Multiple endocrine neoplasia type 2B syndrome is rarely reported in Chinese patients. A 25-year-old Chinese male presented with full-blown clinical features of this syndrome, including bilateral phaeochromocytomas, medullary thyroid carcinoma, and characteristic phenotypic features. One-stage surgical treatment was performed and subsequent genetic analysis confirmed a point mutation at codon 918 in exon 16 of the RET proto-oncogene. The mutation was arising de novo as there was no corresponding mutation found in both this parents or younger sister. Data published to date suggest there is no difference in the genetic and pathophysiologic basis, nor clinical characteristics of multiple endocrine neoplasia type 2B in Chinese patients. As the disease can be lethal, early diagnosis by prompt recognition of the characteristic phenotypic features followed by surgical treatment should improve the outcome. Family screening is essential to identify at-risk family members for prophylactic treatment.published_or_final_versio

Chan, WF

Chang, A

Lam, KSL

Lo, CY

Hong Kong Medical Journal

HKU Scholars Hub

Title Multiple endocrine neoplasia type 2B in a Chinese patientAuthor(s) Chang, A; Chan, WF; Lo, CY; Lam, KSLCitation Hong Kong Medical Journal, 2004, v. 10 n. 3, p. 206-209Issued Date 2004URL http://hdl.handle.net/10722/45152Rights Creative Commons: Attribution 3.0 Hong Kong License206      Hong Kong Med J Vol 10 No 3 June 2004CASE REPORTKey words:Multiple endocrine neoplasia type 2b;Mutation;Oncogene proteins;Thyroidectomy !ff_ !"#$%&'  !"#$% !"#Hong Kong Med J 2004;10:206-9Multiple endocrine neoplasia type 2B ina Chinese patient○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ff_ !"#$%&'()*+,-The University of Hong Kong, Queen MaryHospital, Pokfulam Road, Hong Kong:Division of Endocrine Surgery,Department of SurgeryA Chang, MB, BSWF Chan, MB, BS, FRCS (Edin)CY Lo, MS, FRCS (Edin)Department of MedicineKSL Lam, MD, FRCPCorrespondence to: Dr CY Lo(e-mail: cylo@hkucc.hku.hk)A Chang  WF Chan  CY Lo  KSL Lam  Multiple endocrine neoplasia type 2B syndrome is rarely reported in Chi-nese patients. A 25-year-old Chinese male presented with full-blown clinicalfeatures of this syndrome, including bilateral phaeochromocytomas, med-ullary thyroid carcinoma, and characteristic phenotypic features. One-stagesurgical treatment was performed and subsequent genetic analysis confirmeda point mutation at codon 918 in exon 16 of the RET proto-oncogene. Themutation was arising de novo as there was no corresponding mutation foundin both his parents or younger sister. Data published to date suggest there isno difference in the genetic and pathophysiologic basis, nor clinical charac-teristics of multiple endocrine neoplasia type 2B in Chinese patients. As thedisease can be lethal, early diagnosis by prompt recognition of the charac-teristic phenotypic features followed by surgical treatment should improvethe outcome. Family screening is essential to identify at-risk family mem-bers for prophylactic treatment.ff_ !"#$%&'()*+,-./01*+2345OR !"#$ !"#$%&'()*+,-./0123456789:;!&#<= !"#$%&'()*+,-./01*234567-obq !" NS VNU !"#$%&'()**+,-./01&23!"4 !"#$%&'()*+,$-./0$123456789:,;$ff_ !"#$%&'()*+,-./0/1234'56789:';<=> !"#$%&'()*+,-./0123456*+7$"897:;< !"#$%&'()*!+,-./01234567!89.:;<= !"#$%&'()*+,-.IntroductionMultiple endocrine neoplasia (MEN) type 2 syndromes, including types 2A and2B, are inherited endocrine disorders characterised by the presence of medullarythyroid carcinoma (MTC) and phaeochromocytoma. Multiple endocrine neopla-sia type 2B is typified by a characteristic phenotype with the occurrence of mul-tiple mucosal neuromas and a marfanoid habitus. Intestinal ganglioneuromatosis,corneal nerve thickening, and skeletal abnormalities are often present. Parathy-roid hyperplasia, a common finding in MEN type 2A, is not a feature of MENtype 2B.Multiple endocrine neoplasia type 2B is rarely reported in Chinese patients.In a review of both the English and Chinese literature, only two Chinese patientswith MEN type 2B had been previously reported.1,2 We report in this case studythe surgical treatment of a 25-year-old Chinese man with a full-blown clinicalpicture of MEN type 2B associated with a de novo germline mutation of the RETproto-oncogene gene.Case reportA 25-year-old Chinese man studying in Sydney, Australia, presented to a gen-eral practitioner with throbbing headache associated with an elevated bloodpressure of 240/140 mm Hg. He was referred to the hypertension clinic forinvestigation of a possible secondary cause. His past health was unremarkableexcept for on-and-off chronic constipation since childhood. His father had aHong Kong Med J Vol 10 No 3 June 2004      207Multiple endocrine neoplasia type 2Bhistory of hypertension requiring antihypertensivemedication. Physical examination revealed that thepatient, who was tall and had a slender build, possessedfeatures of marfanoid habitus including a long, thin facewith prognathism, and long limbs. Multiple noduleswere detected in the anterior third of the tongue, buccalmucosa, and lips suggestive of ganglioneuromatosis. Therewas no sign of congestive heart failure. Examination ofthe neck showed no palpable lymph node or thyroidmass while abdominal examination showed a distendedabdomen with grossly dilated and loaded colon. Therewas no ascites, hepatosplenomegaly, or ballotable mass.Per-rectal examination was unremarkable.In view of the characteristic phenotypic features and thepresence of hypertension, MEN type 2B syndrome wassuspected. A 24-hour urinary collection for fractionatedcatecholamines showed significantly elevated levels forcatecholamines and their metabolites, suggestive ofpheochromocytoma. His full blood count, liver and renalfunction tests including serum calcium level were all normal.Results of his thyroid function test were also normal but thebasal calcitonin level was elevated to 29 pmol/L (referencelevel, <7.5 pmol/L).Computed tomography (CT) showed a 6-cm mass and asuspicious nodule measuring 1 cm at the left and rightadrenal glands, respectively. The ascending and transversecolons were noted to be markedly dilated and loadedwith faeces. Metaiodobenzylguanidine scintigraphyconfirmed bilateral adrenal involvement and the uptakewas more intense on the left side (Fig 1). Ultrasono-graphy and CT scan of the neck showed bilateral thyroidnodules with a mildly enlarged right submandibularlymph node. Ultrasonography-guided fine-needleaspiration of the thyroid nodules confirmed the presenceof MTC. However, insufficient aspirate from the sub-mandibular lymph node prevented the confirmation ofnodal metastasis. The patient was treated with phenoxy-benzamine followed by propanolol to control his bloodpressure and as part of the preoperative pharmaco-logical preparation. On receiving a request from the patientto be treated in Hong Kong, the patient was referred to usfor definitive surgical treatment.A one-stage operative procedure with laparotomyand bilateral adrenalectomy followed by cervical explora-tion was planned. During laparotomy, megacolonmeasuring almost 10 cm in diameter was noted at theascending and transverse colon. The phaeochromocy-tomas located at the left and right adrenal glandsmeasured 7 x 6 x 4 cm and 1 cm, respectively. Duringcervical exploration, tumours measuring 1.5 cm and1 cm were found at the right and left upper poles of thy-roid gland, respectively. Intra-operative frozen sectionconfirmed MTC with metastasis to one lateral cervicallymph node. Total thyroidectomy, and central andbilateral neck dissection were performed (Fig 2).Pathology revealed bilateral phaeochromocytomasand multifocal MTC with multiple cervical nodalmetastases. The patient recovered well after the operationand was discharged home on postoperative day 8 withthyroxine, cortisol, fludrocortisone, and calcium supple-ment. Postoperative direct laryngoscopy showed noevidence of cord paresis. Repeated 24-hour urinary levelsof catecholamines were all normal. In addition, both hisbasal and pentagastrin-stimulated calcitonin levels werewithin the normal range.Genetic analysis confirmed a point mutation from ATG(Met) to ACG (Thr) at codon 918 in exon 16 of the RETproto-oncogene but there was no corresponding mutationfound in both his parents or younger sister. Therefore, themutation was considered as arising de novo.Fig 1. A small focus of markedly increased metaiodobenzyl-guanidine uptake demonstrated in the region of the rightadrenal gland and also a large focus of irregularly increaseduptake in the region of the left adrenal gland as shown in the24-hour anterior (a) and posterior (b) images post-injection(a) (b)Chang et al208      Hong Kong Med J Vol 10 No 3 June 2004DiscussionWilliams and Pollock3 first described the association ofMTC, phaeochromocytoma, and multiple mucosalneuromas, and this syndrome was termed MEN type 2B in1975 by Chong et al.4 Multiple endocrine neoplasiatype 2B belongs to a family of heritable endocrinediseases that include MEN type 1, MEN type 2A, andfamilial medullary thyroid carcinoma (FMTC). All MENsyndromes, including MEN type 2B, demonstrate anautosomal dominant pattern of inheritance. As with MENtype 2A and FMTC, MEN type 2B is caused by a defectin the RET proto-oncogene, which lies in chromosome10q11.2 and consists of 21 exons. The RET gene is import-ant in signalling for cell growth and differentiation oftissues derived from neural crest cells, such as C-cell ofthe thyroid gland, the adrenal medulla, the parathyroidgland, and the enteric autonomous nerve plexus. Chinesepatients with MEN type 2A have been found to havegermline mutations at a hot site in codon 634.5,6 ForMEN type 2B, mutation at codon 883 has been recentlyreported in two families7 but over 95% of patients have asingle point mutation in the RET gene, with a substitutionof threonine for methionine at codon 918 in exon 16.The mutation identified in our patient and in the twopreviously reported Chinese patients1,2 is consistent withthat reported from western countries.In MEN type 2 syndrome, there is essentially completepenetrance of the genetic defect but with variableexpressivity because not every patient manifests all thecharacteristics of this syndrome. Medullary thyroid car-cinoma is almost always present in all subtypes of MENtype 2 syndrome while phaeochromocytoma occursin 40% to 50% of all patients. Parathyroid hyperplasiais found in 10% to 20% of patients with MEN type2A but is invariably absent in MEN type 2B. Comparedwith type 2A, which accounts for 90% of MEN type 2syndromes, the MEN type 2B is less common, presentsat an earlier age, and tends to be more aggressive. Theonset of MEN type 2B normally occurs in patients whoare in their first or second decade of life. Patients withMEN type 2B also tend to have a poorer prognosis thanthose with MEN type 2A or FMTC. Genetic inheritanceaccounts for 80% of MEN type 2A patients, while denovo mutations account for 50% of MEN type 2B patients,including the three Chinese patients reported. Dataindicate that patients with MEN type 2B are less likely toreproduce because they die of their disease at an earlierage.Surgical treatment of patients with MEN type 2B isrecommended. Total thyroidectomy with central compart-ment node dissection is the procedure of choice, preferablyon a prophylactic basis at the stage of C-cell hyperplasiabefore the formation of invasive MTC. Bilateral neckdissection should be performed when the central nodeshows metastatic involvement because of the high inci-dence of cervical nodal metastasis. Normocalcitoninaemiaafter calcium and pentagastrin stimulation suggestssurgical cure of the MTC. However, thyroidectomyshould not be undertaken until co-existing pheochromo-cytoma has been excluded or treated to avoid catecho-lamine crisis. The diagnosis of phaeochromocytoma inpatients with MEN type 2 is not different from that ofsporadic phaeochromocytoma. Alpha-followed by beta-blockade is preferred for preoperative pharmacologicalpreparation.Opinions differ with regard to the management ofthe contralateral adrenal gland in patients presentingwith unilateral disease. Bilateral total adrenalectomyat the time of initial surgery is advocated by someclinicians since synchronous tumour or adrenal med-ullary hyperplasia is almost always seen microscopicallyin the contralateral gland and the subsequent need for asecond surgical procedure can be avoided. The price toFig 2. (a) Operative specimens showing a 6-cm and 1-cmphaeochromocytoma at the left and right adrenal glands,respectively; (b) multiple medullary thyroid carcinomas from1 to 1.5 cm in size located at the upper pole of thyroid glandas well as the central and bilateral lymphadenectomyspecimens(a)(b)Hong Kong Med J Vol 10 No 3 June 2004      209Multiple endocrine neoplasia type 2Bpay for bilateral total adrenalectomy is life-long post-operative replacement therapy with adrenal corticalhormones. Therefore, a selective approach by removingonly the affected adrenal gland and closely monitoringthe contralateral side through annual measurementsof 24-hour fractionated catecholamine is preferred. Thisis because not all patients will go on to develop a clin-ically significant contralateral phaeochromocytoma.Although laparoscopic adrenalectomy is the preferredsurgical approach,8 open bilateral adrenalectomy wasopted in our patient because of the anticipated technicaldifficulty associated with a limited dissection spacecaused by the relatively large tumour and the presence ofmegacolon.Gastro-intestinal involvement is not uncommon inMEN type 2B. Over 90% of patients report a variety ofgastro-intestinal complaints including flatulence, abdom-inal distension, abdominal pain, constipation, difficulty inswallowing, and vomiting. It has been reported thatabout 30% of patients with MEN type 2B ultimatelyneed surgery for gastro-intestinal complications.9 Chronicconstipation in patients with MEN type 2B is associatedwith gastro-intestinal ganglioneuromatosis whileconcomitant Hirschsprung’s disease occurs in patientswith MEN type 2A but not 2B syndrome. Our patienthad on-and-off chronic constipation with bowel move-ment every 2 to 3 days. Although his colon was grosslydilated, surgical intervention in the form of subtotalcolectomy will not be attempted unless complicationsarise from his megacolon.Screening is essential to identify asymptomatic carriersfrom family members of patients with MEN type 2syndrome.10 Genetic screening by blood test is the mostcost-effective and least invasive procedure. Genetic analy-sis is conducted on DNA that has been isolated fromperipheral blood leukocytes and amplified using polymer-ase chain reaction techniques.10 Direct DNA sequencingcan identify specific mutations of the RET proto-oncogene.Siblings of patients with MEN type 2B should bescreened as early as 1 year of age since C-cell hyperplasia,a precursor of MTC, can be present when the patientis as young as 3 months old. Prophylactic total thyroidec-tomy before the presence of invasive MTC should beconsidered for RET proto-oncogene carriers to improve theprognosis.ConclusionMultiple endocrine neoplasia type 2B is rarely reportedin the Chinese population compared to the findings inwestern countries. Based on the published data, there isno difference in the genetic and pathophysiologicbasis, or clinical characteristics of MEN type 2B inChinese patients. As the disease can be aggressiveand is associated with a poor prognosis, early diagnosisby prompt recognition of the characteristic phenotypicfeatures followed by an effective surgical treatmentshould improve the outcome. Family screening is essentialto identify at-risk family members for early surgicaltreatment.References1. Chang TJ, Wu SL, Chang TC, Huang SH, Chang TJ. De novo RETproto-oncogene mutation in a patient with multiple endocrine neopla-sia type 2B. J Formos Med Assoc 1999;98:692-7.2. Zhang YF, Hong J, Zhao YJ, et al. A case report and pedigree study ofa single point mutation in RET proto-oncogene and type 2B multipleendocrine neoplasia [in Chinese]. Zhonghua Nei Ke Za Zhi 2003;42:20-3.3. Williams ED, Pollock DJ. Multiple mucosal neuromata with endo-crine tumours: a syndrome allied to von Recklinghausen’s disease. JPathol Bacteriol 1966;91:71-80.4. Chong GC, Beahrs OH, Sizemore GW, Woolner LH. Medullary car-cinoma of the thyroid gland. Cancer 1975;35:695-704.5. Lo CY, Wat NM, Lam KY, Tiu SC, Chan J, Lam KS. Multiple endo-crine neoplasia type 2A in Chinese families. Clin Endocrinol (Oxf)2003;58:528.6. Wu SL, Chang TC, Huang CN, Chuang LM, Chang TJ. GermlineRET proto-oncogene mutations in two Taiwanese families with mul-tiple endocrine neoplasia type 2A. J Formos Med Assoc 1998;97:614-8.7. Smith DP, Houghton C, Ponder BA. Germline mutation of RET codon883 in two cases of de novo MEN 2B. Oncogene 1997;15:1213-7.8. Brunt LM, Lairmore TC, Doherty GM, Quasebarth MA, DeBenedettiM, Moley JF. Adrenalectomy for familial pheochromocytoma in thelaparoscopic era. Ann Surg 2002;235:713-21.9. Cohen MS, Phay JE, Albinson C, et al. Gastrointestinal manifesta-tions of multiple endocrine neoplasia type 2. Ann Surg 2002;235:648-55.10. Ledger GA, Khosla S, Lindor NM, Thibodeau SN, Gharib H. Genetictesting in the diagnosis and management of multiple endocrine neo-plasia type II. Ann Intern Med 1995;122:118-24.

Multiple endocrine neoplasia type 2B in a Chinese patient

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Multiple endocrine neoplasia type 2B in a Chinese patient

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