Recurrent Hyperparathyroidism Due to a Novel CDC73 Splice Mutation

The recognition of hereditary causes of primary hyperparathyroidism (pHPT) is important because clinical care and surveillance differ significantly between sporadic and hereditary pHPT. In addition, the increasing number of genetic tests poses a challenge to classify mutations as benign or pathogenic. Functional work‐up of variants remains a mainstay to provide evidence for pathogenicity. We describe a 52‐year‐old male patient with recurrent pHPT since age 35 years. Despite several neck surgeries with complete parathyroidectomy, he experienced persistent pHPT, necessitating repeated surgery for a forearm autotransplant, which finally resulted in unmeasurable parathyroid hormone (PTH) levels. Genetic testing revealed a new CDC73 variant (c.238‐8G>A [IVS2‐8G>A]), initially classified as a variant of uncertain significance. Parathyroid tissue from the initial surgeries showed loss of heterozygosity. Using an RT‐PCR approach, we show that the mutation leads to the use of a cryptic splice site in peripheral mononuclear cells. In addition, a minigene approach confirms the use of the cryptic splice site in a heterologous cell system. The novel c.238‐8G>A CDC73 variant activates a cryptic splice site, and the functional data provided justify the classification as a likely pathogenic variant. Our results underscore the importance of functional work‐up for variant classification in the absence of other available data, such as presence in disease‐specific databases, other syndromic clinical findings, or family history. In addition, the presented case exemplifies the importance to consider a hereditary condition in young patients with pHPT, particularly those with multi‐gland involvement. © 2017 American Society for Bone and Mineral Research.     

Tissue characterization of head and neck lesions using diffusion-weighted MR imaging with SPLICE

Purpose

The purpose of this study was to evaluate the usefulness of diffusion-weighted (DW) MR imaging with split acquisition of fast spin-echo signals (SPLICE) in the tissue characterization of head and neck mass lesions.

Patients and methods

DW MR images of 67 head and neck mass lesions were obtained using SPLICE with b-factors of 0 and 771 s/mm². The lesions were classified into three categories: 16 cysts, 32 benign tumors, and 19 malignant tumors. After ADC maps were constructed for all lesions, ADC values were calculated and compared among the three categories.

Results

No case showed severe image distortion on DW MR imaging with SPLICE, and reliable ADC maps and ADC values were obtained in all cases. The mean ADC value of cysts was 2.41 ± 0.48 × 10⁻³ mm²/s, which was significantly higher than that of benign (1.48 ± 0.62 × 10⁻³ mm²/s) and malignant (1.23 ± 0.45 × 10⁻³ mm²/s) tumors (P < 0.001). However, there was no significant difference between the ADC values of benign and malignant tumors (P = 0.246). When an ADC value of 2.10 × 10⁻³ mm²/s or higher was used as the diagnostic criterion for cysts, the sensitivity, specificity, and accuracy were 94%, 88%, and 90%, respectively.

Conclusion

SPLICE was considered a recommended DW MR imaging technique for the head and neck. Although ADC values were useful in differentiating cysts from tumors, they contributed little in predicting malignancy.     

Multishot diffusion-weighted SPLICE PROPELLER MRI of the abdomen.

Multishot FSE (fast spin echo)-based diffusion-weighted (DW)-PROPELLER (periodically rotated overlapping parallel lines with enhanced reconstruction) MRI offers the potential to reduce susceptibility artifacts associated with single-shot DW-EPI (echo-planar imaging) approaches. However, DW-PROPELLER in the abdomen is challenging due to the large field-of-view and respiratory motion during DW preparation. Incoherent signal phase due to motion will violate the Carr-Purcell-Meiboom-Gill (CPMG) conditions, leading to destructive interference between spin echo and stimulated echo signals and consequent signal cancellation. The SPLICE (split-echo acquisition of FSE signals) technique can mitigate non-CPMG artifacts in FSE-based sequences. For SPLICE, spin echo and stimulated echo are separated by using imbalanced readout gradients and extended acquisition window. Two signal families each with coherent phase properties are acquired at different intervals within the readout window. Separate reconstruction of these two signal families can avoid destructive phase interference. Phantom studies were performed to validate signal phase properties with different initial magnetization phases. This study evaluated the feasibility of combining SPLICE and PROPELLER for DW imaging of the abdomen. It is demonstrated that DW-SPLICE-PROPELLER can effectively mitigate non-CPMG artifacts and improve DW image quality and apparent diffusion coefficient (ADC) map homogeneity.     

Targeted single-shot methods for diffusion-weighted imaging in the kidneys

Purpose:

To investigate the feasibility of combining the inner‐volume‐imaging (IVI) technique with single‐shot diffusion‐weighted (DW) spin‐echo echo‐planar imaging (SE‐EPI) and DW‐SPLICE (split acquisition of fast spin‐echo) sequences for renal DW imaging.

Materials and Methods:

Renal DWI was performed in 10 healthy volunteers using single‐shot DW‐SE‐EPI, DW‐SPLICE, targeted‐DW‐SE‐EPI, and targeted‐DW‐SPLICE. We compared the quantitative diffusion measurement accuracy and image quality of these targeted‐DW‐SE‐EPI and targeted DW‐SPLICE methods with conventional full field of view (FOV) DW‐SE‐EPI and DW‐SPLICE measurements in phantoms and normal volunteers.

Results:

Compared with full FOV DW‐SE‐EPI and DW‐SPLICE methods, targeted‐DW‐SE‐EPI and targeted‐DW‐SPLICE approaches produced images of superior overall quality with fewer artifacts, less distortion, and reduced spatial blurring in both phantom and volunteer studies. The apparent diffusion coefficient (ADC) values measured with each of the four methods were similar and in agreement with previously published data. There were no statistically significant differences between the ADC values and intravoxel incoherent motion (IVIM) measurements in the kidney cortex and medulla using single‐shot DW‐SE‐EPI, targeted‐DW‐EPI, and targeted‐DW‐SPLICE (P > 0.05).

Conclusion:

Compared with full‐FOV DWI methods, targeted‐DW‐SE‐EPI and targeted‐DW‐SPLICE techniques reduced image distortion and artifacts observed in the single‐shot DW‐SE‐EPI images, reduced blurring in DW‐SPLICE images, and produced comparable quantitative DW and IVIM measurements to those produced with conventional full‐FOV approaches. J. Magn. Reson. Imaging 2011;33:1517–1525. © 2011 Wiley‐Liss, Inc.     

Estrogen Receptor Variants

Estrogen receptor (ER)³ geneexpression in breast epithelium is an intricatelyregulated event. The human ER gene is transcribed fromat least three different promoters which are expressedin a cell- and tissue-specific manner, and result in mRNAisoforms with unique 5'-untranslated exons. The ER isoverexpressed in about two thirds of breast tumors, andeven in early premalignant breast lesions compared with adjacent normal breast epithelium.Furthermore, normal breast epithelium as well as breastcancer tissue contains alternatively spliced ER mRNAvariants where single or multiple exons are skipped. It is still unclear if any or all of the ERmRNA splicing variants are translated in vivo, and if achange in the balance of ER variants could effect tumordevelopment and progression to hormone-independent growth. Although infrequent in primary breastcancer, single amino acid changes within the ER inmetastatic disease which might influence cellproliferation may also contribute to neoplasticprogression of the mammary epithelium.