Department of Endocrine Neoplasia and Hormonal Disorders

NEWSLETTER Volume 3, Issue 1, 2010

Pediatric Endocrine Tumors

®

Steven G. Waguespack, M.D., FAAP, FACE Associate Professor Department of Endocrine Neoplasia and Hormonal Disor- ders; Division of Pediatrics Endocrine tumors Pediatric Endocrine Tumors, An Overview represent a minority of Pituitary Tumors all neoplasms observed Pituitary (PA) represent less than in the pediatric popu- 3% of all supratentorial tumors diagnosed dur- lation and are gener- ing childhood. Over 75% of PAs occur in children ally clinically benign older than 12 years, and females are more com- or low-grade cancers, monly affected than males. Pituitary tumors are although a small percentage of these tumors are usually diagnosed secondary to symptoms of high-grade malignancies requiring multimodal- hormone excess or mass effect, such as visual ity therapies. Although rare, pediatric endocrine disturbance (classically a bitemporal hemiano- tumors are important clinical entities that can psia), headache, or ophthalmoplegia. Patients have unique clinical presentations and genet- may also present with delayed growth and pu- ic causes. As with any rare childhood disease, bertal development due to pituitary hormone treatment is best provided at referral centers hypersecretion, as seen with hyperprolactine- with multidisciplinary expertise in the manage- mia, or hyposecretion, as seen with large PAs ment of such tumors. The Pediatric Endocrine that compress the normal adenohypophyseal Tumor Program at the Children’s Cancer Hos- tissue. The initial workup of a PA is similar to pital of the University of Texas M. D. Anderson adults and includes imaging of the sella turcica, Cancer Center is a multidisciplinary program a comprehensive hormonal evaluation to assess that provides primary evaluation and treat- for hyper- and hypopituitarism, and visual field ment to children and young adults suspected testing for children with large tumors that ap- PERSPECTIVES to have or who are already diagnosed with thy- proach the optic chiasm. are the roid neoplasms, adrenal tumors, pituitary ad- most common PA in childhood, representing enomas, and/or hereditary tumor syndromes. about 50% of cases, followed by ACTH-secret- Our team currently consists of two board-cer- ing adenomas (Cushing disease), somatotroph tified adult and pediatric endocrinologists, Ste- adenomas (gigantism/), and lastly, ven Waguespack, M.D. and Anita Ying, M.D., and clinically nonfunctioning PAs. In contradistinc- Sarah Bottomley, RN, MSN, CPNP, a pediatric tion to adults, (continued on Page 2) nurse practitioner who works closely with both Drs. Waguespack and Ying. Table of Contents This issue of EndoPerspectives is focused on pediatric endocrine tumors. We start with a general overview of the most common endo- Pediatric Endocrine Tumors Page 1 crine neoplasms encountered in the pediatric Upcoming Events Page 2 population. Dr. Ying and Ms. Bottomley review Notes from the Endocrine Faculty Page 4 late effects of endocrine tumors and their treat- Team ment. Thereasa Rich, M.S., C.G.C., reviews the MEN Patient Education Conference Page 4 genetic syndromes most commonly associated ENDO Late Effects of Endocrine Tumors Page 5 with pediatric endocrine tumors and emphasiz- Genetic Counseling and Genetic As- es the role of genetic counseling when taking care of these children. pects of Pediatric Endocrine Tumors Page 6 The Nodule Clinic Page 8 (Waguespack, continued from Page 1) oncogene: multiple endocrine neoplasia type nonfunctioning PAs represent only <5% of 2a (MEN2A) and type 2b (MEN2B). In addition Upcoming Events pediatric pituitary tumors. Although the clini- to the almost complete penetrance of MTC, cal presentation of PAs during childhood is 50% of patients with MEN2A and MEN2B de- AACE 19th Annual Meet- often different compared with adults, the ap- velop and up to 30% of ing and Clinical Congress proach to diagnosis and treatment of these MEN2A patients have parathyroid adenomas, April 21-25, 2010 neoplasms is similar. although these tumors are rarely diagnosed Sheraton Boston Hotel and during childhood. Patients with MEN2B have the John B. Hynes Veterans a distinct phenotype with a characteristic fa- Memorial Convention Center cial appearance, Marfanoid body habitus, and Boston, MA (http://www. a generalized ganglioneuromatosis, mani- aace.com/meetings/cal- fested most obviously by the presence of oral endar/calendar.php) mucosa neuromas. LWPES 2010 Annual Meet- Children with usually pres- ing May 1-3, 2010. Vancou- ent with an asymptomatic thyroid mass and/ ver, Canada. (http://www. or cervical lymphadenopathy. lwpes.org/meetingsEvents/ metastases are present in the majority of PTC pdf/2010LWPESschedule. cases and lung metastases are identified in pdf) up to 20% of cases; metastases to other sites occur but are rare. ATA Spring Meeting of the American Thyroid Association May 13- 16, 2010. Minneapolis, MN (www.thyroid.org)

PTC 8-year-old with Cushing disease and a cys- The Endocrine Society tic pituitary macroadenoma (arrows). LN ENDO 2010, June 19-22, LN 2010. San Diego, CA. Thyroid Tumors (www.endo-society.org) Benign Thyroid Tumors Benign thyroid tumors represent up to 80% 14th International Thy- of all thyroid nodules presenting in the pedi- roid Congress Sept. 11- atric population. The younger a child is at the 16, 2010. Paris, France. (www.itc2010.com) time of presentation, the more likely it is for a solitary nodule to be malignant. The work North American Neuro- up of a thyroid nodule in a child includes the Endocrine Tumor Society laboratory assessment of thyroid function, Annual Conference ultrasound to assess the nodule and regional CT scan of a 6-year-old with papillary thyroid October 29-30, 2010. lymph node characteristics, and fine needle cancer (PTC) and bulky bilateral lymph node Santa Fe, New Mexico aspiration (usually under ultrasound guid- (LN) metastases. (www.nanets.net) ance) for definitive diagnosis. Solid lesions with increased blood flow and the presence Despite a more advanced presentation, 14th Asia-Oceania Con- of microcalcifications are more likely to be children with thyroid cancer usually have an gress of Endocrinology malignant whereas pure cystic lesions are excellent prognosis with anticipated survival December 2-5, 2010. over decades. Part of this clinical phenom- Kuala Lumpur, Malaysia almost always benign. Nuclear scintigraphy (www.aoce2010.com) with 123I or Tc-99m pertechnetate is gener- enon may be due to mutational differences ally not useful in the diagnostic evaluation, between children and adults, in addition to MEN 2010 12th Interna- except in the event of a suppressed TSH. the fact that pediatric PTC is usually very io- tional Workshop on Mul- Malignant Thyroid Tumors dine avid, typically leading to successful treat- tiple Endocrine Neoplasia Malignant neoplasms of the thyroid are ment of distantly metastatic disease after one Sept. 16-18, 2010. Gubbio, Italy (www.men2010.com) rare in the pediatric population, with an in- or more courses of radioactive iodine (RAI) cidence of ≤1 case/million/year in children therapy. under ten years of age to 15.4 cases/million/ Total thyroidectomy and a compartment-ori- year in adolescents ages 15-19, which is the ented lymph node dissection, as indicated, are most commonly affected pediatric age group. best accomplished by surgeons with extensive Over 90% of thyroid cancers occurring in experience in the management of thyroid ma- childhood are (PTC). lignancies. In DTC, radioiodine (using 131I) is Medullary thyroid (MTC) is a very often administered a few weeks after surgery uncommon disease in childhood that almost to ablate any residual normal thyroid tissue always occurs in the context of one of two and treat any residual thyroid cancer that is hereditary endocrine tumor syndromes that iodine-avid; children with MTC do not require arise secondary to activating mutations of the radioiodine ablation. The thyroid stimulating RET (REarranged during Transfection) proto- hormone (TSH) level is suppressed by giving Continued on Page 3 2 (Waguespack, continued from Page 1) to present at an age <5 years. They have a female predomi- supraphysiologic levothyroxine doses in DTC but the TSH is nance and are functional tumors (producing androgens and/ kept normal in MTC. Long-term follow up involves monitor- or glucocorticoids, typically) in >90% of cases. ACT may also ing of tumor markers ( in DTC and / present as an abdominal mass or pain. In children, ACT are as- carcinogenic embryonic antigen in MTC) as well as routine sociated with the Li-Fraumeni syndrome (germline inactivat- imaging based upon the initial extent of disease presenta- ing mutations in the p53 tumor suppressor gene), the Beck- tion. Neck US is generally the most useful imaging modality. with-Wiedemann syndrome (BWS), hemihypertrophy other Traditional chemotherapy has generally not been shown to than that seen as part of BWS, and rarely congenital adrenal be effective in thyroid cancer, but newer anti-cancer agents, hyperplasia. Other rare causes of nodular adrenocortical dis- the oral tyrosine kinase inhibitors, are showing promise in the ease, which usually present with Cushing syndrome, include treatment of children with disease not amenable or respon- Carney’s complex and macronodular adrenal hyperplasia. sive to standard therapeutic approaches. PHEO are more likely to be bilateral, extra-adrenal, malignant, and secondary to a heritable tumor syndrome in children. Most familial PHEO presenting in children are associated with Von-Hippel Lindau syndrome, although MEN2, the familial syndromes due to mutations in the succinate dehydrogenase gene, and neurofibromatosis type 1 are also in the differential diagnosis. Compared with adults, hyperten- Diagnostic thyroid scan in an 11- sion is usually sustained in children and they may lack the typ- year-old with diffuse pulmonary ical triad of headache, palpitations, and diaphoresis. The initial metastases and residual neck test recommended for diagnosis is measurement of plasma disease and/or urine metanephrine levels. Most children with ACT or PHEO are treated with surgical resection, but systemic approaches to therapy are typically re- quired in the case of malignant disease that is present outside of the adrenal gland. Children with PHEO who proceed to sur- gery are pretreated with alpha (and possibly beta) blockade.

In MEN2, there is a correlation between genotype and phe- notype, and the biological aggressiveness of MTC depends on the hereditary setting in which it develops. With the advent of genetic testing for RET mutations, MTC has become one of the few malignancies that can be prevented or cured via pro- phylactic thyroidectomy before it becomes clinically relevant. Recent guidelines have updated recommendations regarding the age of prophylactic thyroidectomy in children who are carriers of a RET mutation.

Adrenal Tumors Adrenocortical tumors (ACT) arise from the outer adrenal ACT cortex whereas pheochromocytomas (PHEO) derive from the catecholamine-producing chromaffin cells of the . The pathologic categorization of ACT in children as benign or malignant does not always correlate to the clinical behavior of these tumors, making it difficult to differentiate Adrenocortical tumor (ACT) in a 12-year-old patient clinically significant adrenocortical from those tu- with Beckwith-Wiedemann Syndrome. mors that retain a good prognosis. ACT are very rare and tend

Newsletter Committee Members ENDOPERSPECTIVES ® is a quarterly publica- Carol Atwood, M.A., F.A.C.H.E. tion of the Department of Endocrine Neopla- Mimi I. Hu, M.D. sia and Hormonal Disorders at The University Lorraine Medina of Texas M. D. Anderson Cancer Center. Linda Roden, M.B.A Lea S. Tatar, M.Ed. Chair Steven G. Waguespack, M.D. Steven I. Sherman, M.D. If interested, please send submissions to Charles Department Administrator Stava, [email protected]. We reserve the Carol Atwood, M.A., F.A.C.H.E. right to edit for length, content, and style. Department of Endocrine Neoplasia and HD website: Editor http://www.mdanderson.org/departments/ Charles Stava, M.S.H.A. endocrinology/ 3 Notes from the Endocrine Faculty Team

Publications: dent on ret proto-oncogene activity. J Clin Endocrinol Metab. 2010 Jan;95(1):439-44. Druker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Wells SA Jr, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Buse JB. Incretin-based therapies for the treatment of type-2 Skinner M, Krebs A, Vasselli J, Schlumberger M. for diabetes: evaluation of the risks and benefits. Diabetes Care. the treatment of patients with locally advanced or metastatic 2010 Feb;33(2):428-33. hereditary medullary thyroid cancer. J Clin Oncol. 2010 Feb Tulloch-Reid M, Skarulis MC, Sherman SI, Sarlis NJ, Santarpia 10;28(5):767-72. L. Long-term eradication of locally recurrent invasive follicular Perrier ND, Balachandran D, Wefel JS, Jimenez C, Busaidy N, thyroid carcinoma after taxane-based concomitant chemora- Morris GS, Dong W, Jackson E, Weaver S, Gantela A, Evans DB, diotherapy. Anticancer Res. 2009 Nov;29(11):4665-71. Grubbs EG, Lee JE. Prospective, randomized, controlled trial of Schlumberger M, Sherman SI. Clinical trials for progressive dif- parathyroidectomy versus observation in patients with “asymp- ferentiated thyroid cancer: patient selection, study design, and tomatic” primary. Surgery. 2009 Dec;146(6):1116-22. recent advances. Thyroid. 2009 Dec;19(12):1393-400. Ayala-Ramirez M, Callender GG, Kupferman ME, Rich TA, Chuang Bhatia A, Rao A, Ang KK, Garden AS, Morrison WH, Rosenthal DI, HH, Trent J, Perrier ND, Goodarzi M, Jimenez C. Paraganglioma Evans DB, Clayman G, Sherman SI, Schwartz DL. Anaplastic thy- syndrome type 1 in a patient with Carney-Stratakis syndrome. roid cancer — clinical outcomes with conformal radiotherapy. Nat Rev Endocrinol. 2010 Feb;6(2):110-5. Head Neck (e-Pub: 11/2009). Habra MA, Jimenez C, Huang SC, Cote GJ, Murphy WA, Gagel Sherman SI. Tyrosine kinase inhibitors and the thyroid. Best RF, Hoff AO. Expression analysis of fibroblast growth factor-23, Pract Res Clin Endocrinol Metab 23(6):713-722, 12/2009. matrix extracellular phosphoglycoprotein, secreted frizzled-re- Waguespack SG, Rich TA. Multiple endocrine neoplasia syn- lated protein-4, and fibroblast growth factor-7: identification of drome 2B in early childhood: long-term benefit of prophylactic fibroblast growth factor-23 and matrix extracellular phosphogly- thyroidectomy. Cancer. 2010 Feb 17 (Epub ahead of print). coprotein as major factors involved in tumor-induced osteomal- Zhu W, Hai T, Ye L, Cote CJ. Medullary thyroid carcinoma cell acia. Endocr Pract 14(9):1108-14, 12/2008. PMID: 19158050. lines contain a self-renewing CD133+ population that is depen- Wish to refer a patient to M. D. Anderson?

Online Referrals: M. D. Anderson has created an online referral process, myMDAnderson, to help you get your patient into M. D. Anderson as quickly as possible. You can use myMDAnderson to follow the treatment your patients receive by viewing transcribed reports and accessing your patients’ schedules. To qualify for this free service, you must be a licensed, practicing physician. To start a referral through myMDAnderson, please access this portal: https://my.mdanderson.org/public/physicians/user/ Telephone Referrals: Physician to Physician referrals to the Dept. of Endocrine Neoplasia and H.D., please call 713-792- 2841. To speak to a New Patient Referral Coordinator, please call 713-563-4400. For Pediatric Referrals (patients less than 18 years of age), please call 713-792-5410 We want to hear from you!

We are always looking for suggestions to improve this newsletter and your input is valuable to us. If you have any sugges- tions or articles to share with us, please contact Charles Stava, Program Manager, Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center at: [email protected], or write to him at: 1515 Holcombe Blvd, Unit 1461, Houston, Texas, 77030.

Multiple Endocrine Neoplasias Patient Education Conference

The Clinical Cancer Genetics (CCG) Program is pleased to announce an upcoming patient-directed conference on Multiple Endocrine Neoplasia Types 1 and 2 (MEN1 & MEN2) to be held on June 26, 2010. The conference will be a wonderful op- portunity for patients and caregivers to learn about the latest developments in clinical care and research focusing on these hereditary syndromes. The agenda will mirror the mission of the CCG program to provide research-driven information about genetic syndromes, genetic risk assessment, testing, and screening for people and their family members who are at increased risk for cancer. Registration is currently on-going for this conference and is free of charge. For more information please see visit our website at www.mdanderson.org/departments/ccg or to register please call 713-745-7391 or email [email protected]. Please see the enclosed flyer for more information about the conference.

4 Late Effects of Endocrine Tumors

Anita K. Ying, M.D. Assistant Professor, Department of Endocrine Neoplasia and Hormonal Dis- orders; Division of Pediatrics Sarah Bottomley, RN, MSN,CPNP Pediatric Endocrine Nurse Practitioner; Supervisor, Mid-Level Providers, Division of Pediatrics and The Children’s Cancer Hospital

The late effects of endocrine tu- will likely be on long-term cabergoline therapy. mors are dependent on the organ involved, extent of disease, age at Thyroid Cancer diagnosis, and treatment modality, The child treated for differentiated thyroid cancer (DTC) which may include surgery, radia- can usually anticipate excellent outcomes and long-term tion, chemotherapy or other thera- survival, and treatment is generally well tolerated with lim- peutics. Additionally, compliance with prescribed hormone ited side effects. However, with the advent of increasingly replacements may impact overall outcomes and quality of aggressive therapies and the prospect of decades of sur- life. Lifelong surveillance by providers familiar with endo- vivorship, it is important to maintain an awareness of the crine tumors and potential sequelae will be required to op- potential early and late adverse events that may impact the timize a survivor’s physical and psychosocial health, ensure patient’s quality of life. early diagnosis of sequelae and provide appropriate inter- One of the unique aspects of DTC is the use of radioac- vention. tive iodine (RAI) in the evaluation and treatment of patients with this disease. Therapy with RAI is generally well toler- Pituitary Tumors ated and safe. Systematic reviews of RAI effects on the go- Long-term effects from pituitary tumors can result from nadal system of men and women with DTC provide reassur- treatment. For those tumors that require surgical resection ing results. In men, there are lab abnormalities in the first 6 or more rarely radiation therapy, varying degrees of hypopi- months after RAI, with normalization usually by 18 months, tuitarism can occur that require lifelong hormone replace- suggesting transient gonadal dysfunction. However, there ment. Treatment of central adrenal insufficiency, diabetes is no evidence of increased rates of infertility. There are rec- insipidus, and hypothyroidism are similar to adult patients ommendations to wait at least four months before attempt- with adjustment for patient weight and age. Depending on ing to have children. the age of onset, graduated dosing of pubertal hormones to In women, FSH values normalize by 12 months and there is assist with induction or maintenance of puberty and fertility no significantly increased risk of infertility, miscarriage, still- assistance may be needed. Growth hormone replacement births, congenital defects, or cancers identified in offspring. prior to fusion of growth plates is generally needed, but Current recommendations state that pregnancy should be continued treatment in adulthood is not always necessary. avoided for 6-12 months after receiving therapeutic RAI doses Studies have shown no increased incidence of tumor recur- so that thyroid function can stabilize and remission of cancer rence in adult patients with prior nonfunctioning pituitary can be verified. RAI should not be given to women who are tumors who receive growth hormone. breast feeding and should be deferred for at least six to eight Cushings syndrome, as a result of a pituitary or adrenal weeks after breast feeding cessation to decrease radiation ex- tumor, can affect growth, puberty, and accrual of bone mass. posure to breast tissue. After hypercortisolism is controlled, these issues can resolve There is growing understanding of the possible late effects with catch-up growth and restoration of bone mass. of RAI, which can include: permanent damage to the salivary Prolactinomas are generally treated with medical therapy glands resulting in chronic xerostomia or salivary duct stones, of dopamine agonists. There has been an association be- excessive dental caries, reduced taste, pulmonary fibrosis (in tween valvular heart disease and dopamine agonist use in those with diffuse pulmonary metastases), fertility issues, and patients treated for Parkinson’s disease. The applicability to the possibility of the development of other cancers (stomach, patients treated for hyperprolactinemia is unclear. Parkin- bladder, colon, salivary gland, breast, and leukemia) after very son’s patients with significant valvular disease have been ex- high cumulative doses of 131I. Therefore, caution should be posed to much higher doses (25 mg/week) than those usual- exercised when giving multiple high doses of RAI to children, ly used in hyperprolactinemic patients (0.5-3mg/week). And particularly in those patients whose disease is more indolent advanced age is strongly associated with increasing preva- and may not require such aggressive therapy. lence of valvulopathy. However, given the longevity with In the patient treated for DTC or medullary thyroid cancer which some patients with prolactinomas must be treated, (MTC), surgical resection can be associated with potential late this data has concerned endocrinologists. There is insuffi- effects, including voice difficulties and hypoparathyroidism. cient evidence to provide consensus guidelines to endocri- If the recurrent laryngeal nerves or the external branches of nologists, but patients should be educated about potential the superior laryngeal nerve are damaged, patients may be risks, treatment should be given at the lowest possible dose hoarse following surgery and require additional surgical pro- for the shortest duration possible, and baseline echocardio- cedures to improve phonation. Continued on page 6 grams can be considered in adulthood in those patients who 5 (Ying and Bottomley, continued from page 5) over 50% of patients reported fatigue as a chronic com- Patients who develop permanent hypoparathyroidism will plaint. Fatigue is frequently reported, even in those with require lifelong vitamin D and oral calcium preparations to normal or mildly suppressed TSH levels, and it is unclear maintain eucalcemia. how to intervene effectively. Studies combining L-thyrox- For the majority of patients, lifelong thyroid hormone ine with triiodothyronine therapy have not shown clear suppressive therapy is needed, compliance of which can benefit, but this may be considered in individual cases. be more challenging during the adolescent/young adult Other reported problems include anxiety, insomnia, tem- years. There has also been concern about the adverse perature sensitivity, skin changes, dryness, and pruritus. cardiac effects of long-term thyroid hormone suppressive At Univesity of Texas M. D. Anderson, we have developed a therapy for DTC. A few studies have shown increased left multidisciplinary survivorship clinic to focus on late effects ventricular mass index (LVMi) in treated patients compared from thyroid cancer. to controls, with resolution of the abnormalities with re- duction in suppressive doses of LT4. In other populations, Thyroid Cancer as a Second Malignancy increased LVMi has been associated with left ventricular Survivors of childhood cancer who have had radiation hypertrophy, which is an important risk factor for cardio- therapy to the neck or total-body irradiation as part of a vascular disease. The importance of this finding for de- stem cell transplant are at a higher risk for the develop- monstrable cardiac disease is unclear and other adverse ment of thyroid cancer later in life. The risk is increased for cardiac effects have not been consistently confirmed. those patients receiving up to 30 Gy to the neck, five years Many survivors of thyroid cancer express ongoing diffi- after irradiation. Therefore, it is important to be monitored culty with problems that may impact quality of life. When with thyroid exam annually by healthcare providers who compared to survivors of other cancers, thyroid cancer sur- are familiar with this potential late-effect of therapy. Ul- vivors are more likely to report memory problems, psycho- trasound with FNA is recommended for palpable nodules, logical issues, and migraine headaches. In another series, but not as regular screening.

Genetic Counseling and Genetic Aspects of Pediatric Endocrine Tumors

Thereasa A. Rich, MS, CGC, Certified Genetic Counselor, Department of Surgical Oncology and Endocrine Center Patient autonomy and informed consent are central guid- detection and treatment of such tumors can prevent seri- ing ethical principles surrounding genetic testing. These ous complications from tumor growth, such as vision loss in concepts are of special consideration in genetic testing for the case of retinal angiomas. children, since individuals under 18 years of age legally can- Mutations in SDHB, SDHD, and SDHC cause FPGL, which not give informed consent The genetic counseling issues is associated with a high lifetime risk to develop paragan- outlined by the American Society of Human Genetics (ASHG) gliomas (PGLs). The typical site that PGLs develop, the risk 1995 policy on genetic testing in minors will be reviewed for a PGL to become malignant, and the inheritance pattern and examined in the context of hereditary endocrine tumor varies between each gene. SDHD mutations are associated syndromes, including multiple endocrine neoplasia types with PGLs that tend to develop predominately from the 1 and 2 (MEN1 and MEN2), von Hippel-Lindau syndrome parasympathetic chain, have a low risk of malignancy, and (VHL), Li-Fraumeni syndrome (LFS) and the familial para- mutations are transmitted in an autosomal dominant pat- ganglioma syndromes (FPGL). tern with parent-of-origin effects –children who inherit a SDHD mutation from their mother are not expected to have Genetic testing is considered appropriate in childhood an increased risk for PGLs, but those that inherit a mutation when the information gained will result in a clear medical from their father do have a high risk. Mutations in SDHC benefit for the child and inappropriate when the informa- are associated with predominately benign parasympathetic tion will not result in medical benefit. PGLs and are inherited in a straightforward autosomal dom- MEN2 has served as a prototypical example of the useful- inant pattern. SDHB mutations are associated with predom- ness of genetic testing in childhood. Patients with MEN2 inately sympathetic PGLs, a relatively high risk for malig- have over a 90% lifetime risk to develop medullary thyroid nancy, and autosomal dominant transmission of mutations. cancer (MTC), which can be prevented or completely treated In all three syndromes, childhood onset of in those diagnosed at an early stage. Children with high risk is possible. Most published management guidelines, which RET mutations are recommended to undergo prophylactic are based on expert opinion, recommend initiating predic- thyroidectomy in early childhood to prevent the develop- tive genetic testing in childhood and screening of mutation ment of MTC. Other select cases involving RET mutations carriers. It is thought that screening and early tumor de- associated with later onset and less aggressive MTC may be tection should, theoretically, benefit a child medically given able to undergo expectant monitoring to delay thyroidec- the slow-growing nature of the tumors and the potential tomy until later in life. for catecholamine hypersecretion. The exception is test- Similarly, patients with VHL benefit from an early diagno- ing children at risk to inherit a SDHD mutation from their sis. While there are no preventive options, surveillance can mother; in such cases, predictive genetic testing should be significantly impact outcomes. Children with VHL are pri- delayed until adulthood since the information would not marily at risk for hemangioblastomas of the central nervous benefit the child medically. system, retinal angiomas, and pheochromocytomas. Early Continued on page 7 6 (Rich, continued from page 7) cent, or young adult learning they have a genetic disease The utility of genetic testing for other hereditary endo- for the first time. crine tumor syndromes is less clear. For example, patients The diagnosis of a genetic syndrome may also result in with MEN1 may occasionally present with childhood onset changes in life planning in terms of the child’s educational endocrine tumors, mainly primary goals, occupational choices, living arrangements (for ex- and pituitary adenomas, however in those that do, the dis- ample, feeling forced to live close to home, caregivers, and ease is typically not life-threatening. It is not clear whether their doctors), and financial planning, including retirement outcomes would be improved if these diseases are de- planning and obtaining various forms of insurance. The tected and treated in childhood versus waiting until early impact of the genetic condition on planning may be ap- adulthood. In situations such as this, where the medical propriate and helpful (for instance, positioning oneself in benefit is uncertain, the ASHG recommends careful coun- a situation of financial stability and insurability by taking seling about the benefits, risks, and limitations of genetic advantage of anti-discrimination laws), or inappropriate testing, and allowing the parents to make the decision. and detrimental (for instance, not pursuing educational or Li-Fraumeni Syndrome is a difficult situation in that pa- career opportunities or financial planning that otherwise tients do have a high risk to develop life-threatening can- would have been pursued). cers in childhood, but there are no screening measures that Finally, the diagnosis of a genetic condition in a child are likely to improve outcomes. LFS is associated with risk reveals information about future reproductive risks for for many different cancer types, but primarily brain tumors, the child and their parents. Children growing up with the soft tissue sarcomas, osteosarcomas, adrenocortical car- knowledge of their reproductive risk could experience sig- cinomas, and breast cancer; and all but the latter may be nificant anxiety, particularly as it relates to relationships, childhood onset. Since individuals with LFS are particularly dating, marriage, and their perceived desirability as a re- prone to radiation-induced malignancies, diagnostic TP53 productive partner. However it could also be argued that testing in children who are already affected with a LFS can- having the information from a young age could help the cer could impact the decision-making when radiation could child develop a mature view of family planning. Parents be a treatment option. In addition, identification of LFS in have the option to consider reproductive options, such as an affected child would alert to the possibility that the par- preimplantation genetic diagnosis and prenatal genetic ents could be at risk for LFS-associated cancers. Predictive testing, which reduce the risk of having another child with genetic testing in childhood is generally discouraged be- a genetic condition. However this raises special concerns in cause there is little medical benefit to the child and the po- terms of how the parents’ reproductive choices may impact tential for psychological harm becomes the predominant the psychology of the affected child (“my parents avoided consideration. having another child like me”). Genetic testing in childhood may be associated with pos- Childhood genetic testing often involves consent from a itive or negative psychological effects and may impact family unit rather than a single individual. As children family dynamics and family planning. get older; they have increasing emotional and intellec- Predictive genetic testing in childhood is discouraged tual capacity to understand the implications of genetic in cases where there is no medical benefit to the child be- testing, and should be increasingly involved in decisions cause there is a real potential for psychosocial harm. While about their own medical care. there is still very little research addressing this topic, mul- Legally, a child is unable to provide informed consent tiple concerns have been raised by experienced geneticists until 18 years of age; however most people can draw from and child psychologists. For the child, a genetic diagno- personal experience that emotional and intellectual matu- sis could negatively impact self-esteem, self-image, and rity cannot always be predicted from age alone. There is expectations out of life. Parents of a child with a genetic a growing trend of involving children in their own medi- diagnosis may perceive their child to be sick or vulnerable cal care since a child’s assent may foster stronger and more resulting in overprotective behaviors, over-reaction to trusting relationships with the healthcare team and poten- common childhood symptoms, and differential treatment tially empower the child such that their long-term health of the child. Even in cases of children who did not inherit outcomes might be improved. the genetic condition in the family, there is the potential In most cases, parental authority is ultimately honored for survivor guilt (“why NOT me?”) and resentment of the given the lack of the legal ability of the child to provide extra attention often paid to the affected sibling. consent and the presumption that parents are promoting While much of the literature on psychosocial implica- the best interests of the child. While uncommon, complex tions of genetic testing focuses on potential harms, there ethical and legal issues can arise if parents and clinicians is also the potential that genetic testing could have a psy- disagree about whether a genetic test is appropriate in a chological benefit. For instance, identifying children who child. are NOT at risk for the hereditary condition in the family Geneticists and genetic counselors are available to help can create a tremendous amount of relief and the child and families and clinicians tackle issues related to childhood family would be spared from the burden of expensive and genetic testing, and in the rare instances of ethical dilem- time-consuming screening exams. For other patients, con- mas, a medical ethics committee can be employed. firmation of a diagnosis reduces uncertainty and allows the family to plan ahead for the medical care their child is ex- pected to need. It is also possible that growing up with the knowledge of a genetic condition from an early age could be less impactful on self-image as an older child, adoles- 7 The University of Texas NONPROFIT M. D. Anderson Cancer Center Endocrine Neoplasia and Hormonal Disorders - Unit 1461 U.S. POSTAGE

PO Box 301402 PAID Houston, Texas 77230-1402 HOUSTON, TX

PERMIT NO. 7052

Thyroid Nodule Clinic Do you need a Resource for a Suspicious Thyroid Nodule? Thyroid nodules are fairly common, representing the most common endocrine neoplasia problem in the United States, but effective evaluation is extremely important to rule out thy- roid cancer. Dr.. Naifa Busaidy, Director of the Thyroid Nodule Clinic now open at M. D. Anderson Cancer Center says, “The clinic serves as a resource for our physicians and all patients with thyroid nodules. We want to be a part of your team in providing an exceptional experience for the community physician and their adult and pediatric patients. Getting a rapid and accurate diagnosis in one place at one time for a patient anxious about whether or not they might have cancer, improves the experience for all those involved. The experienced multidisciplinary team of endocrinologists, surgeons, mid-levels, cytopathologists radiologists and ultrasonographers at M. D. Anderson are here to help you. We also have two pediatric endocrinologists who can evaluate pediatric patients of all ages. All patients receive within one day: - Consultation with a thyroid specialist - Thyroid ultrasound - Thyroid biopsy, if needed - Multidisciplinary conference to discuss treatment options, if needed. The Thyroid Nodule Clinic is located inside the Endocrine Center at M. D. Anderson Cancer Center at 1515 Holcombe in Houston, Texas. For more information or to refer a patient for an appointment: New Patient Referral Coordinators: 713-563-4400, and 713-792-5410 for patients under 18 years of age. Physician to Physician Referrals: 713-792-2841 Online Referrals: https://my.mdanderson.org/

Department of Endocrine Neoplasia and Hormonal Disorders Faculty Steven I. Sherman, M.D., Chair, Professor Mimi I. Hu, M.D., Assistant Professor and Center Medical Director, Endocrine Center Camilo Jimenez, M.D., Assistant Professor Naifa L. Busaidy, M.D., Assistant Professor Victor R. Lavis, M.D., Professor Rozita Bagheri-Yarmand, Ph.D., Assistant Professor Sara Peleg, Ph.D., Associate Professor Maria E. Cabanillas, M.D., Assistant Professor Rena Vassilopoulou-Sellin, M.D, Clinical Professor Gilbert J. Cote, Ph.D., Professor Steven G. Waguespack, M.D., Associate Professor Robert F. Gagel, M.D., Professor Sai Ching Jim Yeung, M.D., Ph.D., Associate Professor Mouhammed A. Habra, M.D., Assistant Professor Anita K. Ying, M.D., Assistant Professor

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