Severe hypercalcemia (>14 mg/dL) is rare in children but can result in coma, arrhythmias and death. In adults, the most common cause of severe hypercalcemia is malignancy (advanced stages), which portends a poor prognosis. Hypercalcemia of malignancy has been rarely reported in children [1]. We present a boy with life-threatening hypercalcemia who was diagnosed with occult acute lymphoblastic leukemia (ALL).

A 4-year-old boy presented with recurrent vomiting, polyuria, polydipsia, extreme irritability, irrelevant talk, constipation and right leg immobility with the history of low back pain for two months. The child was in severe dehydration with altered sensorium, high blood pressure (>99th centile) without any neurological deficit, hepatosplenomegaly or lymphadenopathy. On laboratory investigations, serum calcium was 19.2 mg/dL (ionized 8.2 mg/dL), phosphate 3.7 mg/dL, albumin 3.7 g/dL, alkaline phosphatase 389 IU/L, high urinary calcium: creatinine ratio, 25(OH)D 40 nmol/L (normal 50-250), increased 1,25(OH)2D 271 pmol/L (normal 52-117); and normal venous blood gas, renal function and serum magnesium. He was managed with hydration with double maintenance fluid and intravenous furosemide. Pamidronate (1 mg/kg) was administered over 4 hours by intravenous infusion. The serum calcium improved to 9.2 mg/dL and subsequently fell to 6.8 mg/dL over the next 3 days requiring oral calcium supplementation. A diagnosis of primary hyperparathyroidism was considered based on serum PTH level of 106 pg/ml (15-68.3) and doubtful PTH gland adenoma on ultrasound of neck. Sestamibi scan, 4D CT neck and 4D MRI neck did not identify any parathyroid gland abnormality. A repeat serum PTH was reported low at 1.3 pg/mL with normal calcitonin (<2 pg/mL, normal 0-18.2). Work up for PTH-independent causes of hypercalcemia including granulomatous disease (tuberculosis and angiotensin-converting enzyme levels for sarcoidosis) was normal.

(a)	(b)
Fig. 1 Fluorodeoxyglucose (FDG) PET scan showing extensive lytic changes in skeleton (a) with diffusely increased FDG uptake in spleen (b).

Radiographs showed extensive generalized bony lytic lesions of skull (salt and pepper appearance), phalanges and spine with vertebral collapse. Bone-scan showed metastatic calcification of stomach and bilateral lung secondary to hypercalcemia. In the background of extensive bony lytic lesions and suppressed PTH, malignancy-induced hypercalcemia was considered. Complete blood count, peripheral smear, lactate dehydrogenase (LDH), uric acid and alpha-fetoprotein (AFP) were normal. Bone marrow aspiration and biopsy were normal. Parathyroid related peptide (PTHrP) was also normal <0.8 pmol/L (<1.3). CECT abdomen, chest and neck revealed diffuse geographic lytic lesions with diffuse osteopenia (brown tumor) but no solid tumor was identified. Fluorodeoxyglucose (FDG) PET scan showed extensive lytic changes involving the entire visualized skeleton with diffusely increased FDG uptake in the spleen suggestive of a lymphoproliferative disorder (Fig. 1a, 1b). A repeat bone marrow aspiration and biopsy revealed inconclusive small round cell tumor. Subsequently, a CT-guided bone marrow biopsy was done from iliac crest lesions, which showed 54% malignant cells consistent with round cell tumor. Immuno-histochemistry was positive for PAX5 (B cell marker), T’dt (precursor of lymphocytes), MIC-2, and CD20 (focal) markers and negative for CD3 (T cell marker), CD 56, Chromogranin (neuroendocrine marker), which confirmed the diagnosis of B-cell ALL. He was started on standard-risk induction chemotherapy for ALL (vincristine, L-asparaginase, prednisolone and intra-thecal methotrexate) with which remission was achieved.

In summary, our case presented with severe hypercalcemia, high PTH and parathyroid adenoma on USG neck, pointing towards a diagnosis of primary hyperparathyroidism (PHPT). Occurrence of bony pains and the characteristic salt and pepper appearance of skull in our patient were also consistent with PHPT. However, multiple extensive bony lytic lesions are very rare in PHPT [2]. Serum PTH was found to be suppressed on repeat testing pointing to the possibility of malignancy in the absence of other clinical, haematological or biochemical evidence. Our case report　highlights the importance of repeating hormone assays (PTH) when the clinical picture is inconsistent and the limitations of a single rephine biopsy in detecting occult lymphoblastic malignancies.

Hypercalcemia of malignancy is very rare in children and usually seen in ALL, rhabdomyosarcoma and less often in lymphoma, hepatoblastoma, and neuroblastoma [3]. Hypercalcemia in solid tumor presents late in the disease course and is more resistant to treatment, unlike ALL where it may present early without other clinical manifestations [4]. There are several mechanisms of malignancy-induced hypercalcemia, such as PTHrP by malignant solid tumours and osteolytic metastasis with local release of cytokines including osteoclast activating factor or unregulated extrarenal production of 1,25(OH)2D (in lymphoma and granulomatous diseases) [5]. In one study of 22 ALL patients with hypercalcemia, half had elevated PTHrP thought to be released from blast cells [6]. In our case, the PTHrP was normal and hypercalcemia probably resulted from the extensive osteolytic lesions due to local pro-duction of cytokines and possibly high 1,25(OH)2D levels.