Three cases of multi-generational Gaucher disease and colon cancer from an Ashkenazi Jewish family: A lesson for cascade screening.

Gaucher disease (GD) is one of the commonest lysosomal storage diseases that is inherited in an autosomal recessive manner and affects 1 in 50,000 to 100,000 people in the general population. The frequency is much higher (1 in 500 to 1000) in people of Ashkenazi Jewish heritage due to a founder effect. GD is caused by decreased or absent activity of ß-glucosidase with subsequent accumulation of the substrate glucosylceramide in macrophages due to genetic alterations in the GBA gene. These often accumulate in the spleen, liver and bone marrow. Three types exist, with type 1 being the most common, also referred to as non-neuronopathic GD. A broad clinical spectrum exists; patients of any age may manifest with hepatosplenomegaly, anaemia, thrombocytopenia, lung disease, bone abnormalities or may remain asymptomatic throughout their lifespan. Multi-generational disease does not usually occur because the risk of disease with each pregnancy, presuming both parents are carriers of the condition, is 25%. Herein, we report an Ashkenazi Jewish family with multi-generational GD type 1 and multigenerational colon cancer in the same three individuals, and reinforce the importance of cascade screening in families with genetic conditions.

Hair repigmentation associated with thalidomide use for the treatment of multiple myeloma.

A 75-year-old woman diagnosed with multiple myeloma in 2007 began treatment with monthly melphalan and prednisone for a total of 9 cycles in combination with thalidomide in 2009. The patient subsequently continued on thalidomide for long-term maintenance therapy. 3 years following initiation of thalidomide, the patient mentioned to her oncologist that her hair had become darker over the years. She attributed the change to thalidomide given the temporal relationship and progressive darkening over the course of therapy. The patient denies ever using any hair colouring treatments and had longstanding grey/white hair before beginning thalidomide in 2009. A case of hair repigmentation associated with the use of lenalidomide, a 4-amino-glutamyl analogue of thalidomide, in a patient with multiple myeloma was previously reported in the literature. We report herein the first case of hair repigmentation associated with the use of thalidomide, a related immunomodulatory drug.

Two novel mutations in glucocerebrosidase, C23W and IVS7-1 G>A, identified in Type 1 Gaucher patients heterozygous for N370S.

Gaucher disease is an autosomal recessive lysosomal storage disorder resulting from deficient glucocerebrosidase activity. There have been nearly 300 mutations described to date. Novel mutations can potentially provide insight into the biochemical basis of the disease. Two novel mutations are described in two Type 1 Gaucher patients with N370S compound heterozygosity; a point mutation that causes an amino acid substitution at cysteine residue 23 for tryptophan, and a second point mutation within the splicing element at the 3' end of intron 7. Both mutations were identified by PCR amplification and sequence analysis of patient glucocerebrosidase genomic DNA. Restriction fragment length polymorphism analysis was established for both novel mutations for efficient identification in future patients. Past literature suggests that mutations affecting cysteine residues involved in disulfide bridges, as well as mutations affecting splicing patterns of the glucocerebrosidase transcript, are detrimental to enzyme activity. However, compound heterozygosity with N370S, a mild mutation, will lead to a mild phenotype. The cases reported here support these past findings.

Gaucher disease: a systematic review and meta-analysis of bone complications and their response to treatment.

Type 1 Gaucher disease (GD1) is an inherited lysosomal storage disease, which is often managed by enzyme replacement therapy (ERT). The bone response to ERT is usually slower than visceral and hematological responses. There is uncertainty as to whether an increase in the dosage of ERT has a beneficial effect. The aim of our study was to determine whether or not there is sufficient evidence to make a definitive statement about the effects of ERT and substrate reduction therapy (SRT) on bone marrow infiltration and bone mineral density (BMD) in GD1. We conducted a systematic review of all studies examining the effects of ERT and SRT on bony complications of GD1 published before July 2008. The studies were identified by a computerized search with use of Medline, Embase, The Cochrane Database of Systematic Reviews, The Cochrane Central Register of Controlled Trials (CCTR), and bibliographies of papers subsequently retrieved from the search. Three hundred studies were grouped according to whether they deal with the natural history of GD1 or therapeutic issues, and 17 studies were included in the review. The results from our systematic review suggest that further investigations, such as better analysis of the Gaucher Registry, are needed on the effects of ERT and SRT on bony complications of GD1. Studies on the effects of the newly identified velaglucerase and the plant-derived glucocerebrosidase on bony complications of GD1 are also needed.

Cytogenetic aberrations and immunoglobulin VH gene mutations in clinically benign CD5- monoclonal B-cell lymphocytosis.

The finding of monoclonal B-cell lymphocytosis (MBL) raises questions on the nature of clonal cell expansion and its risk of progression. We identified and characterized 7 cases of clinically benign clonal B-cell lymphocytosis. The clonal lymphocytes were clearly of CD5- and non-chronic lymphocytic leukemia (CLL) phenotype. All cases had mild to moderate absolute lymphocytosis. The clonal population accounted for 95% to 99% of B cells. For a follow-up period of 4 to 16 years, clonal lymphocytosis was persistent but virtually not progressing. Patients' conditions remained clinically stable and asymptomatic. The clonal populations had somatic hypermutations of the VH gene in 6 cases, indicating a germinal center or post-germinal center B-lymphocyte origin. Clonal cytogenetic aberrations were found in 5 of 6 cases, with 2 clones bearing isochromosome 17q that resulted in loss of p53 and 2 other clones with 7q abnormalities. By the presence of absolute lymphocytosis, this series differs from MBL cases identified by sensitive flow cytometry in normal populations. The phenotypic profiles are distinct from that of benign CLL. We suggest these CD5-B-cell lymphocytosis cases may represent an intermediate condition between covert clonal expansions and overt malignancy.

Overexpression of SOCS-2 and SOCS-3 genes reverses erythroid overgrowth and IGF-I hypersensitivity of primary polycythemia vera (PV) cells.

Polycythemia vera (PV), an acquired, chronic, clonal disorder arising in a multipotential hematopoietic progenitor cell, is characterized by hyperplasia of three major myeloid lineages, with a pronounced increase in cells of the erythroid lineage. Erythroid progenitor cells in PV are strikingly hypersensitive to insulin-like growth factor-I (IGF-I); this effect is specific and is mediated through the IGF-I receptor. To investigate the possibility that in PV the increase in number of erythroid progenitors and their hypersensitivity to IGF-I result from a defect in negative regulation of cytokine activity, we examined the expression of members of the SOCS gene family. Circulating mononuclear cells, grown in serum-free methylcellulose medium in the presence of IGF-I, produced BFU-E-derived colonies whose cells revealed a reduction of SOCS-2 and SOCS-3 expression in PV only. Overexpression of these genes in transfected PV cells reduced their erythroid overgrowth and IGF-I hypersensitivity. We hypothesize that a defect in expression of SOCS-2 and SOCS-3 genes may be crucial for the IGF-I hypersensitivity and progressive increase in erythroid cell population size characteristic of PV.

Acute tumor lysis syndrome secondary to hydroxyurea in acute myeloid leukemia.

OBJECTIVE: To report 2 cases of acute tumor lysis syndrome (ATLS) associated with hydroxyurea treatment. CASE SUMMARY: A 79-year-old woman diagnosed with chronic lymphocytic leukemia presented with an acute blastic transformation. She was promptly hydrated, started on allopurinol, and treated with hydroxyurea. About 24 hours later, her biochemistry panel showed parameters consistent with ATLS when compared with pretreatment levels. The second case was a 76-year-old man newly diagnosed with acute myeloid leukemia presenting with high blast fraction. He was given appropriate hydration and allopurinol prophylaxis, and was started on high-dose hydroxyurea treatment. He became symptomatic after 12 hours and results of his blood work were consistent with ATLS. DISCUSSION: ATLS is a well-known metabolic disturbance that occurs after cell destruction of rapidly growing tumors. In standard doses, hydroxyurea leads to cell death in the S phase and is not thought to cause significant cell lysis. However, in large doses, it possibly acts by a different mechanism and had a direct cytolytic effect associated with ATLS in our patients. CONCLUSIONS: Although ATLS caused by hydroxyurea appears to be rare, patients at risk should be closely monitored for this complication. An objective causality assessment using the Naranjo probability scale revealed that the adverse drug reaction was probable between ATLS and hydroxyurea therapy in these 2 patients.

Differentiation of monoclonal B lymphocytosis of undetermined significance (MLUS) and chronic lymphocytic leukemia (CLL) with weak CD5 expression from CD5(-) CLL.

Chronic lymphocytic leukemia (CLL) is recognized as a unique lymphoproliferative disorder of CD5(+) B cells. However, many published series of CLL included a subgroup of CD5(-) cases. CD5(-) B cell CLL is a topic of controversy and its nature and true incidence remain unclear. We in this study performed a retrospective analysis of a total of 128 consecutive patients with a diagnosis of CLL and available immunophenotypic record. Of these, 14 cases were previously considered CD5(-) CLL. From a further analysis of clinical, hematological and immunophenotypic results, we have reclassified seven of the patients as having weak or dim expression of CD5 and four patients as being monoclonal B lymphocytosis of undetermined significance (MLUS). The remaining three cases had clinical and morphological features consistent with prolymphocytic leukemia (PLL) or mixed CLL/PLL. Our results suggest that the CD5(-) phenotype probably does not qualify for CLL. Previous CD5(-) CLL may include false negatives due to heterogeneity of the intensity of CD5 expression, CD5(-) MLUS and variant CLL; the latter likely represents CLL in transformation. All the patients with MLUS were found to have a mild and non-progressing lymphocytosis with CD5(-) phenotype. These features may be used to differentiate them from CLL.

CD5-negative phenotype of monoclonal B-lymphocytosis of undetermined significance (MLUS).

Monoclonal B lymphocytosis of undetermined significance (MLUS) is a benign condition of clonal lymphocytosis. Because of its clonal small lymphocytes and indolent clinical course, MLUS resembles and may be indistinguishable from an early stage of chronic lymphocytic leukemia (CLL). In this study we characterized the immunophenotype of MLUS. The clonal B lymphocytes from three patients of typical MLUS were shown to be CD5(-) and CD23(-) phenotype. Their immunophenotypic features remained unchanged during the clinical course. The results indicate a distinct immunophenotype of MLUS that can be useful for its diagnosis and differentiation from CLL.