Familial Pheochromocytoma Associated with Von Recklinghausen's Disease

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1 CASE REPORT Familial Pheochromocytoma Associated with Von Recklinghausen's Disease Tsuneo Ogawa, Tomohiro Mitsukawa, Tadashi Ishikawa and Kazuo Tamura Wereport a 19-year-old womanwhopresented with headache, vomiting, and elevated blood pressure; pheochromocytomand von Recklinghausen's neurofibromatosis were diagnosed. Her mother had the same skin lesions and was also found to have pheochromocytoma. Both patients underwent surgical resection and the postoperative courses were uneventful; the daughter subsequently married and delivered a healthy child. Although both pheochromocytoma and von Recklinghausen's disease are derived from neuroectoderm and are inherited disorders, concomitant familial occurrence of these two diseases is very rare, only three families have been reported previously worldwide. (Internal Medicine 33: , 1994) Key words: neurofibromatosis, hypertension Introduction von Recklinghausen' s disease, an inherited disorder derived from neuroectoderm, mayrarely be associated with pheochromocytoma. Familial pheochromocytomasare seen in about 5%of patients with pheochromocytoma (1). We experienced a family, in which pheochromocytomas were found in two consecutive generations. In both patients the findings were associated with von Recklinghausen' s neurofibromatosis. Case Report Case1 This patient was a 19-year-old womanwho had had cafe-aulait spots on the skin since birth (Fig. 1); she first noticed subcutaneous nodules at the age of 15. She was well until 1986 whenshe was admitted to our institution because of headache, vomiting, and excessive sweating. Her mother and her younger brother also had cafe-au-lait spots on the skin and subcutaneous nodules. Her family had no history of hypertension. On admission, her blood pressure was 208/1 10 mmhg,and cafe-au-lait spots and subcutaneous nodules on the skin were widespread. A fundoscopic examination showed bilateral papilledema. Cardiac examination revealed accentuated first and second sounds in the right second intercostal space. Nomasses were noted on abdominal palpation. Because of the extremely high blood pressure, papilledema and profuse sweating, we considered a diagnosis of pheochromocytoma. Endocrinological examination revealed a remarkable increase of catecholamine levels: 1 3,700 pg/ml plasma noradrenaline, pg/ml plasma adrenaline, Jig/day urine noradrenaline, and 23 1 jug/day of urine adrenaline. Plasma cortisol, renin, and aldosterone levels were also increased, but slightly. The 75-gram oral glucose tolerance test revealed impaired glucose tolerance. Abdominal computed tomography and ultrasonography of the abdomen demonstrated a mass measuring 5x4x3 cmin size in the left adrenal gland, and the renal arteriography revealed a Fig. 1. A nevus and cafe-au-lait spot on the skin of the back (case1). From the Department of Internal Medicine, Miyazaki Prefectural Hospital, Miyazaki Received for publication June 16, 1993; Accepted for publication December 20, 1993 Reprint requests should be addressed to Dr. Kazuo Tamura, the Department of Internal Medicine, Miyazaki Prefectural Hospital, 5-30 Kitatakamatsu-cho Miyazaki

2 Familial PC with von Recklinghausen hypervascular lesion over the left kidney. Hypertension was controlled with 6 mg of prazosin (ocblocker), 1 00 mg ofatenolol (B-blocker), and 40 mg ofnifedipine (calcium antagonist). The left adrenal mass was resected; it weighed 50 g and measured 5.5x4.5x2.5 cm. The surface of the tumor was dark brownand the cut side was reddish-brown (Fig. 2). Histologically, the tumor was classified as pheochromocytoma with no evidence of malignancy (Fig. 3). The patient' s blood pressure and plasma catecholamine levels were normalized one month after operation (Fig. 4a). Case2 This patient, a44-year-old woman, the mother of case 1, was hospitalized on suspicion offamilial pheochromocytoma. Three years prior to admission, she had experienced an episode of headache and vomiting, but she had no history of hypertension. She had had cafe-au-lait spots and subcutaneous nodules all over the skin since childhood (Fig. 5). Apart from the skin lesions and minimal hypertensive change in the fundi, physical examination showed no significant findings; blood pressure was normal 142/80 mmhg.laboratory examinations showed increased levels of catecholamines in both plasma and urine, with no other hormonal abnormality. Abdominal computed tomography and echography showeda mass of 7x6x5 cm above the left kidney, whereas 13 1I adosterol adrenal scintigraphy showed a hot spot in the right, but not in the left, adrenal gland. 131\ MIBG(metaiodobenzyl guanidine) scintigraphy showed uptake in the left adrenal gland (Fig. 6). After admission, she experienced headache and nausea on three occasions, associated with episodes of high blood pressure, of up to / mmhg;plasma catecholamines during these episodes were higher than whenshe recovered. A left adrenalectomy was performed; the tumor weighed 200 g and measured 7.0x7.5x5.4 cm (Fig. 7). Histologically, the tumor was classified as pheochromocytoma with no malignancy (Fig. 8). Blood pressure and catecholamine levels were within normal levels three days after the operation (Fig. 4b). Table 1 summarizes the catecholamine levels in the plasma, urine, and tumor in cases 1 and 2. The postoperative courses were uneventful for both patients. Wealso examined the younger brother of case 1. His blood pressure was 136/60 mmhg and his plasma and urine catecholamines were within the normal range. Discussion Pheochromocytomais a rare disease which accounts for fewer than 1% of patients with systemic hypertension (2). In 95%of patients, pheochromocytoma is sporadic; in the remaining 5% it is familial (1). Inheritance of familial pheochromocytomais autosomal dominant with high penetrance (3). von Recklinghausen' s disease is an inherited disorder characterized by multiple neurofibroma and cafe-au-lait spots on the skin; the incidence in the general population is one in 3,000 (4). This disorder is also inherited by a dominant trait (5). Fig. 2. Resected tumor of case 1, showing reddish-brown tissue. Fig. 3. Histopathology of the tumor showing pheochromocytoma with no evidence of malignancy (HE stain, x400) (case 1). von Recklinghausen' s neurofibromatosis is found in about 5% of patients with pheochromocytoma (5). The origin of adrenal medullary chromaffinomas and ganglionic neuroblasts is thought to be a precursor of the sympathogonia, originating from the primitive neuroectoderm or neural crest, von Recklinghausen' s disease is also a disease of neuroectodermal dysplasia. Therefore, a close association between the two diseases, i.e., neurofibromatosis and pheochromocytoma, could be considered, although the incidence of such associations is extremely rare. Attempts have recently been made to analyze the tumorigenesis of hereditary tumors by elucidating the location of abnormal genes. The loss of heterozygosity on chromosomes 1, ll, and 22 has been detected in pheochromocytoma,and the occurrence of multiple endocrine neoplasia type 2 is thought to be related to these chromosomal abnormalities (6-8). However, in type 1 neurofibromatosis, which includes von Recklinghausen' s disease, an abnormality Ill

3 Ogawaet al a I -. *' t Prazosin 6mg j Atenolol loomg A) 4 Nifedipine40mg 1 1 ^f * 10,000- *~^-^^ Operation t T 33 \ ^"^ -200 S S ^^ i,ooo- #^W^_ /\V ll ^^^^^ ^^v B Z ion- \ A\ -100 a V -^0 ^ S (1986) Jul. Aug. Sep. Oct. * ' Operation 1 1 'a ]3 10,000- I I i bp bp I "?? *^ -200 i.s.s t^-^^al ~"^*-^---^ ^ ^ 13 is i,ooo- #--^>7y-^-dl----^\A 2 T3 T3 ^^ ~-^"^ \ #- -^. O O <3^ ^ \ ^*-»-^ O O s ^ loo* y^*. y\ "iuu P-( OQ à"s. W W 10- (1986) Sep. Oct. Nov. Dec. Fig. 4. Clinical course; case l(a) and case 2(b). Fig. 5. Subcutaneous nodules in the skin (case 2). of 17ql 1-12, calledthe NF1 gene, has been detected. This gene has been cloned and is thought to be a tumor suppressor gene (9-1 1). Xu et al (12) believe that this gene functions as a tumor suppressor gene in the adrenal medulla. They were led to this conclusion by their findings that loss of heterozygosity was seen in 5 of 7 patients who had both pheochromocytoma and von Recklinghausen' s disease. They explained the concomitant occurrence of these two diseases in terms of chromosomal analysis. Differences in the genes causing the conditions may explain why familial pheochromocytoma is often seen in multiple endocrine neoplasia type 2, but is seldom seen with von Recklinghausen' s disease. Unfortunately, chromosomal analysis was not carried out in the present patients. The concomitant occurrence of familial pheochromocytoma and von Recklinghausen's disease is very rare, only three families having been reported worldwide (13-15). Martin et al (13) reviewed 54 autopsy-proven cases ofpheochromocytomaseen 112

4 Familial PC with von Recklinghausen Fig. 8. Histopathology of the tumor resected from case 2 showing pheochromocytoma with no malignancy (HE stain, x400). Fig I MIBG (metaiodobenzyl guanidine) scintigraphy in case 2 shows high uptake in the left adrenal grand. Table 1. Laboratory findings Fig. 7. Tumor from case 2 was cut in two; the center is necrotized, with cavitation. at the Mayo Clinic over the 50-year period from , and reported 2 familial cases of pheochromocytomaand von Recklinghausen's disease. Svante et al investigated 80 consecutive pheochromocytomapatients operated on from to 1985 (14), and reported one familial pattern (15). In that case, the mother had both pheochromocytoma and von Recklinghausen's disease and the daughter had von Recklinghausen's disease but refused surgery; she was diagnosed with pheochromocytoma only by computed tomography and 131I MIBG scintigraphy. It is important that a meticulous investigation fro pheochromocytoma is pursued in patients with von Recklinghausen's disease and vice versa. References Tank ES, Bartlett JD, Herwig KR, Lapides J. Surgery of the adrenal glands in infancy and childhood. J Urol 106: 280, Manger WM,Gifford RW. Current concepts of pheochromocytoma. Cardiovasc Med 3: 289, Cushman PJ. Familial endocrine tumors. AmJ Med 32: 352, Riccardi VM.Von Recklinghausen neurofibromatosis. N Engl J Med 305: 1617, Manger WM, Glifford RW. Pheochromocytoma. Springer-Verlag, New York, Heidelberg, Berlin, 1977, p Yutaka Y, Katsuhiko Y, Shiro S. Loss ofheterozygosity on chromosomes 1 and ll in sporadic pheochromocytomas. Jpn J Cancer Res 81: 632, Takai S, Tateishi H, Nishisho I, et al. Loss of genes on chromosome 22 in medullary thyroid carcinoma and pheochromocytoma. Jpn J Cancer Res 78: 894, Mathew CGP, Smith BA, Thorpe K, et al. Deletion of genes on chromosome 1 in endocrine neoplasia. Nature 328: 524, Cawthon RM, Weiss R, Gangfeng X, Viskochil D, Culver M, White R. A major segment of the neurofibromatosis type 1 gene: CDNAsequence, genomic structure, and point mutations. Cell 62: 193, Viskochil D, Buchberg AM, Xu G, et al. Deletions and a translocation interrupt acloned gene at the neurofibromatosis type 1 locus. Cell 62: 1 87, Wallace RM, Marchuk DA, Andersen LB, et al. The type 1 neurofibromatosis gene: identification of a large transcript disrupted in 113

5 Ogawaet al three NF1 patients. Science 249: 181, ) Xu W, Mulligan LM, Ponder MA, et al. Loss of NF1 alleles in pheochromocytomas from patients with type 1 neurofibromatosis. Genes ChromosomCancer 4: 337, ) Martin JS, Sheldon GS, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Mayo Clin Proc 56: 354, ) Svante J, Lars-Erik T, Gorden H, Gunnar S. Multiple neuroectodermal abnormalities in pheochromocytoma patients. World J Surg 12: 710, Svante J, Annica D, Goran H, Lars ET, Hakan A. Concomitant occurrence of an adrenal ganglioneuroma and a contralateral pheochromocytomain patient with von Recklinghausen' s neurofibromatosis. Cancer 613: 324,