Refining the phenotype associated with biallelic DNAJC21 mutations.

Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up.

Whole-genome array CGH identifies pathogenic copy number variations in fetuses with major malformations and a normal karyotype.

Despite a wide range of clinical tools, the etiology of mental retardation and multiple congenital malformations remains unknown for many patients. Array-based comparative genomic hybridization (aCGH) has proven to be a valuable tool in these cases, as its pangenomic coverage allows the identification of chromosomal aberrations that are undetectable by other genetic methods targeting specific genomic regions. Therefore, aCGH is increasingly used in clinical genetics, both in the postnatal and the prenatal settings. While the diagnostic yield in the postnatal population has been established at 10-12%, studies investigating fetuses have reported variable results. We used whole-genome aCGH to investigate fetuses presenting at least one major malformation detected on ultrasound, but for whom standard genetic analyses (including karyotype) failed to provide a diagnosis. We identified a clinically significant chromosomal aberration in 8.2% of tested fetuses (4/49), and a result of unclear clinical significance in 12.2% of tested fetuses (6/49). Our results document the value of whole-genome aCGH as a prenatal diagnostic tool and highlight the interpretation difficulties associated with copy number variations of unclear significance.

[Isolated familial corpus callosum agenesis prognosis]. / Les agénésies isolées et familiales du corps calleux sont-elles de bon pronostic?

Agenesia of corpus callosum belongs to a group of cerebral malformations whose prognosis is uncertain. In such cases, assessment of prognosis may benefit from eventual associated fetal, obstetrical or familial features. We report a patient with an isolated corpus callosum agenesia that led to the discovery of a similar malformation in her father. This observation demonstrates that some forms of isolated and familial corpus callosum agenesia could have a favorable outcome. However, the difficulty of the assessment of prognosis in isolated corpus callosum agenesia is emphasized and the question of parental RMI exploration in such a peculiar context is raised.

[Cost per responder associated with romiplostim and rituximab treatment for adult primary immune thrombocytopenia in France]. / Coût par patient répondeur associé au traitement du purpura thrombopénique immunologique primaire par romiplostim et rituximab chez l'adulte en France.

PURPOSE OF THE STUDY: This analysis compared the response rates and cost per responder associated with romiplostim and rituximab in adult immune thrombocytopenia from the French National Health System payer perspective. METHODS: A decision analytic model was developed to estimate the cost per patient and per responder of treating adult immune thrombocytopenia patients with romiplostim versus rituximab over 6 months. A systematic literature review identified phase 3 randomized controlled trials. Published response rates were extracted (response definition: ≥50×10(9) platelets/liter). Resource utilization was based on French and international treatment guidelines, and clinical expert opinion. Unit costs were derived from literature and French reimbursement lists, and included the costs of routine physician visits, treatment administration, and emergency care. Non-responders incurred bleeding-related event costs. RESULTS: The literature review identified a phase 3 randomized controlled trial for romiplostim with a response rate of 83%. Due to a lack of phase 3 randomized controlled trials for rituximab, a systematic review of studies was selected as the best source, reporting a response rate of 62.5%. Romiplostim and rituximab were associated with similar treatment costs, with an estimated cost per patient for romiplostim of €17,456 and €17,068 for rituximab. Rituximab resulted in a 30% higher cost per responder (€27,308 for rituximab versus €21,031 for romiplostim). Romiplostim use reduced drug administration, intravenous immunoglobulin, and bleeding-related hospitalization costs compared to rituximab. CONCLUSIONS: Due to its high efficacy leading to lower bleeding-related costs, romiplostim represents an efficient use of resources for adult immune thrombocytopenia patients in the French healthcare system.

Immortalization and neoplastic transformation of fetal rat intestinal epithelial cells: morphological and cytogenetic analysis, (proto)oncogene expression and effect of gamma-interferon on cell growth.

The permanent SLC-11 and -41 intestinal epithelial cells respectively immortalized by the E1A and large T oncogenes and their clonal derivatives showed a cytogenetic heterogeneity characterized by a near diploidy in SLC-11 and -12 cells and a generalized polyploidy in SLC-41 and -44 cells. Persistence of chromosome translocations and trisomy 3 were observed. The expression of the E1A oncogene in immortalized SLC-11 cells is associated with a strong repression of c-fos transcription during the exponential growth, as compared to the resting phase or to control rat fetal intestinal epithelial cells. The transcription of c-myc was also reduced in SLC-11 cells, especially in confluent cells. A complex relationship between the levels and size of the c-fos, c-myc mRNAs and the expression of the E1A oncogene was therefore observed in SLC-11 cells. Immortalized SLC-11 and -41 cells showed a remarkable growth inhibition in response to recombinant rat gamma-IFN. Neoplastic transformation by activated human Ha-ras in SLC-12T and -44 T cells confer resistance to the antigrowth effects of IFN. The combination of culture conditions using defined medium, membrane matrix (laminin, collagen, proteoglycans) and intestinal mesenchyme revealed the persistence of the undifferentiated phenotype of the E1A, large T-immortalized and Ha-ras-transformed SLC cells in vitro or in the nude mice. In association with the intestinal chick endoderm, SLC-11 cells possess some inductive properties on the differentiation of villi projections arising from the chick endoderm in vivo. In contrast, SLC-41 cells were induced to differentiate in enterocyte-like cells by the intestinal chick mesenchyme. The immortalized and Ha-ras-transformed SLC cells therefore constitute new models in the sequential analysis of the molecular and genetic mechanisms involved in the proliferation, differentiation and oncogene-mediated neoplastic transformation in gut. Further attempts in SLC cell differentiation have to be accomplished using chemical inducers for prolonged periods of time, or by transfection of intestinal epithelial cells using temperature- or glucocorticoid-inducible vectors.

Skin pigmentary anomalies and mosaicism for an acentric marker chromosome originating from 3q.

We report on a 22 year old man with hyperpigmentation distributed along the lines of Blaschko in whom cytogenetic analysis showed mosaicism for an unusual supernumerary marker chromosome. The patient was of normal intelligence and was not dysmorphic. The marker was present in 30% of his lymphocytes and in 6% of his skin fibroblasts from a dark area, while fibroblasts from a light area showed a normal karyotype, 46,XY. We have identified the origin of the marker using fluorescence in situ hybridisation (FISH) with whole chromosome painting probes and YAC specific clones. The marker was found to consist of duplicated chromosome material from the distal part of chromosome 3q and was interpreted as inv dup(3)(qter-->q27.1::q27.1-->qter). Hence, this marker did not include any known centromeric region and no alpha satellite DNA could be detected at the site of the primary constriction. The patient was therefore tetrasomic for 3q27-q29 in the cells containing the marker chromosome. We postulate that, in our case, pigmentary anomalies may result directly from the gain of specific pigmentation genes localised on chromosome 3q.