[Weight loss as a presenting clinical feature of malignancy]. / Gewichtsverlies als uiting van een maligniteit.

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.

[Case reports of deceased patients]. / Casuïstiek van overleden patiënten.

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.

[Whole exome sequencing and whole genome sequencing in undiagnosed disease: of value for certain patient populations]. / 'Whole exome sequencing' en 'whole genome sequencing' bij ziekte zonder diagnose.

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.

[Respectful ethnic profiling in the care sector]. / Respectvol etnisch profileren in de zorg.

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.

The Natural History of Adrenal Insufficiency in X-Linked Adrenoleukodystrophy: An International Collaboration.

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.

[Studying abroad; the other side of the coin]. / Studeren in het buitenland.

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.

Characterization of Classical and Nonclassical Fabry Disease: A Multicenter Study.

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.

Screening, diagnosis, and management of patients with Fabry disease: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference.

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.

Adrenoleukodystrophy - neuroendocrine pathogenesis and redefinition of natural history.

X-Linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids in plasma and tissues. Virtually all men with ALD develop adrenal insufficiency and myelopathy. Approximately 60% of men develop progressive cerebral white matter lesions (known as cerebral ALD). However, one cannot identify these individuals until the early changes are seen using brain imaging. Women with ALD also develop myelopathy, but generally at a later age than men and adrenal insufficiency or cerebral ALD are very rare. Owing to the multisystem symptomatology of the disease, patients can be assessed by the paediatrician, general practitioner, endocrinologist or a neurologist. This Review describes current knowledge on the clinical presentation, diagnosis and treatment of ALD, and highlights gaps in our knowledge of the natural history of the disease owing to an absence of large-scale prospective cohort studies. Such studies are necessary for the identification of new prognostic biomarkers to improve care for patients with ALD, which is particularly relevant now that newborn screening for ALD is being introduced.

Discontinuation of enzyme replacement therapy in Fabry disease in the Dutch cohort.

Fabry disease (FD) is a progressive, multi-organ, lysosomal storage disease. Enzyme replacement therapy (ERT) is available for the treatment of the disease. While the reasons to initiate ERT have been frequently discussed, discontinuation of ERT is rarely reported. In this paper we describe our experiences with stopping ERT in FD. From 1999 through 2015, twenty-one patients discontinued ERT. These patients were generally older and more severely affected in comparison those who continued ERT. The reason to discontinue ERT switched from death or terminal illness in the first years towards treatment failure in more recent years. Three cases are described in more detail. We conclude that discontinuation of ERT should or may be considered in subgroups of FD patients although further studies on the effectiveness of ERT in subgroups of patients and the course of the disease after discontinuation of ERT are needed.

[The 'interesting case' and patient privacy: handling patient data in medical education]. / De 'interessante casus' en patiëntprivacy: Omgaan met patiëntgegevens in het medisch onderwijs.

The use of patient histories has become an essential part of medical education. Patient histories are important for the relevance, effectiveness and appeal of medical education. The sharing of patient-related information in education and further training is expected to increase in the coming years. The sharing of patient information with colleagues, students or other interested parties can conflict with the rules protecting patient privacy. The most important rule in this context is that it is the patients who decide whether their cases can be shown to others for educational purposes. Patient consent is not required if the data or images used have been fully anonymized. If the information can be traced to the patient, consent is required, preferably documented in writing. The teaching physician is responsible for the storage, protection and destruction of patient data and for controlling access to information.

The role of antibodies in enzyme treatments and therapeutic strategies.

Substitution of the defective lysosomal enzyme in lysosomal storage disorders (LSDs) often elicits antibody formation towards the infused protein. Aside from Gaucher disease, antibodies often lead to infusion associated reactions and a reduced biochemical response. In Pompe disease, antibody titer is predictive of clinical outcome, but this is less apparent in other LSDs and warrants further study. Few laboratories are capable of enzyme-antibody determination: often physicians need to rely on the enzyme manufacturer for analysis. Currently, laboratories employ different antibody assays which hamper comparisons between cohorts or treatment regimens. Assay standardisation, including measurement of antibody-related enzyme inhibition, is therefore urgently needed. Successful immunomodulation has been reported in Pompe and in Gaucher disease, with variable success. Immunomodulation regimens that contain temporary depletion of B-cells (anti-CD20) are most used. Bone marrow transplantation in MPS-I results in disappearance of antibodies. No other clinical studies have been conducted in humans with immunomodulation in other LSDs.

Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.

INTRODUCTION: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. METHODS: A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement. RESULTS: For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped. CONCLUSION: The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.

Ten-year outcome of enzyme replacement therapy with agalsidase beta in patients with Fabry disease.

BACKGROUND: Fabry disease results from deficient α-galactosidase A activity and globotriaosylceramide accumulation causing renal insufficiency, strokes, hypertrophic cardiomyopathy and early demise. We assessed the 10-year outcome of recombinant α-galactosidase A therapy. METHODS: The outcomes (severe clinical events, renal function, cardiac structure) of 52/58 patients with classic Fabry disease from the phase 3 clinical trial and extension study, and the Fabry Registry were evaluated. Disease progression rates for patients with low renal involvement (LRI, n=32) or high renal involvement (HRI, n=20) at baseline were assessed. RESULTS: 81% of patients (42/52) did not experience any severe clinical event during the treatment interval and 94% (49/52) were alive at the end of the study period. Ten patients reported a total of 16 events. Patients classified as LRI started therapy 13 years younger than HRI (mean 25 years vs 38 years). Mean slopes for estimated glomerular filtration rate for LRI and HRI were -1.89 mL/min/1.73 m(2)/year and -6.82 mL/min/1.73 m(2)/year, respectively. Overall, the mean left ventricular posterior wall thickness and interventricular septum thickness remained unchanged and normal. Patients who initiated treatment at age ≥ 40 years exhibited significant increase in left ventricular posterior wall thickness and interventricular septum thickness. Mean plasma globotriaosylceramide normalised within 6 months. CONCLUSIONS: This 10-year study documents the effectiveness of agalsidase beta (1 mg/kg/2 weeks) in patients with Fabry disease. Most patients remained alive and event-free. Patients who initiated treatment at a younger age and with less kidney involvement benefited the most from therapy. Patients who initiated treatment at older ages and/or had advanced renal disease experienced disease progression.

Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease.

BACKGROUND: Fabry disease (FD), a lysosomal storage disorder caused by α-galactosidase A (GLA) gene variants, has a heterogeneous phenotype. GLA variants can lead to classical FD, an attenuated non-classical phenotype, or no disease at all. This study investigates the value of plasma globotriaosylsphingosine (lysoGb3) to distinguish between these groups. This is of particular importance in the diagnosis of individuals with a GLA variant and an uncertain diagnosis of FD, lacking characteristic features of classical FD. METHODS: Subjects with GLA variants were grouped as classical, non-classical, uncertain or no FD, using strict phenotypical, biochemical and histological criteria. Plasma lysoGb3 was assessed by LC/MS/MS (normal ≤ 0.6 nmol/L). RESULTS: 154 subjects were grouped into classical (38 males (M), 66 females (F)), non-classical (13 M, 14 F), uncertain (5M, 9 F) or no FD (6M, 3F). All subjects with a classical phenotype had elevated lysoGb3 values (M: range 45-150, F: 1.5-41.5). LysoGb3 values in patients with a non-classical phenotype (M: 1.3-35.7, F: 0.5-2.0) were different from healthy controls (M: p<0.01, F: p<0.05), but females overlapped with controls. In the no-FD group, lysoGb3 was normal. CONCLUSIONS: LysoGb3 is a reliable diagnostic tool to discern classical FD from subjects without FD. This study suggests that the same applies to patients with a non-classical phenotype. LysoGb3 values of female patients overlap with controls. Consequently, in uncertain cases, increased lysoGb3 values are very suggestive for FD, but normal values cannot exclude FD. Confirmation in larger cohorts and data on the specificity of small lysoGb3 increases are necessary.

Hearing loss in adult patients with Fabry disease treated with enzyme replacement therapy.

INTRODUCTION: Data on prevalence, natural history, and effect of enzyme replacement therapy (ERT) on hearing loss (HL) in Fabry disease (FD) are scarce. METHODS: This is a retrospective study with cross-sectional and longitudinal analyses. Low and high-frequency HL in the Dutch FD cohort was studied in four groups: classical and non-classical FD patients with or without ERT. To study effects of ERT, longitudinal data, corrected for age and gender according to ISO-1999 guidelines, were analyzed with mixed models. RESULTS: In the cross-sectional analysis, 107 FD patients (41 males), median age 47.6 years (18.8-80.6) were analyzed. At baseline, i.e., before start of ERT, HL was present in 18 patients (16.8 %), of whom four had bilateral sensorineural HL. HL was more often present in patients with the classical phenotype than non-classical patients (p < 0.01). Likewise, males had more often HL than females. Compared to the general population, FD patients show a median HL of 8.2 dB at low frequencies (p < 0.01) and 29.5 dB at ultra-high frequencies (p < 0.01). Longitudinal analyses (n = 91) revealed that ERT treated patients show a similar rate of decline, not significantly different from healthy controls. CONCLUSION: Adult FD patients, especially classical affected males, show impaired hearing. Longitudinal analyses during ERT in these patients demonstrates a decline of HL similar to healthy controls, but HL present before initiation of therapy cannot be reversed. Whether early therapy can prevent hearing loss is unknown.

Chronic kidney disease and an uncertain diagnosis of Fabry disease: approach to a correct diagnosis.

BACKGROUND AND OBJECTIVES: Screening for Fabry disease (FD), an X-linked lysosomal storage disorder, reveals a significant number of individuals with a genetic variant of unknown significance without classical FD manifestations; these variants in the α-galactosidase A gene often result in a high residual leukocyte α-galactosidase A and it is unclear whether these individuals suffer from FD. Therefore, a structured diagnostic approach is warranted. We present a diagnostic algorithm on how to approach adults with chronic kidney disease and an uncertain diagnosis of FD nephropathy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: A modified Delphi procedure was conducted to reach consensus among 11 FD experts. A systematic review was performed to identify possible criteria that could confirm or exclude FD nephropathy. RESULTS: The gold standard for FD nephropathy was defined as characteristic storage on electron microscopy (EM) in a kidney biopsy in the absence of medication that may induce similar storage. The suggested criteria to confirm FD nephropathy are as follows: 'renal cysts', 'Maltese cross sign', 'immunohistochemical staining of Gb3 in urine' and 'high urinary Gb3'; and to exclude FD nephropathy: 'absence of renal cysts', 'small kidneys' and 'high protein excretion' were rejected because of low or uncertain specificity. Urinary Gb3 may be increased in other kidney diseases and there was no agreement on this criterion, although a third of the panel indicated that it is sufficient to diagnose FD nephropathy. The 'Maltese cross sign' and 'high urinary Gb3' were selected as red flags to suggest the possibility of FD nephropathy, but are not sufficient for a definite diagnosis of FD nephropathy. CONCLUSIONS: In adults with chronic kidney disease, an α-galactosidase A gene variant and an uncertain diagnosis of FD, a kidney biopsy with EM analysis should be performed to confirm or reject the diagnosis of FD nephropathy. Other criteria currently cannot substitute for a biopsy in these cases.

Uncertain diagnosis of fabry disease in patients with neuropathic pain, angiokeratoma or cornea verticillata: consensus on the approach to diagnosis and follow-up.

INTRODUCTION: Individuals with neuropathic pain, angiokeratoma (AK) and/or cornea verticillata (CV) may be tested for Fabry disease (FD). Classical FD is characterised by a specific pattern of these features. When a patient presents with a non-specific pattern, the pathogenicity of a variant in the α-galactosidase A (GLA) gene may be unclear. This uncertainty often leads to considerable distress and inappropriate counselling and treatment. We developed a clinical approach for these individuals with an uncertain diagnosis of FD. MATERIALS AND METHODS: A document was presented to an FD expert panel with background information based on clinical experience and the literature, followed by an online survey and a written recommendation. RESULTS: The 13 experts agreed that the recommendation is intended for individuals with neuropathic pain, AK and/or CV only, i.e. without kidney, heart or brain disease, with an uncertain diagnosis of FD. Only in the presence of FD-specific neuropathic pain (small fibre neuropathy with FD-specific pattern), AK (FD-specific localisations) or CV (without CV inducing medication), FD is confirmed. When these features have a non-specific pattern, there is insufficient evidence for FD. If no alternative diagnosis is found, follow-up is recommended. CONCLUSIONS: In individuals with an uncertain diagnosis of FD, the presence of an FD-specific pattern of CV, AK or neuropathic pain is sufficient to confirm the diagnosis of FD. When these features are non-specific, a definite diagnosis cannot (yet) be established and follow-up is indicated. ERT should be considered only in those patients with a confirmed diagnosis of FD.

High prevalence of primary adrenal insufficiency in Zellweger spectrum disorders.

Zellweger spectrum disorders are a group of autosomal recessive disorders characterized by impaired peroxisome functions. The clinical spectrum is broad, ranging from the classical most severe Zellweger syndrome to patients with a relatively mild phenotype. Treatment options are limited to symptomatic and supportive therapy. During routine follow-up we discovered patients with asymptomatic primary adrenal insufficiency. It is important to detect impaired adrenal function because it has treatment implications. Primary adrenal insufficiency was found in 7/24 patients examined, with 4/7 being asymptomatic. Systematic evaluation of adrenal function, through a Synacthen test, should be included in the clinical management of these patients.

Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in different disease stages.

OBJECTIVE: Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage. DESIGN: Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages. DATA EXTRACTION: Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis. RESULTS: Thirty-one studies were systematically reviewed while six studies were included in the meta-analysis. In patients with a GFR > 60 ml/min/1.73 m(2), decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR < 60 ml/min/1.73 m(2) had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT. CONCLUSION: ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease.