SHORT REPORT

Secondary acute myeloid leukaemia with monosomy 7

in identical adult twins

Gernot Seipelt,1 Ulrich Germing,2 Steffen Koschmieder,1 Angelika BoÈ hme,1 Carlo Aul2 and

Dieter Hoelzer1 1UniversitaÈtsklinik Frankfurt, Medizinische Klinik III, HaÈmatologie/Onkologie, Frankfurt/M, and2Heinrich-Heine-UniversitaÈt DuÈsseldorf, Klinik fuÈr HaÈmatologie, Onkologie und klinische Immunologie, DuÈsseldorf,

Germany

Received 20 September 2001; accepted for publication 21 September 2001

Summary. We report the development of secondary acutemyeloid leukaemia (AML) with monosomy 7 in identicaltwins, both at the age of 52 years. In the ®rst twin,induction therapy resulted in complete remission (CR). Atrelapse 9 months later monosomy 7 was found. The patientdied of sepsis 11 months after diagnosis. The other twinpresented with leucopenia and thrombocytopenia andrefractory anaemia (RA) was diagnosed. During follow-up,¯uorescence in situ hybridization analysis demonstrated

a monosomy 7 in 11% of the cells. Twenty-eight monthsfollowing diagnosis the patient progressed to RA with excessblasts in transformation and induction chemotherapy wasinitiated without achieving CR. Three months later anallogeneic stem cell transplantation from a niece wasperformed, resulting in CR of the secondary AML.

Keywords: adult identical twins, myelodysplastic syndrome,acute myeloid leukaemia, monosomy 7.

This is a rare report of myeloid neoplastic disease in adulttwins who developed monosomy 7 in the course of thedisease. Epidemiological studies suggest that environmental,occupational and genetic factors play a role in the patho-genesis of acute myeloid leukaemia (AML). Familial studieshave demonstrated an increased risk in family members ofpatients with leukaemia. The risk of familial leukaemia maybe increased with consanguinity or inherited chromosomalinstability syndromes such as Fanconi anaemia. It isprobably caused by one of two factors: a rare geneticpredisposition within a family or a common environmentalexposure (Taylor & Birch, 1996). Rare constitutionalchromosome abnormalities associated with AML include a7;20 translocation and a 3;6 translocation (Riccardi et al,1975; Markkanen et al, 1987).

The classic method for determining inheritability of adisease is through twin studies and evaluation of humanleucocyte antigen (HLA) associations. Leukaemia in twinswas ®rst reported in 1928, and further studies havedemonstrated an increased risk in monozygotic twins (Keith& Brown, 1971). The clinical presentation is atypical, withleukaemia usually occurring before the age of 2 years,indicating the probability of an intrauterine transfer of

leukaemia cells from one twin to the other through acommon placental blood vessel (Ford et al, 1998; Ng et al,1999). The appearance of acute leukaemia in both twins,when older than 7 years is, however, very rare.

CASE HISTORY

We report the development of secondary AML after myelo-dysplastic syndrome (MDS) in identical twins at the age of52 years in both patients. The ®rst patient has worked inthe diplomatic service, the other worked in an insurancecompany. There was no family history of an inheriteddisorder. Patient ®ndings are detailed in Table I.

In the ®rst twin, haematological abnormalities werenoted 1 year before the diagnosis of refractory anaemiawith excess blasts in transformation (RAEB-T) was estab-lished at the University of DuÈ sseldorf in July 1998. At thattime, the patient had no karyotypic abnormalities and wastreated with TAD9 (6-thioguanine 2 ´ 100 mg/m2 d 3±9p.o., cytosine arabinoside 100 mg/m2 d 1 + 2 continuousinfusion and 2 ´ 100 mg/m2 d 3±8 i.v., daunorubicin60 mg/m2 d 3±5 i.v) induction therapy and completeremission was achieved. Following HAM consolidation(cytosine arabinoside 2 ´ 3 g/m2 d 1±3, mitoxantrone10 mg/m2 d 3±5), the bone marrow (BM) remained hypo-plastic and the patient remained transfusion dependent forplatelets. Nine months later (7/99), the patient relapsedwith MDS RAEB (18% blast cells in BM) and cytogenetic

Correspondence: Gernot Seipelt, MD, Medical Clinic III, Hematology/

Oncology, University Hospital Frankfurt, Theodor Stern Kai7, 60590 Frankfurt/M, Germany. E-mail: G.Seipelt@em.uni-

frankfurt.de

British Journal of Haematology, 2002, 116, 338±340

338 Ó 2002 Blackwell Science Ltd

analysis revealed a monosomy 7, del 6p, del 15q in20 analysed metaphases. The myelodysplastic syndromefurther progressed to acute leukaemia. The patient devel-oped pneumonia and died of sepsis 11 months afterdiagnosis (November 1999).

In the second twin, leucopenia (3á3 ´ 109/l) and thrombo-cytopenia (128 ´ 109/l) were noted during work-up forHLA identical sibling transplantation, and BM cytologyrevealed refractory anaemia with bilineage dysplasia inAugust 1998. The HLA type in the twins was A2,11;B18,35; C4,5; DR03011,0407; DQ02AB,0301. Duringfollow-up at the University of Frankfurt, BM blasts increasedto 15% 11 months later (July 1999), and ¯uorescencein situ hybridization (FISH) analysis demonstrated a mono-somy 7 in 11% of 200 analysed cells. Conventionalcytogenetics detected no karyotypic abnormalities in 24analysed metaphases. Three months later (October 1999),the BM blasts had decreased to 5% and monosomy 7 wasnot detectable using FISH or polymerase chain reaction(PCR) at that time. Again, 4 months later (February 2000),the bone marrow blasts had increased to 11% withoutdetectable abnormalities by conventional cytogenetics, FISHor PCR. In October 2000, bone marrow blasts furtherincreased to 20%, while the peripheral blood valuesremained stable with a white blood cell (WBC) count,2á4 ´ 109/l, haemoglobin 14á2 g/dl, and a platelet count of82 ´ 109/l. In November 2000, induction chemotherapywith idarubicin 10 mg/m2 d 1±3, cytarabine 100 mg/m2

c.i.v d 1±7 and etoposide 100 mg/m2 d 1±5 was initiated,resulting in a reduction of bone marrow blasts to 10%.In January 2001, an allogeneic stem cell transplantationfrom a niece with a mismatch on the A locus (A2,2) wasperformed, resulting in continuous complete remission ofthe secondary AML (last follow-up September 2001).

DISCUSSION

This is a rare report of myeloid neoplastic disease in adulttwins with monosomy 7 occurring in the course of the

disease in both patients. Development of acute leukaemia inmonozygotic twins is well known in children below the ageof 5 years. The risk ratio is believed to be 1:5 for a twinwhen one is already affected by this disease. About 100cases have been described in the literature (reviewed byTaylor & Birch, 1996). To our knowledge these are the ®rstcases described in which AML occurred in adult twins.Chromosome studies at ®rst relapse revealed multipledeletions in the ®rst twin, whereas the other had varyingcytogenetic ®ndings. It is of interest that monosomy 7 wasdetected in both twins, with spontaneous cytogeneticremission in one of them. Familial acute myeloid leukaemiawith monosomy 7 has been reported in children (Shannonet al, 1992; Minelli et al, 2001) as well as in adults. Inadults the onset of AML occurred at the age of 34 and37 years in two siblings following an antecedent myelodys-plastic phase before development of AML (Kwong et al,2000). Spontaneous remission of monosomy 7 has beenreported in a series of ®ve children with either de novo ortreatment-related MDS and monosomy 7. In four of thesechildren there was a spontaneous and durable haemato-logical and cytogenetic remission (Mantadakis et al, 1999).

Principally, there are several possibilities to explain theonset of this disease in our patients. Possibly some form ofgenetic instability might have led to this rare occurrence ofAML and cytogenetically identical aberrations in the twopatients. A candidate gene would be NAD(P)H-quinoneoxireductase 1, an enzyme that protects cells againstoxidative stress. Mutants of the NQO1 C609T allele havea 47% increased risk of developing an AML (Smith et al,2001). Another factor that may have played a role inleukaemogenesis in the twins may be the HLA type. It hasbeen described that the HLA-phenotype Cw4, present in ourtwins, is associated with a relative risk of 2á06 and Cw3with a relative risk of 1á92 for developing an AML (Bortinet al, 1987). This suggests that Cw3 and Cw4 may bemarkers for leukaemia susceptibility genes.

The occurrence of AML in adult twins suggests thatinheritance of mutations leading to defective responses to

Table I. Course of bone marrow blast count, cytogenetic and ¯uorescence in situ hybridization (FISH) ®ndings in the identical twins with

secondary acute myeloid leukaemia (AML) following myelodysplastic syndrome (MDS).

Patient 07/98 04/99 07/99 10/99 11/00

1Cytogenetic analysis 46, XY in 20

metaphases

n.d. )7, del 6p, del 15q/20

metaphases

± ±

FISH n.d. n.d. n.d. ± ±

Bone marrow blast count 25% 3% 18% ± ±2

Cytogenetic analysis n.d. ±

metaphases

46, XY in 24

metaphases

46, XY in 24

metaphases

46, XY in 14

FISH n.d. ± Monosomy 7 in 11%

of 200 analysed cells

Normal Normal in 200

analysed cells

Bone marrow blast count 1% ± 15% 5% 20%

n.d., not done; underlined entries highlight similar cytogenetic ®ndings in these patients.

Short Report 339

Ó 2002 Blackwell Science Ltd, British Journal of Haematology 116: 338±340

environmental carcinogens, or an inability to detoxifymutagenic chemicals or to repair damage, may play a rolein the genesis of familial leukaemia.

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