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Familial Mosaic Monosomy 7 Syndrome

Synonyms: Familial Leukemia Associated with Monosomy 7, Familial Myelodysplastic Syndrome (MDS) Associated with Monosomy 7, Myelodysplasia and Leukemia Syndrome with Monosomy 7

, PhD, FACMG, , MD, FRCP(C), and , MD.

Author Information
, PhD, FACMG
Scientific Director, Cancer Cytogenetics
Clinical Director, Center for Personalized Diagnostics
Department of Pathology
University of Pennsylvania
Philadelphia, Pennsylvania
, MD, FRCP(C)
Director, Department of Pathology and Laboratory Medicine
St Christopher’s Hospital for Children
Philadelphia, Pennsylvania
, MD
Director, Blood and Bone Marrow Transplant
Department of Pediatrics
Division Pediatric Hematology/Oncology
Nemours/Alfred I DuPont Hospital for Children
Wilmington, Delaware

Initial Posting: ; Last Update: February 7, 2013.

Summary

Disease characteristics. Familial monosomy 7 is typically characterized by early-childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Bone marrow failure/MDS/AML follows within a few months to years of identification of a monosomy 7 cell line in peripheral blood. Nearly all individuals reported with familial mosaic monosomy 7 have died of their disease.

Note: Only a minority of individuals with bone marrow failure/MDS/AML with monosomy 7 fall into the diagnostic category of familial monosomy 7.

Diagnosis/testing. The finding of a monosomy 7 cell line detected during evaluation of a hematologic abnormality or malignancy or during the use of chromosomal studies in the diagnosis of other conditions needs to be confirmed with bone marrow cytogenetic and interphase FISH studies. A bone marrow karyotype of 45,XX,-7 in females or 45,XY,-7 in males, often mosaic with a normal cell line (i.e., 46,XX in females and 46, XY in males), confirms the presence of a monosomy 7 cell line. Of note, individuals with a family history of monosomy 7 (i.e., a sib) may initially have a normal karyotype in peripheral blood and/or bone marrow and over time transition to mosaic monosomy 7 in peripheral blood and/or bone marrow.

Management. Treatment of manifestations: Urgent referral to an oncologist should be considered in those with monosomy 7 (mosaic or non-mosaic). Definitive therapy is bone marrow transplantation (BMT) prior to the emergence of a leukemic clone. It is recommended that sibs who are potential bone marrow donors be evaluated with appropriate cytogenetic studies to determine their suitability.

Prevention of secondary complications: It is unknown if the standard protocols for ablative therapy prior to BMT should be modified.

Surveillance: Annual monitoring of peripheral blood karyotype, hematologic status, and hemoglobin F levels helps identify bone marrow abnormalities (cytopenias and bone marrow dysplasia) prior to the development of AML or MDS.

Evaluation of relatives at risk: In both children and adults with a family history of mosaic monosomy 7, signs and symptoms that cannot be accounted for otherwise should be evaluated by a physician as possible early indications of the disorder.

Genetic counseling. The mode of inheritance of familial monosomy 7 is unknown.

Diagnosis

Clinical Diagnosis

Familial mosaic monosomy 7 is suspected in individuals with:

  • Values consistent with a laboratory’s age-related standards for:
    • Red cell macrocytosis
    • Increased hemoglobin F concentration
  • Evidence of bone marrow insufficiency manifest as any combination of:
    • Thrombocytopenia
    • Neutropenia
    • Anemia

      Note: Severe aplastic anemia has been defined as follows:
      • Granulocyte count <500/mL
      • Platelet count <20,000/mL
      • Reticulocyte count <1% after correction for hematocrit
      • Bone marrow biopsy with <25% of the normal cellularity
  • Myelodysplastic syndrome (MDS) and/or acute myelogenous leukemia (AML)
  • Monosomy 7 in peripheral blood and/or bone marrow cells (see Testing)
  • Family member(s) with any of the above hematologic findings. Sibs are at highest risk and should be evaluated for hematologic differences, particularly when considered as a potential bone marrow transplantation donor.

Note: Usually at the time of initial diagnosis the proband is considered to be a simplex case (i.e., a single occurrence in a family) and the familial nature is unknown and unsuspected until another family member is found to have characteristic hematologic findings. Typically these asymptomatic family members have an unremarkable prior medical history; laboratory findings in these individuals are likely to include macrocytic red blood cells (MCV>94 fL), increased concentrations of hemoglobin F, and low normal platelet counts.

Testing

Histopathology

Bone marrow aspiration (evaluation of fluid aspirated from the marrow spaces for analysis of cellular details) reveals variable but not diagnostic findings depending on degree of progression toward the leukemic stage.

Bone marrow biopsy (evaluation of bone with its marrow spaces) provides best information on overall cellularity and marrow replacement and reveals variable but not diagnostic information depending on degree of progression toward the leukemic stage.

Cytogenetic Testing

Peripheral blood. When monosomy 7 is suspected, the laboratory should be notified to perform unstimulated cytogenetic analysis (i.e., without PHA or other mitogens). See also discussion of FISH in Molecular Genetic Testing.

Bone marrow. Routine cytogenetic studies of the bone marrow demonstrate a 45,XX,-7 karyotype in females and 45,XY,-7 karyotype in males, often mosaic with a normal cell line (i.e., 46,XX in females and 46, XY in males). The level of mosaicism detected can vary.

Note: In unstimulated samples, mitotic cells are more likely than non-mitotic cells to yield cytogenetic results. Thus, detection of a high percentage of monosomy 7 marrow cells by G-band cytogenetic analysis can be attributable to replacement of normal bone marrow cells by abnormal cells or to high mitotic activity of the abnormal cells. See also discussion of FISH in Molecular Genetic Testing.

Note: In some cases treatment with steroids can mask the cytogenetic identification of monosomy 7. However, monosomy 7 would be identifiable by either FISH or chromosomal microarray (CMA) (see Molecular Genetic Testing, Clinical testing).

Nomenclature

  • An example of correct terminology for mosaic monosomy 7 identified in conventional cytogenetic studies is 45,XX,-7[5]/46,XX[15] for a female in whom monosomy 7 is identified in five of 20 cells studied.
  • Before the advent of chromosome banding in 1972, chromosomes were grouped by size and morphology (location of the centromere) because it was not possible to distinguish individual chromosomes. Chromosome 7 was categorized as a “C-group” chromosome.

Additional acquired cytogenetic abnormalities have been seen. Occasionally, rearrangement of chromosome 7 material results in retention of the short arm (7p) and loss of the long arm (7q) resulting in monosomy of 7q (sometimes called “partial monosomy 7”). A minimum band level of 350 is necessary to visualize the deletion in the absence of FISH studies (see Molecular Genetic Testing).

Note: Individuals with familial mosaic monosomy 7 may initially have a normal karyotype in peripheral blood and/or bone marrow and over time transition to mosaic monosomy 7 in peripheral blood and/or bone marrow. Thus, normal cytogenetic studies in either peripheral blood or bone marrow at the onset of hematologic disease do not eliminate the possibility of subsequent loss of a chromosome 7 associated with bone marrow failure, MDS, and/or AML.

Molecular Genetic Testing

Gene(s). The gene(s) involved in familial bone marrow monosomy 7 are unknown. See Molecular Genetic Pathogenesis for discussion of proposed susceptibility genes.

Clinical testing

Deletion/duplication analysis is testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA. A variety of methods may be used; three are commonly used for detection of mosaic monosomy 7:

  • Fluorescent in situ hybridization (FISH)
    • FISH using the probes for the chromosome 7 centromere (D7Z1) and the 7q31 region (e.g., D7S486) on interphase nuclei can confirm the diagnosis of monosomy 7 and determine the percent mosaicism in peripheral blood and bone marrow.
    • Nomenclature: An example of correct terminology for mosaic monosomy 7 identified by FISH studies is nuc ish (D7Z1,D7S486)x1[100/200] for an interphase FISH study for the centromeric region of chromosome 7 and 7q22 region where one signal was observed in 100 out of 200 cells studied.
  • Chromosomal microarray (CMA)
    • Nomenclature: An example of correct terminology for mosaic monosomy 7 identified by targeted CMA studies with probes in 7p22.3-7q36.3 is:
      • arr(7p22.3-7q36.3)(first probe - last probe)x1 if the monosomy was present in all cells.
      • arr(7p22.3-7q36.3)(first probe - last probe)1~2 if mosaicism was present.
    • Nomenclature on test reports varies among laboratories, depending on the probes employed and thus the region of the chromosome interrogated.

Table 1. Summary of Molecular Genetic Testing Used in Familial Mosaic Monosomy 7 Syndrome

Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
Deletion / duplication analysis 2FISHDeletion / monosomy mosaicism100% 3
Chromosomal microarray (CMA) 4Deletion / monosomy mosaicism100% 5
Real-time quantitative PCR 4, 6Deletion / monosomy100% with a sensitivity of ~1:100,000

1. The ability of the test method used to detect a deletion/monosomy that is present on chromosome 7 in the critical region. A pre-onset mosaic monosomy is not detectable with the presently available methodology. Thus, a sib of a person with known mosaic monosomy 7 should be under continuous surveillance.

2. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

3. Minimal detection for mosaicism depends on laboratory cut-off values; typical range: 5%-15%.

4. Loci analyzed are typically D7Z1 and/or D7S486 along with additional chromosome 7 probes.

5. Minimal detection for mosaicism depends on laboratory cut-off values; typical range: 10%-30%.

6. Porta et al [2007]

Testing Strategy

To confirm/establish the diagnosis in a proband, the following algorithm is suggested:

1.

Perform conventional G-banded cytogenetic analysis and CMA on unstimulated peripheral blood. If monosomy 7 is present or there is evidence of bone marrow failure or myelodysplastic features, perform cytogenetic analysis of bone marrow to confirm the diagnosis and to evaluate for other possible chromosome aberrations.

2.

Perform FISH using the probe for the chromosome 7 centromere (D7Z1) and 7q31 region (D7S486) on interphase nuclei to confirm the diagnosis and to determine the percent of mosaicism in peripheral blood and bone marrow.

Clinical Description

Natural History

Familial mosaic monosomy 7 is typically characterized by early-childhood onset of evidence of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), followed by complete bone marrow failure (reviewed in Hess [2001]). Myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) associated with either complete or partial monosomy 7 have been reported in at least 12 pedigrees. For further detailed clinical information regarding affected individuals in some of these pedigrees, click here.

Rapid progression is common in familial cases. Most reports indicate that once a monosomy 7 cell line is identified in peripheral blood, an individual progresses to bone marrow failure/MDS/AML within months to three years. The prognosis is poor, particularly in individuals with a high percentage of monosomy 7 cells in the bone marrow.

Nearly all individuals reported with familial mosaic monosomy 7 have died of their disease.

The majority of persons described are children. Abnormal hematologic findings have been seen in children as young as age nine months and mosaic monosomy 7 in those as young as age five years. Some have been diagnosed as teenagers.

Most affected individuals present with evidence of bone marrow insufficiency such as petechiae, easy bruising, and/or anemia.

Although rare, de novo myelodysplastic syndrome has been described in children, with monosomy 7 seen in 25%-30% of cases. Although not familial cases, these individuals also had a poor response to therapy and were candidates for bone marrow transplantation.

Juvenile myelomonocytic leukemia (JMML) can also present with monosomy 7 and is often seen in neurofibromatosis type 1 (NF1) at an average age of two years (95% of cases are diagnosed before age 4 years). Approximately 15% of cases of JMML are seen in persons with NF1. Additionally, individuals with Noonan syndrome are at an increased risk for JMML or a JMML-like disease in infancy [Choong et al 1999, Kratz et al 2005].

Monosomy 7 can also be seen in sporadic cases of acute myeloid leukemia, myelodysplastic syndrome, and myeloproliferative neoplasms. Although the discovery of monosomy 7 in these cases portends a poor outcome, it is not thought that the majority are associated with the familial entity.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known because the gene(s) in which mutation is causative are unknown.

Penetrance

Penetrance for familial mosaic monosomy 7 is unknown.

Nomenclature

Before the advent of chromosome banding, chromosomes were grouped by size and morphology (location of the centromere) because it was not possible to distinguish individual chromosomes. Using this system, chromosome 7 is categorized as a “C-group” chromosome; thus, familial “C-group monosomy” reported prior to 1972 are presumed to be reports of familial mosaic monosomy 7.

Prevalence

Familial mosaic monosomy 7 is rare; 14 kindreds have been reported in the literature.

Differential Diagnosis

Monosomy 7 has been reported in multiple family members with the following disorders:

  • Cerebellar ataxia/atrophy-pancytopenia syndrome. In five sibs in one family, cerebellar ataxia segregated with either hypoplastic anemia or acute myelogenous leukemia (AML) with monosomy 7 (C-group monosomy) [Li et al 1978, Li et al 1981]. Four of the five sibs died from bone marrow failure or AML. It is unclear whether this is part of the diagnostic spectrum of familial mosaic monosomy 7 or a distinct entity.
  • Familial platelet disorder with propensity to AML (FPD/AML) [Minelli et al 2001, Minelli et al 2004, Jongmans et al 2010]

Monosomy 7 has been reported in individuals with the following disorders in which monosomy 7 is secondary:

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with mosaic monosomy 7, urgent referral to an oncologist for evaluation is recommended.

Treatment of Manifestations

The goal of management in monosomy 7 is early diagnosis so that definitive therapy with bone marrow transplantation (BMT) can be initiated prior to the emergence of a leukemic clone. Once the bone marrow transforms into a dysplastic or leukemic state, the probability that BMT will fail to cure the disease increases significantly.

Since bone marrow transplantation is the only effective treatment for the management of hematologic disease and the familial status of the disorder may not be known, rigorous evaluation of related donors is strongly suggested.

Treatment for acute myelogenous leukemia (AML) is ideally delayed until cytogenetic data are obtained. Children with de novo MDS and AML, in whom monosomy 7 is reported to have an adverse prognosis, are treated on high-risk AML protocols and offered bone marrow transplantation in first remission [Hasle et al 2007]. However, the limited number of reported cases of familial mosaic monosomy 7 makes it difficult to draw conclusions about appropriate timing of therapy.

Prevention of Secondary Complications

It is unclear whether standard protocols for the required ablative therapy prior to BMT should be modified; it is known that persons with cancer predisposition syndromes may be sensitive to the chemical agents and ionizing irradiation used in this procedure.

Surveillance

Follow-up surveillance should be coordinated by specialists in oncology and bone marrow transplantation. The goal is to identify bone marrow abnormalities (cytopenias and bone marrow dysplasia) prior to the development of AML or MDS by annual monitoring of cytogenetic studies in unstimulated peripheral blood, hematologic status, and hemoglobin F levels.

Evaluation of Relatives at Risk

In both children and adults with a family history of mosaic monosomy 7, signs and symptoms that cannot be accounted for otherwise should be evaluated by their physicians as potential early indications of the disorder.

To evaluate sibs at risk, perform cytogenetic studies/CMA on bone marrow or unstimulated peripheral blood (FISH and/or conventional cytogenetics), hematologic studies, and hemoglobin F. If these are normal, it is reasonable to repeat the cytogenetic studies on unstimulated peripheral blood (FISH and/or conventional cytogenetics) or CMA on a yearly basis.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

The mode of inheritance of familial mosaic monosomy 7 is unclear.

In one kindred, eight of 14 first cousins (the offspring of 3 sisters) had aplastic anemia or AML; in those with cytogenetic studies the karyotype evolved to monosomy 7 (or group C monosomy) [Chitambar et al 1983]. Thus, in this family approximately 50% of maternal first cousins inherited a trait that resulted in aplastic anemia or AML in their children. Another kindred with five maternally-related first cousins in two sibships supports a similar mechanism of inheritance. In both of these kindreds both male and female cousins were affected, suggesting that this is not an X-linked trait. This pattern of inheritance would be consistent with either an autosomal dominant disorder with incomplete penetrance [Bodor et al 2012] or a maternally inherited (mitochondrial) disorder. Because the parents of those children do not seem to be affected, OMIM has suggested that this disorder may be inherited in an autosomal recessive manner; however, there is no report of relationships between the fathers of these kindreds, making autosomal recessive inheritance less likely. Although chromosome 7 is an imprinted chromosome, evidence suggests that the predisposing locus is not present on chromosome 7 (see Molecular Genetic Pathogenesis).

Risk to Family Members

Parents of a proband. Monosomy 7 has not been reported in the peripheral blood or bone marrow of the parents of an individual with familial mosaic monosomy 7. This lack of documentation does not rule out risk to the parents of a proband; however, to date no increased risk has been documented.

Sibs of a proband. Sibs of a proband with monosomy 7 may have as much as a 50% chance of developing monosomy 7. However, the overall risk is likely much lower [Hasle & Olsen 1997].

Offspring of a proband. If familial mosaic monosomy 7 has been established and the proband has survived to reproductive age and is fertile, the theoretic risk to offspring of developing the condition is as high as 50%. Two individuals with familial mosaic monosomy 7 are known to have reproduced; no data are available on their offspring.

Other family members. As it is suspected that a transmissible predisposing condition may be affecting other branches of the family, and as there is no way of establishing such predisposition presently, other members of the family are to be considered at increased risk. There is, however, no way of establishing the magnitude of the risk, though sibs are at greatest risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

At this time prenatal diagnosis is not possible as the gene responsible for familial mosaic monosomy 7 is unknown. Monosomy 7 is not expected to be present in tissues sampled prenatally.

Preimplantation genetic diagnosis (PGD) is not currently possible, as there is no known gene or locus.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

No specific resources for Familial Mosaic Monosomy 7 Syndrome have been identified by GeneReviews staff.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table B. OMIM Entries for Familial Mosaic Monosomy 7 Syndrome (View All in OMIM)

252270MONOSOMY 7 OF BONE MARROW

Molecular Genetic Pathogenesis

In familial mosaic monosomy 7, there is a predisposition to monosomy 7 or partial deletion of the long arm of chromosome 7 in the bone marrow and peripheral blood. It is not known whether other tissues may be also affected.

The malignancy appears to be the result of losing the minimal segment(s) on the long arm of chromosome 7, with most reports involving regions between 7q21.3 and 7q34 [Curtiss et al 2005, Cigognini et al 2007, Asou et al 2009]. The predisposing locus that leads to loss of chromosome 7, and thus underlies the disorder, is unknown.

The loss of chromosome 7 or segmental loss of 7q is thought to lead to loss of a tumor suppressor locus [Curtiss et al 2005, Asou et al 2009]. Initially it was thought that the loss of one chromosome 7 was a loss of heterozygosity (LOH) event, with a submicroscopic mutation in an allele on 7q on the retained chromosome 7. However, this theory was tested and the evidence suggests that the predisposing locus is not on the long arm of chromosome 7 [Shannon et al 1989, Minelli et al 2001, Maserati et al 2004]. It had been initially thought that the mechanism followed the Knudson hypothesis of a constitutionally inherited “first hit” mutation, followed by loss of the remaining allele. If this were the case, it would be expected in familial cases that the identical parental chromosome 7 (with the constitutional mutation) would be retained and the other parental chromosome 7 (with the normal allele) would be lost. Using restriction fragment length polymorphism (RFLP) markers to evaluate three unrelated sibling pairs who developed AML with monosomy 7, Shannon et al [1992] determined that in these sibling pairs different parental chromosome 7s were retained, implying that the locus was on a different chromosome. One possibility is the mutator gene suggested by Minelli et al [2001].

In a recent case report, a germline mutation in GATA2 (OMIM 137295) segregated with acquired monosomy 7 in a family [Bodor et al 2012]. In the family described, two cousins with the GATA2 mutation acquired both a monosomy 7 clone and an ASXl1 mutation.

Mutations in CEBPA, encoding CCAAT/enhancer binding protein-α, have been identified in individuals with familial AML [Pabst et al 2008]. In at least one of these families monosomy 7 was seen at presentation.

Familial mosaic monosomy 7 represents a small proportion of mutations found in AML, but is a common finding in therapy-related AML after alkylator chemotherapy.

References

Literature Cited

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Suggested Reading

  1. Gaitonde S, Boumendjel R, Angeles R, Rondelli D. Familial childhood monosomy 7 and associated myelodysplasia. J Pediatr Hematol Oncol. 2010;32:e236–7. [PubMed: 20661156]
  2. Heim S, Mitelman F. Cancer Cytogenetics. 3 ed. Hoboken, NJ: Wiley-Blackwell; 2009.
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Chapter Notes

Acknowledgments

We would like to thank Hope H Punnett, PhD and Carol E Anderson, MD for critical reading of the manuscript.

Revision History

  • 7 February 2013 (me) Comprehensive update posted live
  • 8 July 2010 (me) Review posted live
  • 13 November 2009 (jm) Original submission
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