Genetic Aspects of Familial Thyroid Cancer. Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, United Kingdom

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1 The Oncologist The Oncologist CME Program is located online at To take the CME activity related to this article, you must be a registered user. Clinical Genetics and Genetic Counseling Genetic Aspects of Familial Thyroid Cancer PATRICK J. MORRISON, a A. BREW ATKINSON b a Regional Medical Genetics Centre, Belfast City Hospital, Belfast, United Kingdom; b Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, United Kingdom Key Words. Thyroid cancer Familial RET Medullary Disclosures Patrick J. Morrison: None; A. Brew Atkinson: None. Section editor Paula Ryan has disclosed no financial relationships relevant to the content of this article. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. LEARNING OBJECTIVES 1. Apply the principles of genetics to heritable aspects of thyroid cancer. 2. Explain and discuss presymptomatic gene testing with family members of patients with familial thyroid cancer. 3. Proactively manage patients presenting with a family history of thyroid cancer. CME This article is available for continuing medical education credit at CME.TheOncologist.com. ABSTRACT Familial thyroid cancer is rare, accounting for <10% of thyroid cancer cases. Activating germline point mutations in the RET proto-oncogene are associated with multiple endocrine neoplasia types 2A, 2B, and familial medullary thyroid cancer (FMTC) around 3% of thyroid cancer cases. Familial papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) have been identified as a distinct group of familial thyroid cancers. Sporadic nonmedullary thyroid cancer (NMTC) accounts for 90% of all thyroid cancers about 6% of NMTCs are familial (FNMTC). Although multiple endocrine neoplasia types 2A and 2B and FMTC are well characterized, very little is known about the genetic predisposition to PTC and FTC. In this paper, the genetic types of FMTC and FNMTC are reviewed and the clinical features and screening are outlined. The Oncologist 2009;14: MULTIPLE ENDOCRINE NEOPLASIA The multiple endocrine neoplasia (MEN) syndromes are classified into types 1, 2A, 2B, and familial medullary thyroid cancer (FMTC). All follow autosomal dominant inheritance with reduced penetrance at various ages. Many affected patients have multiple tumors, and presymptomatic screening is available for early detection. MEN-1 MEN-1 comprises the association of parathyroid, pancreatic, intestinal islet, and anterior pituitary tumors [1 4]. Correspondence: Patrick J. Morrison, M.D., Regional Medical Genetics Centre, Belfast City Hospital HSC Trust, Belfast, BT9 7AB, United Kingdom. Telephone: ; Fax: ; patrick.morrison@belfasttrust.hscni.net Received March 12, 2009; accepted for publication April 20, 2009; first published online in The Oncologist Express on May 22, AlphaMed Press /2009/$30.00/0 doi: /theoncologist The Oncologist 2009;14:

2 572 Familial Thyroid Cancer Table 1. Organ systems involved in the MEN-2 syndromes Disease Thyroid Adrenal Parathyroid Enteric ganglia Mucosa Skeletal MEN-2A 100% 50% 70% 25% Rare FMTC 100% MEN-2B 100% 50% 40% 100% 75% HSCR 100% Abbreviations: FMTC, familial medullary thyroid carcinoma; HSCR, Hirschsprung s disease; MEN, multiple endocrine neoplasia. Figure 1. Multiple endocrine neoplasia type 2A pedigree showing affected cases (thyroid cancer and pheochromocytoma, fully shaded; thyroid cancer only, half shaded) and presymptomatic gene carriers (dot). The gene responsible, Menin [1], was cloned in 1997 and is a tumor suppressor gene. Although thyroid adenomas and lipomas all can occur [2, 3], there is no major malignant thyroid involvement in MEN-1 (see [1 4 for further details). MEN-2 MEN-2 is a group of disorders characterized by the presence of medullary thyroid carcinoma [5, 6]. There are three subtypes MEN-2A, MEN-2B, and FMTC. MEN-2A, the most common, is characterized by the triad of medullary thyroid carcinoma (MTC), pheochromocytoma, and occasionally parathyroid adenoma [7]. MEN-2B shares the above features but, in addition, has striking neuroendocrine features, including mucosal ganglioneuromas and dysmorphic facies. The syndrome of FMTC is similar to MEN-2A but with thyroid carcinoma in isolation without evidence of pheochromocytoma or other tumors. Nearly all MEN-2 disorders are caused by mutations in the RET proto-oncogene and are transmitted in an autosomal dominant fashion with a high penetrance and variable expression. A small number of cases of MEN-2 are caused by mutations in the NTRK1 gene [8], recognized in sporadic cases but also in a few families with familial cases. The clinical features are illustrated in Table 1 and a typical family tree is shown in Figure 1. Virtually all cases have MTC as a core feature, with varying frequencies of pheochromocytoma and other neuroendocrine tumors. MEN-2B has a characteristic phenotype with MTC and pheochromocytoma [9]. In MEN-2B, there are additional extra features the face may have a wide-eyed expression with thickening and eversion of the upper eyelid margins and visible tarsal plates. Neuromas may be present on the eyelids and conjunctiva, and prominent thickened corneal nerves that extend to the pupillary area may be seen on slitlamp examination [10]. The eyebrows are large and prominent. The face is elongated, with prominent lips with submucosal nodules present on the vermillion border, often laterally (Fig. 2). Oral manifestations, which are often the first clue to the syndrome in infancy or early childhood, include mucosal neuromas on the anterior dorsal surface of the tongue (Fig. 3). Mucosal neuromas of the tongue are almost pathognomic in the presence of MTC. Other oral features include palatal and pharyngeal neuromas, a high arched palate, and a prominent jaw. There is a Marfanoid habitus in 75% of patients [11], often with proximal muscle wasting and weakness. Other musculoskeletal manifestations include kyphoscoliosis or lordosis, joint laxity, decreased s.c. fat, pes cavus, and slipped capital femoral epiphysis [12]. Gastrointestinal problems include abdominal disten-

3 Morrison, Atkinson 573 Table 2. Suggested surgical timing depending on mutations in RET Age at Level Codon surgery Level 3 883, 918, months Level 2 611, 618, 620, 634 By age 5 Level 1 609, 630, 768, 790, 791, 804, 891 By age 5 10 Figure 2. Multiple endocrine neoplasia type 2B facies showing prominent lips with lip and tongue neuroma. Figure 3. neuromas. Multiple endocrine neoplasia type 2B mucosal sion, megacolon, constipation, or diarrhea resulting from diffuse ganglioneuromatosis. C-cell hyperplasia of the thyroid cells allows calcitonin secretion, and abnormal regulation of hormones allows release of histamine, serotonin, and prostaglandins, among other hormones [13]. Virtually all patients have MTC, which appears to be more aggressive than in MEN-2A, with an average age at death of around 21 years [14]. Because of this shorter survival time, more sporadic cases of MEN-2B than MEN-2A are found. Pheochromocytoma is present in 50% of cases, of which half are multiple and often bilateral. This percentage increases with age and is lower than in MEN-2A, again because of the shorter life span. A small proportion of patients with undiagnosed pheochromocytoma may die from cardiovascular crisis perioperatively [15]. Mutations in the RET gene [16] can cause some types of Hirschsprung s disease (HSCR). HSCR is characterized by aganglionosis of the bowel. There are several causes, with only some cases caused by RET mutations. Unlike HSCR, overgrowth, rather than the absence of enteric ganglia, is a prominent feature of MEN-2B. All four conditions involve expression of RET in embryonic tissues, including thyroid C-cells, the adrenal medulla, the parathyroid, and autonomic nerve plexi of the gut. FMTC occurs when the family history is of MTC only with no additional extrathyroid features, and particularly the absence of pheochromocytoma. By definition, there must be 10 gene carriers with only MTC and cases present 50 years of age. In practice, because pheochromocytoma can often appear late in MEN-2A, FMTC can be difficult to diagnose with certainty and families generally should be treated as having MEN-2A unless rigidly adhering to the definition [17]. MOLECULAR GENETICS The MEN-2 syndromes are inherited as autosomal dominant traits. Linkage to chromosome 10 was described in 1990 [18]. In 1993, mutations in the RET oncogene were described in MEN-2A and FMTC [19, 20]. This was confirmed in 1994 [21]. Over 98% of MEN-2A patients have mutations in exons 10 and 11 of RET. There is a correlation between MEN-2A mutations at codon 634 and pheochromocytoma and parathyroid disease [22, 23]. Ninety-five percent of MEN-2B patients have a specific point mutation at codon 918 in exon 16 of RET, resulting in the replacement of methionine by threonine. Four percent of MEN-2B cases have a novel exon 15 mutation at codon 883 (A883F) [24]. Why 95% of cases have the M918T mutation and 4% have the A883F mutation is not known. Different mutations therefore have varying effects (Table 2) [25].

4 574 Familial Thyroid Cancer 3- to 6-MONTH-OLD CHILD AT RISK FOR MEN-2 FAMILY MUTATION PRESENT FAMILY MUTATION ABSENT CALCITONIN PRESURGERY AT 4-5 YEARS OR SOONER* DISCHARGE FROM FOLLOW-UP SURGERY AT <5 YEARS OR SOONER IF RAISED CALCITONIN ANNUAL FOLLOW-UP SCREENING FOR CALCITONIN (AND LATER FOR PHEOCHROMOCYTOMA FROM AGE 18) *See Table 2 Figure 4. Flow diagram of screening in multiple endocrine neoplasia (MEN) type 2A. 1- to 3-MONTH-OLD CHILD AT RISK FOR MEN-2 MUTATION PRESENT OR DYSMORPHIC CLINICAL FEATURES CALCITONIN EVERY YEAR UNTIL 3-5 YEARS MUTATION ABSENT DISCHARGE FROM FOLLOW-UP SURGERY AT 3-5 YEARS OR SOONER IF RAISED CALCITONIN ANNUAL FOLLOW-UP SCREENING FOR CALCITONIN; PHEOCHROMOCYTOMA SCREENING FROM AGE 10 Figure 5. Flow diagram of screening in multiple endocrine neoplasia (MEN) type 2B. Table 3. Model for structured disclosure of results in infants and children Phase Action 1. Preclinic Liaison with key health professionals (general practioners, endocrinologists, surgeons), personal contact with family 2. Clinic appointment Introduction of team members involved; discussion of genetics, risks, surgical options, DNA tests, and baseline calcitonin; make arrangements for giving results to family 3. Follow-up Results disclosure; arrange follow-up with key clinicians, e.g., endocrinologist and/or surgeon 6-MONTH-OLD CHILD AT RISK FOR MEN-2 MUTATION PRESENT CALCITONIN AT 5, 7, AND 9 YEARS MUTATION ABSENT DISCHARGE FROM FOLLOW-UP SURGERY AT 10 YEARS OR SOONER IF RAISED CALCITONIN BIENNIAL FOLLOW-UP SCREENING FOR CALCITONIN Figure 6. Flow diagram of screening in multiple endocrine neoplasia (MEN) type familial medullary thyroid cancer. AFFECTED MEN-2 CASE ATTENDS CLINIC WITH SCREENING OF MAIN EXONS OF RET MUTATION PRESENT SCREEN FAMILY AS IN MEN-2A PROTOCOL MUTATION ABSENT SUPRAREGIONAL DNA SEQUENCING OR LINKAGE MUTATION POSITIVE MUTATION AND C-CELL NEGATIVE FOLLOW-UP CHILDREN PENTAGASTRIN TEST PRIMARY RELATIVES DECIDING TESTING ON DISCHARGE PARENTS AND SIBLINGS IF INDIVIDUAL FAMILY BASIS NEGATIVE Figure 7. Flow diagram of screening in sporadic medullary thyroid cancer. Abbreviations: MEN, multiple endocrine neoplasia. Table 4. Age-variable screening for pheochromocytoma in MEN-2A patients Age at diagnosis Screening required 18 yrs early Clinical history and examination for BP childhood Annual 24-hour urine analysis 18 yrs Annual clinical history and examination for BP, etc. Annual 24-hr urine analysis CT with or without MRI scan of adrenals at first visit; yearly follow-up Preoperative CT/MRI of adrenals before thyroid or other surgery Abbreviations: BP, blood pressure; CT, computed tomography; MEN, multiple endocrine neoplasia; MRI, magnetic resonance imaging. MANAGEMENT Since the early clinical descriptions of MEN-2A syndrome by Sipple in 1961 and MEN-2B syndrome by Wagenmann in 1922 and by Froboese in 1923, screening has been carried out on clinical grounds. Measurement of basal or stim-

5 Morrison, Atkinson 575 Table 5. Causes of familial nonmedullary thyroid cancer Clinical feature Gene symbol Cell histology Locus MNG MNG1 PTC/MNG 14q21 MNG MNG3 MNG only Xp22 Thyroid tumor with cell oxyphilia TCO PTC 19p13.2 PTC and renal tumors PTCPRN PTC 1q21 PTC and clear cell renal carcinoma PTC t(3;8)(p14.2;q24.1) PTC PTC1 10q11-12 FTC NMTC1 FTC 2q21 Abbreviations: FTC, follicular thyroid carcinoma; MNG, multinodular goiter; PTC, papillary thyroid carcinoma. ulated calcitonin levels allows preventative surgery in atrisk cases. Identification of RET gene mutations in MEN-2A in 1993 and in MEN-2B in 1994 allowed the possibility of direct DNA-based mutation testing. Lips et al. [26] showed that DNA-based testing was superior to clinical screening for the identification of subjects at risk for developing MEN-2. All individuals at risk or suspected of having MEN-2A or MEN-2B should have a mutational analysis for the RET gene as early as possible. In most cases, this provides a presymptomatic diagnosis, or confirms the diagnosis, especially in most cases in which a family mutation is already known. Prophylactic total thyroidectomy [27 29] is advocated for individuals who are shown to inherit the mutation. The ideal age for surgery for MEN-2A patients is much disputed and has become younger (Fig. 4). For MEN-2B, surgery is often preferred in the first year of life [29], because MTCs in MEN-2B patients are particularly aggressive and metastases may occur at an early stage (Fig. 5). DNA testing alone can be an indication for surgery in cases carrying a known family mutation [30, 31]. A model for structured disclosure of results in infants and children is shown in Table 3. Blood screening using calcitonin in early childhood may not be of clinical benefit [32], because there is no evidence that it changes clinical management. Patients with FMTC can have surgery postponed into their teenage years depending on both the mutation and the age of onset in the family (Fig. 6). Management of a possible sporadic case of MEN-2 is by detailed family history and RET mutation screen for the common exons of RET (exons 10, 11, 13, and 14) followed by complete RET sequencing if the common exon screen is negative [24]. If no mutations are found after full sequencing, then the risk for a familial case is low because 98% of mutations are identifiable. Most mutation-negative patients are managed on a case-by-case basis because data in this area are evolving (Fig. 7). Figure 8. Histology of patient showing apparent follicular thyroid carcinoma with nuclear features of papillary thyroid cancer (PTC) crowding with optically clear Orphan-Annie nuclei so the diagnosis is PTC. Continued follow-up of all affected or gene positive individuals should include annual screening for both medullary cancer by basal or stimulated calcitonin and pheochromocytoma by standard biochemical and imaging techniques [33 35] (Table 4). FAMILIAL NONMEDULLARY THYROID CANCER The prevalence of familial nonmedullary thyroid cancer (FNMTC), principally papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is around 6% of thyroid cancers. These tend to be more aggressive than the sporadic form, and isolated or localized gene loci are shown in Table 5. At least three loci are suspected in PTC. The thyroid tumors are characterized by early age at onset, are often bilateral, and may have mixed PTC and FTC features. PTC1 is located on chromosome 10q11-12, and at least two other susceptibility loci are likely. This group of disorders is genetically heterogeneous, and more loci can be expected to be defined in the near future [36 40]. Families may present with an apparent mixed PTC and

6 576 Familial Thyroid Cancer Table 6. Syndromes that include familial nonmedullary thyroid cancer Syndrome Predominant histology Gene symbol Locus Cowden FTC, PTC PTEN 10q22 syndrome Familial PTC (cribiform) APC 5q21 polyposis coli SDHB/SDHD PTC PGL4, PGL1 1p36, 11q23 Carney complex CNC1, CNC2 PRKAR1a 17q23-24, 2p16 Abbreviations: FTC, follicular thyroid carcinoma; PTC, papillary thyroid carcinoma; SDHB/SDHD, succinate dehydrogenase complex subunit B/subunit D. Figure 9. Histology of patient showing papillary thyroid carcinoma showing psammoma bodies. FTC picture. We have seen some autosomal dominant kindreds with mixed PTC and FTC features. One family of three sisters and two affected paternal uncles had histology with two sisters having follicular architecture but with underlying nuclear features of PTC with optically clear orphan-annie eye nuclei (Fig. 8) and with one sister having PTC with psammoma bodies (Fig. 9), so the histology needs to be carefully looked at because these families may actually have a type of PTC and not FTC. Other thyroid cancers occur in other autosomal dominant tumor syndromes, including familial adenomatous polyposis coli (APC), with a preponderance in women 35 years of age, Cowden syndrome (PTEN), and up to 5% of familial paraganglioma syndromes [41] (succinate dehydrogenase complex subunit B and subunit D) (Table 6). A very small proportion of FMNTCs are a result of the MNG1 gene on chromosome 14q, which causes multinodular goiter [42]. Management of FNMTC is similar to that of MEN-2, with total thyroidectomy the surgery of choice. Cowden syndrome (first described by Lloyd and Denis [43] in 1963, who named the condition after their patient Rachel Cowden, who died of bilateral breast cancer in her early 30s) is characterized by multiple hamartomas and trichilemmomas (small warty dermal skin lesions) in association with thyroid disease (adenoma or goiter in 50% and PTC or FTC in 10%), breast fibroadenomas or early malignant disease (70%), and lipomas (40%). Macrocephaly and pigmentation occur in some patients, and endometrial cancer is common. The lifetime risk for thyroid cancer in males and females is around 10% and is predominantly FTC although PTC cases have been noted. CONCLUSIONS FMTC and FNMTC are rare, but much progress is being made in characterizing mutations, hence allowing molecular screening and risk-reducing surgery in these families. RET gene mutations are readily identifiable with current technology and should be accessible in all regions. Families should receive careful genetic counseling to ensure that all at-risk members are aware of the available options. Several new PTC loci are likely to be cloned in the next 2 years and prophylactic surgery and screening in a manner similar to that for MEN-2 may follow. Molecular genetics is steadily reclassifying the pathology of thyroid tumors and providing insights into the pathophysiology and successful management of sporadic thyroid tumors. AUTHOR CONTRIBUTIONS Conception/Design: Patrick J. Morrison Administrative support: Patrick J. Morrison Provision of study materials: Patrick J. Morrison Collection/assembly of data: Patrick J. Morrison, A. Brew Atkinson Data analysis: Patrick J. Morrison, A. Brew Atkinson Manuscript writing: Patrick J. Morrison, A. Brew Atkinson Final approval of manuscript: Patrick J. Morrison, A. Brew Atkinson REFERENCES 1 Chandrasekharappa SC, Guru SC, Manickam P et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 1997;276: Cebrían A, Herrera-Pombo JL, Díez JJ et al. Genetic and clinical analysis in 10 Spanish patients with multiple endocrine neoplasia type 1. Eur J Hum Genet 1999;7: Toliat MR, Berger W, Ropers HH et al. Mutations in the MEN 1 gene in sporadic neuroendocrine tumours of gastroenteropancreatic system. Lancet 1997;350: Bassett JHD, Forbes SA, Pannett AAJ et al. Characterization of mutations in patients with multiple endocrine neoplasia type 1. Am J Hum Genet 1998;62: Hadden DR, O Reilly F, Kennedy L et al. Multiple endocrine neoplasia type 2A: A Northern Ireland and Australian family. Henry Ford Hosp Med J 1987;35:

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