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:

    • 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

Molecular Genetic Testing

Gene(s). The gene(s) involved in familial bone marrow monosomy 7 are unknown. 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 (see following).

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.

Mutations in the CEBPA gene, 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.

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.

• Real-time quantitative PCR

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

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Test Method		Mutations Detected	Mutation Detection Frequency by Test Method 1	Test Availability
Deletion / duplication analysis 2	FISH	Deletion / monosomy mosaicism	100% (minimal detection for mosaicism depends on laboratory cut-off values; typical range is 5%-15%)	Clinical
	Chromosomal microarray (CMA) 3	Deletion / monosomy mosaicism	100% (minimal detection for mosaicism depends on laboratory cut-off values; typical range is 10%-30%)	Clinical
	Real-time quantitative PCR 3, 4	Deletion / monosomy	100% with a sensitivity of ~1:100,000	Clinical

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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 genomic DNA; a variety of methods may be used including quantitative PCR, long range PCR, multiplex ligation dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific). A full chromosomal microarray (CMA) that detects deletions/duplications across the genome may also include this gene/segment.

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

4. Porta et al [2007]

Testing Strategy

To 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.

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.

Genetically Related (Allelic) Disorders

No other distinct phenotypes are known to be associated with familial mosaic monosomy 7; however, monosomy 7 is seen as a secondary finding in a number of monogenic disorders (see Differential Diagnosis).

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.

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 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.

Carroll et al [1985] reported a family in which the proband had petechiae at age nine months with thrombocytopenia, anemia, and neutropenia. When evaluated at age 6½ years for easy bruising and epistaxis, she was found to have macrocytic red blood cells, 17% hemoglobin F, and monosomy 7 in 100% of bone marrow cells. Evaluation of her healthy asymptomatic five-year-old brother as a potential bone marrow donor revealed mild thrombocytopenia, macrocytic red blood cells (MCV 98 fl), 8% hemoglobin F, and monosomy 7 in 100% of bone marrow cells. The proband died of bone marrow failure eight weeks following the start of therapy. Over the next three years her sibling developed hepatosplenomegaly, circulating blasts, and monosomy 7; he died at age 8½ years from post-transplant infections following a bone marrow transplant from his mother.

A second family reported in Carroll et al [1985] had a similar history, in which a four-year-old boy presented with monosomy 7 and AML. During evaluation as a potential donor, his 2½ -year-old brother was found to have peripheral pancytopenia and bone marrow monosomy 7.

Monosomy 7 has been described in one family with late onset of familial AML [Kwong et al 2000]. All three sibs either presented with myeloid malignancies or rapidly progressed from refractory anemia (RA) with an excess of blasts (RAEB) into AML (in the case of the 18-year-old proband). Hematologic examination of these three sibs did not identify macrocytic red blood cells or persistence of hemoglobin F, which could be the manifestation of a different condition associated with monosomy 7 or another natural history of the disorder due to the difference of age of presentation.

In a large kindred described by Chitambar et al [1983] eight of 14 maternal first cousins developed either aplastic anemia or AML (with or without a preleukemic myelodysplastic phase). Those who were studied cytogenetically had either monosomy 7 or monosomy for a C-group chromosome. Hemoglobin F was not mentioned in the report. The fact that half sibs with the same mother developed and died from either aplastic anemia or AML suggests the possibility of a maternally inherited trait that predisposes to monosomy 7 and bone marrow failure.

In another kindred of interest, Larsen & Schimke [1976] reported five maternal first cousins (one sibship of three and one sibship of two) who died of AML with group C monosomy. The mode of inheritance of monosomy 7 was confounded by a history of paternally inherited Noonan syndrome in the sibship of three. The other sibship in the kindred did not have Noonan syndrome or a family history of Noonan syndrome. However, individuals with Noonan syndrome are at an increased risk for juvenile myelomonocytic leukemia (JMML) or a JMML-like disease in infancy [Choong et al 1999, Kratz et al 2005]. The most common abnormality in JMML is monosomy 7.

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.

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 four years). Approximately 15% of cases of JMML are seen in persons with NF1.

Genotype-Phenotype Correlations

No genotype-phenotype correlations are known because the causative gene(s) 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; 12 kindreds have been reported in the literature.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with mosaic monosomy 7, 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, since 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.

Testing 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.

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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

Mode of Inheritance

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

In one kindred 8/14 first cousins (the children of three 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 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 imply that there is no 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 theoretical risk to offspring of developing the condition is as high as 50%. Although 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, Testing Relatives at Risk for information on testing 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. See for a list of laboratories offering DNA banking.

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 available, as there is no known gene or locus.

Molecular Genetic Pathogenesis

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

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.

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.

In several families with familial mosaic monosomy 7, sibs have been studied to establish the parental (i.e., maternal or paternal) origin of the lost chromosome 7 and to determine if the findings are consistent with the Knudson and Strong hypothesis of loss of heterozygosity (LOH). LOH would be the most likely explanation if the same mutated/imprinted parental chromosome 7 were retained in monosomic cells within sib pairs. However, within several kindreds the retained chromosome 7 varied in parental origin [Shannon et al 1989; Minelli et al 2001, Maserati et al 2004], suggesting that other factors on a different chromosome or chromosomes must be operative — including the mutator gene suggested by Minelli et al [2001].

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Suggested Reading

1. Owen C, Barnett M, Fitzgibbon J. Familial myelodysplasia and acute myeloid leukaema-a review. British Journal of Haematology. 2008;140:123–132. [PubMed: 18173751]
2. Heim S, Mitelman F (2009) Cancer Cytogenetics, 3rd ed. Wiley-Blackwell, Hoboken, NJ.

Acknowledgments

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

Revision History

• 8 July 2010 (me) Review posted live

• 13 November 2009 (jm) Original submission