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A patient with monosomy 7 and polyuria
Leukemia Research Vol. 16, No. 6~, pp. 711-715, 1992.
0145-2126/92 $5.00 + .00 Pergamon Press Ltd
Printed in Great Britain.
CASE REPORT A P A T I E N T WITH MONOSOMY 7 AND P O L Y U R I A M. ARMITAGE* and D. G. OSCIER Department of Haematology and *Department of General Medicine, Royal Victoria Hospital, Bournemouth, U.K. S. S A D U L L A H ,
A. R.
K R U G E R , S. BARRINGTON ONSLOW,
(Received 28 September 1991. Accepted 30 October 1991) Abstract--Diabetes insipidus (DI) is a rare complication of leukaemia. An association between monosomy 7 and DI in leukaemias has been proposed. We present a case of phi-positive CML who developed polyuria at the time of lymphoid blast transformation associated with loss of chromosome 7. Biochemical results were not diagnostic of DI and a therapeutic trial of DDAVP was unsuccessful. Post-mortem showed a peripituitary and renal leukaemic infiltrate and although DI is a possibility, the cause of his polyuria remains unresolved.
CASE HISTORY
TABLE 1. RESULTS OF SERUM AND URINE OSMOLALITIES AVrER 20 meg OF INTRANASALDDAVP
A 61-YEAR-OLD patient presented in December 1986 with standard Phi-positive CML in chronic phase. He was treated intermittently with hydroxyurea and busulphan. H e remained stable until August 1990 when he presented with lymphoid blast transformation. Karyotypic analysis showed evidence of clonal evolution with 45 XY,-7,t(9;22). He was treated with busulphan, prednisolone, vincristine and asparaginase. Treatment was complicated by steroidinduced diabetes mellitus which was controlled by oral hypoglycaemic drugs. In October 1990 he was admitted to hospital with dehydration, hyperventilation and polyuria with a urine output of 10-12 1/day. There had been no alteration in his body weight. The only abnormality on clinical examination was a 6 c m hepatomegaly. Laboratory data on admission showed a haemoglobin of 11.9 g/dl, WBC of 2.7 x 109/1 and a platelet count of 14 x 109/1. No blasts were present in the peripheral film. His serum sodium was 125 mmol/1, potassium 4.3 mmol/1, chloride 107 mmol/1 and blood glucose 12.4 mmol/1. Arterial blood gasses confirmed a metabolic acidosis with a p H of 7.34 and serum bicarbonate level of 13 mmol/1. Urine analysis was + + for glucose but negative for ketones. The urine pH was 6. The serum osmolality was 297 mos/kg and the urine osmolality was 375 mos/kg. Lumbar puncture yielded clear CSF with no leukaemic cells. He was treated with intravenous fluids and insulin, but in spite of strict glycaemic control, continued to have polyuria. The combination of a mild hyperchloraemic
Osmolalitiy in mos/kg Time
Serum
Urine
08.00 10.00 12.00 14.00 16.00
294 298 294 296 300
260 332 244 252 252
acidosis with a relatively alkaline urine was compatible with renal tubular dysfunction secondary to leukaemic infiltration of the kidney. However, further chemotherapy failed to control the polyuria and a trial of thiazide diuretics was also ineffective. When repeated, simultaneous samples showed a serum osmolality of 276 mos/kg and a urine osmolality of 184 mos/kg with resolution of the acidosis and a normal urine pH. Although not diagnositic, these results were suggestive of diabetes insipidus. As the patient was not well enough to undergo a formal water deprivation test a therapeutic trial of Desmopression ( D D A V P ) was undertaken (Table 1). There was no clinical or biochemical response and the patient finally died of a septicaemic illness in December 1990. On post-mortem examination, a peripituitary leukaemic infiltrate was found. This did not invade the parenchyma. There was also some patchy leukaemic infiltration in both kidneys which was restricted to the interstitial area (Figs 1 and 2). 711
712
S. SADULLAHet al.
DISCUSSION This patient developed polyuria associated with a lymphoid transformation of chronic myeloid leukaemia. Therapeutic trials of D D A V P and thiazides failed to resolve the problem. Post-mortem findings showed a peripituitary and renal interstitial leukaemic infiltrate. Initially the polyuria was thought to be due to hyperglycaemia. However, correcting the blood glucose level did not decrease his urine output. The absence of hypokalaemia and the fact that the metabolic acidosis and failure to acidify urine were transient is against the diagnosis of a pure renal tubular acidosis. The main differential diagnosis was thus between a cranial or nephrogenic diabetes insipidus. The lack of response to D D V A P does not necessarily exclude the diagnosis of cranial DI as patients with a protracted history of polyuria can initially be resistant to vasopressin [1]. The cause of his polyuria thus remains unresolved. Diabetes insipidus (DI) is a rare but recognised complication of leukaemia. At least 51 patients have been reported in whom symptoms and signs of DI occurred in conjunction with leukaemia [2-7]. It is more often associated with A M L than with ALL. Puolakka et al. suggest that patients with A M L with a preceding history of myelodysplasia have a greater likelihood of developing DI [8]. Only six cases of DI with CML have been reported and these have all been associated with advanced disease [9-11[. Cytology of CSF and radiologic investigation of the nervous system are seldom helpful. Several cases of DI and leukaemia occurred before effective treatment for ieukaemia was available. None the less, recent reports have failed to show the efficacy of antineoplastic therapy or CNS radiation in resolving symptoms in these patients [4, 9]. Symptomatic response with D D A V P can be expected although 15% of teukaemic patients with cranial diabetes insipidus are resistant to vasopressin [12]. At least three cases of nephrogenic diabetes insipidus due to infiltration of the renal tubules have been reported [131. Pathologically there is either a diffuse infiltration of the posterior pituitary gland or thrombotic and haemorrhagic lesions of the small vessels in the hypothalamic nuclei and posterior lobe of the pituitary. Despite the fact that perihypophyseal leukaemic infiltrates are found in as many as 46% of patients at post-mortem examination, overt diabetes insipidus is rarely encountered in this disease [14, 15]. Leukaemic infiltration of the kidney can cause tubular dysfunction but is more commonly asymptomatic and found incidentally at autopsy. In one series of 322 cases, 60% of the patients had renal leukaemic infiltrates post-mortem but only three of these had
clinical evidence of renal impairment [16]. However, in monocytic leukaemias lysozyme release is known to cause tubular damage [17]. An association between monosomy 7 and DI in leukaemic patients has been proposed. Chromosome studies performed in 6 patients with leukaemia and DI showed monosomy 7 in five while the sixth had del 7 (q22). The critical region on chromosome 7 is thought to be 7q22-qter [2, 18, 19]. Monosomy 7 alone or in combination with other chromosomal abnormalities is commonly found in myeloid leukaemias. It is present in about 7% of cases with de n o v o A M L and 28% of cases with secondary A M L [20, 21]. In CML it is not usually seen in the chronic phase but is one of the additional abnormalities which accompany the accelerated phase or lymphoid blast crisis [22]. Interestingly our patient developed monosomy 7 at the time of blast transformation. Whether monosomy 7 is truly over-represented among leukaemic patients with DI needs further evaluation. Also the mechanism by which this predisposition is produced needs to be clarified. REFERENCES 1. Baylis P. H. (1983) Posterior pituitary function in health and disease. Clin. Endocrinol. Metabol. 12, 758. 2. De la Chapelle A. & gahtinen R. (1987) Monosomy 7 predisposes to diabetes insipidus in leukemia and myelodysplastic syndrome. Eur. J. Haemat. 39, 404411. 3. Boga M., Halmy L. & Rutkai P. (1970) Diabetes insipidus occurring with acute leukemia. Haematologia (Budapest) 4, 235-239. 4. Miller V. & Campbell W. (1971) Diabetes insipidus as a complication of leukemia. Cancer 28, 666-673. 5. Betkerur U., Shende A. & Lanzkowsky P. (1977) Acute myeloblastic leukemia presenting with diabetes insipidus. Am. J. Med. Sci. 273, 325-327. 6. Kornberg A., Zimmerman J., Matzner Y. & Polliack A. (1980) Acute lymphoblastic leukemia. Association with vasopressin responsive diabetes insipidus. Arch. Intern. Med. 140, 1236. 7. Newcomer L. N. (1982) Diabetes insipidus associated with central nervous system leukemia. Southern Med. J. 75, 1142-1143. 8. Puolakka K., Korhonen T. & Lahtinen R. (1984) Diabetes insipidus in preleukemic phase of acute myeloid leukemia in 2 patients with empty sella turcica. Scand. J. Haemat. 32, 364-366. 9. Juan D., Hsu S.-D. & Hunter J. (1985) Case report of vasopressin-responsive diabetes insipidus associated with chronic myelogenous leukemia. Cancer 56, 14681469. 10. Landman M. E. & Stumpf H. H. (1965) Diabetes insipidus complicating chronic myelogenous leukemia. J. Med. Soc. New Jersey 62, 205-207. 11. Ungaro P. C., Gonzales J. J., Werk E. E., Mackay J. C. (1984) Chronic myelogenous leukemia presenting clinically as diabetes insipidus. North Carolina Med. J. 45, 640-641.
FIG. 1. Peripituitary leukaemic infiltrate. (a) Leukaemic infiltrate. (b) Capsule. (c) Uninvolved pituitary. (Haematoxylin-Eosin stain, × 100.)
713
FIG. 2. Renal interstitial infiltrate. (a) Leukaemic infiltrate. (b) Normal glomerular architecture. (Haematoxylin-Eosin stain, x 100.)
714
Monosomy 7 and polyuria 12. Laakso W. B. (1964) Diabetes insipidus secondary to acute leukemia. A case report. Am. J. Med. Sci. 247, 451-456. 13. Shurygin D. I. (1960) On diabetes insipidus in patients with acute leukosis. Klin. Med. 28, 132-134. 14. Philippakos D., Kakouros S., Dervenoulas J. & Pontidas E. (1983) Diabetes insipidus as a complication of acute myelomonocytic leukemia. Postgrad. Med. J. 59, 93-94. 15. Masse S. R., Wolk R. W. & Conklin R. H. (1973) Peripituitary gland involvement in acute leukemia in adults. Arch. Pathol. 96, 141-142. 16. Boggs D. R. et al. (1962) The acute leukaemias. Analysis of 322 cases and review of the literature. Medicine 41, 163. 17. Goldman J. E. (1989) Postgraduate Haematology (Hoffbrand A. V. & Lewis S. M., Eds), p. 304. Heineman, Oxford. 18. Montecucco C.. Cazzola M. & Ascari E. (1984) Diabetes insipidus in the pre-leukemic phase of acute
19.
20.
21. 22.
715
nonlymphocytic leukemia. A monosomy 7-associated condition? Letter. Scand. J. Haemat. 33, 326. Dezza L., Cazzola M., Bergamaschi G. et al. (1983) Myelodysplastic syndrome with monosomy 7 in adulthood: a distinct preleukemic disorder. Haematologica 68, 723-735. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984) Abnormalities of chromosome 7 resulting in monosomy 7 or in deletion of the long arm (7q-): review of translocations, breakpoints and associated abnormalities. Cancer Genet. Cytogenet. 11, 300-303. Second International Workshop on Chromosomes in Leukemia, 1979 (1981) Chromosomes in preleukemia. Cancer Genet. Cytogenet. 2, 108-113. Ishihara T., Sasaki M., Oshimura M. et al. (1983) A summary of cytogenetic studies on 534 cases of chronic myelocytic leukemia in Japan. Cancer Genet. Cytogenet. 9, 81-92.
0145-2126/92 $5.00 + .00 Pergamon Press Ltd
Printed in Great Britain.
CASE REPORT A P A T I E N T WITH MONOSOMY 7 AND P O L Y U R I A M. ARMITAGE* and D. G. OSCIER Department of Haematology and *Department of General Medicine, Royal Victoria Hospital, Bournemouth, U.K. S. S A D U L L A H ,
A. R.
K R U G E R , S. BARRINGTON ONSLOW,
(Received 28 September 1991. Accepted 30 October 1991) Abstract--Diabetes insipidus (DI) is a rare complication of leukaemia. An association between monosomy 7 and DI in leukaemias has been proposed. We present a case of phi-positive CML who developed polyuria at the time of lymphoid blast transformation associated with loss of chromosome 7. Biochemical results were not diagnostic of DI and a therapeutic trial of DDAVP was unsuccessful. Post-mortem showed a peripituitary and renal leukaemic infiltrate and although DI is a possibility, the cause of his polyuria remains unresolved.
CASE HISTORY
TABLE 1. RESULTS OF SERUM AND URINE OSMOLALITIES AVrER 20 meg OF INTRANASALDDAVP
A 61-YEAR-OLD patient presented in December 1986 with standard Phi-positive CML in chronic phase. He was treated intermittently with hydroxyurea and busulphan. H e remained stable until August 1990 when he presented with lymphoid blast transformation. Karyotypic analysis showed evidence of clonal evolution with 45 XY,-7,t(9;22). He was treated with busulphan, prednisolone, vincristine and asparaginase. Treatment was complicated by steroidinduced diabetes mellitus which was controlled by oral hypoglycaemic drugs. In October 1990 he was admitted to hospital with dehydration, hyperventilation and polyuria with a urine output of 10-12 1/day. There had been no alteration in his body weight. The only abnormality on clinical examination was a 6 c m hepatomegaly. Laboratory data on admission showed a haemoglobin of 11.9 g/dl, WBC of 2.7 x 109/1 and a platelet count of 14 x 109/1. No blasts were present in the peripheral film. His serum sodium was 125 mmol/1, potassium 4.3 mmol/1, chloride 107 mmol/1 and blood glucose 12.4 mmol/1. Arterial blood gasses confirmed a metabolic acidosis with a p H of 7.34 and serum bicarbonate level of 13 mmol/1. Urine analysis was + + for glucose but negative for ketones. The urine pH was 6. The serum osmolality was 297 mos/kg and the urine osmolality was 375 mos/kg. Lumbar puncture yielded clear CSF with no leukaemic cells. He was treated with intravenous fluids and insulin, but in spite of strict glycaemic control, continued to have polyuria. The combination of a mild hyperchloraemic
Osmolalitiy in mos/kg Time
Serum
Urine
08.00 10.00 12.00 14.00 16.00
294 298 294 296 300
260 332 244 252 252
acidosis with a relatively alkaline urine was compatible with renal tubular dysfunction secondary to leukaemic infiltration of the kidney. However, further chemotherapy failed to control the polyuria and a trial of thiazide diuretics was also ineffective. When repeated, simultaneous samples showed a serum osmolality of 276 mos/kg and a urine osmolality of 184 mos/kg with resolution of the acidosis and a normal urine pH. Although not diagnositic, these results were suggestive of diabetes insipidus. As the patient was not well enough to undergo a formal water deprivation test a therapeutic trial of Desmopression ( D D A V P ) was undertaken (Table 1). There was no clinical or biochemical response and the patient finally died of a septicaemic illness in December 1990. On post-mortem examination, a peripituitary leukaemic infiltrate was found. This did not invade the parenchyma. There was also some patchy leukaemic infiltration in both kidneys which was restricted to the interstitial area (Figs 1 and 2). 711
712
S. SADULLAHet al.
DISCUSSION This patient developed polyuria associated with a lymphoid transformation of chronic myeloid leukaemia. Therapeutic trials of D D A V P and thiazides failed to resolve the problem. Post-mortem findings showed a peripituitary and renal interstitial leukaemic infiltrate. Initially the polyuria was thought to be due to hyperglycaemia. However, correcting the blood glucose level did not decrease his urine output. The absence of hypokalaemia and the fact that the metabolic acidosis and failure to acidify urine were transient is against the diagnosis of a pure renal tubular acidosis. The main differential diagnosis was thus between a cranial or nephrogenic diabetes insipidus. The lack of response to D D V A P does not necessarily exclude the diagnosis of cranial DI as patients with a protracted history of polyuria can initially be resistant to vasopressin [1]. The cause of his polyuria thus remains unresolved. Diabetes insipidus (DI) is a rare but recognised complication of leukaemia. At least 51 patients have been reported in whom symptoms and signs of DI occurred in conjunction with leukaemia [2-7]. It is more often associated with A M L than with ALL. Puolakka et al. suggest that patients with A M L with a preceding history of myelodysplasia have a greater likelihood of developing DI [8]. Only six cases of DI with CML have been reported and these have all been associated with advanced disease [9-11[. Cytology of CSF and radiologic investigation of the nervous system are seldom helpful. Several cases of DI and leukaemia occurred before effective treatment for ieukaemia was available. None the less, recent reports have failed to show the efficacy of antineoplastic therapy or CNS radiation in resolving symptoms in these patients [4, 9]. Symptomatic response with D D A V P can be expected although 15% of teukaemic patients with cranial diabetes insipidus are resistant to vasopressin [12]. At least three cases of nephrogenic diabetes insipidus due to infiltration of the renal tubules have been reported [131. Pathologically there is either a diffuse infiltration of the posterior pituitary gland or thrombotic and haemorrhagic lesions of the small vessels in the hypothalamic nuclei and posterior lobe of the pituitary. Despite the fact that perihypophyseal leukaemic infiltrates are found in as many as 46% of patients at post-mortem examination, overt diabetes insipidus is rarely encountered in this disease [14, 15]. Leukaemic infiltration of the kidney can cause tubular dysfunction but is more commonly asymptomatic and found incidentally at autopsy. In one series of 322 cases, 60% of the patients had renal leukaemic infiltrates post-mortem but only three of these had
clinical evidence of renal impairment [16]. However, in monocytic leukaemias lysozyme release is known to cause tubular damage [17]. An association between monosomy 7 and DI in leukaemic patients has been proposed. Chromosome studies performed in 6 patients with leukaemia and DI showed monosomy 7 in five while the sixth had del 7 (q22). The critical region on chromosome 7 is thought to be 7q22-qter [2, 18, 19]. Monosomy 7 alone or in combination with other chromosomal abnormalities is commonly found in myeloid leukaemias. It is present in about 7% of cases with de n o v o A M L and 28% of cases with secondary A M L [20, 21]. In CML it is not usually seen in the chronic phase but is one of the additional abnormalities which accompany the accelerated phase or lymphoid blast crisis [22]. Interestingly our patient developed monosomy 7 at the time of blast transformation. Whether monosomy 7 is truly over-represented among leukaemic patients with DI needs further evaluation. Also the mechanism by which this predisposition is produced needs to be clarified. REFERENCES 1. Baylis P. H. (1983) Posterior pituitary function in health and disease. Clin. Endocrinol. Metabol. 12, 758. 2. De la Chapelle A. & gahtinen R. (1987) Monosomy 7 predisposes to diabetes insipidus in leukemia and myelodysplastic syndrome. Eur. J. Haemat. 39, 404411. 3. Boga M., Halmy L. & Rutkai P. (1970) Diabetes insipidus occurring with acute leukemia. Haematologia (Budapest) 4, 235-239. 4. Miller V. & Campbell W. (1971) Diabetes insipidus as a complication of leukemia. Cancer 28, 666-673. 5. Betkerur U., Shende A. & Lanzkowsky P. (1977) Acute myeloblastic leukemia presenting with diabetes insipidus. Am. J. Med. Sci. 273, 325-327. 6. Kornberg A., Zimmerman J., Matzner Y. & Polliack A. (1980) Acute lymphoblastic leukemia. Association with vasopressin responsive diabetes insipidus. Arch. Intern. Med. 140, 1236. 7. Newcomer L. N. (1982) Diabetes insipidus associated with central nervous system leukemia. Southern Med. J. 75, 1142-1143. 8. Puolakka K., Korhonen T. & Lahtinen R. (1984) Diabetes insipidus in preleukemic phase of acute myeloid leukemia in 2 patients with empty sella turcica. Scand. J. Haemat. 32, 364-366. 9. Juan D., Hsu S.-D. & Hunter J. (1985) Case report of vasopressin-responsive diabetes insipidus associated with chronic myelogenous leukemia. Cancer 56, 14681469. 10. Landman M. E. & Stumpf H. H. (1965) Diabetes insipidus complicating chronic myelogenous leukemia. J. Med. Soc. New Jersey 62, 205-207. 11. Ungaro P. C., Gonzales J. J., Werk E. E., Mackay J. C. (1984) Chronic myelogenous leukemia presenting clinically as diabetes insipidus. North Carolina Med. J. 45, 640-641.
FIG. 1. Peripituitary leukaemic infiltrate. (a) Leukaemic infiltrate. (b) Capsule. (c) Uninvolved pituitary. (Haematoxylin-Eosin stain, × 100.)
713
FIG. 2. Renal interstitial infiltrate. (a) Leukaemic infiltrate. (b) Normal glomerular architecture. (Haematoxylin-Eosin stain, x 100.)
714
Monosomy 7 and polyuria 12. Laakso W. B. (1964) Diabetes insipidus secondary to acute leukemia. A case report. Am. J. Med. Sci. 247, 451-456. 13. Shurygin D. I. (1960) On diabetes insipidus in patients with acute leukosis. Klin. Med. 28, 132-134. 14. Philippakos D., Kakouros S., Dervenoulas J. & Pontidas E. (1983) Diabetes insipidus as a complication of acute myelomonocytic leukemia. Postgrad. Med. J. 59, 93-94. 15. Masse S. R., Wolk R. W. & Conklin R. H. (1973) Peripituitary gland involvement in acute leukemia in adults. Arch. Pathol. 96, 141-142. 16. Boggs D. R. et al. (1962) The acute leukaemias. Analysis of 322 cases and review of the literature. Medicine 41, 163. 17. Goldman J. E. (1989) Postgraduate Haematology (Hoffbrand A. V. & Lewis S. M., Eds), p. 304. Heineman, Oxford. 18. Montecucco C.. Cazzola M. & Ascari E. (1984) Diabetes insipidus in the pre-leukemic phase of acute
19.
20.
21. 22.
715
nonlymphocytic leukemia. A monosomy 7-associated condition? Letter. Scand. J. Haemat. 33, 326. Dezza L., Cazzola M., Bergamaschi G. et al. (1983) Myelodysplastic syndrome with monosomy 7 in adulthood: a distinct preleukemic disorder. Haematologica 68, 723-735. Fourth International Workshop on Chromosomes in Leukemia, 1982 (1984) Abnormalities of chromosome 7 resulting in monosomy 7 or in deletion of the long arm (7q-): review of translocations, breakpoints and associated abnormalities. Cancer Genet. Cytogenet. 11, 300-303. Second International Workshop on Chromosomes in Leukemia, 1979 (1981) Chromosomes in preleukemia. Cancer Genet. Cytogenet. 2, 108-113. Ishihara T., Sasaki M., Oshimura M. et al. (1983) A summary of cytogenetic studies on 534 cases of chronic myelocytic leukemia in Japan. Cancer Genet. Cytogenet. 9, 81-92.