DiagnosisClinical DiagnosisFamilial mosaic monosomy 7 is suspected in individuals with:Values consistent with a laboratory’s age-related standards for:Red cell macrocytosisIncreased hemoglobin F concentrationEvidence of bone marrow insufficiency manifest as any combination of:ThrombocytopeniaNeutropeniaAnemia
Note: Severe aplastic anemia has been defined as follows:Granulocyte count <500/mLPlatelet count <20,000/mLReticulocyte count <1% after correction for hematocritBone marrow biopsy with <25% of the normal cellularityMyelodysplastic 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.TestingHistopathologyBone 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 TestingPeripheral 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). NomenclatureAn 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 TestingGene(s). The gene(s) involved in familial bone marrow monosomy 7 are unknown. See Molecular Genetic Pathogenesis for discussion of proposed susceptibility genes. Clinical testingDeletion/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 PCRTable 1. Summary of Molecular Genetic Testing Used in Familial Mosaic Monosomy 7 SyndromeView in own windowTest MethodMutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityDeletion / duplication analysis 2FISHDeletion / monosomy mosaicism100% 3Clinical Chromosomal microarray (CMA) 4Deletion / monosomy mosaicism100% 5Real-time quantitative PCR 4, 6Deletion / monosomy100% with a sensitivity of ~1:100,0001. 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 StrategyTo 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.Genetically Related (Allelic) DisordersNo 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 HistoryFamilial 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 CorrelationsNo genotype-phenotype correlations are known because the gene(s) in which mutation is causative are unknown.

Differential DiagnosisMonosomy 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:Aplastic anemiaJuvenile myelomonocytic leukemia (JMML)Bloom syndrome [Aktas et al 2000]Paroxysmal nocturnal hemoglobinuria (PNH)Dyskeratosis congenitaNeurofibromatosis type 1 [Kelleher & Carbone 1991, Maris et al 1997]Fanconi anemiaNoonan syndrome [Choong et al 1999, Kratz et al 2005]Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo 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 ManifestationsThe 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 ComplicationsIt 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.SurveillanceFollow-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 RiskIn 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 InvestigationSearch 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.

Molecular GeneticsInformation 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) View in own window 252270MONOSOMY 7 OF BONE MARROWMolecular Genetic PathogenesisIn 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.