Unexpected weight loss presents a diagnostic challenge as it is associated with a wide range of benign and serious conditions. Although it is readily associated with malignancy, the risk of cancer in adults with unexpected weight loss presenting to primary care is 2% or less. In male patients aged 60 years or older and in patients with concurrent clinical symptoms, signs and abnormal blood test, the risk of cancer increases. Initial testing should include a history including medication review, physical examination and blood tests. Recommended blood tests include a complete blood count, basic metabolic panel, liver function tests, thyroid function tests, C-reactive protein level, erythrocyte sedimentation rate and lactate dehydrogenase measurement. Imaging and invasive testing may be considered based on initial evaluation. When the initial evaluation is unremarkable, an observation period is recommended for young patients in particular.

Publishing a patient history or case report fulfills an important role in education and scientific research. However, this requires proper privacy protection. The main rule is that it must be nearly impossible to identify a patient in the presented case. If complete anonymity is not a possible, or if this is doubtful, publication is only possible after the patient's informed consent. But what if such authorization cannot be obtained, e.g. after a patient's death, or due to unknown whereabouts? In such a situation it should be possible to publish these cases, but only after careful consideration of all interests by authors and editorial board, possibly including opinions of the next of kin.

Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health. We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In vitro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in vivo. In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.

Publishing a patient history or case report fulfills an important role in education and scientific research. However, this requires proper privacy protection. The main rule is that it must be nearly impossible to identify a patient in the presented case. If complete anonymity is not a possible, or if this is doubtful, publication is only possible after the patient's informed consent. But what if such authorization cannot be obtained, e.g. after a patient's death, or due to unknown whereabouts? In such a situation it should be possible to publish these cases, but only after careful consideration of all interests by authors and editorial board, possibly including opinions of the next of kin.

Not only rare diseases are uncommon. There are also rare presentations of common diseases, not to mention rare side effects of infrequently prescribed or new drugs. Not all of these rare disease presentations have a genetic causal component. Additional (genetic or non-genetic) ancillary diagnostic tests, in which some of the inevitably occurring chance findings will present us with new problems, are not the solution for this problem, nor are disease or therapy oriented centres of expertise. The solution should be sought in pattern recognition; not by the individual physician, but through collaboration of physicians who take the time to give meaning to carefully obtained clinical parameters in individual patients. The size and composition of such a - often ad hoc - partnership should be adapted to each individual situation.

Not only rare diseases are uncommon. There are also rare presentations of common diseases, not to mention rare side effects of infrequently prescribed or new drugs. Not all of these rare disease presentations have a genetic causal component. Additional (genetic or non-genetic) ancillary diagnostic tests, in which some of the inevitably occurring chance findings will present us with new problems, are not the solution for this problem, nor are disease or therapy oriented centres of expertise. The solution should be sought in pattern recognition; not by the individual physician, but through collaboration of physicians who take the time to give meaning to carefully obtained clinical parameters in individual patients. The size and composition of such a - often ad hoc - partnership should be adapted to each individual situation.

Whole exome sequencing and whole genome sequencing in undiagnosed disease: of value for certain patient populations Whole exome sequencing and whole genome sequencing (WES/WGS) as a diagnostic tool has become more readily available. A recent study on the diagnostic yield in a highly selected patient population with undiagnosed disease has demonstrated the power of a stringent diagnostic process that includes WES/WGS. Up to one third of patients received a diagnosis, following critical clinical review of tests performed previously, additional targeted biochemical or genetic diagnostic tests and/or the application of WES/WGS. In more than 60% of the resolved cases, WES or WGS played a crucial role. The success of the Undiagnosed Disease Network relies strongly on patient selection, review of clinical symptoms and medical records by a team of specialists, and close collaboration with basic scientists and laboratories to study the clinical impact of possible genetic variations and mutations that are discovered through WES/WGS. Although the results are impressive, it remains to be determined whether such a dedicated approach is feasible in a non-research setting.

Physicians sometimes use ethnicity as part of their clinical reasoning. Using ethnicity can sometimes, however, lead to bias and may lead to discrimination or racial discrimination. In this article we discuss some examples of wrongful medical profiling based on ethnicity, but also show how ethnic profiling can be performed respectfully.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Whole exome sequencing and whole genome sequencing in undiagnosed disease: of value for certain patient populations Whole exome sequencing and whole genome sequencing (WES/WGS) as a diagnostic tool has become more readily available. A recent study on the diagnostic yield in a highly selected patient population with undiagnosed disease has demonstrated the power of a stringent diagnostic process that includes WES/WGS. Up to one third of patients received a diagnosis, following critical clinical review of tests performed previously, additional targeted biochemical or genetic diagnostic tests and/or the application of WES/WGS. In more than 60% of the resolved cases, WES or WGS played a crucial role. The success of the Undiagnosed Disease Network relies strongly on patient selection, review of clinical symptoms and medical records by a team of specialists, and close collaboration with basic scientists and laboratories to study the clinical impact of possible genetic variations and mutations that are discovered through WES/WGS. Although the results are impressive, it remains to be determined whether such a dedicated approach is feasible in a non-research setting.

Context:Primary adrenal insufficiency is an important clinical manifestation of X-linked adrenoleukodystrophy (ALD). Other manifestations include spinal cord disease and/or inflammatory demyelinating cerebral disease. Implementation of newborn screening requires natural history data to develop follow-up recommendations.Objective:To delineate the natural history of adrenal insufficiency in male patients with ALD and to assess associations between the risk for developing adrenal insufficiency, spinal cord disease, or cerebral disease and plasma C26:0/C22:0 and C24:0/C22:0 ratios, which are diagnostic biomarkers for ALD.Design:Retrospective review of medical records.Setting:Two international tertiary referral centers of expertise for ALD.Patients:Male patients with ALD followed at the centers between 2002 and 2016.Main Outcome Measures:The primary endpoint was adrenal insufficiency; secondary endpoints were spinal cord and cerebral disease.Results:Data on 159 male patients was available. The probability of developing adrenal insufficiency was described with survival analysis. Median time until adrenal insufficiency was 14 years (95% CI, 9.70 to 18.30 years). The cumulative proportion of patients who developed adrenal insufficiency was age-dependent and highest in early childhood [0 to 10 years, 46.8% (SEM 0.041%); 11 to 40 years, 28.6% (SEM, 0.037%); >40 years, 5.6% (SEM, 0.038%)]. No association between clinical manifestations and plasma ratios was detected with Cox model or Spearman correlation.Conclusions:Lifetime prevalence of adrenal insufficiency in male patients with ALD is ~80%. Adrenal insufficiency risk is time-dependent and warrants age-dependent follow-up. Besides on-demand testing if symptoms manifest, we suggest a minimum of adrenal testing every 4 to 6 months for patients age ≤10 years, annual testing for those age 11 to 40 years, and solely on-demand testing for those age >40 years.

All Dutch universities encourage their medical students to follow part of their Bachelor's or Master's degree abroad. In doing so, students encounter other cultures and see medicine from a global perspective, including possible inequalities in health care access. Though it is well-known that these experiences often have a profound impact on an individual student, little is known as to whether this also leads to better future physicians. More importantly, travelling to certain areas where endemic infections occur poses an additional risk. Universities should inform students adequately about possible health risks, while travelling abroad for their studies. Students should realize that in addition to it potentially being a great experience, despite all precautions, it could also be a negative experience and there is the possibility of contracting a disease.

A 61-year-old Ghanaian woman presented with dizziness and low oxygen saturations whereupon a methaemoglobin level of 24.9% was obtained. Initially it was thought to be caused by an unknown toxin. However, failure to normalise spontaneously and a short recurrence following administration of methylene blue suggested a congenital cause. Subsequently a novel variant in the CYB5R3 gene, coding for Cytochrome b5 reductase, was demonstrated. Absence of polycythaemia prompted additional analysis for a concomitant haemoglobinopathy.

BACKGROUND:Hearing loss (HL) is a well-known feature of Fabry disease (FD). Its presence and characteristics have mainly been studied in adult patients, while only limited data are available on the presence and degree of HL in children with FD. This prompted us to study hearing sensitivity in pediatric FD patients. METHODS:All available audiograms of the Dutch and Norwegian children with FD were retrospectively collected. First, hearing sensitivity was determined by studying hearing thresholds at low, high, and ultra-high frequencies in children with FD and comparing them to zero dB HL, i.e., healthy children. In addition, the presence and type of slight/mild HL (defined as hearing thresholds at low frequencies of 25-40 dB HL) and moderate to severe HL (hearing thresholds >40 dB HL) at first visit were analyzed. If available, follow-up data were used to estimate the natural course of hearing sensitivity and HL in children with FD. RESULTS:One-hundred-thirteen audiograms of 47 children with FD (20 boys, median age at first audiogram 12.0 (range 5.1-18.0) years) were analyzed. At baseline, slight/mild or moderate to severe HL was present in three children (6.4%, 2 boys). Follow-up measurements showed that three additional children developed HL before the age of 18. Of these six children, five had sensorineural HL, most likely caused by FD. Compared to healthy children (zero dB HL), FD children showed increased hearing thresholds at all frequencies (p < 0.01), which was most prominent at ultra-high frequencies (>8 kHz). Hearing sensitivity at these ultra-high frequencies deteriorated in a period of 5 years of follow-up. CONCLUSION:A minority of children with FD show slight/mild or moderate to severe HL, but their hearing thresholds are poorer than the reference values for normal-hearing children. Clinical trials in FD children should demonstrate whether HL can be prevented or reversed by early treatment and should specifically study ultra-high frequencies.

Fabry disease leads to renal, cardiac, and cerebrovascular manifestations. Phenotypic differences between classically and nonclassically affected patients are evident, but there are few data on the natural course of classical and nonclassical disease in men and women. To describe the natural course of Fabry disease stratified by sex and phenotype, we retrospectively assessed event-free survival from birth to the first clinical visit (before enzyme replacement therapy) in 499 adult patients (mean age 43 years old; 41% men; 57% with the classical phenotype) from three international centers of excellence. We classified patients by phenotype on the basis of characteristic symptoms and enzyme activity. Men and women with classical Fabry disease had higher event rate than did those with nonclassical disease (hazard ratio for men, 5.63, 95% confidence interval, 3.17 to 10.00; P <0.001; hazard ratio for women, 2.88, 95% confidence interval, 1.54 to 5.40; P <0.001). Furthermore, men with classical Fabry disease had lower eGFR, higher left ventricular mass, and higher plasma globotriaosylsphingosine concentrations than men with nonclassical Fabry disease or women with either phenotype ( P <0.001). In conclusion, before treatment with enzyme replacement therapy, men with classical Fabry disease had a history of more events than men with nonclassical disease or women with either phenotype; women with classical Fabry disease were more likely to develop complications than women with nonclassical disease. These data may support the development of new guidelines for the monitoring and treatment of Fabry disease and studies on the effects of intervention in subgroups of patients.

Patients with Fabry disease (FD) are at a high risk for developing chronic kidney disease and cardiovascular disease. The availability of specific but costly therapy has elevated the profile of this rare condition. This KDIGO conference addressed controversial areas in the diagnosis, screening, and management of FD, and included enzyme replacement therapy and nonspecific standard-of-care therapy for the various manifestations of FD. Despite marked advances in patient care and improved overall outlook, there is a need to better understand the pathogenesis of this glycosphingolipidosis and to determine the appropriate age to initiate therapy in all types of patients. The need to develop more effective specific therapies was also emphasized.

Background: Neuropathic pain is one of the key features of (classical) Fabry disease (FD). No randomized clinical trials comparing effectiveness of different pain management strategies have been performed. This review aims to give an overview of existing pain management strategies.Methods: PubMed and Embase were searched up to September 2014 for relevant articles on treatment of neuropathic pain in FD.Results: Seven-hundred-thirty-one articles were identified of which 26 were included in the analysis. Studies reported on 55 individuals in total, with group-sizes ranging from 1 to 8. Carbamazepine appeared most beneficial: complete pain relief in 5/25, partial relief in 17/25, and no benefit in 3/25 patients. Phenytoin resulted in complete relief in 1/27, partial relief in 12/27 and no benefit in 6/27 patients. In 8 patients a significant reduction in the frequency of pain attacks was described. Gabapentin caused partial relief in 6/7 and no relief in 1/7 patients. Little evidence was reported for SSNRI's or treatment combinations. Adverse-effects were reported in all treatment strategies.Conclusions: Only for carbamazepine, phenytoin and gabapentin there is evidence of effectiveness in neuropathic pain due to FD, but comparison of effectiveness between these drugs is lacking. In routine clinical practice adverseeffects may discourage use of carbamazepine and phenytoin in favor of second-generation antiepileptic drugs, but this is currently not supported by clinical evidence. This review suffers greatly from incomplete outcome reports and a predominance of case reports, which emphasizes the need for robust clinical trials and observational cohort studies.