Fadoo, Zehra

Mushtaq, Naureen

Saleem, Ali Faisal

Wali, Rabia

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eCommons@AKUDepartment of Paediatrics and Child Health Division of Woman and Child HealthJuly 2012Acute lymphoblastic leukemia in a child withFanconi’s anemiaNaureen MushtaqAga Khan UniversityRabia WaliShaukat Khanum Cancer and Research HospitalZehra FadooAga Khan UniversityAli Faisal SaleemAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatrPart of the Pediatrics CommonsRecommended CitationMushtaq, N., Wali, R., Fadoo, Z., Saleem, A. F. (2012). Acute lymphoblastic leukemia in a child with Fanconi’s anemia. Journal of theCollege of Physicians and Surgeons Pakistan, 22(7), 458-460.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_women_childhealth_paediatr/162458 Journal of the College of Physicians and Surgeons Pakistan 2012, Vol. 22 (7): 458-460INTRODUCTIONFanconi anaemia (FA) is a constitutional pancytopeniaof childhood with mostly autosomal recessiveinheritance  with diverse clinical heterogeneity includingcongenital malformations, progressive bone marrowfailure and high propensity for cancer in long-term,mostly solid tumours and carcinoma of head, neck andupper oesophagus followed by carcinoma of vulvaand/or anus and lower oesophagus; however, it is alsoassociated with acute leukemia with marked predis-position with acute myeloid leukemia (AML) and rarelyacute lymphoblastic leukemia (ALL).1,2 Myelodysplasticsyndromes may follow clinically overt aplastic anaemiaor develop without a detectable antecedent.3 Theincidence of AML or myelodysplastic syndrome in FA isapproximately 15%.4 All patients have underlyingabnormal chromosome fragility seen in metaphasepreparations which was enhanced by adding clastogenicagents such as diepoxybutane.4,5 Growth hormone (GH)therapy for FA can also lead to ALL.6 Sensitivity to DNAdamaging agents limits therapy in patients with FA;however, severe toxicity and marrow aplasia withouthaematological recovery has also been described in theliterature.7FA transformation into ALL is a rare phenomenon. Thereare very few case reports in the literature. Here wepresent this rare entity of FA with ALL.CASE REPORTThe patient was a 13 years old girl at presentation to thehaematology and oncology clinic with prolonged historyof blood transfusion since last 6 years. She had noprevious records available. However, she was onregular once fortnightly packed cell transfusion andweekly platelet transfusion. On examination, she wasshort statured with microcephaly, having triangularfacies and areas of hyperpigmentation. There was noorganomegaly or lymphadenopathy. She had six siblingsand they were healthy when she presented to us.Because of FA suspicion her laboratory workup wasdone. Her complete blood count showed pancytopenia,with < 20% cellularity of bone marrow on trephine biopsyand chromosomal breaks was positive. She was kept onsupportive management and planned for haematopoieticstem cell transplantation (HSCT). Her human leukocyteantigen (HLA) typing along with her siblings was alsodone. Unfortunately, the patient's HLA matched donorwas also positive for chromosomal breaks.Two months later she presented in emergency withjaundice, abdominal pain, swelling of feet and abdominaldistension. Her laboratory work-up was positive forHepatitis B virus active infection and with theconsultation with infectious diseases expert she wasstarted on anti-hepatitis B therapy. Later on, her generalcondition improved.After 2 months she again presented to the emergencyroom with intermittent fever and worsening pallor. Herexamination showed marked hepatosplenomegaly.Laboratory work-up revealed pancytopenia with 63%blast cells; Bone marrow flow-cytometry was consistentwith Pre-B ALL.Her clinical status deteriorated rapidly and she becamevitally unstable. She was planned for four- drug inductionCASE REPORTAcute Lymphoblastic Leukemia in a Child with Fanconi's AnaemiaNaureen Mushtaq1, Rabia Wali2, Zehra Fadoo1 and Ali Faisal Saleem1ABSTRACTFanconi anaemia (FA) is an autosomal recessive inherited disorder with progressive bone marrow failure, associatedcongenital malformation and solid and haematological malignancies. Acute myeloid leukemia is the commonesthaematological malignancy followed by myelodysplastic syndrome in children with FA. FA transformed into acutelymphoblastic leukemia (ALL) is a rare phenomenon and one of the rarest haematological malignancies associated withthis disorder. We are reporting a 13 years old girl with FA and positive chromosomal breakage. She required regular bloodproduct transfusion. She was planned for haematopoietic stem cell transplantation (HSCT) but the sibling-matched donorwas found to have chromosomal breaks as well. Later on, her peripheral smear showed blast cell. Bone marrow showedpre-B ALL. She was started on chemotherapy but died shortly due to complications of the treatment. For this rare conditionconservative management is indeed essential, however, safe and appropriate chemotherapy regimen is needed.Key words: Fanconi anaemia.   Acute lymphoblastic leukemia.   Bone marrow failure.1 Department of Paediatrics and Child Health, Aga Khan UniversityHospital, Karachi.2 Department of Paediatrics, Shaukat Khanum Cancer and ResearchHospital, Lahore.Correspondence: Dr. Naureen Mushtaq, C-87 Block 4,Gulshan-e-Iqbal, Karachi.E-mail: naureen.mushtaq@aku.eduReceived October 29, 2011;  accepted February 17, 2012.therapy (vincristine, L-asparaginase, prednisolone anddaunorubicin) as per ALL protocol, but because of hersevere diastolic dysfunction daunorubicin was omittedfrom the chemotherapy. She succumbed to infection anddied on the 7th day of induction therapy withsepticaemia; however, none of her cultures werepositive.DISCUSSIONFanconi anaemia (FA) is a genetic disorder characterizedby congenital abnormalities, cancer predisposition, andprogressive pancytopenia. The cellular phenotype of FAis characterized by increased sensitivity to DNA cross-linking or alkylating agents that block DNA replicationand RNA transcription.8FA children typically present in the first decade of life onrecognition of aplastic anaemia.1 The classic features ofFA consist of thumb and radial absence malformations;less obvious features include a deeper cleft between thefirst two digits. The gold standard for FA quantifychromosomal breakage in cells exposed to cross-linkingagents to which FA cells are hypersensitive.2FA patients have a very high risk of developingprogressive bone marrow failure along with an increasedrisk of future long-term malignancies. The most frequentmalignancy in FA is acute myeloid leukemia (AML) witha cumulative incidence of 33% by 40 years of age.8This patient developed ALL which is rare, but possibleacute leukemia in FA. The FA-related leukemias differfrom leukemia in the general population in severalimportant ways.9 In FA patients, 94% of the acuteleukemias are myeloid and only 6% are lymphoidcompared with 84% of the acute leukemias beinglymphoid in general paediatric population. The agedistribution for acute leukemia in FA was normallydistributed around a mode of 14 years; however, in thegeneral population in which the incidence of AML ishigher in infants, it was declined to around age 10, andthen rises slightly in the late teens.2 The age of thispatient was 13 years when she diagnosed as ALL.Cancer risk assessment was done for FA. Table Ishowed the three studies with their haematologicalfrequency of malignancies. First was a literature reviewof 1300 reported cases of FA from 1927 to 2001;10second was of 754 FA patients from the InternationalFanconi Anaemia Registry (IFAR) ascertained from1982 to 2001,8 while the third was a cross-sectionalstudy of 145 North American patients during 2000.11 Itwas seen that the cumulative incidence of ALL in FA was0.5% (12/2200 patients).There is dearth of knowledge of ALL in FA and to thebest of the authors' knowledge there has been no casereported of FA with ALL from our region. A Dutch studyreported a 7 years old boy with FA who developed pre-leukemia and was not treated because of the knowncomplications of cytostatic in FA and the bad prognosisand later on he died. Another study from Poland,reported 2 children with Fanconi anaemia whodeveloped acute lymphoblastic leukemia at the age of 4and 12 years.12The treatment of FA with ALL is very scanty in literature.Borriello reported the case of a patient affected by T-cellALL without the clinical features specific for FA.3Because of severe chemotherapy toxicity, occurring withseveral episodes of marrow aplasia leading to life-threatening infections, a suspicion of FA diagnosis led usto perform the chromosomal breakage study using thediepoxybutane (DEB) test, which was found to bepositive. The patient was treated on lines of T-cell ALLinduction therapy comprising of vincristine, L-asparaginase,anthracylines, steroids and cyclophosphamide.3The index patient was also planned for four-druginduction therapy with vincristine, daunorubicin, steroidsand L-asparaginase; but as patient had sub-optimalcardiac function anthracyline was omitted for the timebeing. The patient died on 7th day of her inductiontherapy due to septicaemia.In conclusion, the existence of ALL in patients with FA israrely reported and further work is needed to determinethe appropriate chemotherapy regimen in thesepatients.REFERENCES1. Bagby GC, Alter BP. Fanconi anaemia. Semin Hematol 2006;43:147-56.2. Green AM, Kupfer GM. Fanconi anaemia. Hematol Oncol Clin NorthAm 2009; 23:193-214.3. Borriello A, Locasciulli A, Bianco AM, Criscuolo M, Conti V,Grammatico P, et al. A novel Leu153Ser mutation of the Fanconianaemia FANCD2 gene is associated with severe chemotherapytoxicity in a paediatric T-cell acute lymphoblastic leukemia.Leukemia 2007; 21:72-8.4. Auerbach AD. Fanconi anaemia and its diagnosis. Mutat Res 2009;668:4-10.5. Miglierina R, Le Coniat M, Gendron M, Berger R. Diagnosis ofFanconi's anaemia by flow cytometry. Nouv Rev Fr Hematol 1990;32:391-3.Table I: Studies with FA cases along with their haematologicalmalignancies distribution.Total casesStudies of Fanconi Haematological malignanciesanaemiaAML MDS ALL Total haematologicalmalignanciesAlter BP (2003) (10) 1301 109 89 07 205Rosenberg PS (2003) (11) 145 09 23 – 32Kutler DI (2003) (8) 754 60 53 05 120Total cases 2200 – – 12++ –++ ALL incidence 0.5 (12/2200)Abbreviations: AML = Acute myeloid leukemia;  MDS = Myelodysplastic syndrome;ALL = Acute lymphoblastic lymphoma;      Acute lymphoblastic leukemia in a child with Fanconi's anaemiaJournal of the College of Physicians and Surgeons Pakistan 2012, Vol. 22 (7): 458-460 459Naureen Mushtaq, Rabia Wali, Zehra Fadoo and Ali Faisal Saleem460 Journal of the College of Physicians and Surgeons Pakistan 2012, Vol. 22 (7): 458-4606. Butturini A, Bernasconi S, Izzi G, Gertner JM, Gale RP. Shortstature, Fanconi's anaemia, and risk of leukaemia after growthhormone therapy. Lancet 1994; 343:1576.7. Mehta PA, Ileri T, Harris RE, Williams DA, Mo J, Smolarek T,et al. Chemotherapy for myeloid malignancy in children withFanconi anaemia. Pediatr Blood Cancer 2007; 48:668-72.8. Kutler DI, Singh B, Satagopan J, Batish SD, Berwick M,Giampietro PF, et al. A 20-year perspective on the Inter-national Fanconi Anaemia Registry (IFAR). Blood 2003; 101:1249-56.9. Ries LAG, Krapcho M, Mariotto A, Miller BA, Feuer EJ, Clegg L,et al, editors. SEER cancer statistics review: 1975-2004.Bethesda: National Cancer Institute; 2007.10. Alter BP. Cancer in Fanconi anaemia: 1927-2001. Cancer 2003;97:425-40.11. Rosenberg PS, Greene MH, Alter BP. Cancer incidence inpersons with Fanconi anaemia. Blood 2003; 101:822-6.12. Janik-Moszant A, Bubala H, Stojewska M, Sonta-Jakimczyk D.[Acute lymphoblastic leukemia in children with Fanconianaemia]. Wiad Lek 1998; 51:285-8. Polish.l l l l lOl l l l l

Acute lymphoblastic leukemia in a child with Fanconi’s anemia

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Acute lymphoblastic leukemia in a child with Fanconi’s anemia

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