Long-term hematopoietic dysfunction in patients with large-scale mitochondrial DNA deletion syndromes.

BACKGROUND: Pearson syndrome (PS) and Kearns-Sayre syndrome (KSS) are single large-scale mitochondrial DNA deletion (SLSMD) syndromes. PS is characterized by severe, transient childhood cytopenia, whereas KSS typically manifests later in life without hematologic abnormalities. Despite distinct clinical presentations, both share a common mitochondrial DNA deletion. Recent observations suggest a potential link between PS progression and myeloid malignancy development, indicating that bone marrow failure (BMF) may be a key aspect of PS pathology and potentially universal across SLSMDs. METHODS: This study explores longitudinal hematological manifestations of SLSMD syndromes, focusing on bone marrow (BM) dysfunction. RESULTS: Sixteen patients with SLSMDs (13 PS and 3 KSS) were followed, of whom 75% experienced cytopenia, necessitating blood transfusions in 56%. Despite achieving transfusion independence at a median age of 24 months, persistent hematological abnormalities were noted. Comprehensive longitudinal BM studies were conducted in 62% of subjects and consistently revealed signs of marrow dysfunction, even without concurrent cytopenia. Median BM cellularity at a median age of four years and eight months was 50%, with histological signs of dyserythropoiesis, abnormal megakaryocytes, and signs suggesting myelodysplasia. Reduced CD34+ counts and BM colony-forming unit capacity were noted, alongside chromosome 7 aberrations in 16% of patients on cytogenetic studies. CONCLUSIONS: Our findings establish BM dysfunction as a persistent hallmark of SLSMD syndromes, posing a risk of clonal evolution and acquisition of chromosome 7 aberrations. This aligns with recent literature, emphasizing enduring BMF in SLSMD syndromes and advocating for tailored hematological monitoring guidelines for this unique patient cohort.

Higher prevalence of poor prognostic markers at a younger age in adult patients with myelodysplastic syndrome - evaluation of a large cohort in India.

BACKGROUND: The karyotype is a major determinant of prognosis in myelodysplastic syndrome (MDS). Details of the cytogenetic profile of MDS in South Asia are limited because cytogenetic services are not widely available. METHODS: We performed a retrospective analysis of the cytogenetic and clinicopathologic profile of adult primary MDS seen consecutively at a tertiary-care centre in South India between 2003 and 2017. Patients were re-categorised according to the 2022 World Health Organisation (WHO) and the International Consensus classifications (ICC). RESULTS: There were 936 patients aged 18-86 years (median age 53, 65% males), with MDS with del 5q, low blasts and increased blasts in 7.5%, 58.4% and 34.1% respectively. Clonal abnormalities were seen in 55% of patients, with solitary abnormalities in 29.8% and complex karyotypes (CK, ≥ 3 abnormalities) in 15%. The most frequent abnormalities were monosomy 7/deletion 7q (16.1%), deletion 5q (14.5%), trisomy 8 (11.5%), and deletion 20q (5.1%). Cytogenetic prognosis groups were distributed as follows: very good, 2%; good, 55.6%; intermediate, 16.2%; poor, 15%; very poor, 11.2%. Clinical (IPSS-R) risk stratification (842 patients) showed: very low-risk, 3.9%; low-risk, 30.9%; intermediate-risk, 24.2%; high-risk, 21%; very high-risk, 20%. Age-adjustment (IPSS-RA) raised the very low-risk group to 12.4%; the other groups decreased by 1-3% each. CONCLUSION: The most significant finding of this cytogenetic analysis of MDS in India is that abnormal karyotypes with poor prognosis markers including monosomy 7 and CK were more frequent than in most other reports, among patients who were overall younger. Trisomy 8, deletion 20q, the IPSS-R intermediate-risk and both high-risk groups were more common than in the West. Trisomy 8 was less common than in South-East Asia while CK and deletion 20q were comparable. Evaluation of such large cohorts highlights the unique features of MDS in different parts of the world. These findings suggest that there could be differences in predisposing factors, environmental or genetic, and emphasise the need for further exploration to better understand the varied nature of MDS.

Genomic characterization of AML with aberrations of chromosome 7: a multinational cohort of 519 patients.

BACKGROUND: Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood. METHODS: To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines. RESULTS: In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7-most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or -7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66-3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56-3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25-4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33-4.04]; P = 0.003). By contrast, IDH2-mutated patients (9%) displayed prolonged OS (HR, 0.51 [95% CI 0.30-0.88]; P = 0.0015) and durable responses (RFS: HR, 0.5 [95% CI 0.26-0.96]; P = 0.036). CONCLUSION: This work unraveled formerly underestimated genetic lesions and provides a comprehensive overview of the spectrum of recurrent gene mutations and their clinical relevance in AML with abn(7). KMT2C mutations are among the most frequent gene mutations in this heterogeneous AML subgroup and warrant further functional investigation.

Exploring Multiple Endocrinological Issues and Dysautonomia in a Rare Case: Hypoparathyroidism in MIRAGE Syndrome.

MIRAGE syndrome is a rare multisystemic disorder characterized by various manifestations, such as myelodysplasia, susceptibility to infections, growth retardation, adrenal hypoplasia, genital anomalies, and enteropathy. In the literature, there have been rare cases of dysautonomia. We present a 6.5-year-old girl, who was first admitted to our department with short stature. On follow up, she exhibited multiple endocrinological issues, including transient hypothyroidism, primary hypoparathyroidism and dysautonomia, along with multisystem involvement. Further investigations revealed recurrent moniliasis, low IgM levels, and transient monosomy 7 in the bone marrow. Whole exome sequencing revealed a heterozygous pathogenic variant of SAMD9 (c.2159del; p.Asn720ThrfsTer35). Additional complications observed during follow-up included medullary nephrocalcinosis, hypomagnesemia, hypermagnesiuria, hypophosphatemia, decreased glomerular filtration rate, and nephrotic proteinuria. The patient also developed hyperglycemia, which was managed with low-dose insulin. This case highlights the diagnostic challenges and the diverse phenotypic presentation observed in MIRAGE syndrome.

New-Onset Monosomy 7-Induced Pancytopenia in a 66-Year-Old Woman.

Myelodysplastic syndrome (MDS) is characterized by failure to initiate hematopoiesis or impaired maturation of cells, often presenting with pancytopenias with or without associated fatigue, infections, or inappropriate bleeding and bruising. Karyotype analyses of MDS patients commonly show deletion of the q arm of chromosome 7, suggesting loss of this region is likely implicated in the insufficient hematopoiesis seen in MDS. The predisposition to deletion of 7q is commonly inherited, with clinical presentation in early childhood associated with pancytopenia or hematological malignancy. In this case, we present a 66-year-old female who was incidentally found to be pancytopenic in the emergency department while being evaluated for dyspnea, with a bone marrow biopsy later confirming a diagnosis of MDS with monosomy 7. Sporadic loss of 7q can occur at any stage in life without any family history of hematological disease. Our patient has no known personal or family history of MDS, with normal blood counts during hospitalization three years prior, suggesting de novo loss of 7q occurring at greater than 60 years of age.

Clinical Features of Clonal Cytogenetic Abnormalities in Philadelphia-negative Cells Developed During Tyrosine Kinase Inhibitor Treatment.

Most clonal cytogenetic abnormalities of Philadelphia-negative cells (CCA/Ph-) occurring during tyrosine kinase inhibitor (TKI) treatment are transient, and the development of secondary myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) is rare, but the frequency and clinical significance in Japanese patients are still unknown. We herein report four patients who developed CCA/Ph- during TKI therapy and were diagnosed with secondary MDS/AML. The duration from TKI therapy initiation to MDS/AML onset ranged from 3 to 48 months, and the survival ranged from 5 to 84 months. The occurrence of CCA/Ph- with MDS/AML may be associated with a poor prognosis, and careful follow-up is recommended for patients who receive TKI therapy.

Cytogenetics in the management of myelodysplastic neoplasms (myelodysplastic syndromes, MDS): Guidelines from the groupe francophone de cytogénétique hématologique (GFCH).

Myelodysplastic neoplasms (MDS) are clonal hematopoietic neoplasms. Chromosomal abnormalities (CAs) are detected in 40-45% of de novo MDS and up to 80% of post-cytotoxic therapy MDS (MDS-pCT). Lately, several changes appeared in World Health Organization (WHO) classification and International Consensus Classification (ICC). The novel 'biallelic TP53 inactivation' (also called 'multi-hit TP53') MDS entity requires systematic investigation of TP53 locus (17p13.1). The ICC maintains CA allowing the diagnosis of MDS without dysplasia (del(5q), del(7q), -7 and complex karyotype). Deletion 5q is the only CA, still representing a low blast class of its own, if isolated or associated with one additional CA other than -7 or del(7q) and without multi-hit TP53. It represents one of the most frequent aberrations in adults' MDS, with chromosome 7 aberrations, and trisomy 8. Conversely, translocations are rarer in MDS. In children, del(5q) is very rare while -7 and del(7q) are predominant. Identification of a germline predisposition is key in childhood MDS. Aberrations of chromosomes 5, 7 and 17 are the most frequent in MDS-pCT, grouped in complex karyotypes. Despite the ever-increasing importance of molecular features, cytogenetics remains a major part of diagnosis and prognosis. In 2022, a molecular international prognostic score (IPSS-M) was proposed, combining the prognostic value of mutated genes to the previous scoring parameters (IPSS-R) including cytogenetics, still essential. A karyotype on bone marrow remains mandatory at diagnosis of MDS with complementary molecular analyses now required. Analyses with FISH or other technologies providing similar information can be necessary to complete and help in case of karyotype failure, for doubtful CA, for clonality assessment, and for detection of TP53 deletion to assess TP53 biallelic alterations.

Cytogenetics in the management of hematologic neoplasms with germline predisposition: guidelines from the Groupe Francophone de Cytogénétique Hématologique (GFCH).

The number of predisposing genes is continuously growing with the widespread availability of DNA sequencing, increasing the prevalence of hematologic malignancies with germline predisposition. Cytogenetic analyses provide an effective approach for the recognition of these malignancies with germline predisposition, which is critical for proper diagnosis, optimal treatment and genetic counseling. Based on the World Health Organization and the international consensus classifications as well as the European LeukemiaNet recommendations, this review first presents an advanced classification of neoplasms with germline predisposition focused on the acquired cytogenetic alterations during leukemogenesis. The various genetic rescue mechanisms and the progression to transformation are then explained. The review also outlines the specific constitutional and somatic cytogenetic aberrations indicative of germline predisposition disorders in B-acute lymphoblastic leukemia (ALL), T-ALL, bone marrow failure syndrome and myeloid neoplasms. An emphasis is made on monosomy 7 in the predisposition field, its frequency and diagnosis impact as well as its various circumstances of occurrence. Lastly, we propose cytogenetic technical recommendations and guidelines for clinical reporting of these specific aberrations.

Gilteritinib Affects the Selection of Dominant Clones in Clonal Hematopoiesis: Sequential Genetic Analysis of an FLT3-ITD Positive AML Patient with Long-Term Gilteritinib Therapy.

We performed sequential molecular analyses of a 75-year-old woman with de novo FLT3-ITD positive acute myeloid leukemia (AML) who had received gilteritinib therapy for 43 months. At the time of diagnosis, her karyotype was normal; however, FLT3-ITD, NPM1, DNMT3A, and IDH2 mutations were detected. She received induction therapy with daunorubicin and cytarabine and achieved hematological complete remission (HCR). After attaining HCR, she underwent consolidation therapy with azacytidine or cytarabine, aclarubicin, and granulocyte-colony stimulating factor. However, AML relapsed eight months after the first HCR. FLT3-ITD and NPM1 mutations were persistently positive, and the patient received gilteritinib therapy. Although the FLT3-ITD clone was not detected during gilteritinib treatment, a clone harboring monosomy 7 and CBL mutations emerged. Bone marrow examinations at 15, 24, and 32 months after gilteritinib treatment revealed multi-lineage blood cell dysplasia without an increase in myeloblasts. After 33 months of treatment, gilteritinib was discontinued for two months because to ileus development, and the FLT3-ITD clone was detected again. Gilteritinib treatment was restarted, and FLT3-ITD became negative. Our analysis demonstrated that: (1) hematopoiesis derived from gilteritinib-resistant clones was generated by long-term gilteritinib treatment, and (2) FLT3-ITD clones regained clonal dominance in the absence of FLT3 inhibition. These findings suggest that gilteritinib affects the selection of dominant clones during clonal hematopoiesis.

Partial trisomy 9p and partial monosomy 7p of an infant inherited from maternal balanced translocation: a case report.

BACKGROUND: Subchromosomal deletions and duplications are the leading cause of congenital malformations and mental retardation in children. With the recent clinical application of genomic microarrays in the evaluation of patients with developmental delays and congenital malformations, it has led to the discovery of several new microdeletion and microduplication syndromes. However, there are no published reports involving patients with both microduplications in the 9p21.1-p24.3 region and microdeletions in the 7p22.1-p22.3 region. CASE PRESENTATION: We report an infant with an autosomal abnormality confirmed by conventional karyotype combined with copy number variations sequencing (CNV-seq), showing the patient with an unbalanced translocation. The karyotype of the patient was 46, XX, der (7)t (7;9) (p22; p21) and CNV-seq results showed an approximately 32.34-Mb duplication in 9p21.1-p24.3 (200000-32540000) and an approximately 3.3-Mb deletion in 7p22.2-p22.3 (40000-3340000). CONCLUSIONS: The patient carried an unbalanced translocation 46, XX, der (7)t (7;9) (p22; p21) derived from her mother. The clinical presentation is closely related to the size and position of the missing and duplicated chromosomes. To our knowledge, the simultaneous occurrence of de novo partial trisomy 9p(9p21.1-p24.3) and partial monosomy 7p (7p22.2-p22.3) has not previously been reported up until now. The present study additionally demonstrated that CNV-seq combined with karyotype is able to reliably detect unbalanced submicroscopic chromosomal aberrations.

Integrated analysis of genotype and phenotype reveals clonal evolution and cytogenetically driven disruption of myeloid cell maturation in myelodysplastic syndromes.

BACKGROUND: Myelodysplastic syndromes (MDS) are a heterogenous collection of clonal bone marrow diseases characterized by cytopenias, abnormal karyotypes, molecular abnormalities, and dysplasia by flow cytometry and/or morphology. The progression of MDS to severe cytopenias and/or overt leukemia is associated with the accumulation of additional cytogenetic abnormalities, suggesting clonal evolution. The impact of these accumulated abnormalities on myeloid maturation and the severity of the disease is poorly understood. METHODS: Bone marrow specimens from 16 patients with cytogenetic abnormalities were flow cytometrically sorted into three myeloid populations: progenitors, immature myeloid cells, and mature myeloid cells. Fluorescence in situ hybridization analysis was performed on each to determine the distribution of chromosomal abnormalities during myeloid maturation. RESULTS: Our findings revealed three distinct distributions of cytogenetic abnormalities across myeloid maturation, each of which corresponded to specific cytogenetic abnormalities. Group 1 had continuous distribution across all maturational stages and contained patients with a single cytogenetic aberration associated with good-to-intermediate prognosis; Group 2 had accumulation of abnormalities in immature cells and contained patients with high-risk monosomy 7; and Group 3 had abnormalities defining the founding clone equally distributed across maturational stages while subclonal abnormalities were enriched in progenitor cells and contained patients with multiple, non-monosomy 7, abnormalities with evidence of clonal evolution. CONCLUSIONS: Our findings demonstrate that low-risk abnormalities (e.g., del(20q) and trisomy 8) occurring in the founding clone display a markedly different disease etiology, with respect to myeloid maturation, than monosomy 7 or abnormalities acquired in subclones, which result in a disruption of myeloid cell maturation in MDS.

The First Case of Adult Granular Acute Lymphoblastic Leukemia with DNMT3A Mutation and Monosomy 7.

Granular acute lymphoblastic leukemia (ALL) is defined by the presence of intracytoplasmic granules in lymphoblastic blasts, mimicking acute myeloblastic leukemia. The disease is extremely rare in adults, and hence, the characteristics thereof are poorly understood. We report a case of a 70-year-old man diagnosed with granular ALL. Bone marrow examination showed blasts with azurophilic granules in the cytoplasm, but immunophenotyping showed B-ALL with aberrant expression of myeloid antigens CD13 and CD33. Karyotyping revealed monosomy 7, and targeted NGS showed DNMT3A mutation, which suggested poor prognosis. Despite conventional chemotherapy treatment, the patient did not achieve complete remission. He declined further chemotherapy treatment and was maintained on only supportive care. This is the first report of adult granular ALL with DNMT3A mutation and monosomy 7.

[Novel germline SAMD9 mutation in an elderly patient with myelodysplastic syndrome].

An 80-year-old Japanese male patient presented to our hospital with complaints of fatigue. His peripheral blood tests revealed pancytopenia with predominant lymphocytes and without blasts. The bone marrow (BM) aspiration was unsuccessful due to a dry tap, and the subsequent BM biopsy revealed hypocellular marrow with fibrosis. He was diagnosed with myelodysplastic syndrome (MDS) with excess blasts (EB)-2 based on CD34-positive cells. The chromosome analysis of the BM revealed monosomy 7, and the SAMD9 W22* mutation was detected (variant allele frequency [VAF] of 51.22%) using next-generation sequencing. An identical mutation was observed in the buccal mucosa (VAF of 50%), which was confirmed as a germline mutation. The SAMD9 gene mutation is reported as one of the causative genes for MIRAGE syndrome and child-onset MDS. The present case was considered a loss-of-function mutation due to the near full-length SAMD9 deletion. This is the first adult case of MDS with SAMD9 W22* as a germline mutation.

Discovery of MIRAGE syndrome.

Since the first report in 2009, whole exome sequencing has become the most effective and efficient research tool in human genetics. MIRAGE syndrome is a novel single-gene disorder discovered through whole-exome sequencing for pediatric patients with adrenal insufficiency of unknown etiology, and is caused by de novo heterozygous variants in SAMD9. MIRAGE syndrome was initially discovered as a systemic disease affecting multiple systems, including hematopoietic, immune, endocrine, and gastrointestinal systems but later studies revealed a subset of patients with myelodysplastic syndrome as the sole manifestation. In addition, pathogenic variants in SAMD9L, a paralog gene of SAMD9, were reported to cause an inherited disorder of the hematopoietic system and central nervous system, called ataxia-pancytopenia syndrome. This article reviews the history of MIRAGE syndrome from its discovery to the proposal of SAMD9/SAMD9L syndromes, and discusses directions for future research.

[Hypernatremia and polyuria in a female patient with an initial diagnosis of secondary acute myeloid leukemia]. / Hypernatriämie und Polyurie bei einer Patientin mit Erstdiagnose einer sekundären akuten myeloischen Leukämie.

A 66-year-old female patient with the initial diagnosis of acute myeloid leukemia is reported. Paraneoplastic syndrome manifested as hypernatremia due to central diabetes insipidus (CDI), which could be controlled with the administration of desmopressin. After initiation of the induction therapy, the required desmopressin administration could be reduced and terminated. In the further course, the early increasing polyuria and hypernatremia indicated the primary refractory acute myeloid leukemia.

Case Report: Refractory Cytopenia With a Switch From a Transient Monosomy 7 to a Disease-Ameliorating del(20q) in a NHEJ1-Deficient Long-term Survivor.

We report the case of a male Pakistani patient with a pathogenic homozygous loss of function variant in the non-homologous end-joining factor 1 (NHEJ1) gene. The growth retarded and microcephalic boy with clinodactyly of both hands and hyperpigmentation of the skin suffered from recurrent respiratory infections. He was five and a half years old when he came to our attention with refractory cytopenia and monosomy 7. Hematopoietic stem cell transplantation was considered but not feasible because there was no suitable donor available. Monosomy 7 was not detected anymore in subsequent bone marrow biopsies that were repeated in yearly intervals. Instead, seven and a half years later, a novel clone with a del(20q) appeared and steadily increased thereafter. In parallel, the patient's blood count, which had remained stable for over 20 years without necessitating any specific therapeutic interventions, improved gradually and the erythropoiesis-associated dysplasia resolved.

18F-Fluorodeoxyglucose Positron Emission Tomography/Magnetic Resonance Imaging Appearance of Gastrointestinal Behcet's Disease.

Behcet's syndrome (BS) is a variable vessel vasculitis with multi-organ involvement. Recurrent episodes of oral and genital ulcers, papulopustular and erythema nodosum-like skin lesions, and arthritis are relatively more frequent, whereas uveitis, venous and arterial lesions, nervous system, and gastrointestinal involvement are less common, but are severe manifestations. The frequency of gastrointestinal involvement shows important variation between countries as more common in the Far East and the United States, and much less common in Turkey and the Middle East. The main clinical signs of gastrointestinal Behcet's disease include abdominal pain, diarrhea, blood in the stool, fever, and weight loss. Ulcers seen in the terminal ileum, cecum, and ascending colon are common endoscopic findings. Herein, we presented the positron emission tomography/magnetic resonance imaging findings of gastrointestinal involvement in BS.

A prognostic approach on a case of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia with monosomy-7.

In this work, we present the first case of a Ph-positive ALL Moroccan girl with t(9;22)(q34;q11) and monosomy-7. She was diagnosed with Ph-positive ALL based on bone marrow examination, immunophenotyping, and cytogenetic analysis. She relapsed after treatment with the persistence of the Ph chromosome and the appearance of a monosomy-7.

Myelodysplastic syndrome presenting with central diabetes insipidus is associated with monosomy 7, visible or hidden: report of two cases and literature review.

BACKGROUND: Central diabetes insipidus (CDI) is a rare complication of myelodysplastic syndrome (MDS). Although the cytogenetic features of patients with MDS and CDI are not clear, CDI in patients with acute myeloid leukemia (AML) is associated with chromosome 7 and/or 3 anomalies. CASE PRESENTATION: In this report, we describe two patients with MDS and concurrent CDI, and in one of them, CDI was the first manifestation. One patient had monosomy 7 on metaphase cytogenetics (MC). Monosomy 7 and numerous cytogenetic abnormalities were found in the other patient using single-nucleotide polymorphism array (SNP-A) karyotyping, while the MC did not uncover monosomy 7. In this manuscript we also reviewed reported cases of MDS with diabetes insipidus (DI-MDS) to summarize the relationship between DI-MDS and karyotype, and explore the best treatment strategy for DI-MDS. CONCLUSIONS: DI-MDS is closely related to monosomy 7. Allogeneic hematopoietic stem cell transplantation may be the only effective treatment for DI-MDS. The SNP-A-based karyotyping is helpful to reveal subtle cytogenetic abnormalities and unveil their roles in the clinical features of MDS.