Myhre syndrome in adulthood: clinical variability and emerging genotype-phenotype correlations.

Myhre syndrome (MS, MIM 139210) is a rare multisystemic disorder caused by recurrent pathogenic missense variants in SMAD4. The clinical features have been mainly documented in childhood and comprise variable neurocognitive development, recognizable craniofacial features, a short stature with a pseudo-muscular build, hearing loss, thickened skin, joint limitations, diverse cardiovascular and airway manifestations, and increased fibrosis often following trauma or surgery. In contrast, adults with MS are underreported obscuring potential clinical variability. Here, we describe 24 adults with MS, including 17 diagnosed after the age of 18 years old, and we review the literature on adults with MS. Overall, our cohort shows a milder phenotype as well as lower mortality rates compared to what has been published in literature. Individuals with a codon 500 variant in SMAD4 present with a more pronounced neurodevelopmental and systemic phenotype. However, in contrast to the literature, we observe cardiovascular abnormalities in individuals with the p.(Arg496Cys) variant. In addition, we describe scoliosis as a new manifestation and we report fertility in two additional males with the p.(Arg496Cys). In conclusion, our study contributes novel insights into the clinical variability of MS and underscores the importance of variant-specific considerations, and we provide recommendations for the management of MS in adulthood.

Shunt Nephritis: A Case of Mistaken Identity.

BACKGROUND: Membranoproliferative glomerulonephritis is a histological pattern of glomerular injury due to the deposition of immune complexes and complement factors. It is associated with bacterial and viral infections, auto-immune diseases such as systemic lupus erythematosus and Sjögren's syndrome, monoclonal gammopathy, and complement disorders (dense deposit disease and C3 glomerulopathy).  Case presentation: This is the report of a 25-year-old male with membranoproliferative glomerulonephritis who was initially treated for systemic lupus erythematosus, but who was later diagnosed with nephritis due to a chronic infection of a central nervous system shunt, last revised at the age of 3 years old. DISCUSSION: We highlight the challenges in making an early diagnosis of shunt nephritis, and succinctly discuss the clinical, biochemical, histopathological findings, and differential diagnosis of this type of infection-related glomerulonephritis.

Carbamoylated Nail Proteins as Assessed by Near-Infrared Analysis are Associated with Load of Uremic Toxins and Mortality in Hemodialysis Patients.

Carbamoylation is an important risk factor for accelerated atherogenesis and mortality in patients undergoing hemodialysis (HD). We intended to explore whether carbamoylation as assessed by near-infrared (NIR) analysis of nail proteins is associated with (a) serum concentrations of representative uremic toxins and (b) mortality in HD patients. A total of 53 healthy volunteers and 84 consecutive HD patients were enrolled in this cross-sectional cohort study. Standard laboratory methods were used to measure routine parameters, whereas levels of uremic toxins were determined using reversed-phase high-performance liquid chromatography (RP-HPLC). Spectra of distal fingernail clippings were obtained using an Avantes NIR spectrometer and processed using chemometric data analysis. The second derivative of the peak intensity at 1494 nm attributed to N-H amide bands from NH2 of carbamoyl (-CONH2) groups was higher in HD patients than in control subjects (p < 0.0001). Peak intensity levels were associated with age and plasma levels of representative uremic toxins. Cox-regression analysis revealed a significant association with all-cause mortality, even after adjustment for age. In conclusion, our data revealed that carbamoylation as assessed by NIR analysis of nail proteins is associated with serum concentrations of uremic toxins and also with mortality in HD patients. Further research to explore whether it is a surrogate marker or a hard indicator of mortality risk is warranted.

Estimating the Level of Carbamoylated Plasma Non-High-Density Lipoproteins Using Infrared Spectroscopy.

BACKGROUND: The increased cardiovascular morbidity and mortality observed in chronic kidney disease (CKD) patients can be partly explained by the presence of carbamoylated lipoproteins. Lipid profiles can be determined with infrared spectroscopy. In this paper, the effects of carbamoylation on spectral changes of non-high-density lipoproteins (non-HDL) were studied. METHODS: In the present study, fasting serum samples were obtained from 84 CKD patients (CKD stage 3-5: n = 37 and CKD stage 5d (hemodialysis): n = 47) and from 45 healthy subjects. In vitro carbamoylation of serum lipoproteins from healthy subjects was performed using increasing concentrations of potassium cyanate. Lipoprotein-containing pellets were isolated by precipitation of non-HDL. The amount of carbamoylated serum non-HDL was estimated using attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy, followed by soft independent modelling by class analogy analysis. RESULTS: Carbamoylation resulted in a small increase of the amide I band (1714-1589 cm-1) of the infrared spectroscopy (IR) spectrum. A significant difference in the amide II/amide I area under the curves (AUC) ratio was observed between healthy subjects and CKD patients, as well as between the two CKD groups (non-dialysis versus hemodialysis patients). CONCLUSIONS: ATR-FTIR spectroscopy can be considered as a novel method to detect non-HDL carbamoylation.

Urinary myeloid IgA Fc alpha receptor (CD89) and transglutaminase-2 as new biomarkers for active IgA nephropathy and henoch-Schönlein purpura nephritis.

BACKGROUND: IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) are glomerular diseases that share a common and central pathogenic mechanism. The formation of immune complexes containing IgA1, myeloid IgA Fc alpha receptor (FcαRI/CD89) and transglutaminase-2 (TG2) is observed in both conditions. Therefore, urinary CD89 and TG2 could be potential biomarkers to identify active IgAN/HSPN. METHODS: In this multicenter study, 160 patients with IgAN or HSPN were enrolled. Urinary concentrations of CD89 and TG2, as well as some other biochemical parameters, were measured. RESULTS: Urinary CD89 and TG2 were lower in patients with active IgAN/HSPN compared to IgAN/HSPN patients in complete remission (P < 0.001). The CD89xTG2 formula had a high ability to discriminate active from inactive IgAN/HSPN in both situations: CD89xTG2/proteinuria ratio (AUC: 0.84, P < 0.001, sensitivity: 76%, specificity: 74%) and CD89xTG2/urinary creatinine ratio (AUC: 0.82, P < 0.001, sensitivity: 75%, specificity: 74%). Significant correlations between urinary CD89 and TG2 (r = 0.711, P < 0.001), proteinuria and urinary CD89 (r = - 0.585, P < 0.001), and proteinuria and urinary TG2 (r = - 0.620, P < 0.001) were observed. CONCLUSIONS: Determination of CD89 and TG2 in urine samples can be useful to identify patients with active IgAN/HSPN.

An abnormally glycosylated isoform of erythropoietin in hemangioblastoma is associated with polycythemia.

BACKGROUND: Hemangioblastomas express erythropoietin and the patients often present with polycythemia. METHODS: Serum erythropoietin was measured using a commercial immunoassay, a functional erythropoietin assay and iso-electric focusing. RESULTS: Despite the polycythemia, serum erythropoietin remained low, while a functional erythropoietin-assay showed a 4-5 higher activity in serum compared to the immunoassay. Iso-electric focusing of serum erythropoietin indicated overrepresentation of highly sialylated erythropoietin isoforms produced by the tumor. As a result, altered affinity of the monoclonal antibody used in the immunoassay for the hypersialylated isoforms was suggested. CONCLUSION: Analysis of erythropoietin isoforms may be helpful in distinguishing the ectopic erythropoietin isoforms from normally glycosylated erythropoietin.

Soluble transferrin receptor in urine, a new biomarker for IgA nephropathy and Henoch-Schönlein purpura nephritis.

OBJECTIVES: IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephritis (HSPN) might represent different ends of a continuous spectrum of glomerular disease. In both conditions, upregulated soluble transferrin receptor (sTfR) might be excreted in urine, which could be a potential biomarker to monitor disease activity and therapeutic response. METHODS: In this pilot study, 132 Caucasian patients consulting the Nephrology Department at the Ghent University Hospital because of a glomerulopathy and 50 normal controls were included. Urinary sTfR concentrations were determined in concentrated urine using a newly developed latex-enhanced immunonephelometric assay. RESULTS: Median urinary sTfR concentration was higher in patients with a primary glomerulopathy than in healthy subjects (p<0.0001). More importantly, absolute median levels of urinary sTfR were markedly higher in patients with active IgAN or HSPN [10µg/L, 95% confidence interval (CI): 6-18µg/L] in comparison with those with other morphological types of glomerulopathy (2µg/L, 95%CI: 1-4µg/L) (p<0.0001). A statistically significant difference in urinary sTfR concentration was observed between patients with active IgAN or HSPN and patients who had achieved partial or complete remission (p<0.0001). Multiple regression analysis with urinary sTfR as dependent variable revealed that proteinuria was the main predictor of urinary sTfR concentration (r(2)=0.52, p<0.001). CONCLUSION: Determination of sTfR in urine is a new and sensitive method for a potential biomarker of IgAN and HSPN.