A 10-year-old girl presented with complaints of bed-wetting at night, increased daytime uninary frequency and increased thirst for last six months. On examination, her weight was 27.5 kg (25th centile), height was 129 cm (10 th centile), and blood pressure (BP) varied from 180/140 to 124/100 mmHg. BP was elevated in all four limbs (right upper 160/110, left upper 156/112, right lower 170/116 and left lower 176/120), and did not show any significant postural variation. All the peripheral pulses were well palpable and there was no radio-radial or radio-femoral delay. Fundus examination revealed bilateral grade IV hypertensive retinopathy. Electrocardiogram (ECG) showed evidence of left ventricular hypertrophy. A 24-hour urine output was documented as 8 mL/kg/hour, confirming polyuria.

Laboratory investigations showed a hemoglobin of 12.4 g/dL, serum sodium (Na) ranging from 118-126 meq/L, serum potassium (K) ranging from 2.5-3.2 meq/L, urea 24 mg/dL, creatinine 0.8 mg/dL, serum albumin 4.2 g/dL and random blood sugar 67mg/dL. Urinalysis revealed urine protein of 3+ (300mg/dL) and no RBCs or pus cells. Spot urine protein to creatinine ratio (Up/Uc) was 6.4 mg/mg. Venous blood gas analysis showed mild metabolic alkalosis (PH 7.47, HCO3 28.3). Thyroid function test and serum parathormone (PTH) report was normal. A possibility of HHS due to renal artery stenosis was kept in view of polyuria, polydipsia, hypertension, hyponatremia and hypokalemia.

As the child presented with hypertensive emergency, injection labetalol was administered, which was later substituted with oral formulation. Subsequently, other antihypertensives were added in combination (Amlodipine, Clonidine and Enalapril). Despite using multiple antihypertensives, BP remained elevated above 95th centile. Prazosin was added in the pre-operative period, which resulted in near normalization of BP.

The child underwent open laparotomy and left salpingo-oophorectomy was performed. An ovarian mass measuring 5x4x3.5 cubic centimeter with an external pearly white capsule was removed. Microscopic examination revealed a monomorphic population of round cells with abundant granular cytoplasm arranged in the classical zellballen pattern. On immunohisto-chemistry, tumor cells expressed synpatophysin and cytokeratin (Web Fig. 1). A final diagnosis of ovarian paraganglioma was made based on histopathology report. Two weeks after surgery, her BP was normal (112/66 mm Hg), polyuria subsided and biochemical parameters (serum Na and K) normalized. Antihypertensives were gradually tapered and omitted over next 6 weeks. At last follow-up (2 years after surgery), she was normotensive, off medication and had not shown any sign of tumor recurrence.

Paragangliomas are rare extra-adrenal catecholamine-secreting tumors located in paravertebral axis and sympathetic nerve branches in pelvic organs, and secrete nor-epinephrine. Parasympathetic variety is located in head and neck, and are generally non-secretory [5]. Paragangliomas have been rarely reported in ovary, uterus and vagina, constituting only 2% of all gynecological tract tumors [6-8]. Clinical features are often nonspecific and tumor detection may be incidental. Polyuria and polydipsia as presenting complaints have been reported earlier in a 9-year-old boy with pheochromocytoma [9].

The child in our report presented with polyuria, polydipsia, hypertension and hyponatremia – similar to clinical and biochemical features of HHS. Release of natriuretic peptides (BNP and ANP) with rapid elevation of BP might have resulted in polyuria and hyponatremia by pressure natriuresis. Natriuretic peptides suppress sodium reabsorption at thiazide-sensitive distal convoluted tubules and thereby increase its delivery to the downstream collecting ducts, where aldosterone stimulates secretion of potassium resulting in hypokalemia [10]. Unlike renovascular hypertension, where renal ischemia is central to activation of renin-angiotensin system (RAS) and subsequent HHS, in our case, hypovolemia secondary to polyuria might have resulted in activation of RAS. We postulate that intense thirst and release of anti-diuretic hormone due to hypovolemia resulting from polyuria could have also contributed to the development of hyponatremia in our case. Proteinuria could have resulted from glomerular hyperfilteration secondary to hypertension; resolution of proteinuria with BP control after surgery validates the same.

Paragangliomas can occur sporadically or in association with familial syndromes like multiple endocrine neoplasia (MEN) type 2, Von Hippel-Lindau disease, and neurofibromatosis type 1. Our case did not have any features suggestive of familial syndromes. However, genetic testing, urinary/plasma metanephrines, plasma aldosterone and FDG PET could not be performed because of financial constraints.

Treatment of paragangliomas is chiefly surgical. Adequate preoperative BP control is mandatory to avoid intra operative rise in BP due to excessive release of catecholamines. Use of selective alpha-1 adrenergic receptor blocker in preoperative period is more rationale and effective way to control BP in children with pheochromocytoma/paraganglioma. Beta blockade is instituted following alpha blockade to offset reflex tachycardia and should never be started before adequate alpha blockade to prevent risk of severe hypertensive crisis from unopposed alpha-1 receptor stimulation [5].

To conclude, HHS may be a manifestation of paraneoplastic syndrome. A high index of clinical suspicion, CT or MRI of abdomen, and estimation of urinary and serum catecholamines may help to clinch these rare causes.

Contributors: MK,AD,KM: initial work-up and case management; VM: performed the surgery; NM: made the histopathological diagnosis; AD: prepared the initial draft; MK,NM,KM: revised the draft. All the authors approved the final version of the manuscript.

Funding: None; Competing Interest: None stated.

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