York platelet syndrome is a CRAC channelopathy due to gain-of-function mutations in STIM1.

Store-operated Ca(2+) entry is the major route of replenishment of intracellular Ca(2+) in animal cells in response to the depletion of Ca(2+) stores in the endoplasmic reticulum. It is primarily mediated by the Ca(2+)-selective release-activated Ca(2+) (CRAC) channel, which consists of the pore-forming subunits ORAI1-3 and the Ca(2+) sensors, STIM1 and STIM2. Recessive loss-of-function mutations in STIM1 or ORAI1 result in immune deficiency and nonprogressive myopathy. Heterozygous gain-of-function mutations in STIM1 cause non-syndromic myopathies as well as syndromic forms of miosis and myopathy with tubular aggregates and Stormorken syndrome; some of these syndromic forms are associated with thrombocytopenia. Increased concentration of Ca(2+) as a result of store-operated Ca(2+) entry is essential for platelet activation. The York Platelet syndrome (YPS) is characterized by thrombocytopenia, striking ultrastructural platelet abnormalities including giant electron-opaque organelles and massive, multilayered target bodies and deficiency of platelet Ca(2+) storage in delta granules. We present clinical and molecular findings in 7 YPS patients from 4 families, demonstrating that YPS patients have a chronic myopathy associated with rimmed vacuoles and heterozygous gain-of-function STIM1 mutations. These findings expand the phenotypic spectrum of STIM1-related human disorders and define the molecular basis of YPS.

The York platelet syndrome: a fourth case with unusual pathologic features.

The present report describes a fourth patient with platelet pathological features identical to those found in the first three cases with the York platelet syndrome (YPS), as well as other findings that suggest he may be a variant. His platelets contain the same giant opaque and target organelles found earlier, as well as enlarged organelles with a gray appearing matrix. It is possible that the giant structures have the same source, but are at different stages of development. The fourth patient has platelet pathology suggestive of other thrombocyte disorders. He has many large platelets and normal sized thrombocytes nearly devoid of alpha granules. As a result, he was originally thought to have the gray platelet syndrome. He also has significant numbers of platelets attached to platelets and platelets in platelets as seen in patients with the X-linked GATA-1 mutation. Some of the fourth YPS patient's platelets contained massive alpha granules suggesting the possibility of the Paris Trousseau Jacobson Syndrome. Yet, none of these other platelet disorders had giant dense organelles like those found in YPS thrombocytes. As a result, it is reasonable to include this child with the other three, and diagnose him as a patient with the YPS.

Flat epithelial atypia with and without atypical ductal hyperplasia: to re-excise or not. Results of a 5-year prospective study.

Flat epithelial atypia (FEA) of the breast have a tendency to calcify and, as such, are becoming increasingly detected by mammography. There is no consensus yet on whether to excise these lesions or not after diagnosis on core needle biopsies (CNB). We reviewed 3,948 cases of breast CNB between June 2004 and June 2009 correlating histomorphologic, radiological, and clinical features. There were 3.7 % (145/3,948) pure FEA and 1.5 % (58/3,948) concomitant FEA and atypical ductal hyperplasia (ADH). In the pure FEA population, 46.2 % (67/145) had microcalcifications on mammography with 65.5 % (95/145) of patients undergoing subsequent excisional biopsies with the following findings: benign 20 % (19/95), ADH 37.9 % (36/95), ductal carcinoma in situ (DCIS) 1.1 % (1/95), and DCIS and invasive ductal carcinoma (IDC) 2.1 % (2/95). In the concomitant FEA and ADH group, 86.2 % (50/58) patients had microcalcifications on radiograph with 74.1 % (43/58) of patients undergoing subsequent excisions with: benign 23.3 % (10/43), DCIS 9.3 % (4/43), DCIS and IDC 4.7 % (2/43), DCIS + lobular carcinoma in situ + invasive lobular carcinoma 2.3 % (1/43), and tubular carcinoma 2.3 % (1/43). The incidence of carcinoma in the FEA + ADH group is 18.6 % (8/43) and 3.2 % (3/95) for the pure FEA group. This difference is statistically significant (p = 0.0016). The relative risk of carcinoma in the ADH + FEA group versus the pure FEA group is 6.4773, with 95 % CI of 1.8432 and 22.76 24. Five-year mean follow-up in the unexcised pure FEA did not show any malignancies. These findings suggest that pure FEA has a very low association with carcinoma, and these patients may benefit from close clinical and mammographic follow-up while the combined pure FEA and ADH cases may be re-excised.

Follicular large cell lymphoma localized to the testis in children.

PURPOSE: Primary follicular lymphoma of the testis in childhood is rare with only 6 cases previously reported. We present 3 additional cases. MATERIALS AND METHODS: We extensively analyzed primary follicular lymphoma of the testis in 3 boys. Clinical data were obtained by reviewing patient charts. RESULTS: The patients were 4, 5 and 11 years old, respectively. Two patients presented with painless unilateral testicular enlargement and 1 presented with unilateral hydrocele. Laboratory findings were within normal limits in all patients. Radical orchiectomy was done in all cases. The excised testes were partially or completely replaced by tumor. In all cases the features were those of follicular, large cell-type malignant lymphoma. Tumor cells in all cases were CD20 and CDw75 positive, focally CD23 positive and bcl-2 negative, while in 2 they were CD10 positive and bcl-6 positive. Surface Ig was absent in the 2 cases studied. Karyotyping in 1 case showed a normal karyotype. Staging revealed no evidence of extratesticular disease. All patients underwent combination chemotherapy and were in complete remission 7 to 59 months after therapy. CONCLUSIONS: We present 3 cases of pediatric primary follicular lymphoma of the testis. Pathological findings and clinical features were similar to those in the 6 previously reported cases and suggest that primary pediatric testicular follicular lymphoma may represent unique subset of follicular lymphoma with a particularly good prognosis.

Diagnosis of calcium pyrophosphate dihydrate deposition disease by fine needle aspiration biopsy: a case report.

BACKGROUND: Calcium pyrophosphate dihydrate deposition disease is a relatively rare disease with variable clinical presentations. CASE: A 73-year-old man presented with worsening lower back pain and fever. Fine needle aspiration biopsy of the lumbar vertebral bodies (L3-L4) revealed abundant neutrophils admixed with small, birefringent, rhomboid crystals in Diff-Quik-stained smears. These crystals were confirmed as calcium pyrophosphate dihydrate on cell block sections. A diagnosis of osteomyelitis and calcium pyrophosphate dihydrate deposition disease was rendered. The patient was treated with antibiotics and responded well. CONCLUSION: Calcium pyrophosphate dihydrate deposition disease can be diagnosed by fine needle aspiration biopsy, and an accurate diagnosis can be greatly facilitated by cell block sections. However, such a diagnosis may be neglected if the specimen is not carefully inspected.