Cadotte, Marcel

Cantin, Jacques

Forster-Gibson, Cynthia

Lacroix, André

Schurch, Walter

Sturtridge, William C.

Verdy, Maurice B.

Weber, Andrée M.

Henry Ford Health System Scholarly Commons

Henry Ford Hospital Medical Journal Volume 32 Number 4 First International Workshop on MEN-2 Article 11 12-1984 A French Canadian Family with Multiple Endocrine Neoplasia Type 2 Syndromes Maurice B. Verdy Marcel Cadotte Walter Schurch William C. Sturtridge Jacques Cantin See next page for additional authors Follow this and additional works at: https://scholarlycommons.henryford.com/hfhmedjournal  Part of the Life Sciences Commons, Medical Specialties Commons, and the Public Health Commons Recommended Citation Verdy, Maurice B.; Cadotte, Marcel; Schurch, Walter; Sturtridge, William C.; Cantin, Jacques; Weber, Andrée M.; Lacroix, André; and Forster-Gibson, Cynthia (1984) "A French Canadian Family with Multiple Endocrine Neoplasia Type 2 Syndromes," Henry Ford Hospital Medical Journal : Vol. 32 : No. 4 , 251-253. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol32/iss4/11 This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons. A French Canadian Family with Multiple Endocrine Neoplasia Type 2 Syndromes Authors Maurice B. Verdy, Marcel Cadotte, Walter Schurch, William C. Sturtridge, Jacques Cantin, Andrée M. Weber, André Lacroix, and Cynthia Forster-Gibson This article is available in Henry Ford Hospital Medical Journal: https://scholarlycommons.henryford.com/hfhmedjournal/vol32/iss4/11 Henry Ford Hosp Med J Vol 32, No 4, 1984 A French Canadian Family with Multiple Endocrine Neoplasia Type 2 Syndromes Maurice B. Verdy, MD,* Marcel Cadotte, MD,* Walter Schurch, MD,* William C. Sturtridge, MD,** Jacques Cantin, MD,* Andree M. Weber, MD,*=' Andre Lacroix, MD,* and Cynthia Forster-Gibson, PhD**** 3 i n c e 1975 we have invest igated a large French-Canadian family f rom the Lac St-jean area who have the mul t ip le endocr ine neoplasia type-2 (MEN-2) syn-drome. As wel l as the typical MEN-2A clinical findings of m e d u l l a r y c a r c i n o m a of t he t h y r o i d (MTC) , pheochromocytoma, and hyperparathyroidism, we ob-served the unusual findings of aganglionic megacolon, skeletal abnormalit ies, and one case of Cushing's dis-ease (1-5). In 1976 we initiated a screening program for MTC in this family (Figure), which now comprises 126 individuals. The propositus (subject 1.7) presented with a cervical metastasis of MTC in 1975 and underwent a total thy-roidectomy. A family history of thyroid cancer was traced in his mother (subject 1) and maternal cousin (subject 9.3). His maternal grandmother had a thyroid-ectomy in 1938, which also proved to be MTC. The yearly screening consists of calcitonin measurement (6), basal and after pentagastrin stimulation (0.5 mcg/kg, intravenously). Catecholamines (plasma and urine) were measured basally and after glucagon injection (1 mg, intravenously) in all subjects with MTC. During the course of the studies, we observed a normal chromosome variant 16qh-H in some members of the family (4). The data indicated that the MEN-2A locus and 16qh-i- were not l inked, but a linkage analysis was not done at that t ime. The results of a linkage analysis presented here indicate that the MEN-2A locus and the chromosome variant 16qh-i- are not closely l inked. Results of MTC Screening During the last eight years, 12 new cases of MTC and one case of C-cell hyperplasia have been found at sur-gery. Elevation of calcitonin levels after thyroidectomy persisted in four of the six patients who presented with palpable tumors but in only one of the 10 patients who had no palpable tumor. In subject 1.3, the pentagastrin test became positive four years after thyroidectomy. The propositus died in 1983 wi th cervical, mediastinal, and disseminated metastases. Figure Abbreviated Pedigree of French-Canadian Family with MEN-2 Subjects of generation II are identified by a single arabic number, those of generation III by two arabic numbers (the first being their father's or mother's). In generation IV, only families wi th megacolon are illustrated. Karyotype has not been done in deceased (+) subjects of generation I and II nor in subjects 4.12 and 6.4. Key: Medullary carcinoma of the thyroid = Chromosome 16qh 4- = ^ B Submitted for publicatioti: July 24, 1984 Accepted for publication: Deceinber 13, 1984 •University of Montreal, Hotel-Dieu Hospital '•University of Toronto, Division of Endocrinology and Metabolism, Toronto General Hospital •••University of Montreal, Department of Pediatry, Ste-)ustine Hospital ••••Queen's University. Division of Medical Genetics, Kingston, Ontario Address reprint requests to Dr, Verdy, H6tel-Dieu Hospital, 3840 rue St-Urbain, Montreal, Canada, H2W 1T8, 251 Verdy, Cadotte, Schurch, et al Two of the patients had pheochromocytomas, and one had hyperparathyroidism (5). Patient 9.3 was operated on for MTC in 1974 and presented with clinical and biochemical evidence of pheochromocytoma in 1979. At surgery a right adrenal pheochromocytoma and bi-lateral adrenal medullary hyperplasia were found. Sub-ject 6 died of cerebral hemorrhage with blood pressure of 300/180; s y m p t o m s sugges t i ve of p h e o c h r o -mocytoma had been present for several years. Adrenal medullary hyperplasia was present in subject 5 at au-topsy; no hypertension was known in this individual. Subject 1, who had a thyroidectomy for MTC in 1958 and has had normal calcitonin levels since, had elevated serum calcium levels in 1976. A parathyroid adenoma (oxyphil cells) was removed in 1977, but the hyper-calcemia persists. Our total experience is summarized in Table I. TABLE I Endocrine Gland Pathology on MEN-2 Cases Found by Screening and Before Screening Thyroid 16 medullary carcinoma (12 new cases) 1 C-cell hyperplasia 1 undifferentiated cancer Parathyroid 1 adenoma (-1- MTC) 1 hyperplasia (normocal-cemic -I- MTC) Adrenal medulla 1 pheochromocytoma (proven) (-I- MTC) 1 pheochromocytoma (clinical) 1 adrenal medulla hyperplasia (-1- undifferentiated cancer) Pituitary 1 adenoma (Cushing) Other Clinical Findings in the Family Hirschprung's disease Aganglionic megacolon was present in nine family members (Table II). In the MEN-2B syndrome, mega-co lon has been observed secondary to gang l io -neuromatos is of en ter ic plexuses. In th is fami ly , aganglionic megacolon could be genetically related to MEN-2A. Hirschprung's disease is one of the neuro-cristopathies described by Bolande (7), and one case of agangl ionic megaco lon has been repo r ted in as-sociation wi th a pheochromocytoma (8). The fact that all the cases wi th megacolon in this family were born f rom mothers who had MTC could be important in establish-ing a relationship between aganglionic megacolon and the MEN-2 syndrome. On the other hand, it is not possible at this stage to establish whether Hirsch-prung's disease is determined by the same mutation as the MEN-2A syndrome, since only one patient (1.3) had both diseases. Other cases were either too young or died at too early an age for diagnosis of MEN-2. If aganglionic megacolon is an effect of the MEN-2A gene in this family, it may be a different mutation f rom those previously described. TABLE II Nine Patients with Hirschprung's Disease 3 Unproven cases — Died at 4 to 12 days; #2 — intestinal obstruction #3 — intestinal obstruction #1.2 —intestinal obstruction 6 Proven cases — #1.3 —Symptoms since birth Operated at age 19 Medullary thyroid carcinoma Thyroidectomy at age 33 #1.5.1— Symptoms at birth Operated at first week #1.5.3— Symptoms at birth Ultrashort segment Partial sphincterectomy at 5 years #6.1.1— Symptoms at birth Died at 6 weeks; autopsy done #6.1.2— Symptoms at 2 months Operated; well #6.1.5— Symptoms at birth Operated; well Skeletal abnormalities Skeletal abnormal i t ies, wh ich are usually found in MEN-2B, were present in many members of the family; spina bifida (five subjects), hemisacralization (four), slipped femoral epiphysis (one), prognathism (three), pes cavus (two), and pectus excavatus (three). The most frequent f inding (17 subjects) was a short four th meta-carpal. No mucosal neuromas have been observed in this family. Cushing's disease Subject4.5 was cured of typical Cushing's disease by the removal of a 3 mm pituitary adenoma (Dr. jules Hardy). Her calcitonin levels have always been normal. Since pituitary tumors have been reported in patients wi th MTC (9-12), its occurrence in this famiiy may not be purely incidental. Linkage Studies Using the Chromosome Marker 16qh -i-In 29 subjects (Figure) we found an elongation of the secondary constriction of chromosome 16 (16qh -i-). This f inding was not always associated wi th MTC, and we suggest that MEN-2A is not likely transmitted by that 252 French Canad ian M E N - 2 chromosome (4). Lod scores (Z) were calculated to test for linkage between the MEN-2 locus and the 16qh-i-marker; the age-of-onset, corrected version (13) of the computer program LIPED (14) was used. The lod scores in Table III indicate that the two loci are not wi th in one and probably not wi th in five centiMorgans on chro-mosome 16. Recombination Fraction Lod Scores TABLE III Lod Scores for Linkage Analysis Between the Locus for MEN-2A and qh Region of Chromosome 16 0 .01 .05 .10 .15 .20 .25 .30 .40 •12.49 - 2 . 2 9 - 1 . 6 7 - 1 . 4 7 - 1 . 3 5 - 1 . 1 7 - 0 . 8 8 - 0 . 5 9 - 0 . 1 4 Lod scores were calculated by the computer program LIPED (14) revised for variable age of onset (13). References Verdy M , Cholette JP, Cantin J, Lacroix A, Sturtr idge WC. Cal-c ium infusion and pentagastrin inject ion in diagnosis of med-ullary thyro id carcinoma. Can Med Assoc J 1978;119:29-35, Schurch W, Babai F, Boivin Y, Verdy M, Light electron micro-scopic and studies on the morphogenesis of familial medullary thyro id carcinoma, Virchows Arch (Pathol Anat) 1977;376:29-46. Verdy M , Weber A M , Roy CC, Mor in CL, Cadotte M, Brochu P. Hirschsprung's disease and mult ip le endocr ine neoplasia type 2. J Pediatr Gastroenterol Nutr 1982;1:603-7. Cadotte M , Verdy M, Lacroix A, Sturtr idge W. A family w i th a 16qh+ ch romosome and mu l t ip le endocr ine neoplasia type 2. Hum Pathol 1982;13:1056. Verdy M , Lacroix A, Sturtr idge W, e ta l , N6oplasie endocr in ienne m u l t i p l e , t ype 2 ( s y n d r o m e de S ipp le ) . U n i o n M e d Can 1985;114:49-59. Deftos LJ. Immunoassay for human calci tonin, I, Me thod , Metab-ol ism 1971;20:1122-8. Bolande RP. The neurocristopathies. A uni fy ing concept of dis-ease ar is ing in neura l crest ma ldeve lopmen t . H u m Pathol 1974;5:409-29. 8. Shocket E, Teloh HA. Case reports: Agangl ionic megacolon, p h e o c h r o m o c y t o m a , mega loure te r and n e u r o f i b r o m a : Co-occurrence of several neural abnormal i t ies. Ann J Dis Chi ld 1957;94:185-91. 9, Wol f LM, Dubuisson M , Schrub JCL, Metayer J, Laumonier R. Syndrome de Sipple associe a des adenomes hypophysaires et parathyroidiens. Ann Endocrinol 1972;33:455-63. 10. Robert F, Pelletier G, Hardy J. Pituitary adenomas in Cushing's disease. Arch Pathol Lab Med 1978;102:448-55. Hansen PO, Hansen M, Hansen H H , Rose B. Mul t ip le endocr ine adenomatosis of mixed type. Acta M e d Scand 1976;200:327-31. Bruno O D , Barrera EG, Caputi EM, et al. The association of p i tu i tary adenoma, thy ro id medul lary carc inoma and pheo-chromocytoma in a patient w i th Cushing's disease. Horm Res 1980;13:340. Hodge SE, Mor ton A, Tideman S, Kidd KK, Spence MA. Age-of-onset correct ion available for l inkage analysis (LIPED), Am J Hum Genet 1979;31:761-2, Ot t J, A computer program for l inkage analysis of general human pedigrees. Am J Hum Genet 1974;26:588-97, 11, 12, 13. 14 253 

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A French Canadian Family with Multiple Endocrine Neoplasia Type 2 Syndromes

A French Canadian Family with Multiple Endocrine Neoplasia Type 2 Syndromes

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