X-linked Sideroblastic Anemia (XLSA, MIM# 300751) is due to mutations in the erythroid-specific form of 5-aminolevulinate synthase (ALAS2) gene. Main features of this condition are microcytic anemia, iron deposits in the mitochondria of erythroid precursors (ring sideroblasts) and an X linked pattern of inheritance. However, up to one third of described cases have been reported in females mainly due to a highly skewed X-chromosome inactivation (Ducamp, Kannengiesser et al. 2011). We report for the first time in a large four generations pedigree a new mutation in ALAS2 gene inducing a Male Lethal X-linked Syndrome ascertained through an adult heterozygous female with a mild form of congenital sideroblastic anemia (CSA). The propositus of this non consanguineous family (Fig 1; individual III;9) was a female from European ancestry. She exhibited a unexplained congenital, non regenerative, macrocytic (MCV 107fL, moderate anemia (Hb 10.4 g/dL), (first assessment at 6 years old). RBC transfusions were required only twice during pregnancy. The diagnosis of CSA was made at 23 years old when the bone marrow aspiration performed, showed 38% of ring sideroblasts. Erythrocyte protoporphyrin concentration was measured in the female proband carrying an ALAS2 mutation. The protoporphyrin concentration was within the normal range of values: 1.6 µmoles/L of red blood cells (less than 1.9 µmoles/L of red blood cells), as previously observed in XLSA cases. The level of serum ferritin was 224ng/ml (N:11-306) and transferrin saturation was 90%. A heterozygote ALAS2 deleterious missense mutation c.622G>T,p.Val208Phe affecting a conserved amino acid was found. A constitutive skewed X-chromosome inactivation was demonstrated as previously reported in affected females with XLSA. However erythroid bone marrow precursor did not exhibited different pattern repartition in term of apoptosis or dyserythropoisesis. Her daughter and her mother exhibited the same mutation but did not have skewed X-chromosome inactivation and were unaffected with a normal blood count. A close inspection of the pedigree confirms a large female predominance (22 females/ 7 males) over four generations (/F/M ratio 3.1). No affected male were identified in the pedigree. Moreover a high level of miscarriage was found only in female carrying the ALAS2 mutation, as shown in the pedigree (Fig. 1). Adding the number of miscarriage (18 over the four generations) to the number of males alive the ratio of M/F over 4 generation is close of 1: 1.04 (24/23). These data highly suggest an X-linked dominant disorder with pre natal male lethality. Our pedigree confirms the non redundant role of the erythroid-specific form of delta-aminolevulinate synthase in foetal hematopoïesis; Moreover our propositus case showed that in case of X-linked Sideroblastic Anemia (XLSA) affected female, a research of excess of miscarriage in the pedigree should be considered and should evocate a male lethal XLSA. This should have an impact in term of genetic counselling. Disclosures: No relevant conflicts of interest to declare.
Background Immunoglobulin D (IgD) multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% of cases with limited information is available regarding the prognosis of these isotypes. They have been considered to have a more aggressive course than the more common Immunoglobulin of IgG and IgA isotypes in the era of conventional chemotherapy. Several studies have reported the outcome of IgD MM after autologous hematopoietic stem cell transplantation (ASCT) in recent years, but none in the context of novel agents currently the backbone of almost all if not all lines of therapy upfront. We sought to study the prognostic impact of novel agents used upfront on IgD MM treated in several IFM (Intergroupe Francophone du Myélome) centres. Method This study has included a group of 21 patients with IgD MM that were treated from 1994 to 2012 across 5 IFM centres. IgD MM was diagnosed as outline in international consensus criteria. Response and survival criteria were used as depicted in the IMWG consensus criteria published. Results Median age was 59 years (min max 38-80), sex ratio was 1.7, 75% had lambda light chain, 65% had severe bone disease and 20% one to 3 bone lesions, 55% had severe renal insufficiency, 30% had hypercalcemia, 55% profound anemia. Finally, 39% had adverse FISH either del17p or t(4;14) on bone marrow plasma cells and 50% were ISS 3 with beta2M greater than 5mg/L. 80% had receive novel agents containing regimens upfront, including 70% in the context of ASCT and 75% a bortezomib-based regimen. Overall, 65% reached at least VGPR with a median time to first response at 4 months (IQ 1-5). IgD MM had a greater chance to reach VGPR on bortezomib-based regimen, 80% versus 50% for patients on thalidomide-based regimen; furthermore, ASCT also improved the depth of response rate with 85% versus 20% that reached VGPR, respectively (p=0.022). The presence of renal insufficiency at initiation did not affect the incidence and depth of response rate as expected. With a median follow-up of 65 months, 40% have relapsed and 35% have died. The median TTP and OS was 3 years (CI95% 3;7) and 6 years (CI95% 5;9), respectively. Although not significant due to the limited number of patients the median OS was much shorter in the group treated with conventional agents as to novel agents, 5 years (2;8) versus not reached with a 6-year event free of 53%. Similarly, the patients that have received a thalidomide-based regimen upfront had a shorter OS as to bortezomib-based regimen, 1.9 years (1;nr) versus 5.8 years (2;9) although not statistically significant. Interestingly, ASCT improved TTP but not OS, with 1.6 years (1;2.5) versus not reached (6-year event free is 63%) as median TTP in patients non ASCT and ASCT, respectively (p=0.045). Conclusion Despite the retrospective analysis and the small number of patients, our study showed that the use of ASCT and bortezomib-based regimen improve the prognosis of IgD MM. This data analysis confirms that IgD MM should be treated according to current guidelines upfront that recommend use of a bortezomib-based regimen in the context of ASCT in fit patients. Treatment options including the role of consolidation and maintenance may further improve the outcomes of these patients. Disclosures: No relevant conflicts of interest to declare.
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