Phaeochromocytoma in a Child Presenting With Post‐Streptococcal Glomerulonephritis and Hypertensive Encephalopathy—Case Report

Phaeochromocytomas and paragangliomas are catecholamine-secreting tumours arising from adrenal chromaffin cells or autonomic paraganglia outside of the adrenal medulla, respectively. Phaeochromocytomas and paragangliomas are rare tumours, with an estimated incidence of 0.58/100000 cases per year [1], of which 10% are diagnosed in childhood [2]. Phaeochromocytomas in children are more likely to be genetic, compared to adults, with up to 80% of tumours associated with MEN2, VHL, NF1 or familial paraganglioma-phaeochromocytoma syndromes (PPGL genes) [2]. Common presenting signs and symptoms of catecholamine-secreting tumours include hypertension—in children this may be sustained rather than paroxysmal [3], headaches, sweating, nausea, tachycardia, or palpitations [4]. The diagnosis is usually suspected due to clinical presentation with hypertension in young children, severe hypertension not responding to typical measures, or a family history of familial disease, and confirmed with biochemical testing in the form of spot sample urinary catecholamines or plasma metanephrines before localisation using CT or MRI. Acute post-Streptococcal glomerulonephritis (APSGN), which also commonly presents with hypertension, is the most common form of glomerulonephritis among Australian and New Zealand children, with Indigenous children being vastly over-represented in all reports of APSGN [5]. Aboriginal Australians, particularly those living in rural and remote regions, carry a high disease burden, secondary to social disadvantage, poverty, overcrowding and remoteness. In a study from the Northern Territory between 2009 and 2016, the incidence of APSGN in Aboriginal Australian children under 15 years old was 124 per 100 000 person-years [6]. Therefore, when considering secondary causes of acute hypertension, especially among at-risk populations, APSGN is a much more common diagnosis than PPGL. An 11-year-old Aboriginal Australian male from a remote community in Western Australia presented to a metropolitan hospital emergency department following a generalised tonic–clonic seizure. He was noted to be hypertensive with a systolic blood pressure of up to 200 mmHg. His family reported a two-week history of mild behavioural changes. He also had a cough the preceding week, before becoming acutely unwell with a headache and vomiting for 2 days. There were no coryzal symptoms, visual changes or focal neurological signs/symptoms over the preceding days; though urine output was reportedly low. The child had a previous history of APSGN at 4 years old. A preceding skin infection was documented. Investigations revealed an acute kidney injury (AKI, peak creatinine 70 umol/L), with low C3 and elevated ASOT and anti-DNAse B; a renal ultrasound performed at the time was normal on the right but poorly visualised on the left due to poor cooperation with the study. At the time, he was acutely managed with salt and fluid restriction, phenoxymethylpenicillin, regular furosemide and nifedipine. The AKI resolved and blood pressure was downtrending. Follow-up in the remote area paediatric clinic was intermittent over the interval years, but blood pressures were noted to be elevated (between 125/70 and 150/83 mmHg). His medical history was also significant for obesity with insulin resistance, left foot cellulitis, acute otitis media, previous subclinical hypothyroidism, and dental caries. He had also been diagnosed with a neurobehavioural disorder and had been prescribed risperidone but was only intermittently compliant with this. There was a family history of Type 2 diabetes and renal impairment, but no known history of NF1, VHL or other genetic syndromes. On admission to the tertiary paediatric hospital, his respiratory examination was unremarkable. His heart rate was 78 beats/min, and he was hypertensive at 160/94 mmHg (whilst being on labetalol 25 mg/h and GTN 2 mL/h prior to transfer to tertiary care). He was afebrile. He was alert with a GCS of 14 and a grossly unremarkable neurological exam. His abdomen was soft and non-tender with no palpable masses. He had widespread scabies skin lesions across his body, without erythema or fluctuance. He also had acanthosis nigricans and weighed 78 kg. An MRI-brain demonstrated changes consistent with posterior reversible encephalopathy syndrome, as well as a possible pituitary haemorrhage. An elevated creatinine of 145 umol/L (eGFR 40 mL/min/1.73 m2) and low complement levels (C3 < 0.15 g/L, C4 0.11 g/L), with raised streptococcal serology (ASOT 805 IU/mL, antiDNAse B 674 IU/mL) and the presence of haematuria and proteinuria suggested APSGN as the cause of his hypertension. However, despite the use of multiple, concurrent antihypertensive agents (amlodipine and isradipine, atenolol, clonidine and hydralazine), he had a persistent systolic blood pressure of more than 140 mmHg. Further assessment included normal urinary cortisol level, renal tract ultrasound (including Doppler assessment), and aldosterone and renin levels. Prolactin (1100 mU/L) was raised, possibly due to pituitary haemorrhage, risperidone use, or metabolic syndrome. Subsequently, urine and plasma metanephrines were found to be persistently elevated (Table 1). A PET-CT then demonstrated a left adrenal mass suspicious for phaeochromocytoma (Figure 1). An FDG-PET further characterised the phaeochromocytoma and revealed a right pelvic nodule and pancreatic lesion—the latter favouring a primary neuroendocrine tumour (PNET). Preoperative medical stabilisation was achieved with the addition of phenoxybenzamine. The patient then underwent a left retroperitoneoscopic adrenal-sparing tumour resection and laparoscopic excision of the right pelvic lymph node. Histopathology confirmed the left adrenal tumour was consistent with a phaeochromocytoma, and the right pelvic lymph node with a synchronous primary paraganglioma. Furthermore, the phaeochromocytoma has a PASS score of 18/20, which in addition to the loss of SDHB immunohistological staining was indicative of malignant potential. Genetic testing returned with a diagnosis of a heterozygous missense pathogenic variant in the VHL gene: c.499C>T p.(Arg167Trp). The patient is under ongoing radiological and multidisciplinary surveillance for VHL and the presumed pancreatic PNET. He has not required any further antihypertensive treatment. This is a case of an Aboriginal Australian boy who presented with a hypertensive crisis determined to be due to phaeochromocytoma in the setting of VHL disease. It is likely that he also had concurrent APSGN, with both clinical and laboratory suggestive criteria being met, noting the previous history of APSGN and a recent preceding skin infection. However, the treating team avoided anchoring bias and completed a broad secondary screen when the patient failed to respond to treatment as expected. The patient's elevated metanephrines were identified and triggered further radiological investigation for alternate causes. VHL is an autosomal dominant condition with a reported incidence of 1 per 36.000 to 91.000. Males and females are equally affected, as are all ethnic groups. Approximately 20% of cases are due to a de novo pathogenic variant. The American Academy of Paediatrics reports VHL accounts for 49% of gene mutations causing phaeochromocytomas and paragangliomas [7]. VHL is associated with an increased risk of benign and malignant tumours—including renal clear cell carcinoma, phaeochromocytoma, retinal angiomas and CNS haemangioblastomas. The mean age of developing phaeochromocytomas for individuals with VHL is 25 years, with up to 30% lifetime risk by age 70 [8]. Pathogenic missense variants have an increased association with VHL Type 2 and phaeochromocytomas, whilst truncating variants have an increased association with VHL Type 1 and other tumours [9]. The diagnostic tests for catecholamine excess are fractionated plasma and/or urine metanephrines and normetanephrines [7]. EviQ national risk management guidelines for VHL include annual ophthalmology review from age 1 for retinal haemangioblastomas, annual blood pressure monitoring from age 2 and plasma metanephrines from age 5 for phaeochromocytomas, biennial brain/spine MRIs from age 11 for cerebellar/spinal haemangioblastomas, biennial audiometry from age 11 for endolymphatic sac tumours and biennial abdominal MRIs from age 15 to screen for renal cell carcinoma and PNETs (Table 2) [8, 10]. Screening for PPGL is no longer recommended as a routine investigation for most children presenting with hypertension. However, children with hypertension that is severe or unresponsive to treatment need a broad secondary screen. The presence of a common aetiology does not exclude the coexistence of other causes. The authors have nothing to report. The authors have nothing to report. The patient's mother has given verbal consent for this case report to be published. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.