Indian Journal of Cancer
Home  ICS  Feedback Subscribe Top cited articles Login 
Users Online :319
Small font sizeDefault font sizeIncrease font size
Navigate here
  Search
 
  Ahead of print
  
Resource links
    Search Pubmed for
 
    -  Sharma S
    -  Kanvinde P
    -  Rao S
    -  Mudaliar S

 
  In this article
   Abstract
  Introduction
  Case History
  Discussion
   References
   Article Tables

 Article Access Statistics
    Viewed142    
    PDF Downloaded15    

Recommend this journal

 

Previous Article  Table of Contents  Next Article
CASE REPORT
Ahead of print publication
 

Disturbances of calcium homeostasis in a child with acute lymphoblastic leukemia


1 Division of Pediatric Endocrinology, Department of Pediatric Medicine, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai, Maharashtra, India
2 Division of Pediatric Hematology and Oncology, Department of Pediatric Medicine, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai, Maharashtra, India

Date of Submission05-May-2019
Date of Decision18-Oct-2019
Date of Acceptance30-Oct-2019
Date of Web Publication14-Sep-2020

Correspondence Address:
Shreya Sharma,
Division of Pediatric Endocrinology, Department of Pediatric Medicine, Bai Jerbai Wadia Hospital for Children, Parel, Mumbai, Maharashtra
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_399_19

  Abstract 


Hypercalcemia is a rare presentation of childhood acute lymphoblastic leukemia (ALL), and presents with nonspecific symptoms. A 11-year old boy developed severe hypercalcemia during initial presentation and relapse of ALL. Both times, he subsequently developed transient symptomatic hypocalcemia, associated with hypomagnesemia and renal tubulopathy. Disturbances in calcium homeostasis may rarely be the sole presenting feature of ALL in children, as a paraneoplastic syndrome, or may arise as a consequence of the malignancy and its treatment. Along with other measures, early recognition of malignancy and initiation of treatment play a key role in correcting calcium disturbances.


Keywords: Children, hypercalcemia, hypocalcemia, leukemia, malignancy



How to cite this URL:
Sharma S, Kanvinde P, Rao S, Mudaliar S. Disturbances of calcium homeostasis in a child with acute lymphoblastic leukemia. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 20]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=295073





  Introduction Top


Hypercalcemia is a rare presentation of childhood acute lymphoblastic leukemia (ALL). In a large retrospective study carried out at St. Jude's Children's Cancer Hospital over a period of 29 years and involving 2,816 patients with acute leukemia/lymphoma, the prevalence of hypercalcemia at the time of diagnosis was found to be only 0.3%.[1]

This case report aims to highlight how calcium disturbances may rarely be a harbinger of malignancy, symptoms of which may not be easily identifiable clinically. Baseline biochemical investigations may reveal unexpected biochemical abnormalities, apart from tumor lysis syndrome, and hence become a major player in the evaluation of leukemia patients.


  Case History Top


A 11-year-old boy presented with complaints of vomiting, decreased appetite, weight loss, polyuria and abdominal pain on and off since 1 month. He was pale but did not have other clinical signs suggestive of a blood malignancy like lymphadenopathy or organomegaly.

Initial laboratory studies were as follows: Complete blood count included: white blood cell (WBC) counts: 32.2 × 109/L (reference range: 4.5 - 13.0 x 103/mm3), absolute neutrophil count (ANC): 4,800 (reference range: 1500-9500/mm3) and absolute lymphocyte count (ALC): 27,400 (reference range: 1000-5000/mm3), hemoglobin (Hb): 7.9 g/dL (reference range: 13.0–16.0 g/dL), platelet: 1.4 × 109/L (reference range: 150,000-450,000 lakhs/mm3), serum calcium (Ca): 15 mg/dL (reference range: 8.5-10.5 mg/dL), phosphorus (PO4): 3.5 mg/dL(reference range: 2.5-4.5 mg/dL), and alkaline phosphatase (ALP): 224 U/L (reference range:130-417 U/L). Serum levels of intact PTH (iPTH) and 25-(OH)D were <3 pg/mL (10–65 pg/mL) and 15 ng/mL (20–50 ng/mL), respectively. Other investigations were as follows – Sodium (Na): 135 mmol/L, Potassium (K): 3.6 mmol/L, ionized calcium (iCa): 1.7 mEQ/L, blood urea nitrogen (BUN): 22, creatinine (Cr): 2.3 mg/dL, uric acid: 4 mg/dL, lactate dehydrogenase (LDH): 2138 U/L, magnesium (Mg): 1.8 mg/dL, and albumin (Alb): 4 g/dL. Venous blood gas (VBG) was normal [Table 1].
Table 1: Laboratory parameters at different stages of presentation

Click here to view


Despite severe hypercalcemia, there were no significant electrocardiographic changes. The corrected QT interval (QTc) was in the normal range.

Blood counts showed anemia and leukocytosis with lymphocytic predominance. Peripheral smear picture was conducive with blood malignancy. Chest X-ray was normal and abdominal ultrasound showed liver and spleen to be of normal size. Ultrasonogram of kidneys revealed increased echogenicity of kidneys.

Bone marrow aspiration and flow cytometry were consistent with early pre-B-cell ALL phenotype. Cytogenetic analysis of bone marrow showed no evidence of BCR/ABL or MLL translocation/ETV6/RUNX1 fusion or t(17;19). Cytogenetic analysis showed diploidy (83%) and hyperdiploidy (17%).

The child was hospitalized for treatment and close monitoring of severe hypercalcemia. Calcium containing medications were stopped and calcium restricted diet was advised. Aggressive hydration with diuretic use lead to minor decrease in serum calcium level; hence, this was followed on day 3 by intravenous pamidronate infusion (1 mg/kg). Pre-phase steroid in the form of prednisolone (60 mg/m2/day) were started by day 7. Hypercalcemia and accompanying renal insufficiency resolved after 1 week.

An unusual occurrence 1 week postresolution of hypercalcemia was symptomatic hypocalcemia leading to tetany (lowest Ca – 7 mg/dL), which was accompanied by hypomagnesemia (Mg – 1.2 mg/dL), hypermagnesuria {fractional excretion of magnesium [FEMg] >4 (N range: 0.5–4)},[2] and hypercalciuria. This was accompanied with an inappropriate PTH response owing probably to hypomagnesemia (iPTH – 20.9 pg/mL for corresponding calcium of 7.5 mg/dL). There was accompanying renal insufficiency with elevated creatinine, but no evidence of tumor lysis syndrome

[Table 1]. Child was started on intravenous calcium and intramuscular magnesium supplements followed by oral magnesium and calcium, which he continued to require on follow-up.

The patient underwent chemotherapy protocol Indian Childhood Collaborative Leukemia Protocol (ICiCle)[3] during which he received prednisolone, vincristine, daunorubicin, L-asparaginase, cyclophosphamide, methotrexate, dexamethasone, cytarabine, doxorubicin, and intrathecal methotrexate. Child tolerated chemotherapy well, with no complications. Approximately one and half years into maintenance chemotherapy (fourth cycle), he developed nausea, vomiting, abdominal pain, and polyuria.

Laboratory studies now revealed: Hb: 12 g/dL, WBC: 18 × 109/L (lymphocyte: 70%, Polymorphonuclear cells (PMN): 30%, atypical cells), platelet count: 150,000, Ca: 16 mg/dL, PO4:3 mg/dL, ALP: 240 U/L, BUN: 17, Cr: 1.8 mg/dL, Na: 137 mmol/L, K: 4 mmol/L, uric acid: 4.2 mg/dL, LDH: 1,890 U/L, Alb: 3.8 g/dL, 25-OHD: 26 ng/mL, 1,25-(OH)2 D3:36 pg/mL (15–75 pg/mL), and iPTH: <3 pg/mL [Table 1].

Bone marrow aspirate and flow cytometry confirmed pre-B-cell ALL relapse. When only minimal reduction in calcium levels was achieved with hydration and diuresis with furosemide, intravenous pamidronate (1 mg/kg) single dose, and oral prednisolone were given after which there was a reduction of calcium to 12 g/dL. Child was started on UK ALL R3 relapse protocol-mitoxantrone, vincristine, l-asparaginase, cyclophosphamide, methotrexate, dexamethasone, and cytarabine.

The child again started developing hypocalcemia, with hypomagnesemia on day 5 of treatment. Once again, there were elevated urinary magnesium and calcium losses with an inappropriately low PTH response to hypocalcemia [Table 1].

He required parenteral calcium and magnesium followed by oral replacement (Magnesium hydroxide -2 g/day). After this, the child was lost to follow-up.


  Discussion Top


This case demonstrates that childhood ALL may present in an atypical form with hypercalcemia before the occurrence of common and usual signs and symptoms of ALL, although the symptoms of the two may be overlapping.

There are two main mechanisms of hypercalcemia in malignancy: localized bone destruction by invasive cancer cells with the participation of various cytokines, and osteoclastic bone resorption mediated by humoral tumor-derived factors of which parathyroid hormone-related peptide (PTHrP) is the major factor that acts by increasing osteoclastic bone resorption, renal resorption of calcium, and renal phosphate loss.[4],[5]

In our patient, the serum phosphorus level was low and serum 1,25-(OH)2 vitamin D level was normal with suppressed iPTH level, indicating that PTHrP mediated hypercalcemia was likely. Therapy in such cases is aimed at reducing or eliminating the tumor burden, increasing renal calcium clearance, and inhibiting osteoclastic bone resorption.

The subsequent urinary magnesium losses, and hypercalciuria could be explained by prolonged diuretic use and cytotoxic chemotherapy leading to tubulopathy. Leukemia itself may contribute to renal tubular damage. It was postulated that dysfunction of the ion channel that regulates magnesium homeostasis- transient receptor potential melastatin (TRPM6) channel in distal convoluted tubules, lead to urinary magnesium losses.[6] A state of functional hypoparathyroidism then ensues secondary to hypomagnesemia. Bisphosphonate use may have exacerbated hypocalcemia, in this case, by reducing bone turnover.

Our case illustrates the disturbance in calcium homeostasis that can accompany other symptoms of leukemia and exacerbate the morbidity associated with it. Given that most patients with childhood ALL who present with hypercalcemia at diagnosis have nonspecific symptoms, diagnosis and treatment are delayed in these patients. Hence, regular monitoring of calcium and magnesium is advocated to avoid unpleasant surprises during management and follow up in these patients.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
McKay C, Furman WL. Hypercalcemia complicating childhood malignancies. Cancer 1993;72:256-60.  Back to cited text no. 1
    
2.
Elisaf M, Panteli K, Theodorou J, Siamopoulos KC. Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia. Magnes Res 1997;10:315-20.  Back to cited text no. 2
    
3.
Saha V,et al. Randomised open label phase IV study for patients with newly diagnosed Acute Lymphoblastic Leukaemia (Indian Childhood Collaborative Leukaemia Group Study ALL 2014) CTRI/2015/12/006434. Available from: http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=13445&EncHid=userName==006434. [Last accessed on 2020 Aug 29].  Back to cited text no. 3
    
4.
Mundy GR, Ibbotson KJ, D'Souza SM, Simpson EL, Jacobs JW, Martin TJ. The hypercalcemia of cancer. Clinical implications and pathogenic mechanisms. N Engl J Med 1984;310:1718-27.  Back to cited text no. 4
    
5.
Inukai T, Hirose K, Inaba T, Kurosawa H, Hama A, Inada H, et al. Hypercalcemia in childhood acute lymphoblastic leukemia: Frequent implication of parathyroid hormone-related peptide and E2A-HLF from translocation 17;19. Leukemia 2007;21:288-96.  Back to cited text no. 5
    
6.
Schlingmann KP, Waldegger S, Konrad M, Chubanov V, Gudermann T. TRPM6 and TRPM7—Gatekeepers of human magnesium metabolism. Biochim Biophys Acta BBA-Mol Basis Dis 2007;1772:813-21.  Back to cited text no. 6
    



 
 
    Tables

  [Table 1]



 

Top
Previous Article  Next Article

    

  Site Map | What's new | Copyright and Disclaimer
  Online since 1st April '07
  2007 - Indian Journal of Cancer | Published by Wolters Kluwer - Medknow