¹Hôpital Saint André, service de Cardiologie/Hypertension artérielle, Bordeaux, France

²Hôpital Pellegrin, service d'urologie, Bordeaux, France

³Hôpital Pellegrin-Enfants, département de pédiatrie, Bordeaux, France

⁴Hôpital Pellegrin, département d'anesthésie réanimation III, Bordeaux, France

⁵Hôpital Pellegrin-Enfants, service de génétique médicale, Bordeaux, France

Correspondence to: P Gosse, service de Cardiologie/Hypertension artérielle Hôpital Saint André, 1 rue Jean Burguet, 33075 Bordeaux cedex, France. E-mail: philippe.gosse@chu-bordeaux.fr

We report the case of a 20-year-old female patient with Beckwith-Wiedemann syndrome presenting with high blood pressure and bilateral adrenal pheochromocytoma successfully removed with laparoscopy in the same time. To our knowledge, the present case is the first observation of a bilateral pheochromocytoma occurring in the Beckwith-Wiedemann syndrome. It provides further support for a genetic anomaly in this condition. Our case also indicates the interest of laparoscopy for the surgical treatment of adrenal pheochromo- cytoma, even in bilateral tumors.

Journal of Human Hypertension (2002) 16, 281-284. DOI: 10.1038/sj/jhh/1001378

bilateral adrenal pheochromocytoma; laparoscopy; Beckwith-Wiedemann syndrome

Case report

We report the case of a 20-year-old female patient with Beckwith-Wiedemann syndrome admitted to hospital for investigation of hypertension associated with malaise.

Beckwith-Wiedemann syndrome was diagnosed within a few days of birth from the association of hydramnios, omphalocele, right hemihypertrophy affecting the pelvis and upper and lower limbs, hepatomegaly and episodes of hypoglycaemia. In view of the possible occurrence of nesidioblastosis in this syndrome, the patient was treated with diazoxide followed by partial pancreatectomy. By age 14, the patient had developed bilateral mammary adenofibroma predominantly in the right breast, which was treated with tamoxifen over a period of 3 years. In view of tumor progression, this treatment had been resumed over the previous year. Surgical removal of the mammary adenofibroma in the near future was being considered in view of the risk of neoplasic degeneration.

Over the past few weeks the patient had complained of malaise with palpitations, visual clouding, sensations of weakness, profuse sweating and muco-cutaneous pallor. These episodes of malaise occurred without warning, lasted a few minutes and resolved spontaneously. The initial hypothesis of hypoglycaemia attributed to hyperinsulinaemia from partial regeneration of the pancreas was ruled out by measurement of blood glucose levels at critical times.

The patient was fitted with a device for measuring ambulatory blood pressure over 24 h in view of the observation of office blood pressures ranging from 160/110 mm Hg to 200/150 mm Hg. This confirmed a systolo-diastolic hypertension throughout the circadian cycle with values exceeding 140/100 mm Hg most of the time.

Laboratory investigations (electrolytes, potassium, urea, creatininaemia, liver enzymes, blood cell count, coagulation, sedimentation rate, and proteinuria over 24 h) were normal. The electrocardiogram at rest showed a sinus rhythm with inversion of the T wave in the lower lateral territory (DII, DIII, aVf, V4, V5, V6). Transthoracic echocardiography showed a hyperechogenicity in the right half of the endocardial septum and the free wall of the right ventricle, which nevertheless appeared to be of normal dimensions and movement. There was no abnormality of segmental kinetics nor evidence of valve pathology.

An initial abdominal CT scan coupled with venous angiography revealed a bilateral tumoral process in the adrenal glands. A 20 mm tumor was observed in the internal arm of the right adrenal gland and a similar one in the body of the left adrenal gland. The right kidney was much larger than the left. Moreover, the right calyces were abnormal, irregular and slightly dilated. The renal arteries were normal.

A subsequent CT scan of the right kidney confirmed the dilation of the calyces of the upper and median group that appeared to be due to blood or stones, but not to a tumoral process. The bilateral adrenal tumors had central necrotic zones. Angio-MRI with gadolinium confirmed these findings.

At this stage of the investigation, we received the results of plasma and urinary catecholamines and their metabolites assays. The total urinary metanephrines were elevated fluctuating between 6 and 7 mg/24 h (normal value <1 mg/24 h). The total urinary catecholamines were also raised to 2640 g/24 h (normal value <250 g/24 h). The urinary methoxylated derivatives were elevated: 3-0-methyl noradrenaline to 37.456 nmol/24 h (reference limits <2000), 3-0-methyl-adrenaline to 2396 nmol/24 h (reference limits <1000), 3-0-methyl-dopamine to 3901 nmol/24 h (reference limits <2000). Free urinary catecholamines were elevated: noradrenaline to 9490 nmol/24 h (ref- erence limits <400), adrenaline to 103 nmol/24 h (reference limits <100). Plasma catecholamines assayed outside episodes of malaise were normal.

Exploration of the renin-angiotensin system revealed frank secondary hyperaldosteronism: Lying renin activity 5.9 ng/ml.h (reference limits <2.5), plasma aldosterone 734 pmol/l (reference limits <500), urinary aldosterone 144 nmol/24 h (reference limits <69). Levels were moderately increased on standing up and were reduced by ACE inhibitors. Plasma cortisol was moderately raised at different times over the circadian cycle.

Strong suspicion of a bilateral adrenal pheochromocytoma prompted MIBG scintigraphy, which only showed increased binding in the hepatic region. No abnormal binding of tracer, particularly in the liver, was detected on somatostatin A scintigraphy (In 111).

A diagnosis of bilateral adrenal pheochromocytoma without secondary locations with secondary hyperaldosteronism and a consequent hypercortisolism was made. Bilateral adrenalectomy was thus envisaged. The patient was reluctant to undergo laparotomy in view of the size of the post-operative scar and the prospect of further surgery on the mammary adenofibromas in the event of degeneration. After informing the patient and family of the risks and benefits of the various surgical approaches and in view of her surgical history, a decision in favour of laparoscopy was made. Treatment with intravenous urapidil, a selective alpha-1 blocker, matched to the fluctuations in blood pressure was commenced a few days before surgery and maintained throughout the operation. The surgeons employed a transperitoneal approach on the right side and a retroperitoneal one on the left. The operation lasted 6 h (interval between anaesthetic induction and resuscitation). Plasma catecholamines were assayed and blood pressure determined throughout the operation (Table 1). Later histological analysis of tissue samples confirmed the diagnosis of bilateral pheochromocytoma.

Replacement therapy with hydrocortisone was commenced. The post-operative course was uneventful and the patient left the surgical unit 4 days after operation. Blood pressure soon after operation was normal without any treatment. On re-examination of the patient 1 month after operation, urinary methoxylated derivatives had returned to normal, and blood pressure was also in the normal range in the absence of any specific treatment. The patient will be seen at yearly intervals when urinary methoxylated derivatives will be assayed. She has been re-examined at 1 year follow-up and she is going well with normal blood pressure and normal urinary dosages.

Discussion

Comments on the association of Beckwith-Wiedemann syndrome and bilateral pheochromocytoma

The Beckwith-Wiedemann syndrome is an overgrowth syndrome associating multiple abnormalities with a high risk of embryonic tumors.¹ This syndrome is frequently associated with malignant tumors, especially nephroblastoma or Wilms' tumor.² Other malignant tumors described in this syndrome include hepatoblastoma, neuroblastoma, corticorticoadrenaloma and rhabdomyosarcoma. The incidence of a malignant tumor irrespective of site is around 7.5% in this syndrome and appears highest in cases of hemihypertrophy.

In this particular case, the tumors developed in the adrenal medulla, whereas this syndrome is generally associated with risk of corticoadrenaloma. To our knowledge, the present case is the first observation of a bilateral pheochromocytoma occurring in the Beckwith-Wiedemann syndrome. The only reference to a similar cases was a report in 1976 of a unilateral malignant pheochromocytoma complicating a congenital hemihypertrophy syndrome.³ The Beckwith-Wiedemann syndrome is most often sporadic, but approximately 15% of cases are hereditary. Cytogenetic anomalies^4,5 involving chromosome 11p15 have been described in a few patients. This chromosome region harbours the gene IGF2. An error in parental genomic imprinting is thought to be involved in the Beckwith-Wiedemann syndrome, whether sporadic or of hereditary origin, and a paternal disomy in chromosome region 11p15.5 has also been observed in some cases. Furthermore, loss of the chromosome 11p15 allele has been demonstrated in cells of some cancers (nephroblastoma, rhabdomyosarcoma), pointing to inactivation of a tumor suppressor gene in the incriminated region. Apart from IGF2, genes H19, P57KIP2, QVLQT1 and GOK⁶ are thought to be susceptible to imprinting in this chromosome region and may be involved in the Beckwith-Wiedemann syndrome as well as in the development of certain tumors. Although the genetic factors involved in pheochromocytoma remain to be elucidated, the incidence of this tumor appears to be higher in multiple endocrine neoplasias (NEM) as well as in the Von Hippel-Lindau syndrome where tumors are generally bilateral.⁷ There are some similarities between the Beckwith-Wiedemann syndrome an the Von Hippel-Lindau syndrome: pheochromocytoma are often bilateral in the Von Hippel-Lindau syndrome which is also associated with pancreatic and kidney tumors. In both syndromes inactivation of a tumor suppressor gene have been incriminated.⁸

Comments on the surgical approach by laparoscopy

We report here a bilateral adrenalectomy by laparoscopy for treatment of a bilateral pheochromocytoma. Numerous authors have reported the interest of laparoscopy: less bleeding, lighter anaesthesia, smaller scar, less post-operative pain, faster recovery of intestinal transit, similar duration of operation for trained surgical teams, reduction in hospital stay.^9,10 Nevertheless, laparoscopy for such cases does involve certain risks that need to be evaluated: risk of dissemination of malignant cells, risk of catecholergic discharge during manipulation of the tumor or induction of pneumoperitoneum, risk of shock on removal of the tumor. Because of the scarcity of bilateral pheochromocytoma the experience of removal through laparoscopy remains limited.^11,12,13 The haemodynamic management during surgery of pheochromocytoma¹⁴ requires careful preoperative medication. Pre-and per-operative urapidil by intravenous perfusion with dosage matched to blood pressure, as has been described for the laparoscopic removal of unilateral pheochromocytomas,^15,16 was used with success in our bilateral intervention. In our patient (Table 1), the sharp increase in plasma cathecholamine levels after pneumoperitoneum and manipulation of each tumor underlines the need for adequate alpha receptor blockade and the clear-cut fall in catecholamine levels following removal of each tumor confirmed the bilateral nature of the disorder. Although it was our first experience of bilateral laparoscopy for pheochromocytoma, we did not encounter any haemodynamic problems. To avoid long-term hormonal replacement therapy, selective tumorectomy may be envisaged in certain cases.^17,18 The neoplasic risk of the adrenal tumors in our patient with Beckwith-Wiedemann syndrome favoured the decision for bilateral total adrenalectomy.

Comments on the sensitivity of MIBG scintigraphy for the detection of pheochromocytoma

In our patient, the abdominal scintigrams (labelled with MIBG or somatostatin) appeared normal, although histological examination of tissue samples removed during surgery confirmed the presence of a bilateral pheochromocytoma. Scintigraphy is nevertheless considered to be an examination of choice for the diagnosis and monitoring of relapses of pheochromocytoma.^19,20,21 However false-negative results have been described and are more frequent in bilateral and malignant pheochromocytoma.^8,22 The diagnosis of pheochromocytoma should be based on a series of examinations, including tomodensitometric scans and assay of urinary or plasma methoxylated derivatives. The post-operative management of pheochromocytoma has yet to be standardized and awaits validation of various exploratory techniques, especially in view of the fact that relapses may occur several years afterwards.²³

Comments on the observation of secondary hyperaldosteronism

There have been numerous reports^24,25 of enhanced activity of the renin-angiotensin system in patients with pheochromocytoma. This have been linked to the stimulation of renin by cathecholamins through renal juxtaglomerular apparatus beta receptors.

Conclusions

This observation of a bilateral pheochromocytoma in a patient with Beckwith-Wiedemann syndrome is noteworthy on several counts. It provides further support for a genetic anomaly in this condition, which would indicate the value of early screening and the possibility of gene therapy. Our case also indicated the interest of laparoscopy for the surgical treatment. It is now recognised to be a technique of choice for interventions of this kind. Lastly this observation points out that scintigraphy (MIBG or somatostatin labelled) may show false-negative results, highlighting the difficulty in selection of methods for monitoring this potentially serious condition.

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Table 1 Plasma catecholamine levels and blood pressure during surgery