An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis.

Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.

Conservative treatment for uncomplicated appendicitis in children: the CONTRACT feasibility study, including feasibility RCT.

BACKGROUND: Although non-operative treatment is known to be effective for the treatment of uncomplicated acute appendicitis in children, randomised trial data comparing important outcomes of non-operative treatment with those of appendicectomy are lacking. OBJECTIVES: The objectives were to ascertain the feasibility of conducting a multicentre randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of a non-operative treatment pathway with appendicectomy for the treatment of uncomplicated acute appendicitis in children. DESIGN: This was a mixed-methods study, which included a feasibility randomised controlled trial, embedded and parallel qualitative and survey studies, a parallel health economic feasibility study and the development of a core outcome set. SETTING: This study was set in three specialist NHS paediatric surgical units in England. PARTICIPANTS: Children (aged 4-15 years) clinically diagnosed with uncomplicated acute appendicitis participated in the feasibility randomised controlled trial. Children, their families, recruiting clinicians and other health-care professionals involved in caring for children with appendicitis took part in the qualitative study. UK specialist paediatric surgeons took part in the survey. Specialist paediatric surgeons, adult general surgeons who treat children, and children and young people who previously had appendicitis, along with their families, took part in the development of the core outcome set. INTERVENTIONS: Participants in the feasibility randomised controlled trial were randomised to a non-operative treatment pathway (broad-spectrum antibiotics and active observation) or appendicectomy. MAIN OUTCOME MEASURES: The primary outcome measure was the proportion of eligible patients recruited to the feasibility trial. DATA SOURCES: Data were sourced from NHS case notes, questionnaire responses, transcribed audio-recordings of recruitment discussions and qualitative interviews. RESULTS: Overall, 50% (95% confidence interval 40% to 59%) of 115 eligible patients approached about the trial agreed to participate and were randomised. There was high acceptance of randomisation and good adherence to trial procedures and follow-up (follow-up rates of 89%, 85% and 85% at 6 weeks, 3 months and 6 months, respectively). More participants had perforated appendicitis than had been anticipated. Qualitative work enabled us to communicate about the trial effectively with patients and families, to design and deliver bespoke training to optimise recruitment and to understand how to optimise the design and delivery of a future trial. The health economic study indicated that the main cost drivers are the ward stay cost and the cost of the operation; it has also informed quality-of-life assessment methods for future work. A core outcome set for the treatment of uncomplicated acute appendicitis in children and young people was developed, containing 14 outcomes. There is adequate surgeon interest to justify proceeding to an effectiveness trial, with 51% of those surveyed expressing a willingness to recruit with an unchanged trial protocol. LIMITATIONS: Because the feasibility randomised controlled trial was performed in only three centres, successful recruitment across a larger number of sites cannot be guaranteed. However, the qualitative work has informed a bespoke training package to facilitate this. Although survey results suggest adequate clinician interest to make a larger trial possible, actual participation may differ, and equipoise may have changed over time. CONCLUSIONS: A future effectiveness trial is feasible, following limited additional preparation, to establish appropriate outcome measures and case identification. It is recommended to include a limited package of qualitative work to optimise recruitment, in particular at new centres. FUTURE WORK: Prior to proceeding to an effectiveness trial, there is a need to develop a robust method for distinguishing children with uncomplicated acute appendicitis from those with more advanced appendicitis, and to reach agreement on a primary outcome measure and effect size that is acceptable to all stakeholder groups involved. TRIAL REGISTRATION: Current Controlled Trials ISRCTN15830435. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 10. See the NIHR Journals Library website for further project information.

Appendicitis is usually treated with an operation to remove the appendix. But we have learned, from other research, that some children with appendicitis may not need an operation, and could be treated with antibiotics instead. To find out how these two different treatments compare with one another, we need to do a big study. First, though, we need to see if doing that kind of study would even be possible (or 'feasible'). We carried out a feasibility study that had several parts. First, we did a small study with children who had appendicitis, whereby children were randomly allocated to have either antibiotics or an operation, with an equal chance of having either treatment. Second, we asked parents and health-care staff about why they wanted, or did not want, to take part in that small study. This helped us to understand how to make a bigger future study as acceptable as possible to children, families and surgeons. Third, we asked parents, patients and surgeons what they think are the most important things ­ or 'outcomes' ­ we should look at in future research on children who have appendicitis. From that, we developed a list of outcomes that should be included in our future big study, so we can be certain that the research we do is likely to help parents and surgeons. Overall, we established that a future big study is feasible and we have plenty of information to help us with how to plan it best, so that it has the greatest possible chance of success. We were also guided in all of these steps of the research by a group of parents, children and young people, some of whom had appendicitis and some of whom did not.

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2.

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G>T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic ß cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2 We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.

Bi-allelic CLPB mutations cause cataract, renal cysts, nephrocalcinosis and 3-methylglutaconic aciduria, a novel disorder of mitochondrial protein disaggregation.

Whole exome sequencing was used to investigate the genetic cause of mitochondrial disease in two siblings with a syndrome of congenital lamellar cataracts associated with nephrocalcinosis, medullary cysts and 3-methylglutaconic aciduria. Autosomal recessive inheritance in a gene encoding a mitochondrially targeted protein was assumed; the only variants which satisfied these criteria were c.1882C>T (p.Arg628Cys) and c.1915G>A (p.Glu639Lys) in the CLPB gene, encoding a heat shock protein/chaperonin responsible for disaggregating mitochondrial and cytosolic proteins. Functional studies, including quantitative PCR (qPCR) and Western blot, support pathogenicity of these mutations. Furthermore, molecular modelling suggests that the mutations disrupt interactions between subunits so that the CLPB hexamer cannot form or is unstable, thus impairing its role as a protein disaggregase. We conclude that accumulation of protein aggregates underlies the development of cataracts and nephrocalcinosis in CLPB deficiency, which is a novel genetic cause of 3-methylglutaconic aciduria. A common mitochondrial cause for 3-methylglutaconic aciduria appears to be disruption of the architecture of the mitochondrial membranes, as in Barth syndrome (tafazzin deficiency), Sengers syndrome (acylglycerol kinase deficiency) and MEGDEL syndrome (impaired remodelling of the mitochondrial membrane lipids because of SERAC1 mutations). We now propose that perturbation of the mitochondrial membranes by abnormal protein aggregates leads to 3-methylglutaconic aciduria in CLPB deficiency.

Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment.

Inactivating mutations in phosphate-regulating endopeptidase (PHEX) cause X-linked hypophosphatemic rickets (XLHR) characterized by phosphaturia, hypophosphatemia, bony deformities, and growth retardation. We assessed the efficacy of combined calcitriol and orally administered phosphate (Pi) therapy on longitudinal growth in relation to age at treatment onset in a retrospective, single-center review of children with XLHR and documented PHEX mutations. Growth was compared in those who started treatment before (G1; N = 10; six boys) and after (G2; N = 13; five boys) 1 year old. Median height standard deviation score (HSDS) at treatment onset was normal in G1: 0.1 [interquartile range (IR) -1.3 to 0.4) and significantly (p = 0.004) lower in G2 (IR -2.1 (-2.8 to -1.4). Treatment duration was similar [G1 8.5 (4.0-15.2) vs G2 11.9 (6.2-14.3) years; p = 0.56], as were prescribed phosphate and calcitriol doses. Recent HSDS was significantly (p = 0.009) better in G1 [-0.7 (-1.5 to 0.3)] vs G2 [-2.0 (-2.3 to -1.0)]. No effects of gender or genotype on growth could be identified. Children with PHEX-associated XLHR benefit from early treatment and can achieve normal growth. Minimal catchup growth was seen in those who started treatment later. Our findings emphasize the importance of early diagnosis to allow treatment before growth has been compromised.