突变;c.436+1G>A 为PHEX基因的新突变。     

Tyrosinemia: A Review

Hypertyrosinemia encompasses several entities, of which tyrosinemia type I (or hepatorenal tyrosinemia, HT1) results in the most extensive clinical and pathological manifestations involving mainly the liver, kidney, and peripheral nerves. The clinical findings range from a severe hepatopathy of early infancy to chronic liver disease and rickets in the older child; gradual refinements in the diagnosis and medical management of this disorder have greatly altered its natural course, mirroring recent advances in the field of metabolic diseases in the past quarter century. Hepatorenal tyrosinemia is the inborn error with the highest incidence of progression to hepatocellular carcinoma, likely due to profound mutagenic effects and influences on the cell cycle by accumulated metabolites. The appropriate follow-up of patients with cirrhosis, the proper timing of liver transplantation in the prevention of carcinoma, and the long-term evolution of chronic renal disease remain important unresolved issues. The introduction of a new pharmacologic agent, NTBC, holds the hope of significantly alleviating some of the burdens of this disease. Mouse models of this disease have permitted the exploration of newer treatment modalities, such as gene therapy by viral vectors, including ex vivo and in utero methods. Finally, recent observations on spontaneous genetic reversion of the mutation in HT1 livers challenge conventional concepts in human genetics. Received November 15, 2000; accepted December 7, 2000.     

Live donor liver transplantation for type 1 tyrosinemia: An analysis of 15 patients

Type 1 tyrosinemia is a rare metabolic disorder of the tyrosine degradation pathway. Due to the rarity of the disease, the best evidence literature offers is limited to guidelines based on expert opinions and optimal treatment is still a debate. LT serves as a definitive treatment of the defective metabolic pathway in the liver along with other serious disease manifestations such as LF and HCC. Nitisinone is a relatively new agent that is currently recommended for the medical management of the disease. Its mechanism of action is well understood, and efficacy is well established when started presymptomatically. This study aims to evaluate outcomes of 15 patients with type 1 tyrosinemia who underwent LT in nitisinone era and discuss its effect on prevention of HCC. A LT database of 1037 patients was reviewed. Data from 15 patients with type 1 tyrosinemia were retrospectively analyzed. All the patients except one were treated with nitisinone prior to LT. Most common indications for LT were LF and suspicious nodules. Seven patients had HCC. Mortality rate was 20% (n = 3). Nitisinone treatment has opened new horizons in the management of type 1 tyrosinemia, but LT still remains the only option for the patients developing LF and in the event of HCC. Neonatal screening programs utilizing blood succinyl acetone as the marker should be encouraged especially in the countries, such as Turkey, with high prevalence of consanguineous marriages.     

Three novel PHEX gene mutations in Japanese patients with X-linked hypophosphatemic rickets

X-linked hypophosphatemic rickets (XLH) is an X-linked dominant disorder characterized by renal phosphate wasting, abnormal vitamin D metabolism, and defects of bone mineralization. The phosphate-regulating gene on the X-chromosome (PHEX) that is defective in XLH has been cloned, and its location identified at Xp22.1. It has been recognized to be homologous to certain endopeptidases. So far, a variety of PHEX mutations have been identified mainly in European and North American patients with XLH. To analyze the molecular basis of four unrelated Japanese families with XLH, we determined the nucleotide sequence of the PHEX gene of affected members. We detected a new nonsense mutation (R198X) in exon 5, a new 3 nucleotides insertion mutation in exon 12 and a new missense mutation (L160R) in exon 5 as well as a previously reported nonsense mutation in exon 8 (R291X). These results suggest that: 1) PHEX gene mutations are responsible for XLH in Japanese patients, and 2) PHEX gene mutations are heterogeneous in the Japanese population similarly to other ethnic populations.