Central diabetes insipidus (DI) is well-documented as a presenting feature of myelodysplastic syndrome and acute myeloid leukemia in adults. However, DI is unusual in pediatric patients with myeloid malignancies. We report here this rare complication in a child with neurofibromatosis type 1 who developed juvenile myelomonocytic leukemia and monosomy 7. Our case and previously reported cases of DI arising as a complication in myeloid malignancies demonstrate a close association with deletion of chromosome 7. The clinical characteristics and outcomes of these uncommon cases in children are reviewed and discussed.postprin

Chan, GCF

Chiang, AKS

Ha, SY

Lukito, JB

So, JCC

Surapolchai, P

Wan, TSK

HKU Scholars Hub

Title Central Diabetes Insipidus: An Unusual Complication in a ChildWith Juvenile Myelomonocytic Leukemia and Monosomy 7Author(s) Surapolchai, P; Ha, SY; Chan, GCF; Lukito, JB; Wan, TSK; So,JCC; Chiang, AKSCitation Journal of Pediatric Hematology and Oncology, 2013, v. 35 n. 2,p. e84-e87Issued Date 2013URL http://hdl.handle.net/10722/183764RightsThis is a non-final version of an article published in final form inJournal of Pediatric Hematology and Oncology, 2013, v. 35 n. 2,p. e84-e87Journal of Pediatric Hematology and Oncology Central diabetes insipidus: an unusual complication in a child with juvenilemyelomonocytic leukemia and monosomy 7--Manuscript Draft-- Manuscript Number:Full Title: Central diabetes insipidus: an unusual complication in a child with juvenilemyelomonocytic leukemia and monosomy 7Article Type: Clinical and Laboratory ObservationsSection/Category: OncologyKeywords: JMML;  monosomy 7;  diabetes insipidus;  neurofibromatosis.Corresponding Author: Alan Kwok-Shing Chiang, MBChB, PhD, FRCPCHLi Ka Shing Faculty of Medicine, The University of Hong KongHong Kong,  CHINACorresponding Author SecondaryInformation:Corresponding Author's Institution: Li Ka Shing Faculty of Medicine, The University of Hong KongCorresponding Author's SecondaryInstitution:First Author: Pacharapan Surapolchai, MDFirst Author Secondary Information:Order of Authors: Pacharapan Surapolchai, MDShau-Yin Ha, MBBS, FRCPCH, FRCPathGodfrey Chi-Fung Chan, MD, DMD, MSc, FRCPCHJohannes B Lukito, MDThomas S K Wan, PhD, FRCPath(UK)Chi-Chiu So, MBBS, FRCPath(UK)Alan Kwok-Shing Chiang, MBChB, PhD, FRCPCHOrder of Authors Secondary Information:Manuscript Region of Origin: HONG KONGAbstract: Central diabetes insipidus (DI) is well documented as a presenting feature ofmyelodysplastic syndrome and acute myeloid leukemia in adults. However, DI isunusual in pediatric patients with myeloid malignancies. We report here this rarecomplication in a child with neurofibromatosis type 1 who developed juvenilemyelomonocytic leukemia and monosomy 7. Our case and previously reported casesof DI arising as a complication in myeloid malignancies demonstrate a closeassociation with deletion of chromosome 7. The clinical characteristics and outcomesof these uncommon cases in children are reviewed and discussed.Powered by Editorial Manager® and Preprint Manager® from Aries Systems CorporationCentral diabetes insipidus: an unusual complication in a child with juvenile myelomonocytic leukemia and monosomy 7  Pacharapan Surapolchai, MD1,4 SY Ha, MBBS, FRCPCH, FRCPath1 Godfrey CF Chan, MD, DMD, MSc, FRCPCH1 Johannes B Lukito, MD3 Thomas SK Wan, PhD, FRCPath(UK)2 CC So, MB, BS, FRCPath(UK)2 Alan KS Chiang, MBChB, PhD, FRCPCH1   1 Department of Paediatrics and Adolescent Medicine and 2 Department of Pathology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Pokfulam, Hong Kong, China; 3 Pantai Indah Kapuk Hospital, Jakarta, Indonesia; 4 Department of Pediatrics, Faculty of Medicine, Thammasat University, Pathumthani, Thailand.        *Complete Manuscript(including title page,abstract, text and references)Correspondence author:   Alan KS Chiang Clinical Associate Professor & Honorary Consultant Children's Centre of Cancers & Blood Diseases Department of Paediatrics & Adolescent Medicine The University of Hong Kong Queen Mary Hospital, Pokfulam  Hong Kong, China Tel: 852-22554091 Fax: 852-28551523 Email: chiangak@hku.hk   Abstract word count: 90 Text word count: 1084 Number of tables and figures: 1 figure and 1 table Short running title: DI in a child with JMML and monosomy 7   Keywords: JMML, monosomy 7, diabetes insipidus, neurofibromatosisABSTRACT Central diabetes insipidus (DI) is well documented as a presenting feature of myelodysplastic syndrome and acute myeloid leukemia in adults. However, DI is unusual in pediatric patients with myeloid malignancies. We report here this rare complication in a child with neurofibromatosis type 1 who developed juvenile myelomonocytic leukemia and monosomy 7. Our case and previously reported cases of DI arising as a complication in myeloid malignancies demonstrate a close association with deletion of chromosome 7. The clinical characteristics and outcomes of these uncommon cases in children are reviewed and discussed.                INTRODUCTION Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloid malignancy of childhood. This disorder is currently classified under myelodysplastic/ myeloproliferative neoplasms (MDS/MPN) in children by the World Health Organization (WHO) [1]. Hepatosplenomegaly, lymphadenopathy, and constitutional symptoms are the most common presenting features [2]. Even though central DI had been described in association with other myeloid malignancies of adults, it is rare in JMML. Niemeyer et al [2] described only one case with DI in a retrospective study of 110 JMML cases. Hasle et al [3] reported 43 JMML cases with monosomy 7 and two of them presented with DI. A review of previous local data of 21 JMML patients in Hong Kong showed that 3 of them had monosomy 7 but none of them was complicated with DI (Chan GCF, unpublished data). We describe here our first case of JMML patient with neurofibromatosis type 1 (NF1) and monosomy 7 who was complicated by central DI, and compare the clinical and laboratory features with those in the literature.  CASE REPORT A previously healthy 8-year-old Indonesian girl was found to have leucocytosis, monocytosis, and mild anemia during an episode of acute diarrhea. An initial bone marrow study revealed increased myelomonocytic series which was compatible with a myeloproliferative disorder. A diagnosis of JMML was suspected. In the subsequent two months, she complained of progressive abdominal distension, polydipsia and polyuria. She was admitted into hospital in a semi-comatose state with dehydration. A complete blood count showed marked leukocytosis of 90 x 109/L, with hemoglobin (Hb) 9.9 g/dL and platelet count 79 x 109/L. After rehydration, she received one course of cytarabine and etoposide (100 mg/m2/day intravenous infusion for each) for 5 days, followed by low dose cytarabine (20 mg/m2/day) for 5 days. Her condition stabilized and she was transferred to our center for further workup. On admission, she was found to have multiple café-au-lait spots (>6 and each >5 mm in greatest diameter) and hepatosplenomegaly. The patient's mother had multiple café-au-lait macules and scattered neurofibromas consistent with NF1. The clinical findings of café au lait macules and NF1 in a first-degree relative established the diagnosis of NF1 in our patient [4]. Repeated peripheral blood examination showed a leucoerythroblastic picture, with Hb 10.7 g/L, white blood cell count 23.6 x 109/L (monocyte 31%, blast 7%), and platelet count 56 x 109/L. Her Hb F was 1%. Repeated bone marrow examination revealed active granulopoiesis and dysplastic megakaryocytes. Marrow blast count was 18%. Cytogenetic analysis showed monosomy 7 (Fig. 1A). Utilizing fluorescence in situ hybridization, monosomy 7 was demonstrated in 88.5% of the marrow nucleated cells (Fig. 1B). The cerebral spinal fluid examination was unremarkable. Anterior pituitary function testing was normal. Magnetic resonance imaging (MRI) of the brain showed absence of a normal bright spot over the posterior pituitary gland without thickening of the pituitary stalk (Fig. 1C and D). Central DI was subsequently confirmed by biochemical and imaging studies. A diagnosis of central DI complicating JMML with monosomy 7 in a patient with NF1 was made, according to the WHO Classification [1]. Her polyuria resolved dramatically after commencing desmopressin (DDAVP). The patient was returned to her referring pediatrician, pending for an appropriate donor for hematopoietic stem cell transplantation (HSCT).   DISCUSSION The association of central DI and myeloid malignancies has been uncommonly reported, even though peri-hypophyseal leukemic infiltrates were found in 46% of adult patients with acute leukemia at postmortem [5]. The onset of DI is variable, but usually occurs as a presenting feature of the myeloid malignancies [6]. The possible mechanisms include leukemic infiltration, leukostasis, thrombosis, fibrosis, infection, and hemorrhage in the hypothalamo-neurohypophyseal system [7]. In most patients the MRI findings are normal. Classical finding of disappearance of the physiological hyperintense signal, termed “bright spot”, at the neurohypophysis is caused by the loss of the vasopressin-containing vesicles in the posterior pituitary. Thickened infundibulum is also seen in some reported cases [6,7]. Loss of the bright spot at the posterior pituitary has been suggested to be related to leukemic infiltration.   Of note, cases of acute myeloid leukemia (AML)/MDS complicated by DI have been reported to be associated with abnormalities of chromosome 7 [monosomy 7 or del(7q)] and/or chromosome 3 [inv(3)(q21q26) or t(3;3)(q21;q26)] [6-8]. Cytogenetic analysis also revealed monosomy 7 in our JMML patient, again supporting the postulation that this karyotypic change is one factor contributing to the development of DI. For patients with partial or complete monosomy 7, the neutrophil migration gene in 7q22~qter region is lost, which increases susceptibility to infection and may predispose patients to onset of DI [9]. Moreover, because most circulating arginine vasopressin (ADH) is bound to the platelets, thrombocytosis related to dysthrombopoiesis in monosomy 7 and/or 3q21q26 syndrome may interfere with level and function of circulating ADH [10].    Review of the English literature of pediatric myeloid malignancies and DI yielded nine cases (Table 1) [11-19]. Seven of these (78%) patients had DI at diagnosis of AML/MDS. Cytogenetic data were available in four patients, of whom monosomy 7 and/or inversion of chromosome 3 was most commonly detected. Two patients had AML/MDS associated with NF1 and monosomy 7. Imaging studies were performed in five patients and only one patient had loss of pituitary bright spot and enhancement of infundibulum. Two of three patients, who underwent postmortem examination, had leukemic infiltration in the posterior pituitary and one patient had suspected destruction of the hypothalamic nuclei by either infarction or arachnoid infiltration. Only two of the nine patients (22%) achieved disease remission with resolution of DI. Interestingly, Harb et al [6] also found that reported cases of AML complicated by DI with monosomy 7 (n = 25) had a trend towards lower complete remission (CR) and survival rates than those with other chromosomal aberrations (n = 6). Furthermore, AML cases with monosomy 7 and DI had worse CR rate than AML with monosomy 7 but without DI.   In conclusion, DI is a rare but important complication of myeloid malignancies in both adults and children and tends to occur early in the disease course. It is closely associated with the karyotypic abnormality of monosomy 7. The pathophysiological link between DI and monosomy 7 is unclear. Whether the complication of DI has additional poor prognostic implication is difficult to assess because of the rarity of such cases and the inherent poor prognosis of myeloid malignancies associated with monosomy 7 or 3q21q26 rearrangement. Nevertheless, it is important to recognize this unique complication in pediatric patients with myeloid malignancies and provide timely supportive treatment to prevent dehydration, electrolyte disturbances and aggravation of leukostasis-related complications.    Declaration of Interests The authors report no potential conflicts of Interests.  REFERENCES 1. Baumann I, Bennett JM, Niemeyer CM, et al. Juvenile myelomonocytic leukemia. In: Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW, editors. World Health Organization classification of tumours of haematopoietic and lympoid tissues. Lyon: IARC Press; 2008. pp 82-84. 2. Niemeyer CM, Aricò M, Basso G, et al. Chronic myelomonocytic leukemia in childhood: a report of 110 cases. Blood 1997;89:3534-3543. 3. Hasle H, Aricò M, Basso G, et al. Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. European Working Group on MDS in Childhood (EWOG-MDS). Leukemia 1999;13:376-385. 4. Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol 1988 ;45:575-578.  5. Masse SR, Wolk RW, Conklin RH. Peripituitary gland involvement in acute leukemia in adults. Arch Pathol 1973;96:141-142. 6. Harb A, Tan W, Wilding GE, et al. Acute myeloid leukemia and diabetes insipidus with monosomy 7. Cancer Genet Cytogenet 2009;190:97-100. 7. Müller CI, Engelhardt M, Laubenberger J, et al. Myelodysplastic syndrome in transformation to acute myeloid leukemia presenting with diabetes insipidus: due to pituitary infiltration association with abnormalities of chromosomes 3 and 7. Eur J Haematol 2002;69:115-119. 8. Lavabre-Bertrand T, Bourquard P, Chiesa J, et al. Diabetes insipidus revealing acute myelogenous leukaemia with a high platelet count, monosomy 7 and abnormalities of chromosome 3: a new entity? Eur J Haematol 2001;66:66-69.  9. Ruutu P, Ruutu T, Repo H, et al. Defective neutrophil migration in monosomy-7. Blood 1981;58:739-745. 10. Nussey SS, Ang VTY, Bevan DH, et al. Human platelet arginine vasopressin. Clin Endocrinol 1986;24:427-433. 11. Joseph MC, Levin SE. Leukemia and diabetes insipidus. Case report with unexpected effect of cortisone. Br Med J 1956;1:1328-1332. 12. Roy S 3rd, Johnson WW. Diabetes insipidus in a child with erythromyelocytic leukemia. Am J Dis Child 1970;119:82-85. 13. Bergman GE, Baluarte HJ, Naiman JL. Diabetes insipidus as a presenting manifestation of acute myelogenous leukemia. J Pediatr 1976;88:355. 14. Betkerur U, Shende A, Lanzkowsky P. Acute myeloblastic leukemia presenting with diabetes insipidus. Am J Med Sci 1977;273:325-327. 15. Diltek I, Uysal A, Demirer T, et al. Acute myeloblastic leukemia associated with hyperleukocytosis and diabetes insipidus. Leuk Lymphoma 1998;30:657-660. 16. Kanabar DJ, Betts DR, Gibbons B, et al. Monosomy 7, diabetes insipidus and acute myeloid leukemia in childhood. Pediatr Hematol Oncol 1994;11:111-114. 17. Frangoul HA, Shaw DW, Hawkins D, et al. Diabetes insipidus as a presenting symptom of acute myelogenous leukemia. J Pediatr Hematol Oncol 2000;22:457-459. 18. Wössmann W, Borkhardt A, Gossen R, et al. Acute myeloid leukemia presenting with diabetes insipidus. Eur J Pediatr 2002;161:161-162. 19. Kollen WJ, Ball LM, Snijder P, et al. Diabetes insipidus in a child with a monosomy-7 associated myelodysplastic syndrome and neurofibromatosis I. Med Pediatr Oncol 2003;40:257-259.     Fig. 1. A: Karyotype showing monosomy 7 (arrow; G-banding with trypsin-Giemsa). B: Fluorescence in situ hybridization analysis of interphase cells using centromeric probe for chromosome 7, showing the presence of monosomy 7 that appears as single distinct red fluorescence signal within marrow cells. C: Sagittal, T1-weighted magnetic resonance (MRI) image, representing disappearance of the physiological signal („„bright spot‟‟) of the posterior pituitary (arrow). D: Coronal T1-weighted MRI image after gadolinium, disclosing normal sized pituitary stalk (arrow) and no enhancing lesion of hypothalamus and posterior pituitary.                          Figure (TIF or EPS only; 300 ppi images and 1200 ppi Line-Art)Click here to download high resolution imageTABLE 1. Literature Review of diabetes insipidus in associated with childhood myeloid malignancies.    Reference  Age (years)/ Gender Type of myeloid malignancies Cytogenetics Onset of DI,  from diagnosis Imaging Outcome Survival from diagnosis Histopathology of hypothalamus and neurohypophysis  Joseph et al, 1956 [11] 10/ male AML  NA At diagnosis NA Died of disease progression 2 months Leukemic infiltration in posterior pituitary Roy et al, 1970 [12] 3.5/ male AML (FAB-M6) NA 4 months NA  Died of infection  6 months Leukemic infiltration in pituitary stalk Bergman et al, 1976 [13] 8/ female  AML  NA  At diagnosis  NA  Died of disease relapse 3 months Areas of gliosis and hemosiderin pigment containing in hypothalamus and posterior pituitary Betkerur et al, 1977 [14] 9/ female  AML NA  At diagnosis NA Died of disease progression 2 months NA Kanabar et al, 1994 [15] 7/ male  AML (FAB-M2) Monosomy 7 At diagnosis normala No CR after three courses of induction NA NA Diltek et al,  1998 [16] 16/ male AML (FAB-M4) NA At diagnosis normala Died of bleeding 2 days NA Frangoul et al,  2000 [17] 11/ male AML (FAB-M2) 47, XXY At diagnosis No bright spot, thickened and enhancing pituitary stalkb Alive, in remission after CMT NA NA Wössmann     et al,  2002 [18] 11/ male AML (FAB-M7) 45, XY, inv(3)(q21q26), –7 At diagnosis normalb Died of infection in post-HSCT 10 months  NA Kollen et al,  2003 [19] 6/ male MDS (RAEB) Monosomy 7 6 months normalb Alive, in remission after HSCT NA NA a, computed tomography of brain. b, magnetic resonance imaging of brain AML, acute myeloid leukemia; FAB, French American British grouping; CMT, chemotherapy; CR, complete remission; DI, diabetes insipidus; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; NA, not applicable; RAEB, refractory anemia with excessive blasts.  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Central Diabetes Insipidus: An Unusual Complication in a Child With Juvenile Myelomonocytic Leukemia and Monosomy 7

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Central Diabetes Insipidus: An Unusual Complication in a Child With Juvenile Myelomonocytic Leukemia and Monosomy 7

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