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.

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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. K E Y W O R D S developmental and epileptic encephalopathy, Dravet syndrome, SCN1B

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.

A 40 year old Indian man with a history of chronic lower back pain presented with an acute worsening of his back pain, bilateral lower extremity pain and bladder difficulty.The patient's back pain had initially begun approximately 2 years prior. He treated himself intermittently with ibuprofen, with good relief, and the pain gradually resolved. Ayear and a half later, the patient began to experience increasingly worse back pain, as well as numbness of his left leg. He went to his primary care physician and a diagnosis of piriformis syndrome was rendered. He was given steroid and botulinum toxin injections with some relief. During this time, the patient was traveling to India to visit an ailing family member. He had an acute worsening of symptoms prior to presentation at our facility, and was prescribed a muscle relaxant, physical therapy and hydrocodone by his primary care physician.However, the patient began to experience a complete loss of sensation in his left foot, subjective bilateral lower extremity weakness (left greater than right), and urinary hesitancy with a sensation of fullness and an inability to completely void his bladder. This prompted him to seek emergent medical attention, at which time an MRI was performed and imaging demonstrated a heterogeneously enhancing L4-S1 cystic lesion that was compressing the nerve roots (Fig. 1). The differential diagnosis included a number of possibilities, although there was the most concern for a malignancy of the spine. Imaging demonstrated no additional lesions or masses, including of the remainder of the spine as well as the brain. The patient denied any other symptoms, including urinary/bowel incontinence, saddle anesthesia, fevers, chills or changes in vision.Due to the patient's progressive symptoms, with compressive symptoms from the mass, and the need for diagnosis, surgery was indicated and the patient was taken for surgical intervention the next day. A laminectomy was performed at L4, L5 and S1. The dura was incised, tacked away, and the arachnoid space was entered to reveal a 2.5 cm cystic mass with tissue herniation through the opening. Fenestration of the cyst was then performed, and the tissue was sent to pathology for microscopic examination. PATHOLOGICAL FINDINGSHistologic examination of the specimen showed a fibrous pseudo-capsule that surrounded a retracted and collapsed cyst. The fibrous pseudo-capsule was composed of collagenous tissue with minimal inflammatory cells, including lymphocytes and eosinophils, with a layer of histiocytes adjacent to the cyst. The cyst itself was comprised of an outer layer of homogenous eosinophlic material, consistent with tegument, with a row of viable cells with clear cytoplasm and small round nuclei (tegumental cells), and loose edematous stroma with numerous calcospherites ( Fig. 2A, 2B). The histologic findings were consistent with larval forms and cysticercosis.The patient was doing well in the immediate postoperative period, although his postoperative course was complicated by a pulmonary embolus formation...