A mosaic variant in CTNNB1/β-catenin as a novel cause for osteopathia striata with cranial sclerosis

Context: Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of beta-catenin via AXIN stabilization, acting as a negative regulator of the WNT/beta-catenin signaling pathway, a central pathway in bone formation.Objective: In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1.Results: Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for beta-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the beta-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the beta-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn beta-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn beta-catenin.Conclusion: In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.Metabolic health: pathophysiological trajectories and therap

Correction to: Outcomes of parathyroidectomy versus calcimimetics for secondary hyperparathyroidism and kidney transplantation:a propensity-matched analysis

The original version of this article unfortunately contained a mistake on the fifth and eleventh author names, from Schelto Kruijf to Schelto Kruijff and from Tessa van Ginhoven to Tessa M. van Ginhoven. The corrected author names are shown below. Schelto Kruijff and Tessa M. van Ginhoven

Outcomes of parathyroidectomy versus calcimimetics for secondary hyperparathyroidism and kidney transplantation:a propensity-matched analysis

Purpose: Calcimimetics are currently indicated for severe secondary hyperparathyroidism (SHPT). However, the role of parathyroidectomy (PTX) for these patients is still under debate, and its impact on subsequent kidney transplantation (KTX) is unclear. In this study, we compare the outcomes of kidney transplantation after PTX or medical treatment. Methods: Patients who underwent KTX and had SHPT were analyzed retrospectively. Two groups were selected (patients who had either PTX or calcimimetics prior to KTX) using a propensity score for sex, age, donor type, and parathyroid hormone levels (PTH) during dialysis. The primary outcome was graft failure, and secondary outcomes were surgical KTX complications, survival, serum PTH, serum calcium, and serum phosphate levels post-KTX. Results: Matching succeeded for 92 patients. After PTX, PTH was significantly lower on the day of KTX as well as at 1 and 3 years post-KTX (14.00 pmol/L (3.80–34.00) vs. 71.30 pmol/L (30.70–108.30), p < 0.01, 10.10 pmol/L (2.00–21.00) vs. 32.35 pmol/L (21.58–51.76), p < 0.01 and 13.00 pmol/L (6.00–16.60) vs. 19.25 pmol/L (13.03–31.88), p = 0.027, respectively). No significant differences in post-KTX calcium and phosphate levels were noted between groups. Severe KTX complications were more common in the calcimimetics group (56.5% vs. 30.4%, p = 0.047). There were no differences in 10-year graft failure and overall survival. Conclusion: PTX resulted in lower PTH after KTX in comparison to patients who received calcimimetics. Severe complications were more common after calcimimetics, but graft failure and overall survival were similar

Timing of Parathyroidectomy Does Not Influence Renal Function After Kidney Transplantation

BACKGROUND: Parathyroidectomy (PTx) is the treatment of choice for end-stage renal disease (ESRD) patients with therapy-resistant hyperparathyroidism (HPT). The optimal timing of PTx for ESRD-related HPT-before or after kidney transplantation (KTx)-is subject of debate.METHODS: Patients with ESRD-related HPT who underwent both PTx and KTx between 1994 and 2015 were included in a multicenter retrospective study in four university hospitals. Two groups were formed according to treatment sequence: PTx before KTx (PTxKTx) and PTx after KTx (KTxPTx). Primary endpoint was renal function (eGFR, CKD-EPI) between both groups at several time points post-transplantation. Correlation between the timing of PTx and KTx and the course of eGFR was assessed using generalized estimating equations (GEE).RESULTS: The PTxKTx group consisted of 102 (55.1%) and the KTxPTx group of 83 (44.9%) patients. Recipient age, donor type, PTx type, and pre-KTx PTH levels were significantly different between groups. At 5 years after transplantation, eGFR was similar in the PTxKTx group (eGFR 44.5 ± 4.0 ml/min/1.73 m2) and KTxPTx group (40.0 ± 6.4 ml/min/1.73 m2, p = 0.43). The unadjusted GEE model showed that timing of PTx was not correlated with graft function over time (mean difference -1.0 ml/min/1.73 m2, 95% confidence interval -8.4 to 6.4, p = 0.79). Adjustment for potential confounders including recipient age and sex, various donor characteristics, PTx type, and PTH levels did not materially influence the results.CONCLUSIONS: In this multicenter cohort study, timing of PTx before or after KTx does not independently impact graft function over time.</p

Hepatitis C virus infection among transmission-prone medical personnel

Hepatitis C virus (HCV)-infected physicians have been reported to infect some of their patients during exposure-prone procedures (EPPs). There is no European consensus on the policy for the prevention of this transmission. To help define an appropriate preventive policy, we determined the prevalence of HCV infection among EPP-performing medical personnel in the Academic Medical Center in Amsterdam, the Netherlands. The prevalence of HCV infection was studied among 729 EPP-performing health care workers. Serum samples, stored after post-hepatitis B virus (HBV) vaccination testing in the years 2000–2009, were tested for HCV antibodies. Repeat reactive samples were confirmed by immunoblot assay and the detection of HCV RNA. The average age of the 729 health care workers was 39 years (range 18–66), suggesting a considerable cumulative occupational exposure to the blood. Nevertheless, only one of the 729 workers (0.14%; 95% confidence interval [CI]: <0.01% to 0.85%) was tested and confirmed to be positive for anti-HCV and positive for HCV RNA, which is comparable to the prevalence of HCV among Amsterdam citizens. Against this background, for the protection of personnel and patients, careful follow-up after needlestick injuries may be sufficient. If a zero-risk approach is desirable and costs are less relevant, the recurrent screening of EPP-performing personnel for HCV is superior to the follow-up of reported occupational exposures

Identification of compound heterozygous variants in LRP4 D\demonstrates that a pathogenic variant outside the third beta-propeller domain can cause sclerosteosis

Sclerosteosis is a high bone mass disorder, caused by pathogenic variants in the genes encoding sclerostin or LRP4. Both proteins form a complex that strongly inhibits canonical WNT signaling activity, a pathway of major importance in bone formation. So far, all reported disease-causing variants are located in the third beta-propeller domain of LRP4, which is essential for the interaction with sclerostin. Here, we report the identification of two compound heterozygous variants, a known p.Arg1170Gln and a novel p.Arg632His variant, in a patient with a sclerosteosis phenotype. Interestingly, the novel variant is located in the first beta-propeller domain, which is known to be indispensable for the interaction with agrin. However, using luciferase reporter assays, we demonstrated that both the p.Arg1170Gln and the p.Arg632His variant in LRP4 reduced the inhibitory capacity of sclerostin on canonical WNT signaling activity. In conclusion, this study is the first to demonstrate that a pathogenic variant in the first beta-propeller domain of LRP4 can contribute to the development of sclerosteosis, which broadens the mutational spectrum of the disorder.Diabetes mellitus: pathophysiological changes and therap