Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype

Sarthy, Jay F.; Zha, Ji; Babushok, Daria V.; Shenoy, Archana; Fan, Jian-Meng; Wertheim, Gerald; Himebauch, Adam S.; Munchel, Ashley T.; Taraseviciute, Agne; Yang, Samuel; Shima, Hirohito; Narumi, Shunji; Meshinchi, Soheil; Olson, Timothy S.

doi:10.1182/bloodadvances.2017012682

Cited by 30 publications

(35 citation statements)

References 6 publications

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“…Several of these medical issues are similar to those reported in the report by Sarthy et al [14]. Despite a complicated acute transplant course, all 4 patients with MIRAGE syndrome in our series survived.…”

Section: Discussionsupporting

confidence: 90%

“…Wilson and colleagues [21] reported a patient with MIRAGE syndrome who underwent reduced-intensity conditioning and unrelated donor HCT that led to resolution of monosomy 7 MDS. Sarthy et al [14] described a patient with marrow failure and another patient with MDS who had severe MIRAGE phenotypes and underwent HCT after reduced-intensity conditioning. Comorbidities, including enteropathy, electrolyte imbalances, adrenal crises, bacteremia, and lung disease, significantly led to a complicated transplant course and ultimately death in both cases.…”

Section: Discussionmentioning

confidence: 99%

“…Hematopoietic cell transplantation (HCT) therapy has been included in some reports, but transplantation details are lacking. A recent article by Sarthy et al [14] documented 2 children with MIRAGE syndrome who succumbed to posttransplant complications due to syndrome-related comorbidities. We aimed to obtain a more complete assessment of transplant outcomes and the challenges and complications encountered in these patients.…”

Section: Introductionmentioning

confidence: 99%

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Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations

Ahmed

Farooqi

Lugt

et al. 2019

Biology of Blood and Marrow Transplantation

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A B S T R A C T Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L-associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/ SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations

Ahmed

Farooqi

Lugt

et al. 2019

Biology of Blood and Marrow Transplantation

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“…In this report, we describe a patient with MIRAGE syndrome secondary to a novel heterozygous, missense variant detected in the SAMD9 gene. Prior published reports on MIRAGE syndrome patients report different SAMD9 variants and phenotypic features (Supporting Information Table S1) as well as variation in the location of mutations along the gene (Figure ). Arginine predominant mutations have been recognized in prior publications, but the specific reason for the predominance is yet not well understood .…”

Section: Discussionmentioning

confidence: 97%

A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases

Perisa

Rose

Varga

et al. 2019

Pediatric Blood & Cancer

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We present here a case of MIRAGE syndrome due to novel variant (c.2318T>C) in the sterile α motif domain‐containing protein 9 (SAMD9) gene. Previous reports have described the clinical phenotype, which includes myelodysplasia, recurrent infections, restriction of growth and development, adrenal insufficiency, genitourinary abnormalities, and enteropathies, often resulting in fatality within the first few years of life. This report illustrates the variability in phenotype by describing an 11‐year‐old male, diagnosed with MIRAGE at age 9 years when his novel variant was identified through whole exome sequencing. A brief review of previously published cases of MIRAGE syndrome and the genotypic and phenotypic spectrum are presented.

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“…As there is evidence demonstrating that the clinical spectrum of MIRAGE syndrome varies among subjects, accumulation of variant data and clarification of the genotype-phenotype correlation is a requisite to improve medical management of MIRAGE syndrome. To date,~40 cases of MIRAGE syndrome have been reported 1,2,4,[7][8][9][10][11][12][13][14][15][16][17][18] . Although the identified variants are scattered throughout the entire coding sequence with missense variants being most frequent, in vitro functional assays have revealed the consistent growth restriction phenotype of mutated SAMD9 protein.…”

mentioning

confidence: 99%

MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene

et al. 2020

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MIRAGE syndrome is a recently identified disorder characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. It is caused by a gain-of-function variant in the SAMD9 gene, but there is limited knowledge regarding the genotype-phenotype correlation. We herein report a Japanese patient with MIRAGE syndrome carrying a novel de novo heterozygous missense variant in the SAMD9 gene (c.4435 G > T; p. Ala1479Ser). MIRAGE syndrome (OMIM #617053) is a recently discovered disorder with multifaceted clinical features, including myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy 1. Additional associated features are developmental retardation, dysmorphism, chronic lung disease, and central nervous system abnormalities. MIRAGE syndrome is caused by a gain-of-function variant in the SAMD9 gene on the long arm of chromosome 7 (7q21.2), encoding sterile alpha motif domain-containing protein 9, which functions in endosome fusion and regulates cell growth in in vitro models 1,2. However, the precise mechanisms by which variants in the SAMD9 gene cause the MIRAGE phenotype are largely unknown. In addition, a wide range of phenotypes with a high mortality rate has been implicated with little understanding of the genotypephenotype correlation due to the paucity of genetically diagnosed subjects. Therefore, the accumulation of patient-based knowledge with underlying genetic information is essential to better understand the clinical outcome, its relation to genotype, and molecular insights of

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Poor outcome with hematopoietic stem cell transplantation for bone marrow failure and MDS with severe MIRAGE syndrome phenotype

Abstract: Key Points Success of hematopoietic stem cell transplantation for MIRAGE syndrome may be limited by syndrome-specific comorbidities. SAMD9 mutations associated with MIRAGE syndrome are a newly described cause of congenital amegakaryocytic thrombocytopenia.

Cited by 30 publications

References 6 publications

Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations

Outcomes of Hematopoietic Cell Transplantation in Patients with Germline SAMD9/SAMD9L Mutations

A novel SAMD9 variant identified in patient with MIRAGE syndrome: Further defining syndromic phenotype and review of previous cases

MIRAGE syndrome caused by a novel missense variant (p.Ala1479Ser) in the SAMD9 gene

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