Deletion of protein tyrosine phosphatase,non-receptor type 4 (PTPN4) in twins with a Rett syndrome-like phenotype

Rett syndrome (RTT), a neurodevelopmental disorder that predominantly affects females, is primarily caused by variants in MECP2. Variants in other genes such as CDKL5 and FOXG1 are usually associated with individuals who manifest distinct phenotypes that may overlap with RTT. Individuals with phenotypes suggestive of RTT are typically screened for variants in MECP2 and then subsequently the other genes dependent on the specific phenotype. Even with this screening strategy, there are individuals in whom no causative variant can be identified, suggesting that there are other novel genes that contribute to the RTT phenotype. Here we report a de novo deletion of protein tyrosine phosphatase, non-receptor type 4 (PTPN4) in identical twins with a RTT-like phenotype. We also demonstrate the reduced expression of Ptpn4 in a Mecp2 null mouse model of RTT, as well as the activation of the PTPN4 promoter by MeCP2. Our findings suggest that PTPN4 should be considered for addition to the growing list of genes that warrant screening in individuals with a RTT-like phenotype.     

Cerebral hypomyelination associated with biallelic variants of FIG4

The lipid phosphatase gene FIG4 is responsible for Yunis‐Varón syndrome and Charcot‐Marie‐Tooth disease Type 4J, a peripheral neuropathy. We now describe four families with FIG4 variants and prominent abnormalities of central nervous system (CNS) white matter (leukoencephalopathy), with onset in early childhood, ranging from severe hypomyelination to mild undermyelination, in addition to peripheral neuropathy. Affected individuals inherited biallelic FIG4 variants from heterozygous parents. Cultured fibroblasts exhibit enlarged vacuoles characteristic of FIG4 dysfunction. Two unrelated families segregate the same G>A variant in the +1 position of intron 21 in the homozygous state in one family and compound heterozygous in the other. This mutation in the splice donor site of exon 21 results in read‐through from exon 20 into intron 20 and truncation of the final 115 C‐terminal amino acids of FIG4, with retention of partial function. The observed CNS white matter disorder in these families is consistent with the myelination defects in the FIG4 null mouse and the known role of FIG4 in oligodendrocyte maturation. The families described here the expanded clinical spectrum of FIG4 deficiency to include leukoencephalopathy.     

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant

Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh‐like syndrome identified homozygous protein‐truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C‐terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Our data suggest that the hypomorphic effect of the TIMMDC1 protein‐truncating variant does not constitute a dual diagnosis in this individual. We recommend cautious assessment of variants in the C‐terminus of TIMMDC1 and emphasize the need to consider the caveats detailed within the American College of Medical Genetics and Genomics (ACMG) criteria when assessing variants.     

Minimizing complications during retropubic radical prostatectomy - is ureteral stenting necessary?

Objectives and aims

To avoid damage to the ureters during bladder neck preparation in radical prostatectomy for prostate cancer, it may be helpful to insert ureteral stents temporarily or to intravenously administer indigo carmine dye for enhanced visualisation of ureteric orifices. We evaluated our bladder neck preserving technique at radical prostatectomy with regard to ureteric injuries.

Patients and methods

We analysed 369 consecutive radical prostatectomies operated in our clinic in a bladder neck preserving technique. The following parameters were assessed in this retrospective study: number of prophylactic ureteric stent insertions, application of indigo carmine dye, observed injuries of the ureters by the surgeon, postoperative increase of serum creatinine and postoperative status of kidney ultrasound.

Results

In 7/369 prostatectomies (1.90%) a ureteric stent insertion was performed, indigo carmine was not applied to any patient at all, yet no intraoperative injury of a ureter was observed by a surgeon. No revision was necessary due to a ureteral injury within the observation period of one year after surgery. In 17 patients with preoperative normal creatinine value a pathological value was observed on the first postoperative day (mean 1.4 mg/dl). In these patients no consecutive postrenal acute renal failure was observed, no hydronephrosis was monitored by ultrasound and no further intervention was necessary.

Conclusions

Bladder neck preserving operation technique does not implicate the need of prophylactic ureteric stent insertions and has no higher incidence of ureteric injuries.     

Perioperative search for circulating tumor cells in patients undergoing radical cystectomy for bladder cancer

Objective

Despite having an organ confined tumor stage at the time of radical cystectomy, a certain number of bladder cancer patients will develop local or distant metastases over time. Currently there are no reliable serum markers for monitoring and evaluating risk profiles of urothelial cancers. Several studies suggest that detection of Circulating Tumor Cells (CTC) may correlate with disease status and prognosis at baseline and early in the treatment of cancers. The presence of CTCs in whole blood before and during radical cystectomy could provide further information on disease status, and could be used as an indicator to determine the need for adjuvant or even perioperative chemotherapy.

Methods

From 03/2009 to 05/2009, five patients with histologically proven transitional cell carcinoma of the urinary bladder participated in this study. All patients were admitted to the hospital for radical cystectomy (rCx). A standard or extended lymph node dissection was performed in all cases. Preoperative CT or MRI scans revealed no distant or local metastases. Median age was 66.8 years (55-81 yrs). After obtaining informed consent from each patient, approximately 30 mL of peripheral blood was taken immediately before rCx and again during surgical removal of the urinary bladder from the patients'' body. As additional parameters, operation time (OR) for surgical removal of the bladder and the amount of blood volume that was used for the detection of CTCs were recorded. Obtained blood samples were processed using the Cell-Search System (Veridex^©) within 48 hours of collection. CTCs were identified and quantitated using the Cell-Search System, followed by re-evaluation of the provided results by specially trained and experienced personal. (CS, SH)

Results

CTCs were detected before and during surgical removal of the urinary bladder in one of five patients (20%). In the one patient positive for CTC, two CTCs were detected in the blood sample that was obtained before surgery (analyzed blood volume was 25 mL). There was one CTC detected in the blood sample that was obtained during surgical removal of the urinary bladder (analyzed blood volume was 27 mL). There was no rise in the amount of CTCs during surgical procedure. The final pathological report of this patient showed an advanced tumor stage (T3b, N0, R1). In the other patients, no CTCs were detected at all, neither before rCX nor right after surgical removal of the bladder. Pathological stage for these patients ranged from pT1m G3 -pT2b G3. None of these patients showed lymph node involvement. An average of 14.6 lymph nodes (5-40 LNs) were obtained. OR time to surgical removal of the urinary bladder ranged from 60 minutes to 150 minutes (mean 82 min.).

Conclusions

Although only a very small group of patients was analyzed in this study, the presence of CTCs seems to be correlated with an advanced tumor stage. Therefore the detection of CTCs could be used for an optimized assessment of a patient''s disease status in urothelial cancer. A further aim of this study was to assess whether surgical manipulation during radical cystectomy is associated with a release of CTCs into the vascular system. None of the patients who were negative for CTCs before surgery showed CTCs during surgical removal of the bladder, suggesting that there was no release of CTCs during surgery. However, further study is needed to prove these findings and evaluate the significance of CTCs as an indicator for therapeutic decisions.     

Snapping knee syndrome in an athlete caused by the semitendinosus and gracilis tendons. A case report

We report a case of symptomatic subluxation of the semitendinosus and gracilis over the posteromedial corner of the tibia manifesting with snapping. This is the first such case recorded in non-Asian population and in a high-demand athlete. Snapping was reproduced on active extension of the knee and at initiation of flexion and could be readily palpated over the posteromedial aspect of the tibia. Dynamic ultrasound, a key diagnostic tool in such conditions, revealed abrupt anterior subluxation of the semitendinosus and gracilis tendons during active terminal extension over the insertion of the semimembranosus as well as areas of tendinopathy corresponding with the site of subluxation. Due to failure of conservative treatment, surgery was undertaken, involving tenotomy and resection of a 10-12 cm segment of the semitendinosus and gracilis. The patient returned to the same level of sporting activities within 4 months and remained symptom-free 18 months post-operatively. The role of eccentric loading of the knee joint, as well as the "protective" role of the accessory tendinous bands and aponeurotic expansions of the semitendinosus and gracilis is discussed.