American Journal of Medical Genetics 37:375-383 (1990)

Multiple Endocrine Neoplasia: How Many Syndromes? R. Neil Schimke Dewartment of Medicine. Division of Metabolism, Endocrinology and Genetics, Kansas University Medical School, Kdnsas city, Kansas ’

The phrase multiple endocrine neoplasia (MEN)generally denotes a n association of tumors so specific as to constitute a syndrome. Three well-recognized such syndromes exist. All are autosomal dominant traits and all have been tentatively mapped to specific chromosomes. Other purported endocrine tumor syndromes have been suggested either as new entities or as subtypes of the existing MEN syndromes. The evidence in favor of these contentions is examined critically. Only one “new” association. that of pheochromocytomas and islet cell tumors, seems reasonable, and even in this setting, some relatives have had manifestations of von HippelLindau syndrome. There is no compelling reason why such conditions as von Hippel-Lindau syndrome, peripheral neurofibromatosis, McCune-Albright syndrome, and others should be reclassified as MEN syndromes, although awareness of their collective endocrine abnormalities is clinically important. KEY WORDS: overlap syndrome, endocrine tumor association, candidate syndrome, autosomal dominant inheritance INTRODUCTION The term multiple endocrine neoplasia (MEN) has been in the medical literature for many years. Originally it implied a coincidence of 2 endocrine tumors that was interesting, not necessarily causal, but perhaps related via some underlying mechanism. Later it became evident that certain endocrine tumor associations were significant and indeed, were heritable, as exemplified by the classic MEN syndromes. In more recent years, the literature has become replete with reports purporting to show either a fundamental identity between the origiReceived for publication November 20, 1989; revision received March 5, 1990. Address reprint requests to R.N. Schimke, M.D., Department of Medicine, Kansas University Medical School, 39th and Rainbow Boulevard, Kansas City, KS 66103.

0 1990 Wiley-Liss, Inc.

nal MEN syndromes, or purporting to identify new mixed tumor syndromes. Here, I would like to examine these various endocrine tumor associations and their possible relationship both to the recognized MEN syndromes and to each other. The review is meant to be comprehensive and critical, but not exhaustive. Single cases of any number of endocrine tumor combinations are possible, but in and of themselves shed no particular light on the basic question.

THE CLASSIC MEN SYNDROMES There are 3 well-recognized MEN syndromes, each inherited as an autosomal dominant trait. The manifestation of the syndromes are well known and have been reviewed extensively [Lips et al., 19841. However, in order to put possible new syndromes in proper perspective, a brief summary of the salient aspects of these conditions is in order. MEN-1 MEN-1 comprises tumors of the parathyroids, pancreas, and pituitary. The hypersecretory state is usually appropriate, but ectopic hormone production, generally by the islet cell tumor, may simulate primary glandular dysfunction [Ramsay et al., 19881.Thyroid involvement has been described but the clinical and histopathologic picture is so varied that, given the commonality of thyroid disease, it is unlikely that the thyroid gland is primarily affected. Adrenocortical lesions also have been noted in 20-50% of patients with MEN-1. Bilateral hyperplasia with the Cushing syndrome is generally explicable on the basis of a basophilic adenoma of the pituitary or is secondary to ectopic ACTH or corticotropin-releasing hormone (CRH) secretion, often by a pancreatic neoplasm. Adrenocortical adenomas are probably the most commonly described lesion in the various reports, but they rarely function. The more general use of computed tomography (CT) scans has demonstrated that small adenomas in the adrenal gland are common in the general population and, if unassociated with hormone hypersecretion, assume little if any pathologic significance. Only a single patient with an aldosteronoma has been reported in a MEN-1 family and this could well have been coincidental [Ballard et al., 19641. Non-familial aldosteronomas have been recorded in conjunction with pituitary and islet cell tumors [Gould et al., 19871,with a pituitary adenoma [Dluhy and Will-

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iams, 1969; Doumith et al., 1982; Herd, 19841, and with perhaps to alteration of a contiguous gene [Gagel et al., hyperparathyroidism [Fortig et al., 19801. While these 19891. cases could represent sporadic examples of the MEN-1 MEN-2B syndrome, on balance it appears that primary adrenoMTC and pheochromocytomas are integral compocortical involvement is not a n intrinsic part of the condition. Carcinoid tumors, usually but not always located nents of MEN-2B, but these patients have a distinctive in the foregut, have also been described [Williams and body habitus, multiple mucosal neuromas and ganCelestin, 1962; Farhangi et al., 19871. This tumor asso- glioneuromas, and no parathyroid involvement ciation is probably significant as vertical transmission [Schimke et al., 19681. They probably have a worse progof carcinoid tumors in a MEN-1 family has been noted nosis overall than MEN-2A, although prolonged sur[Bear et al., 19851. The carcinoid tumors may also be a vival has been seen [Kullberg et al., 19871 (personal observation). Given the endocrine similarity of source of ectopic peptides, especially ACTH. There is good evidence that the MEN-1 gene is on the MEN-2A and 2B, it is possible that the 2 genes are long arm of chromosome 11 [Larsson et al., 1988; Na- allelic, and preliminary evidence for a chromosome 10 kamura et al., 1989; Bale et al., 19891. The basic genetic location for MEN-2B has been recorded [Jackson et al., lesion has not yet been clarified. Allelic deletions of 19881. genes in the chromosome l l q 1 3 region have been found OVERLAP SYNDROMES in both pancreatic and parathyroid tumors in MEN-1 A number of individual cases have been recorded in [Thakker et al., 1989; Friedman et al., 19891, indicating that the basic oncogenic process may be initiated in a which the manifestations or organ involvement overlap fashion similar to that seen with retinoblastoma 2 MEN syndromes, especially MEN-1 and 2A. Such [Schimke, 19861. The discovery of a circulating para- reports have stimulated speculation that the MEN synthyroid mitogenic factor in some patients is interesting, dromes a t the very least are not pure entities. For exambut does not explain the other endocrine tumors, since ple, Cameron et al. [19781reported the Zollinger-Ellison the serum factor had no effect on pancreatic or pituitary (Z-E) syndrome in a patient with MEN-2A. However, the source of the excessive gastrin was not determined. Gastissue in vitro [Brandi et al., 19861. trin-releasing peptide immunoreactivity has been deMEN-2A scribed with MTC [Matsubayashi et al., 19843, and in MEN-2A includes medullary thyroid carcinoma one instance antral gastrinosis (pseudo-Z-E syndrome) (MTC) and pheochromocytoma. Parathyroid adenomas was found in conjunction with MTC without evidence of or hyperplasia has been reported with sufficient fre- a pancreatic tumor [Polak et al., 19723. Steiner et al. [19681noted the Cushingsyndrome with quency that these glands probably are primarily involved by the basic gene defect, but the issue is contro- MEN-2A. Ectopic ACTH from the MTC was excluded, versial. Many patients are asymptomatic, there is not but the thyroid tumor as a source of corticotropin-releasalways good correlation between the immunologic and ing hormone (CRH), a quite reasonable possibility, was biologic activity of circulating PTH, and a t least on not [Tourniaire et al., 19801. Moreover, ectopic ACTH occasion, hypercalcemia may be due to increased beta- secretion by a pheochromocytoma has been noted in a adrenergic stimulation of the parathyroids by phe- patient with MEN-2A [Mendonca et al., 19881. ochromocytoma-derived catecholamines [Swinton et al., Pituitary tumors have been reported with MEN-2A 19721.There is no good evidence one way or another that on 3 occasions [Wolf et al., 1972; Dupond et al., 1984; calcitonin secreted by MTC plays any role in para- Bertrand et al., 19871. In one instance, the tumor was thyroid hyperplasia. The absence of parathyroid hyper- nonfunctional and a n incidental autopsy finding, plasia in sporadic MTC suggests that parathyroid in- whereas in the other 2 excessive prolactin production volvement is a primary part of MEN-2A [Jackson et al., was noted. The ready availability of a prolactin radioim19891. MTC is also well known to secrete a variety of munoassay has shown prolactinomas to be relatively ectopic hormones, such that initial symptomatology common in the general population, and the 2 cases may be coincidental. A single patient with MTC who was a may be quite confusing. The MEN-2A gene is located on chromosome 10 member of a MEN-1 kindred has been described [Eberle [Mathew et al., 1987; Simpson et al., 1987; Sobel et al., et al., 19791. Another report notes a single individual 19881. Since both MTC and pheochromocytoma are pre- with MTC who also had pancreatic nesidioblastosis and ceded by hyperplasia of the respective progenitor cells, microadenomas with pancreatic polypeptide hyperthe 2-hit mutational model for carcinogenesis is attrac- secretion [Jerkins et al., 19871. Boden and Owen [19771 tive. However, allele loss of chromosome 10 genes has reported MTC in one member of a family with hypernot yet been found with MEN-2A, so the issue remains glucagonemia. The circulating glucagon had a high moin doubt. Once the mutant gene is specifically identified, lecular weight and was unassociated with symptoms. development of DNA probes directed toward the same This was undoubtedly a proteolytic error and not a fachromosome region in hyperplastic or adenomatous milial pancreatic tumor. All the above reports are either of sporadic patients parathyroid tissue might answer the question of primary vs. secondary parathyroid involvement in with no family history of the MEN syndromes or are MEN-2A. Similar studies might elucidate whether cu- sporadic occurrences of a n “overlap” tumor in a family taneous lichen amyloidosis seen in some families with setting of a specific MEN syndrome. Given this informaMEN-2A is a n integral feature of the syndrome or is due tion, it seems reasonable to conclude that none of the

MEN Syndrome foregoing case reports provides evidence against the contention that the MEN syndromes are discrete entities. Since the MEN-1 and 2A genes are definitely localized to different chromosomes, the evidence is overwhelmingly in favor of distinctive disorders with occasional coincidental findings. VARIANTS OF THE MEN SYNDROMES From time to time reports also appear of endocrine tumor combinations that prompt some to suggest the existence of variant or subtype MEN syndromes, especially of MEN-1. Most involve hyperparathyroidism, which has been described in conjunction with a host of other endocrine tumors (Table I). Without exception, all are isolated case reports. Some of these tumor combinations may represent new MEN-1 mutations or seemingly sporadic cases in inadequately investigated families. Similarly, carcinoid tumors have been recorded in association with a number ofother endocrine tumors. As previously mentioned, carcinoids are probably an integral manifestation of MEN-1. On embryologic grounds, it would not be surprising to see such tumors with either MEN-2A or -2B. However, available evidence supporting this potential relationship is meager, consisting of a carcinoid with MTC on one occasion [Dah et al., 19871 and separate reports of carcinoid tumors with pheochromocytomas [Barnard and Jacobson, 1965; Warner and Blaustein, 1970; Morris and Q m m s , 1980; Dah et al., 19871. Again, all are single case reports with no family history of either tumor. In one of the patients with pheochromocytoma and carcinoid, the latter tumor was in the duodenum [Barnard and Jacobson, 19651. As will be seen later, duodenal carcinoids and pheochromocytoma are unusual but specific endocrine abnormalities of von Recklinghausen disease. In the case report in question, no mention was made of neurofibromatosis, but the patient was 13 years old, and it is well known that neurofibromatosis may be difficult to diagnose in young individuals. One must also be cautious when associating carcinoids with other endocrine

TABLE I. The Spectrum of Non-Familial Endocrine Tumors Reuorted in Patients With Hyperparathyroidism Tumors

Reference

Pituitary adenoma, papillary thyroid carcinoma Pituitary adenoma, papillary thyroid carcinoma, ovarian thecoma Pituitary adenoma, aldosteronoma Aldosteronoma

Dralle and Altenahr 119791

Adrenal carcinoma Carcinoid Carcinoid, MTC Pheochromocytoma Paraganglioma

Borit and Blanshard [19791

Herd [19841 Fortig et al. [19801; Hellman et al. [19801 Raker et al. [19621 Alberti-Flor et al. [19851 Marchevesky and Dikman [1979] Cohen et al. 119861 Palmer and Sawyers [1978]; Steelv et al. 119871

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tumors due to the fact that carcinoids, especially in the foregut, are particularly likely to secrete ectopic peptide hormones, including hypothalamic-releasing factors, and hence may be responsible for secondary endocrine tumor syndromes [Shalet et al., 1979; Leveston et al., 19811. It has been suggested that certain families with MEN-1 who have high incidence of prolactinomas have a variant form of the syndrome [Prosser e t al., 1979; Farid et al., 1980; Bear et al., 19851. Given the fact that the pituitary is regularly involved in MEN-1, hyperprolactinemia would hardly be unexpected, and as such, provides no firm evidence of a syndrome subtype. A report of an increased incidence of autonomous thyroid nodules with hypothalamic-pituitary Cushing disease should not be considered a MEN-1 variant since there was no family history of either condition and, as mentioned earlier, the thyroid does not seem to be basically involved by the MEN-1 gene defect [Semple and Thomson, 19861. CANDIDATE M E N SYNDROME Pheochromocytomas and Islet Cell Tumors Carney et al. [1980] have reported 3 families in which various members had pheochromocytomas, often bilateral, and islet cell tumors. The latter were occasionally multicentric and/or malignant. The findings are reminiscent of the tumor combination seen in the von Hippel-Lindau syndrome (vide infra) but no evidence of this condition was noted in any relative in that report. Interestingly, in one of the 3 families, the proband had peripheral neurofibromatosis (NF) and pheochromocytoma, but no islet cell tumors. No other relatives had NF. The inheritance of the dual endocrinopathy was consistent with a variable expressed autosomal dominant trait. Other authors have documented the pheochromocytoma-islet cell association in sporadic patients [Mori et al., 1977; Tateishi et al., 1978; Nathan et al., 1980; Zeller et al., 1982; Yao et al., 1983; Sellevold et al., 19851 although in one instance there was a family history of pheochromocytoma [Heikkinen and Akerblom, 19771. In an isolated case, a unilateral pheochromocytoma was accompanied by multiple pancreatic gastrinomas, a functional parathyroid adenoma, and Cushing syndrome secondary to a n adrenal adenoma [Alberts et al., 19801. There are 2 additional single case reports of what might be the same condition although the combination was of non-adrenal paragangliomas and islet cell tumors [Goodof and Lischer, 1943; Hashimoto et al., 19861. One of the 2 patients also had metastatic bronchial carcinoid and Cushing syndrome, the latter due to ectopic secretion of both ACTH and CRH by the mediastinal paraganglioma [Hashimoto et al., 19861. A caveat to the identification of this tumor combination as a distinct syndrome is the report of Hull et al. [1979] of sibs with von Hippel-Lindau syndrome who had both pheochromocytoma and islet cell adenomas. Hence, before the pheochromocytoma-islet cell association is accepted as a MEN syndrome, the von Hippel-Lindau syndrome should be excluded.

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Pheochromocytomas and Pituitary Tumors Janson et al. 119781 reported a 3-generation kindred in which the proposita had bilateral pheochromocytomas and a pituitary tumor, her daughter had multiple pheochromocytomas and islet cell tumors, and the granddaughter had a unilateral pheochromocytoma. However, both the proposita and her daughter had renal cysts andlor cystadenomas, again raising the specter of the von Hippel-Lindau syndrome. It has become evident that most people with this latter condition lack the characteristic hemangioblastomas, but have multiple visceral cysts, particularly in the kidney, liver, and pancreas [Levine et al., 19821. However, pituitary tumors are not a currently recognized facet of the von Hippel-Lindau syndrome. Single case reports document the association of pheochromocytomas with pituitary tumors, mostly growth hormone secreting [Khan and Mullen, 1964; German and Flanagan, 1964; O’Higgins et al., 1967; Miller and Wynn. 1971; Anderson et al., 1981; Myers and Eversman, 19811. The 2 endocrine tumors were generally widely disparate in time, one pheochromocytoma patient even having been derived from the original series of pituitary tumors described by Cushing [German and Flanagan, 19641. In 2 of these cases, the pheochromocytoma and pituitary adenomas were accompanied by hyperparathyroidism [Anderson et al., 1981; Myers and Eversman, 19811, although a s noted earlier, pheochromocytomas have been primarily responsible for excess PTH secretion on occasion. Three further reports document either pituitary adenomas andlor acromegaly with extra-adrenal paragangliomas [Fahri et al., 1976; Berg et al., 1976; Lazzara-Hernandez et al., 19821. Two of these patients also had hyperparathyroidism, and one of these 2 had metastatic bronchial carcinoid [Berg et al., 19761.The other patient, a female, had in addition to parathyroid hyperplasia, multicentric papillary thyroid carcinoid [Lazzara-Hernandez et al., 19821. Her daughter and granddaughter both had goiters and some X-ray and other physical evidence of carotid body tumors, but the evidence was weak. The family was from Mexico City and there is a well-known association between high altitude and a n increased evidence of paragangliomas, especially carotid body tumors. Also there appears to be a n increased frequency of differentiated thyroid carcinomas with paragangliomas for reasons not entirely clear [Parry et al., 19821. It is conceivable the thyroid lesion in the proband was serendipidously detected, since there is ample autopsy evidence that the incidence of small foci of differentiated thyroid cancer, asymptomatic in life, is fairly high. On balance, the currently available evidence does not support a syndromal relationship between pituitary tumors per se and pheochromocytomas. Peripheral Neurofibromatosis Griffiths et al. [1987] have summarized the evidence that NF has a n endocrine component and suggested it be designated as an MEN syndrome. Pheochromocytomas are well known to occur, albeit infrequently. Less well recognized is that patients with NF also may have carcinoid tumors which are almost invariably located in the

duodenum, have a distinct histologic pattern, and possess characteristic somatostatin immunoreactivity [Swinburn et al., 19881. Other endocrine tumors described with NF include both medullary and nonmedullary thyroid carcinomas [Brasfield and Das Gupta, 1972; Nakamura et al., 19861, hyperparathyroidism [Hoppe et al., 19861,and adrenocortical adenomas [Sartori et al., 19891. MTC has been recorded on only 2 occasions, a somewhat surprising finding given the existence involvement of neural crest derivatives in NF [Hansen et al., 1976; Pages et al., 19701.On the other hand, since peripheral NF has such a high frequency in the general population, neither thyroid nor parathyroid involvement should be considered unusual. Whether the patient described by Aach and Kissane [19691 with a mediastinal neurofibrosarcoma, a n islet cell tumor, and hyperparathyroidism should be considered as having NF is problematic especially since there was a family history of hyperparathyroidism and not of NF. It is more likely the patient had MEN-1 with a coincidental neurosarcoma. The report by Garcia et al. [1978] of a 13-year-old boy with NF and the ZollingerEllison syndrome secondary to a primary gastrin-secreting neuroendocrine tumor ofthe stomach is less easy to classify although the tumor might be considered an example of a foregut carcinoid, and therefore reconcilable with the observations of Grifiths et al. [1987].

Von Hippel-Lindau Syndrome In addition to pheochromocytoma, the endocrine component of the von Hippel-Lindau syndrome should be expanded to include pancreatic islet cell tumors [Griffiths et al., 19871. These are usually nonfunctional, but either immunochemical evidence or hypersecretion of glucagon, insulin, vasoactive intestinal polypeptide, and calcitonin has been noted [Legre et al., 1960; Mulshine et al., 1984; Cornish et al., 19841. In contrast to NF, neither pancreatic nor duodenal somatostatinoma has been reported although a single instance of metastatic carcinoid, primary unknown, has been described [Kees, 19801. Hypercalcemia has been recorded in the von Hippel-Lindau syndrome in association with pheochromocytoma, but the elevated serum calcium was corrected by surgical removal of the adrenal tumor [Atuk et al., 19791. A carotid body tumor (extra-adrenal paraganglioma) also has been seen in a patient with von Hippel-Lindau syndrome [Jennings et al., 19881. McCune-Albright Syndrome Polyostotic fibrous dysplasia, cafe-au-lait pigmentation, and precocious puberty characterize this disorder. The sexual precocity is more common in females than males, and oddly enough may be either gonadotropin dependent or independent [Foster et al., 19861, and transition from primary gonadal precocity to hypothalamicpituitary control a t the time of normal puberty has been documented [Pasquino et al., 19871. Other reported endocrine abnormalities of the syndrome include pheochromocytoma, hyperparathyroidism, hyperthyroidism, Cushing syndrome, and gigantism or acromegaly, the presence of which has prompted the suggestion t h a t the condition be considered another

MEN Syndrome

multiple endocrine neoplasia syndrome [DiGeorge, 19751. However, critical evaluation of the endocrine associations renders this suggestion suspect. First of all, pheochromocytoma has been reported in only a single individual who was 71 years old at the time of diagnosis [Kissel et al., 19721. Second, the oft-quoted reference to coexisting hyperparathyroidism occurred in adults who had fibrous dysplasia but no reported pigmentary anomalies or sexual precocity [Ehrig and Wilson, 19721. Third, while multiple patients with hyperthyroidism have been described, there is no good evidence that the thyroid hyperactivity is anything other than the usual immune-mediated form [Firat and Stutzman, 1968; Samuel et al., 1972; D’Armiento et al., 19831. The absence of other components of Graves disease such as ophthalmopathy or dermopathy in the case reports is not necessarily indicative of some non-immunologicprimary thyroid hypertrophy because these abnormalities are not common in children in any case. In one instance where specific studies were done, long-acting thyroidstimulating (LATS) activity was detected in the serum [Samuel et al., 19721. Two patients with Cushing syndrome have been clearly delineated. In one instance, the excess cortisol secretion was not suppressible by the high-dose dexamethasone regimen and an adrenal adenoma was removed [Benjamin and McRoberts, 19731; however, the other adrenal was noted to exhibit nodular hyperplasia at autopsy. The remaining patient with Cushing syndrome also had non-pigmented, nodular adrenal hyperplasia with undetectable serum ACTH levels [Danon et al., 19751. Gigantism or acromegaly has been in the McCuneAlbright syndrome on a number of occasions [Firat and Stutzman, 1968; Lightner et al., 1975; Polychronakos et al., 1982; Chung et al., 1983; Nakagawa et al., 1985; Cuttler et al., 19891.Because some patients exhibit associated hyperprolactinemia, and because of the oft-noted central sexual precocity, a hypothalamic basis for the endocrine hyperplasia has been entertained. This does not explain the primary gonadal precocity in some patients or the seemingly hypothalamic-pituitary-independent adrenal hyperplasia in others. Virtually all cases of the McCune-Albright syndrome are sporadic, as the one reported pedigree purportedly demonstrating autosomal dominant inheritance is not completely convincing [Alvarez-Arratia et al., 19831. The only monozygotic twins reported were phenotypically discordant [Lemli, 19771.Happle [19861has offered the intriguing suggestion that McCune-Albright syndrome is a lethal autosomal dominant trait with survivors being mosaic. This contention will be virtually impossible to prove, at least until such time as the causal gene or genes is mapped.

Schweitzer-Cagianut-CarneySyndrome A rather unusual complex of cardiac, breast, and cutaneous myxomas; pigmented skin lesions; and micronodular adrenal hyperplasia, initially described by Schweitzer-Cagianut et al. [1980], has been best delineated by Carney et al. in a number of publications [Shenoy et al., 1984; Carney et al., 1985, 19861. The

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adrenal lesions are pigmented and appear to be autonomous, although not all patients present with the Cushing syndrome. The condition is inherited as a variable autosomal dominant trait. Additional endocrine components in some patients include acromegaly secondary to a pituitary adenoma, and either Sertoli or Leydig cell tumors of the testes. As is generally the rule with familial endocrine tumors, the testicular lesions are often bilateral, and the Leydig cell variety may cause isosexual precocity with suppressed serum gonadotropin levels, indicating that the steroid cell hyperplasia is primary. Carney [1987] has postulated that a homologous sex cord tumor of the ovary will eventually be reported in affected females. Rare non-endocrine visceral tumors such as schwannomas and fibrolamellar hepatomas may complicate the clinical picture [Danoff et al., 19871. The precise genetic lesion is unknown. Some have suggested that the adrenal hyperplasia is secondary to circulating stimulatory antibodies analogous to Graves’ disease [Teding van Berkhout et al., 1986; Wulffraat et al., 1988; Young et al., 19891 although it is difficult to account for the other components of the syndrome on this basis. Conceivably, all familial cases of micronodular pigmented adrenal hyperplasia may be examples of this syndrome, since it is possible that the cutaneous findings are so mild as to be overlooked in some patients, particularly those who are not overly cushingoid in appearance [Arce et al., 1978; Bohm et al., 1983; Donaldson et al., 1981; Larsen et al., 1986; Hodge and Froesch, 19881.

DISCUSSION It would seem to be of little value to re- or subclassify peripheral NF as a MEN syndrome. Pheochromocytomas probably occur in less than 1% of cases [Brasfield and Das Gupta, 19721, and duodenal carcinoids appear to be even rarer. Similarly, the endocrine aspects of von Hippell-Lindau syndrome are even less frequent than in NF, especially the islet cell tumors. The McCune-Albright syndrome remains poorly defined from a genetic perspective and may well be heterogenous. Moreover, a unifying hypothalamic basis for the endocrine changes of the syndrome has not been totally excluded. The Schweitzer-Cagianut-Carney syndrome appears t o possess the requisite endocrine involvement to warrant inclusion of this syndrome under the MEN rubric. However, the incidence of the disorder is unknown such that the frequency of multiple endocrine tumors is impossible to ascertain. Moreover, the presence of adrenal stimulating antibodies in this condition suggests that the endocrine tumors in this syndrome have an autoimmune pathogenosis analogous to Graves’disease [Young et al., 19891. Given the other tumorous components of the syndrome, which thus far cannot be explained on an immune-mediated basis, it may be more proper to consider this disorder as a phacomatosis or hamartoma syndrome at least until the clinical spectrum becomes clearer and the endocrine gland hyperplasia is pathogenetically better defined. The pheochromocytoma-islet cell association de-

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scribed by Carney et al. [19801 was clearly familial. However, it will be exceedingly important in future individuals and future families to exclude the von Hippel-Lindau syndrome since the 2 endocrine tumors occur separately and together in this syndrome. Such a comparative study should be facilitated by the localization of the von Hippel-Lindau gene to chromosome 3p and by the recent evidence that the gene is a recessive oncogene [Tory et al., 19891. It is further possible that the pheochromocytoma-islet cell association as a potential MEN syndrome can be broadened to include pituitary tumors. Interestingly, most of the reported pituitary adenomas secreted growth hormone. Although, as mentioned earlier, the adrenal medullary tumor and pituitary lesion generally occurred a t a considerable temporal interval, acromegaly has been described on the basis of excess secretion of growthhormone-releasing hormone from a n adrenal pheochromocytoma [Roth et al., 19861, and such ectopic secretion must be excluded before accepting any such case as being a n example of a true, possibly heritable endocrine tumor syndrome. Since both hyperparathyroidism and carcinoid tumors have been found in some cases of the pheochromocytoma-islet cellpituitary triat, it is conceivable that a few of the patients noted in Table I also fall into this potential “new” MEN syndrome category.

CONCLUSIONS The data supporting the existence of the original 3 MEN syndromes have withstood the test of time. The best current evidence supports the contention that they are due to different genes, although MEN-2A and -2B may be allelic. Patients with overlapping tumor endocrinopathies do exist but they are mostly sporadic and the nature of the overlap, whether primary or due to ectopic production of some trophic factor, has rarely been either established, or even more importantly, excluded. One decent candidate for a new MEN syndrome is the association of pheochromocytoma (and perhaps extraadrenal paragangliomas) and islet cell tumors of the pancreas with or without pituitary and parathyroid adenomas. However, some of these patients have had other abnormalities that suggest they have the von Hippel-Lindau syndrome or a secondary endocrinopathy. Hence, before the pheochromocytoma-islet cell association is added as MEN-3, careful study needs to be done not only on the probands but on other relatives a s well, especially those first-degree relatives who have no endocrine symptoms. Moreover, while recognizably difficult, before any endocrine tumor association is accepted as such, ectopic trophic hormone production should be excluded insofar as possible. An additional valuable investigative venture would be to examine individual tumors in patients with multiple endocrine tumors for loss of possibly specific constitutional restriction fragment length polymorphisms (RFLP) a s has been accomplished in MEN-1 and in other combined malignancies such as familial retinoblastoma and associated osteogenic sarcoma [Benedict et al., 19881. Well-documented reports of endocrine tumor combinations should be encouraged if any sense is to be made

of the clearly confusing literature. It is probable that a t least one and perhaps additional MEN syndromes exist. However, at present the data are insufficient to support the existence of more than the 3 types originally described, in the aggregate, more than 20 years ago.

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