What is the recommended approach for cytogenetic screening and management of individuals with suspected monosomy 7 (loss of one chromosome 7)?

Cytogenetic Screening for Monosomy 7

Diagnostic Testing at Initial Evaluation

All patients with suspected myeloid neoplasms must undergo conventional cytogenetic analysis (G-banding) of bone marrow aspirate with analysis of at least 20 metaphases to detect monosomy 7, as this abnormality is one of the most critical prognostic factors determining treatment strategy. 1

Primary Screening Methods

• Conventional cytogenetics (G-banding) is the gold standard first-line test and should be performed on bone marrow aspirate in all patients with suspected MDS, AML, or MDS/MPN 1
• At least 20 metaphases must be analyzed to exclude the presence of a chromosomally abnormal clone with 95% confidence 1
• Results should be obtained within 5-7 days, and abnormal karyotypes may be diagnosed from blood specimens if bone marrow aspiration fails 1

Supplementary FISH Testing

FISH analysis for monosomy 7 is mandatory in specific clinical scenarios where conventional cytogenetics fails or rapid results are needed:

• When conventional cytogenetics yields no metaphases or poor-quality metaphases, FISH for monosomy 7 (and del(7q)) must be performed 1
• FISH for monosomy 7 detection is specifically recommended in pediatric patients due to the prognostic value of this aberration 1
• In cases of repeated cytogenetic failure, FISH may complement conventional analysis and can detect abnormalities in up to 15% of karyotypically normal MDS patients 1
• FISH is particularly useful when rapid diagnostic information is needed for therapeutic decision-making 1

Molecular and Array-Based Testing

• SNP array analysis should be performed when conventional cytogenetics and FISH fail to detect abnormalities, as it can identify copy-neutral loss of heterozygosity (CN-LOH) involving chromosome 7 1
• Array analysis is emerging as an important complementary tool in MDS, though it cannot replace conventional cytogenetics for comprehensive screening 1

Risk Stratification and Clinical Implications

High-Risk Features Requiring Immediate Action

Monosomy 7 represents a high-risk cytogenetic abnormality that mandates immediate evaluation for allogeneic hematopoietic stem cell transplantation (HSCT), as it is associated with poor response to chemotherapy alone, high relapse rates, and shortened survival. 2

• Monosomy 7 is classified in the adverse risk category in both AML and MDS prognostic scoring systems (ELN 2017 for AML, IPSS-R for MDS) 1
• The presence of monosomy 7 provides presumptive evidence of MDS even in the absence of definitive morphologic features (dysplasia in <10% of cells) 1

Syndrome-Specific Considerations

In patients with germline predisposition syndromes, monosomy 7 is a critical marker of malignant transformation:

• GATA2 deficiency: Monosomy 7 is a high-risk feature strongly associated with malignant transformation, particularly when accompanied by somatic mutations in SETBP1, ASXL1, RUNX1, and RAS pathway genes; proceed directly to allogeneic HSCT 2
• Fanconi Anemia: Monosomy 7, along with gain of 1q or 3q and somatic RUNX1 mutations, indicates progression to MDS/AML and is an indication for allogeneic HSCT 2
• SAMD9/SAMD9L syndromes: Approximately 50% of patients with monosomy 7 acquire additional leukemia-driver mutations (SETBP1, ASXL1, RUNX1, RAS pathway genes), indicating progression risk 2

Concomitant Cytogenetic Abnormalities

The prognosis of monosomy 7 is significantly influenced by additional cytogenetic abnormalities 3:

• Monosomy 7 with or without complex karyotype (CK) in the absence of monosomal karyotype (MK), -5/5q-, abn(17p), or inv(3) has relatively better outcomes after HSCT (48% 2-year LFS in first remission) 3
• Addition of MK, -5/5q-, abn(17p), or inv(3) identifies a subgroup with particularly poor prognosis even after HSCT (17-28% 2-year LFS) 3

Monitoring and Follow-Up

Baseline and Serial Molecular Testing

Serial somatic gene panels must be performed from bone marrow specimens at baseline and with each subsequent evaluation for patients with germline predisposition syndromes including Fanconi Anemia, GATA2 deficiency, Shwachman-Diamond syndrome, severe congenital neutropenia, and germline SAMD9/SAMD9L, ERCC6L2, and RUNX1 pathogenic variants. 2

HLA Typing

• High-resolution molecular HLA typing (classes I and II) should be performed at diagnosis for patients aged <55 years who are candidates for allogeneic HSCT 2

Surveillance in High-Risk Populations

For children with leukemia-predisposing conditions at high risk for MDS/AML 1:

• Perform CBCs every 3-4 months for highest-risk diseases (e.g., Fanconi anemia), even if counts are stable 1
• If cytopenia develops or worsens over two or more measurements, perform bone marrow aspirate/biopsy with cytogenetics 1
• Annual bone marrow evaluation with cytogenetic analysis should be offered for children at greatest risk for bone marrow failure and/or MDS/AML, examining for evolution of hematopoietic clones with high-risk cytogenetics such as monosomy 7 1

Follow-Up After Treatment

• When monosomy 7 was detected at diagnosis, chromosome analysis is appropriate for follow-up 1
• If a normal result is obtained at follow-up, a minimum of 20 metaphases should be analyzed or scored for the diagnostic abnormality 1
• For minimal residual disease detection, quantitative PCR, other molecular technologies, and multi-parametric flow cytometry are preferable to cytogenetics 1

Treatment Approach

Intensive chemotherapy alone has historically shown poor outcomes in monosomy 7 cases, with frequent treatment resistance and early relapse; chemotherapy may be used as a bridge to transplant in cases with excess blasts but should not be considered definitive therapy. 2

• Allogeneic HSCT is the only potentially curative therapy for most patients with monosomy 7 2
• Treatment decisions should be made urgently given the aggressive nature and poor prognosis of monosomy 7-associated myeloid neoplasms 2

Critical Pitfalls to Avoid

• Do not rely solely on FISH if conventional cytogenetics is feasible, as FISH can only detect targeted abnormalities and may miss complex karyotypes or additional prognostically relevant abnormalities 1
• Do not dismiss the significance of a single abnormal metaphase with monosomy 7; further screening or testing by another technique is required to determine clonality 1
• For chromosome loss, ensure at least three metaphases show the abnormality to meet ISCN clonality criteria, and exclude cells with artifactual random losses 1
• Do not delay evaluation for HSCT while pursuing additional chemotherapy cycles, as monosomy 7 confers chemotherapy resistance 2