1Medical Hypotheses MedtmlHypOrheea (1992) 38,X4-367 e Longman croup UKLtd 1992
Dominant Familial Syndromes with Endocrine Hyperfunction: An Additional Syndrome? L. E. MALLETTE Medical and Research Services 111E, VA Medical Center and Division of Endocrinology and Metabolism, Saylor College of Medicine, 2002 Holcombe Ski, Houston TX 77030, USA (Reprint requests to author)
Abstract - At least 8 separate dominant syndromes have been described which have hyperfunctioning endocrine tumors as an important component. Scattered reports in the literature suggest that there may be an additional syndrome, in which extra-adrenal paragangliomas (often multiple), pituitary adenomas, and parathyroid hyperplasia coexist. Of 3 such cases described to date, 2 have included information about the family history, which in each case suggested dominant inheritance. This would presumably be a less common syndrome than the others recognized previously, so that full evaluation of endocrine findings and family history in future cases will be important for developing our understanding of the syndrome.
Introduction There are at least 8 well established dominant hereditary syndromes which include hyperfunctioning endocrine tumors as an important component (Table 1). Many clinical reports over the last 20 years have presented individual patients with a combination of endocrinopathies that seemed to overlap 2 or more of these categories. Some of the reported patients have represented apparently sporadic cases, perhaps occurring on the basis of a recessive trait and thus unlikely to appear frequently in the population. Other patients have been members of a kindred which is clearly affected by one of the well established syndromes listed in Table 1, but who happened to have developed an ‘outlying neoplasm, i.e. one not
characteristic of their family’s basic syndrome. Here there are 3 possibilities. First, the outlying tumor may have occurred by coincidence, on a sporadic basis and not governed in any way by the familial disorder. Second, the outlying tumor may have arisen as a secondary change. For example, ectopic production of a releasing hormone may account for some pituitary tumors in MEN2a patients. Third, the outlying tumor might actually be governed by the basic disease allele, but occur with an incidence which, while increased relative to that in the normal population, is still too low to permit statistical recognition until a very large experience is accumulated with the syndrome. Thus, these single cases with an ‘outlying’ tumor do not necessarily mandate that a new syndrome be postulated. Only if multiple family members were
Date received 22 November 1991 Date accepted 23 December 199 1
364
DoMINANTPAlmJAL
365
SYNDROMES &HORMONE HypERpuNClTON
Table 1 Established hereditary (dominant) with endocrine hyporfunction
syndromes
1. Multiple endocrine neoplasia type 1 (%?nner’s syndrome, chromosome 11) Parathyroidhyperplasia Pituitaryadenoma Islet cell adenomaand carcinoma Thymic and foregutcarcinoidtumors Lipoma 2. Multiple endocrine neoplasia (type 2a (SippIe’s syndrome, chromosome 10) Medullarythyroidcarcinoma Phcochromocytoma Parathyroidhyperplasiaand adeuomas Carciuoidtumor 3. Multipte endocrine neoplasia type 2b (mucosal neuromatosis, chromosome 10) Medullarycarcinoma Phcochromocytoma Multiplemucosal neuromas
shown to exhibit the new combination of tumors should a new syndrome be considered. Even then, it is possible that a given family would show a frequent occurrence of a tumor that is normally an infrequent component of the basic syndrome (different penetrance of a manifestation in different families, presumably on the basis of different ‘modifying genes’). These generally infrequent components of a syndrome are often recognized only after many families and a large number of individuals with a given syndrome have been studied. For example, islet cell tumors are a central and frequent component of MEN1 (17,18), but were eventually recognized to be increased in incidence in von Hippel-Lindau’s disease as well (3, 4, 6). Likewise, carcinoid tumors arc relatively common in MENl, but have also been found to be increased in frequency in MEN2 (19). Definitive proof of the existence of a new syndrome would then require that its chromosomal location be identified and shown to be distinct from that of other syndromes. A novel syndrome
4. von Hippel-Lindau’s disease (chromosome 3) (l-6) Phcochromocytoma CNS hemaogioblastoma Retinalangioma Renal cell carcinoma Islet cell adenoma Visceral cysts 4a FamiUal pheochromocytoma (variant ofvon Hippel-Lindau?) (7,8) Pheochromccytoma Islet cell adenomas (7) 5. Neurofibromatosis type 1 (chromosome 17) (9,10,11) Multipleneurofibromas CNS tumors Phcochromocytoma(paraganglioma) Parsthyroidadenoma 6. Familial cystic parathyroid adenomatosk with fibroosseous jaw tumors (12,13) Multiple parathyroidadenomas Fibroosseousjaw tumours 7. Familial papillary thyroid carcinoma (14,lS) 8. Familial arrhenoblastoma and thyroid adenoma (16) Figures in parenthesesare references
The medical literature on ‘overlap syndromes’ contains 3 instances of an unusual combination of tumors which may be distinct from the other hereditary syndromes (Table 2). The presence of a suggestive family history in 2 of the cases is sufficient for this to be postulated as an additional hereditary endocrine syndrome. The elements of this postulated new syndrome are extra-adrenal paragangliomas (often multiple), pituitary adenomas, and parathyroid hyperplasia. Fahri (20) described a lPyear-old woman with multiple functional extra-adrenal paragangliomas, acromegaily and hypercalcemic hyperparathyroidism The patient had from parathyroid hyperplasia. multiple pigmented nevi, but no other endocrine abnormality. Her father and 1 sister also had multiple pigmented nevi, but refused endocrine testing. Larraza-Hemandez (21) reported the autopsy findings for a 70-year-old woman who died suddenly. She had bilateral carotid body paragangliomas, a pituitary adenoma of unknown function, and parathyroid hyperplasia Since serum calcium and creatiniue had not been measured, it was not known whether the parathyroid hyperplasia was primary or secondary. She also had a gastric leiomyoma, a papillary thyroid carcinoma, and amyloidosis. The patient’s daughter and granddaughter were normocalcemic, but each had strong evidence of a pituitary
366
ManICAL nvPoTmSE.s
Table 2 A new type of hexxlitary multiple endocrine neoplasia? Qf
Agel
sitesof
Pituitary
Parathyroid
Sex
extra-adrenal
tumor
inwlvement
Skinfindings
Otherpndfngs
Family h&tory
Multiple
None
Fatherand sisterwith
paragangliomas
Fabri(20)
19F
Multiple sites
Acromegally Prbnary hypezplasia
pigmentednevi
multiple pigmented nevi; evaluationrefused
Larraza-
61 F
Helllall&Z
Bilateral
Adenoma
Hypeqlasis
carotid bodies
(unknown
(serumcalcium
fktioll)
not measured)
(21)
Not mentioned
Gastricleio-
Daughterand grand-
myoma; papillary daughterboth had thyroidcaminoma; enlargedsella tumica, amyloidosis
visual field cuts and sonographicevidence of bilateralcarotid bcdy tumors;intervention l&Wed
Bmg (22)
36F
Cervical chemodectoma,
Acromegally Primary hyperplasia
probablyof vagus nerve
Not mentioned
Antral and
Not given
duodenalGcell hyperplasia; bronchial carcinoid
a new type of multiple endocrine neoplasia syndrome. The fact that 3 consecutive generations were definitely affected in I family and 2 consecutive generations probably affected in another leads me to hypothesize that this may indeed represent a dominant syndrome. Does the literaturesuggest any otherexplanation for the fmdings in these patients? Camey described an apparentlysporadic syndrome characterixedby a triad of tumors that includes multiple functioning extra-adrenalparagangliomas. The other tumors were gastric epithelioid leiomyosarcomas and pulmonary chondromas (23). This triad occurs almost exclusively in females (15 of 16 cases) and is often diagnosed at an early age. Carney reported no evidence of parathyroid. pituitary, pancreatic, or thyroid tumors in these patients, and did not report any unusual skin pigmentation. None of the patients had a positive family history of endocrinopathy, although many of the reports admittedly did not include family screening or history. Camey stated that there was no evidence for a dominant inheritance. Nevertheless, Discussion multicentxicity of the tumors suggested that the The unique combination of endocrine tumors in these syndrome had a hereditary basis, presumably patients leads to the hypothesis that this may represent recessive. The gastric leiomyoma in our patient 2
tumor (an enlarged sella turcica and visual field defects) and sonographic evidence of bilateralcarotid body tumors. pigmented nevi were not mentioned in this report. Again, the family refused further investigation. Berg (22) described a 36-year-old woman with a large cervical chemodectoma, probably originating in the vagus nerve, a pituitary tumor causing clinical acromegally, and parathyroid hyperplasia with hypercalcemia. Other findings included G-cell hyperplasia of the gastic antrum and duodenum and a bronchial carcinoid tumor. No mention was made of skin pigmentary changes. The case was presented as an MEN1 patient whose chemodectoma overlapped into the MEN2 category. Only by study of multiple members of this family might the basic disease be ascertained with certainty, and no family history was reported.
DohiINANTFAMlLlAL
367
SYNDR0hfR.S& HORMONEHXRRPUNCI-ION
(Table 1) is reminiscent of the Camey triad, but none of the patients in Table 1 had pulmonary chondromas or other gastric tumors at postmortem examination. Family screening was not sufficient, of course, to exclude these tumors in other family members. Conclusion The 3 cases reported in the literature with a unique combination of endocrine tumor, multiple chemodectomas, pituitary adenoma and parathyroid hyperplasia, with strong suggestion of dominant inheritance in 2 cases suggests that an additional dominant syndrome with hyperfunctioning endocrine tumors may exist. If so, this new syndrome will prove to be far less common than the previously recognized syndromes (Table l), making it important that all future cases be discovered and studied in detail. Any patient found to have a paraganglioma with either parathyroid hyperplasia or a pituitary tumor should undergo rigorous personal and family screening in an effort to expand our knowledge about this hypothesized new syndrome.
8.
9.
10.
11.
12.
13.
14. 15. 16. 17.
References 18. 1. Janson K L, Roberts J A, Varela M. Multiple endocrine adenomatosis: in support of the common origin theories. Journal of Urology 119: 161,1978. 2. Pmbst A. Lots M, Heitz P. Von Hippel-Lindau’s disease, sytingomyelia and multiple endocrine tumors: a complex neumendocrinopathy. Vimhows Archives (pathologisches Anatomie) 378: 265,1978. 3. Hull M T, Warfel K A, Muller J, Higgins J T. Familial islet cell tumors in Von Hippel-Lindau’s disease. Cancer 44: 1523, 1979. 4. Mulshinc J L, Tubbs R, Sheeler L R, Gifford R W. Case teporb clinical significance of the association of the von Hippel-Lindau disease with pheochnnnocytoma and pancreatic apudoma. American Journal of the Medical Sciences 288: 212.1984. 5. Seizinger B I& Rouleau G A, &elms L J, et al. Von HippelLindau disease maps totheregion of chromosome 3 associated with renal ccl1 caminoma. Natum 332: 268,198s. 6. Binkovitx L A, Johnson C D, Stephens D H. Islet cell tumors in von Hippel-Lindau dkeasez increased prevalence and mlationship to the multiple endoaine neoplasias. American JournalofRoengtenology 15% 501.1990. 7. Cushman P Jr. Familial endocrine tumors: report of two unmlatedkindndaffeccedwithpheochromocytomas,onealsowith
19.
20.
21.
22.
23.
multiple thyroid carcinomas. American Journal of Medicine 32: 352.1962. CameyJA,GoVL,GordonH,NotthcuttRC,PeataeAG, Sheps S G. Familial pheochmmocytoma and islet cell tumor of the pancreas. American Journal of Medicine 68: 515,198O. Daly D, Kaye M, Estmda R L. NeuroEbmmatosis and hyperparathymidism - a new syndrome? Canadian Medical Association Journal 103: 258,1973. Chakmbarti S. Murugesan A, Atida E J. The association of neumfibtomatosis and hypqarathymidism. American Journal of Surgery 137: 417.1979. Barker D, Wright E, Nguyen K, et al. Gene for von Recklinhausen neurofibmmatosis is the pericentromeric region of chromosome 17. Science 236: 1100,1987. Mallet& L E Malini S, Rappapott M P, Kirkland J L. Familial cystic parathymid adenomatosis. AM& of Internal Medicine 107: 54.1987. Jackson C E, Norum R A. Boyd S B, Talpos G B. Wilson S D, Taggart R T, Mallette L E. Hereditary hyperparathyroidism and multiple ossifying jaw tibromas: A clinically and genetically distinct syndrome. Surgery 108: 1006,199O. Phade V R, Lawrence W R, Max M H. Familial papillary carcinoma. Archives of Surgery 116: 836,198l. Late K, Andersen K, Nordal E. Btennhord 0 I. Familial occurrence of papillary carcinoma. Cancer 46: 1291,198O. Jensen RD. Norris H J, Fraumeni J F Jr. Familial arrhenoblastoma and thyroid adenoma. Cancer 33: 218,1974. Wermer P. Genetic aspects of adenomatosis of endocrine glands. American Journal of Medicine 16: 363, 1954. Moldawer M P, Nardi G L. Raker J W. Concomitance of multiple adenomas of parathyroids and pancreatic islets with tumor of pituitary: syndrome with familial incidence. Ametican Journal of the Medical Sciences 228: 190.1954. Duh Q Y, Hybarger C P, Geist R, Gamsu G, Goodman P C, Gooding GA, Clark 0 H. Caminoids associated with multiple endocrine neoplasia syndmmes. American Journal of Surgery 154: 142.1987. Fahri F, D&man S H, Lawson W, Cobin R H. Zak F G. Paragangliomatosis associated with multiple endocrine adenomas. Archives of Pathology and Laboratory Medicine 100: 495,1976. Larmxa-Hemandez 0. AlbomsSaavedra J, Benavidcs G, Krause L G. Perez-Metixaldi J C, Ginxo A. Multiple endocrine neoplasia. Pituitary adenoma, multicentric papillary thyroid carcinoma, bilateral carotid body paraganglioma. parathyroid hyperplasia. gastric leiomyoma, and systemic amyloidosis. American Journal of Clinical Pathology 78: 527,1982. Berg B, Bj6rklund A. Grimelius L, Jngemansson S, Latsson L, Stenram U. Akerman M. A new pattem of multiple endocrine adenomatosis. Acta Medica Scandinavica 200~321, 1976. Carney J A. The triad of gastric epitheloid leiomyosarcoma, functioning extra adrenal paraganglioma and pulmonary chondmma. Cancer 43: 374,1979.
Dominant Familial Syndromes with Endocrine Hyperfunction: An Additional Syndrome? L. E. MALLETTE Medical and Research Services 111E, VA Medical Center and Division of Endocrinology and Metabolism, Saylor College of Medicine, 2002 Holcombe Ski, Houston TX 77030, USA (Reprint requests to author)
Abstract - At least 8 separate dominant syndromes have been described which have hyperfunctioning endocrine tumors as an important component. Scattered reports in the literature suggest that there may be an additional syndrome, in which extra-adrenal paragangliomas (often multiple), pituitary adenomas, and parathyroid hyperplasia coexist. Of 3 such cases described to date, 2 have included information about the family history, which in each case suggested dominant inheritance. This would presumably be a less common syndrome than the others recognized previously, so that full evaluation of endocrine findings and family history in future cases will be important for developing our understanding of the syndrome.
Introduction There are at least 8 well established dominant hereditary syndromes which include hyperfunctioning endocrine tumors as an important component (Table 1). Many clinical reports over the last 20 years have presented individual patients with a combination of endocrinopathies that seemed to overlap 2 or more of these categories. Some of the reported patients have represented apparently sporadic cases, perhaps occurring on the basis of a recessive trait and thus unlikely to appear frequently in the population. Other patients have been members of a kindred which is clearly affected by one of the well established syndromes listed in Table 1, but who happened to have developed an ‘outlying neoplasm, i.e. one not
characteristic of their family’s basic syndrome. Here there are 3 possibilities. First, the outlying tumor may have occurred by coincidence, on a sporadic basis and not governed in any way by the familial disorder. Second, the outlying tumor may have arisen as a secondary change. For example, ectopic production of a releasing hormone may account for some pituitary tumors in MEN2a patients. Third, the outlying tumor might actually be governed by the basic disease allele, but occur with an incidence which, while increased relative to that in the normal population, is still too low to permit statistical recognition until a very large experience is accumulated with the syndrome. Thus, these single cases with an ‘outlying’ tumor do not necessarily mandate that a new syndrome be postulated. Only if multiple family members were
Date received 22 November 1991 Date accepted 23 December 199 1
364
DoMINANTPAlmJAL
365
SYNDROMES &HORMONE HypERpuNClTON
Table 1 Established hereditary (dominant) with endocrine hyporfunction
syndromes
1. Multiple endocrine neoplasia type 1 (%?nner’s syndrome, chromosome 11) Parathyroidhyperplasia Pituitaryadenoma Islet cell adenomaand carcinoma Thymic and foregutcarcinoidtumors Lipoma 2. Multiple endocrine neoplasia (type 2a (SippIe’s syndrome, chromosome 10) Medullarythyroidcarcinoma Phcochromocytoma Parathyroidhyperplasiaand adeuomas Carciuoidtumor 3. Multipte endocrine neoplasia type 2b (mucosal neuromatosis, chromosome 10) Medullarycarcinoma Phcochromocytoma Multiplemucosal neuromas
shown to exhibit the new combination of tumors should a new syndrome be considered. Even then, it is possible that a given family would show a frequent occurrence of a tumor that is normally an infrequent component of the basic syndrome (different penetrance of a manifestation in different families, presumably on the basis of different ‘modifying genes’). These generally infrequent components of a syndrome are often recognized only after many families and a large number of individuals with a given syndrome have been studied. For example, islet cell tumors are a central and frequent component of MEN1 (17,18), but were eventually recognized to be increased in incidence in von Hippel-Lindau’s disease as well (3, 4, 6). Likewise, carcinoid tumors arc relatively common in MENl, but have also been found to be increased in frequency in MEN2 (19). Definitive proof of the existence of a new syndrome would then require that its chromosomal location be identified and shown to be distinct from that of other syndromes. A novel syndrome
4. von Hippel-Lindau’s disease (chromosome 3) (l-6) Phcochromocytoma CNS hemaogioblastoma Retinalangioma Renal cell carcinoma Islet cell adenoma Visceral cysts 4a FamiUal pheochromocytoma (variant ofvon Hippel-Lindau?) (7,8) Pheochromccytoma Islet cell adenomas (7) 5. Neurofibromatosis type 1 (chromosome 17) (9,10,11) Multipleneurofibromas CNS tumors Phcochromocytoma(paraganglioma) Parsthyroidadenoma 6. Familial cystic parathyroid adenomatosk with fibroosseous jaw tumors (12,13) Multiple parathyroidadenomas Fibroosseousjaw tumours 7. Familial papillary thyroid carcinoma (14,lS) 8. Familial arrhenoblastoma and thyroid adenoma (16) Figures in parenthesesare references
The medical literature on ‘overlap syndromes’ contains 3 instances of an unusual combination of tumors which may be distinct from the other hereditary syndromes (Table 2). The presence of a suggestive family history in 2 of the cases is sufficient for this to be postulated as an additional hereditary endocrine syndrome. The elements of this postulated new syndrome are extra-adrenal paragangliomas (often multiple), pituitary adenomas, and parathyroid hyperplasia. Fahri (20) described a lPyear-old woman with multiple functional extra-adrenal paragangliomas, acromegaily and hypercalcemic hyperparathyroidism The patient had from parathyroid hyperplasia. multiple pigmented nevi, but no other endocrine abnormality. Her father and 1 sister also had multiple pigmented nevi, but refused endocrine testing. Larraza-Hemandez (21) reported the autopsy findings for a 70-year-old woman who died suddenly. She had bilateral carotid body paragangliomas, a pituitary adenoma of unknown function, and parathyroid hyperplasia Since serum calcium and creatiniue had not been measured, it was not known whether the parathyroid hyperplasia was primary or secondary. She also had a gastric leiomyoma, a papillary thyroid carcinoma, and amyloidosis. The patient’s daughter and granddaughter were normocalcemic, but each had strong evidence of a pituitary
366
ManICAL nvPoTmSE.s
Table 2 A new type of hexxlitary multiple endocrine neoplasia? Qf
Agel
sitesof
Pituitary
Parathyroid
Sex
extra-adrenal
tumor
inwlvement
Skinfindings
Otherpndfngs
Family h&tory
Multiple
None
Fatherand sisterwith
paragangliomas
Fabri(20)
19F
Multiple sites
Acromegally Prbnary hypezplasia
pigmentednevi
multiple pigmented nevi; evaluationrefused
Larraza-
61 F
Helllall&Z
Bilateral
Adenoma
Hypeqlasis
carotid bodies
(unknown
(serumcalcium
fktioll)
not measured)
(21)
Not mentioned
Gastricleio-
Daughterand grand-
myoma; papillary daughterboth had thyroidcaminoma; enlargedsella tumica, amyloidosis
visual field cuts and sonographicevidence of bilateralcarotid bcdy tumors;intervention l&Wed
Bmg (22)
36F
Cervical chemodectoma,
Acromegally Primary hyperplasia
probablyof vagus nerve
Not mentioned
Antral and
Not given
duodenalGcell hyperplasia; bronchial carcinoid
a new type of multiple endocrine neoplasia syndrome. The fact that 3 consecutive generations were definitely affected in I family and 2 consecutive generations probably affected in another leads me to hypothesize that this may indeed represent a dominant syndrome. Does the literaturesuggest any otherexplanation for the fmdings in these patients? Camey described an apparentlysporadic syndrome characterixedby a triad of tumors that includes multiple functioning extra-adrenalparagangliomas. The other tumors were gastric epithelioid leiomyosarcomas and pulmonary chondromas (23). This triad occurs almost exclusively in females (15 of 16 cases) and is often diagnosed at an early age. Carney reported no evidence of parathyroid. pituitary, pancreatic, or thyroid tumors in these patients, and did not report any unusual skin pigmentation. None of the patients had a positive family history of endocrinopathy, although many of the reports admittedly did not include family screening or history. Camey stated that there was no evidence for a dominant inheritance. Nevertheless, Discussion multicentxicity of the tumors suggested that the The unique combination of endocrine tumors in these syndrome had a hereditary basis, presumably patients leads to the hypothesis that this may represent recessive. The gastric leiomyoma in our patient 2
tumor (an enlarged sella turcica and visual field defects) and sonographic evidence of bilateralcarotid body tumors. pigmented nevi were not mentioned in this report. Again, the family refused further investigation. Berg (22) described a 36-year-old woman with a large cervical chemodectoma, probably originating in the vagus nerve, a pituitary tumor causing clinical acromegally, and parathyroid hyperplasia with hypercalcemia. Other findings included G-cell hyperplasia of the gastic antrum and duodenum and a bronchial carcinoid tumor. No mention was made of skin pigmentary changes. The case was presented as an MEN1 patient whose chemodectoma overlapped into the MEN2 category. Only by study of multiple members of this family might the basic disease be ascertained with certainty, and no family history was reported.
DohiINANTFAMlLlAL
367
SYNDR0hfR.S& HORMONEHXRRPUNCI-ION
(Table 1) is reminiscent of the Camey triad, but none of the patients in Table 1 had pulmonary chondromas or other gastric tumors at postmortem examination. Family screening was not sufficient, of course, to exclude these tumors in other family members. Conclusion The 3 cases reported in the literature with a unique combination of endocrine tumor, multiple chemodectomas, pituitary adenoma and parathyroid hyperplasia, with strong suggestion of dominant inheritance in 2 cases suggests that an additional dominant syndrome with hyperfunctioning endocrine tumors may exist. If so, this new syndrome will prove to be far less common than the previously recognized syndromes (Table l), making it important that all future cases be discovered and studied in detail. Any patient found to have a paraganglioma with either parathyroid hyperplasia or a pituitary tumor should undergo rigorous personal and family screening in an effort to expand our knowledge about this hypothesized new syndrome.
8.
9.
10.
11.
12.
13.
14. 15. 16. 17.
References 18. 1. Janson K L, Roberts J A, Varela M. Multiple endocrine adenomatosis: in support of the common origin theories. Journal of Urology 119: 161,1978. 2. Pmbst A. Lots M, Heitz P. Von Hippel-Lindau’s disease, sytingomyelia and multiple endocrine tumors: a complex neumendocrinopathy. Vimhows Archives (pathologisches Anatomie) 378: 265,1978. 3. Hull M T, Warfel K A, Muller J, Higgins J T. Familial islet cell tumors in Von Hippel-Lindau’s disease. Cancer 44: 1523, 1979. 4. Mulshinc J L, Tubbs R, Sheeler L R, Gifford R W. Case teporb clinical significance of the association of the von Hippel-Lindau disease with pheochnnnocytoma and pancreatic apudoma. American Journal of the Medical Sciences 288: 212.1984. 5. Seizinger B I& Rouleau G A, &elms L J, et al. Von HippelLindau disease maps totheregion of chromosome 3 associated with renal ccl1 caminoma. Natum 332: 268,198s. 6. Binkovitx L A, Johnson C D, Stephens D H. Islet cell tumors in von Hippel-Lindau dkeasez increased prevalence and mlationship to the multiple endoaine neoplasias. American JournalofRoengtenology 15% 501.1990. 7. Cushman P Jr. Familial endocrine tumors: report of two unmlatedkindndaffeccedwithpheochromocytomas,onealsowith
19.
20.
21.
22.
23.
multiple thyroid carcinomas. American Journal of Medicine 32: 352.1962. CameyJA,GoVL,GordonH,NotthcuttRC,PeataeAG, Sheps S G. Familial pheochmmocytoma and islet cell tumor of the pancreas. American Journal of Medicine 68: 515,198O. Daly D, Kaye M, Estmda R L. NeuroEbmmatosis and hyperparathymidism - a new syndrome? Canadian Medical Association Journal 103: 258,1973. Chakmbarti S. Murugesan A, Atida E J. The association of neumfibtomatosis and hypqarathymidism. American Journal of Surgery 137: 417.1979. Barker D, Wright E, Nguyen K, et al. Gene for von Recklinhausen neurofibmmatosis is the pericentromeric region of chromosome 17. Science 236: 1100,1987. Mallet& L E Malini S, Rappapott M P, Kirkland J L. Familial cystic parathymid adenomatosis. AM& of Internal Medicine 107: 54.1987. Jackson C E, Norum R A. Boyd S B, Talpos G B. Wilson S D, Taggart R T, Mallette L E. Hereditary hyperparathyroidism and multiple ossifying jaw tibromas: A clinically and genetically distinct syndrome. Surgery 108: 1006,199O. Phade V R, Lawrence W R, Max M H. Familial papillary carcinoma. Archives of Surgery 116: 836,198l. Late K, Andersen K, Nordal E. Btennhord 0 I. Familial occurrence of papillary carcinoma. Cancer 46: 1291,198O. Jensen RD. Norris H J, Fraumeni J F Jr. Familial arrhenoblastoma and thyroid adenoma. Cancer 33: 218,1974. Wermer P. Genetic aspects of adenomatosis of endocrine glands. American Journal of Medicine 16: 363, 1954. Moldawer M P, Nardi G L. Raker J W. Concomitance of multiple adenomas of parathyroids and pancreatic islets with tumor of pituitary: syndrome with familial incidence. Ametican Journal of the Medical Sciences 228: 190.1954. Duh Q Y, Hybarger C P, Geist R, Gamsu G, Goodman P C, Gooding GA, Clark 0 H. Caminoids associated with multiple endocrine neoplasia syndmmes. American Journal of Surgery 154: 142.1987. Fahri F, D&man S H, Lawson W, Cobin R H. Zak F G. Paragangliomatosis associated with multiple endocrine adenomas. Archives of Pathology and Laboratory Medicine 100: 495,1976. Larmxa-Hemandez 0. AlbomsSaavedra J, Benavidcs G, Krause L G. Perez-Metixaldi J C, Ginxo A. Multiple endocrine neoplasia. Pituitary adenoma, multicentric papillary thyroid carcinoma, bilateral carotid body paraganglioma. parathyroid hyperplasia. gastric leiomyoma, and systemic amyloidosis. American Journal of Clinical Pathology 78: 527,1982. Berg B, Bj6rklund A. Grimelius L, Jngemansson S, Latsson L, Stenram U. Akerman M. A new pattem of multiple endocrine adenomatosis. Acta Medica Scandinavica 200~321, 1976. Carney J A. The triad of gastric epitheloid leiomyosarcoma, functioning extra adrenal paraganglioma and pulmonary chondmma. Cancer 43: 374,1979.
