Developmental and epileptic encephalopathy in two siblings with a novel, homozygous missense variant in SCN1B.

Developmental and epileptic encephalopathies are genetic disorders in which both the developmental disability and the frequent epileptic activity are the effect of a specific gene variant. While heterozygous variants in SCN1B have been described in families with generalized epilepsy with febrile seizures plus, Type 1, only three cases of homozygous, missense variants in SCN1B have been reported in association with autosomal recessive inheritance of a severe developmental and epileptic encephalopathy. We present two siblings who are homozygous for a novel, missense variant in SCN1B, c.265C>T, predicting p.Arg89Cys. The proband is an 11-year-old female with infantile-onset, fever-induced, intractable generalized tonic-clonic seizures, myoclonic seizures, and developmental slowing and autism spectrum disorder occurring later in the course of the disease. Her 4-year-old brother had a similar epilepsy phenotype, but still displays normal development. This variant has not been previously reported in the homozygous state in control databases. The variant was predicted to be damaging and occurred in the vicinity of other epileptic encephalopathy-associated missense variants that are biallelic and located in the extracellular immunoglobulin loop domain of the protein, which mediates interaction of the beta-1 subunit with cellular adhesion molecules. Our report is the first set of siblings with homozygosity for the p.Arg89Cys variant in SCN1B and further implicates biallelic mutations in this gene as a cause of epileptic encephalopathy mimicking Dravet syndrome. Interestingly, the phenotype we observed was milder compared to that previously described in patients with recessive SCN1B mutations.

Yield of biliary stent cytology: Is it time to think lean?

Background and study aims During evaluation of pancreaticobiliary strictures, it is common practice to send biliary stents for cytologic analysis. However, in recent years, complementary tissue acquisition techniques ranging from cholangioscopy to fine-needle biopsy have improved the ability to acquire tissue and diagnose malignancy. Data are limited on the current diagnostic yield and cost effectiveness of biliary stent analysis. Patients and methods We performed a retrospective study of all pancreaticobiliary stents sent for analysis in a tertiary care academic medical center from June 2013 to September 2016. Patient demographics, stent information, and final diagnosis history were collected through chart review. Costs were determined using published reimbursement rates for Medicare. Results Two hundred thirty-one stents from 175 patients were sent for cytologic analysis during the study period. Of the 62 stents obtained from patients ultimately diagnosed with malignancy, only one (1.6 %) had positive cytology for malignant cells, while the others were acellular/non-diagnostic (2/62, 3.2 %), negative (48/62, 77.4 %), or atypical (11/62, 17.7 %). The sensitivity of stent cytology for diagnosis of malignancy was 1.6 % (1/62). No cases were identified in which stent cytology changed clinical management. From a payer perspective, the mean estimated cost for each stent cytologic analysis is greater than $ 70.00. Conclusions While stent cytologic analysis is a common clinical practice, the diagnostic yield and cost effectiveness of the practice must be reevaluated. With the rise of newer diagnostic technologies such as digital cholangioscopy and endoscopic ultrasound-guided fine-needle biopsy, it may be time to "think lean" and acknowledge a sunset for biliary stent cytology.

Diagnostic utility of fluorescence in situ hybridization testing on cytology cell blocks for the definitive classification of salivary gland neoplasms.

INTRODUCTION: Fine needle aspiration biopsy (FNAB) is a minimally invasive modality to evaluate salivary gland neoplasms and help guide clinical management. However, significant overlap in the cytomorphology findings among salivary gland neoplasms often renders the definitive diagnosis challenging. Recently, a number of benign and malignant salivary gland tumors have been characterized by specific chromosomal aberrations detectable using fluorescence in situ hybridization (FISH) testing. In the present study, we evaluated the role of FISH testing performed on cytology cell blocks in the diagnosis of salivary gland neoplasms by FNAB. MATERIALS AND METHODS: The data from 57 cases of primary salivary gland tumors diagnosed using FNAB at our institution and sent for ancillary FISH testing between 2012 and 2017 were retrospectively reviewed. The FISH studies were performed on cytology cell blocks, and break-apart probes were used to detect characteristic gene rearrangements for PLAG1, MYB, MAML2, and ETV6 for pleomorphic adenoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, and secretory carcinoma (mammary analogue secretory carcinoma), respectively. Of the 57 cases sent for FISH testing, 6 were excluded because of FISH analysis failure (insufficient cell block cellularity). RESULTS: Of the 51 cases included in the analysis, 15 samples were successfully subclassified after FISH testing, and 10 of these 15 FISH-positive cases were diagnostically confirmed by the surgical pathology review of excision material. Forty cases overall had undergone subsequent excision with the histopathologic follow-up diagnosis available, and all subclassified cases had concordant FNAB, FISH, and excision diagnoses. CONCLUSIONS: FISH testing performed on cytology cell blocks is a useful adjunct in establishing the diagnosis of salivary gland neoplasms by FNAB.

Cutaneous double-hit B-cell lymphoma: an aggressive form of B-cell lymphoma with a propensity for cutaneous dissemination.

Diffuse large cell B-cell lymphoma of the skin is most commonly represented by diffuse large cell variants of primary cutaneous follicle center cell lymphoma and the leg-type lymphoma. In a minority of cases, the infiltrates are an expression of stage 4 disease of established extracutaneous B-cell lymphoma. We describe 3 patients with an aggressive form of B-cell lymphoma secondarily involving the skin. Two of the patients were in the ninth decade of life, whereas 1 patient was 34 years of age. In the elderly patients, there was an antecedent and/or concurrent history of follicular lymphoma, whereas in the younger patient, the tumor was a de novo presentation of this aggressive form of lymphoma. The elderly patients succumbed to their disease within less than a year from the time of diagnosis, whereas 1 patient is alive but with persistent and progressive disease despite chemotherapeutic intervention. The infiltrates in all 3 cases were diffuse and composed of large malignant hematopoietic cells that exhibited a round nucleus with a finely dispersed chromatin. Phenotypically, the tumor cells were Bcl-2 and CD10 positive, whereas Bcl-6 and Mum-1 showed variable positivity. One case showed combined Mum-1 positivity along with an acute lymphoblastic lymphoma phenotype, including the absence of CD20 expression. In each case, there was a c-MYC and BCL2/IGH rearrangement diagnostic of double-hit lymphoma. In one case, there was an additional BCL6 rearrangement, defining what is in essence triple-hit lymphoma. In conclusion, double-hit lymphoma is an aggressive form of B-cell neoplasia resistant to standard chemotherapy regimens, which in many but not all cases represents tumor progression in the setting of a lower grade B-cell malignancy.

Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients.

Diamond-Blackfan anemia (DBA), a congenital bone-marrow-failure syndrome, is characterized by red blood cell aplasia, macrocytic anemia, clinical heterogeneity, and increased risk of malignancy. Although anemia is the most prominent feature of DBA, the disease is also characterized by growth retardation and congenital anomalies that are present in approximately 30%-50% of patients. The disease has been associated with mutations in four ribosomal protein (RP) genes, RPS19, RPS24, RPS17, and RPL35A, in about 30% of patients. However, the genetic basis of the remaining 70% of cases is still unknown. Here, we report the second known mutation in RPS17 and probable pathogenic mutations in three more RP genes, RPL5, RPL11, and RPS7. In addition, we identified rare variants of unknown significance in three other genes, RPL36, RPS15, and RPS27A. Remarkably, careful review of the clinical data showed that mutations in RPL5 are associated with multiple physical abnormalities, including craniofacial, thumb, and heart anomalies, whereas isolated thumb malformations are predominantly present in patients carrying mutations in RPL11. We also demonstrate that mutations of RPL5, RPL11, or RPS7 in DBA cells is associated with diverse defects in the maturation of ribosomal RNAs in the large or the small ribosomal subunit production pathway, expanding the repertoire of ribosomal RNA processing defects associated with DBA.