Assessment of Depression,Anxiety,Quality of Life,and Coping in Long-Standing Multiple Endocrine Neoplasia Type 2 Patients

Abstract

Background:

Data on psychological harm in multiple endocrine neoplasia type 2 (MEN2) are scarce.

Objectives:

The aim of this study was to assess anxiety, depression, quality of life, and coping in long-standing MEN2 patients.

Patients and Methods:

Patients were 43 adults (age ≥18 years) with clinical and genetic diagnosis of MEN2 and long-term follow-up (10.6 ± 8.2 years; range 1–33 years). This was a cross-sectional study with qualitative and quantitative psychological assessment using semi-directed interviews and HADS, EORTC QLQ C30, and MINI-MAC scales. Adopting clinical criteria from 2015 ATA Guidelines on MEN2, biochemical cure (39%; 16/41), persistence/recurrence (61%; 25/41), and stable chronic disease (22/41) of medullary thyroid carcinoma (MTC) were scored. Pheochromocytoma affected 19 (44%) patients, with previous adrenalectomy in 17 of them.

Results:

Overall, anxiety (42%; mean score 11 ± 2.9; range 8–18; anxiety is defined as a score ≥8) and depression (26%; mean score 11 ± 3.8; range 8–20; depression is defined as a score ≥8) symptoms were frequent. Patients who transmitted RET mutations to a child had higher scores for weakness-discouragement/anxious preoccupation and lower scores for cognitive, emotional, and physical functioning (p < 0.05). Feelings of guilt were present in 35% of patients with mutation-positive children. Lower mean score values for depression and anxiety and higher scores for role, cognitive, and emotional functioning were noticed in 33 patients who were well-informed about their disease (p < 0.05). Fighting spirit was more frequently found in patients with multiple surgical procedures (p = 0.019) and controlled chronic adrenal insufficiency (p = 0.024). Patients with MEN2-related stress-inducing factors had lower scores for fighting spirit and cognitive functioning and higher scores for insomnia and dyspnea (p < 0.05). Eleven patients required sustained psychotherapeutic treatment. Mean global health status was relatively good in MEN2 cases (68.1 ± 22.3), and the cured group had higher physical functioning (p = 0.021).

Conclusions:

Psychological distress is likely chronic in MEN2 patients. This study identified diverse MEN2-related factors (degree of information on disease, mutation-positive children, number of surgeries, comorbidities, stress-inducing factors, and cure) interfering positively or negatively with the results of the psychometrics scales. The active investigation of these factors and the applied psychological assessment protocol are useful to identify MEN2 patients requiring psychological assistance.

Introduction

Cancer patients may frequently develop psychological effects such as anxiety and depression as a consequence of fear of recurrence, stress over surgery, and low self-esteem (1). Thus, standard-of-care guidelines for distress management in oncologic patients have been established (2). Presently, advances in therapy and early diagnosis have significantly increased the cure rate of several types of cancer, or have allowed patients to live with stable disease for prolonged periods.

In familial cancer syndromes, psychosocial challenges include the stigmatization and burden conferred by positive mutation carrier status, fear of social discrimination, decision making on reproduction, issues related to genetic testing in relatives and offspring, feelings of guilt for transmission of a germline mutation to descendants, and direct influences on a couple relationship or between parents and children, among others. Moreover, these factors may potentially amplify psychological distress in patients with hereditary cancer (3 –5).

Recently, sporadic and multiple endocrine neoplasia type 2 (MEN2)-related medullary thyroid carcinoma (MTC) have been extensively reviewed (6 –11). Contrasting with most cancers, MTC is often a slow-growing carcinoma. Patients usually live prolonged periods with stable advanced disease and frequently have a higher global health status and potential long-term survival. In MTC associated with MEN2, in which the diagnosis is often performed at earlier stages than observed with the sporadic form of MTC (6,7,12 –17), patients and relatives can be facing the psychosocial challenges associated with familial cancer syndromes outlined above. In this scenario, MEN2-related MTC is a good model to study the psychological impact on the quality of life (QoL) and psychological adjustments in patients living with cancer as a chronic disease.

In addition, treatment-related complications may occur in a substantial number of MEN2-related MTC patients, such as hypoparathyroidism after total thyroidectomy, adrenal insufficiency due to bilateral adrenalectomy, and postsurgical hypothyroidism. These clinical conditions, even if appropriately treated with supplementation therapy, are usually associated with lower health-related quality of life (HRQoL) (18 –22).

Early psychological studies in MEN2 have focused on the distress related to genetic counseling and the disclosure of RET genetic testing results to patients and their at-risk descendants (3,4,23 –25). However, scarce data are available on the psychological consequences of MEN2 independent of genetic testing disclosure (26,27).

The current study assessed anxiety and depressive symptoms, HRQoL, and psychological adjustment in a subset of 43 MEN2 patients living for years with MTC or at potential risk of MTC recurrence.

Material and Methods

Patients

The study was conducted between November 2011 and March 2015 and was approved by the local ethics committee (CAPPesq) of the University of São Paulo School of Medicine and the national ethics committee (CONEP). A signed informed consent was obtained from all studied individuals. Only patients with at least one year of clinical and genetic diagnosis and follow-up of MEN2 were invited to participate. Thus, a chronicity status was secured in all patients, tentatively excluding immediate and direct influences of the disclosure of genetic test results at the time of the psychological interview. Other eligibility criteria included the following: patients with stable apparent or occult metastatic disease, cervical recurrent MTC or slowly progressive distant metastasis, and biochemically cured patients after total thyroidectomy (basal serum calcitonin levels <2 pg/mL).

The exclusion criteria were as follows: negative RET status, young RET-mutation carrier individuals (<18 years), mental disease, brain metastasis, recent chemotherapy and/or radiotherapy (<6 months), end-stage advanced disease at the time of interview, quickly progressive advanced MTC, uncontrolled hypothyroidism, hypoparathyroidism, or adrenal insufficiency.

All patients were participants of the MEN2 clinical screening program performed by the authors' group since 1985 at the Endocrine Genetics Unit. RET genetic testing and genetic counseling have been offered to all MEN2 patients and their at-risk relatives since 1999. Overall, 43 adult patients from unrelated 12 families, following the inclusion and exclusion criteria, agreed to participate: 11 index cases and 32 family members with clinical and genetic diagnosis of MEN2 (Table 1). A large family was defined as a family with five or more affected members.

Table 1.

Clinical and Genetic Characteristics of 43 MEN2 Patients

Characteristics	n (%)
Sex
Male	19 (44)
Female	24 (56)
Syndrome and phenotypic variants/genotype
1. MEN2A (12 families)	42 (98)
Typical (classical) MEN2A (3 families)	11 (26)
c.1858T>C, p.C620R (1 family)	1 (2)
c.1900T>C, p.C634R (1 family)	8 (19)
c.1901G>A, p.C634Y^a (1 family)	2 (5)
MEN2A and CLA (5 families) 7/17 patients with CLA	17 (39)
c.1900T>C, p.C634R (2 families)	3 (7)
c.1901G>A, p.C634Y (1 family)	2 (5)
c.1901G>A, p.C634Y^a (1 family)	7 (16)
c.1901G>A, p.C634Y^a (1 family)	5 (11)
MEN2A and HD (2 families) 2/11 patients with HD	11 (26)
c.1858T>C, p.C620R:
MEN2A/HD (1 family)	4 (10)
MEN2/HD (1 family)	7 (16)
MEN2A (1 family)	3 (7)
c.2410G>A, p.V804M (MTC only)
2. MEN2B (1 family)	1 (2)
c.2753T>C, p.M918T
MTC	43 (100)
Previous surgery	41/43 (95)
Cured (cancer survivors)	16/41 (39)
Not cured (chronic oncologic patients):	25/41 (61)
Stable metastatic disease (occult or distant)	22/41 (54)
Cervical recurrent/ distant slowly progressive disease	3/41 (7)
Type of surgeries
Prophylactic thyroidectomy	1/41 (2)
Total thyroidectomy	21/41 (51)
Total thyroidectomy + cervical lymph node dissection	19/41 (47)
Additional surgical procedures of cervical lymph node dissection	16/41 (41)
Total cervical surgeries: 57
Persistent hypoparathyroidism	12/41 (29)
No previous surgery (1 case awaiting for surgery; 1 case refused it)	2/43 (5)
Pheo	18 (42)
Bilateral Pheo	12/18 (67)
Unilateral Pheo	6/18 (33)
Previous surgery	16/18 (89)
Types of surgery
Unilateral adrenalectomy	4/16 (25)
Bilateral adrenalectomy	12/16 (75)
Synchronous	5/12 (42)
Asynchronous	7/12 (58)
Total number of adrenal surgeries: 23
Adrenal insufficiency in glucocorticoid/mineralocorticoid therapy	12/18 (67)
Waiting for surgery	2/18 (11)
Hirschsprung disease	2/43 (5%)
Distal colectomy + corrective surgery of intestinal transit
Number of surgeries
0	1 (2)
1	18 (42)
2	12 (28)
3	10 (24)
4	1 (2)
6	1 (2)
Total number of surgeries: 82

The p.C634Y mutation and the allelic variant p.Y791F segregated in MEN2 patients of four families (59).

MEN2, multiple endocrine neoplasia type 2; MEN2A, MEN type 2A; MEN2B, MEN type 2B; MTC, medullary thyroid cancer; Pheo, pheochromocytoma; CLA, cutaneous lichen amyloidosis; HD, Hirschsprung Disease; n, number; Reference sequence, NC_000010.10 for genomic DNA and NM_020630.4 for cDNA.

The clinical criteria recently established by the 2015 American Thyroid Association (ATA) Guidelines for MTC were applied to define MEN2A, MEN2B, and the four phenotypic variants of MEN2A: classical MEN2A, MEN2A associated with Hirschsprung Disease, MEN2A with cutaneous lichen amyloidosis, and isolated familial MTC (7).

Methods

In the present cross-sectional study, semi-directed interviews, psychological assessment instruments, and review and analysis of medical records were applied.

Semi-directed interview

Patients were classified according to sex, age, marital status, education level, occupation, and number of children. Feelings of guilt associated with the possibility of transmitting the genetic mutation, current disease status (active disease or cured), and satisfaction degree with information previously offered about the disease were addressed. Three psychological scales usually applied to cancer patients were selected. The tests were initially developed in English (28 –30) and then translated to and statistically validated in Portuguese (31 –33).

Hospital Anxiety and Depression scale

The Hospital Anxiety and Depression scale (HADS) defines the presence or absence of distress through application of a questionnaire including 14 items: seven questions directed to investigate depression (HADS-D) and seven to assess anxiety (HADS-A). The total scores for each subscale—depression and anxiety—ranges from 0 to 21. Scores of ≥8 in both subscales are suggestive of an anxiety disorder or depression. The scale has the advantage of being appropriate for cancer patients, allowing the exclusion of physical signs and symptoms that could interfere in assessing depression and anxiety (28,31,34,35).

European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30

The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ C30) is a psychological assessment tool widely used to evaluate QoL in cancer patients (29,36). It consists of 30 questions for assessing general aspects of HRQoL in cancer patients. The results are converted to a linear score ranging from 0 to 100. For functional and global health domains, 0 means the worst HRQoL status and 100 represents the best status. For the symptoms scale, higher scores correspond to higher intensity of symptoms and lower HRQoL status (29,33,36,37). Additionally, patients were assessed with the Eastern Cooperative Oncology Group (ECOG) performance status scale (29).

Scale of Mental Adjustment to Cancer: Factorial Structure

The MINI-MAC was developed to assess different types and degrees of psychological adjustment during lifetime of oncologic patients. It is based on 29 questions related with reactions of patients to cancer, which are answered following a Likert scale of four points reflecting levels of agreement: level 1, this is not remotely applicable to me; level 2, it is not applicable to me; level 3, it applies to me; and level 4, it applies fully to me. The questionnaire defines five subscales: discouragement-weakness, anxious preoccupation, fighting spirit, cognitive avoidance, and fatalism. The highest score corresponds to the greatest endorsement of the adjustment response (30,32). Demographic/clinical characteristics and genetic profiles of the 43 MEN2 patients were obtained through a review of medical records and semi-directed interviews.

Data analysis

Data analysis was performed qualitatively and quantitatively. The issues of semi-directed interviews were analyzed using the technique of content analysis. Quantitative data were analyzed using SPSS for Windows v16.0 (SPSS, Inc., Chicago, IL). Spearman correlation was applied to analyze relations between the scales of anxiety, depression, fighting spirit, and the other scales. Tests were performed with a significance level of 5%.

Results

Clinical and genetic profile

The clinical and genetic characteristics of the 43 MEN2 patients are shown in Table 1. A MEN2A phenotype was present in 98% (42/43) of cases, whereas a MEN2B syndrome was identified in one (2%) case. The latter patient with MEN2B had a milder clinical presentation of MTC, characterized by a slower progression and lower aggressiveness than that expected for patients harboring a M918T mutation. Despite the late MTC diagnosis (at 17 years of age) and therapy (total thyroidectomy + cervical lymph node dissection), this patient had stable and persistent biochemical disease characterized by mildly elevated calcitonin levels (33 pg/mL) for a long period of follow-up (7 years). A typical MEN2A phenotype was present in 11 patients from three families harboring RET mutations: p.C634R (n = 8), p.C634Y (n = 2), and p.C620R (n = 1). MEN2A associated with cutaneous lichen amyloidosis was seen in five families involving 17 affected cases: 14 patients carrying a p.C634Y and three carrying a p.C634R mutation, seven of whom exhibited cutaneous lichen amyloidosis. The phenotypic variant of MEN2A associated with Hirschsprung Disease was identified in one patient in each of two unrelated families harboring a p.C620R mutation (Table 1). In the first family with associated Hirschsprung Disease, pheochromocytoma (Pheo) was present in one of the four patients with MTC, while it was absent in all seven affected members with MTC in the second MEN2 family (38). The affected members of one family with a p.V804M mutation developed only MTC, and the three subjects were >50 years of age from two generations (Table 1).

MTC was detected in all 43 patients, of whom 41 (95%) had been previously submitted to total thyroidectomy: 39% (16/41) were biochemically cured of MTC after surgery, and 61% (25/41) had persistent/recurrent disease. Thus, previous surgical treatment of MTC was not performed in only two patients: one (p.C634Y) previously underwent bilateral adrenalectomy for Pheo and was waiting for thyroidectomy, whereas the other (p.V804M), with mildly high basal calcitonin levels and positive calcium test, refused surgery. Twelve patients required long-term therapy with oral calcium and calcitriol due to persistent postsurgical hypoparathyroidism (29%; 12/41; Table 1).

Pheo was diagnosed in 18 (42%) patients, and 16 of whom were previously submitted to adrenalectomy: 12 bilateral (5 synchronous; 7 asynchronous) and four unilateral. The two remaining patients have recently been diagnosed with unilateral disease, and psychological interviews preceded adrenalectomy. All 12 patients with adrenal insufficiency secondary to bilateral adrenalectomy were treated with glucocorticoid/mineralocorticoid substitution and were clinically well controlled at the time of the psychological evaluation (Table 1).

Two patients underwent intestinal surgery for Hirschsprung Disease during the first year of life. Overall, 41 patients were submitted to 82 surgical procedures for MEN2 (M = 2.0 surgery/patient; range 1–6 surgeries; Table 1).

MEN2-related MTC: long-term follow-up

Long-term follow-up of MEN2-related MTC cases was documented (Table 2). The duration of the follow-up, considered as the time interval between the first surgery and psychological interviews, was 10.6 ± 8.2 years (range 1–33 years). Most patients (34; 81%) had the first surgery 3–33 years before the psychological interview. Furthermore, illustrating the relatively long follow-up, the mean time interval between the last surgery and the psychological interview was 5.5 ± 4.6 years (range 1–15 years). Most patients (28; 67%) had the last surgery 3–15 years before the psychological interview (Table 2).

Table 2.

Potentially Stressful Factors, Psychological Complaints, Disorders, and Adjustment Types Observed in 43 Chronic MEN2 Patients, Following the Administration of Psychological Assessment Instruments (Semi-Directed Interview, HADS, and MINI-MAC)

Long-standing follow-up, M_age ; range (years)
a. Psychological interview	39.3 ± 14.7; 19–70
b. First surgery	28.1 ± 15.1; 5–67
c. Last surgery	33.3 ± 15.7; 8–67
Correlations: a versus b (p < 0.001); a versus c (p < 0.001)
Time interval between first surgery and psychological interview: 10.6 ± 8.2; 1–33
Time interval between last surgery and psychological interview: 5.5 ± 4.6; 1–15
Semi-directed interview
1. Stressful potentially factors, n (%)
Patients with RET mutation-positive children	17 (40)
Expectancy for results of genetic testing	7 (16)
Waiting for the own surgery	4 (9)
Waiting for surgery of their children	1 (2)
Slowly progressive distant metastasis	2 (5)
Total	30 (70)
2. Feelings of guilt from transmission of the mutation to their children, n (%)
Presence of guilt	6 (35)
Absence of guilt	11 (65)
HADS, n (%)
Anxiety symptoms (score ≥8)	18 (42%)
	Score: 11 ± 2.9, range 8–18
Depression symptoms (score ≥8)	11 (26%)
	Score: 11 ± 3.8, range 8–20
Clinically relevant anxiety symptoms (score ≥11)	12 (28%)
	Score: 13 ± 2.6, range 11–18
Clinically relevant depression symptoms (score ≥11)	5 (12%)
	Score: 14 ± 3.6, range 11–20
MINI-MAC (scale from 1 to 4), ^a M ± SD
Weakness-discouragement	1.5 ± 0.84
Anxious preoccupation	1.9 ± 0.95
Fighting spirit	3.3 ± 0.77
Cognitive avoidance	2.56 ± 1.17
Fatalism	3.1 ± 0.90

An average value closer to the maximum value (of 4) represents a higher level of coping used by the cancer patient, as follows: level 1, this is not remotely applicable to me; level 2, this is not applicable to me; level 3, this applies to me; level 4, this applies fully to me.

HADS, Hospital Anxiety and Depression scale; MINI-MAC, scale of mental adjustment to cancer: factorial structure; SD, standard deviation.

Most patients with persistent MTC (85%; 22/25) had stable disease characterized by occult biochemical disease or structural/biochemical disease with clear evidence of stable distant metastasis. Three other patients presented slowly progressive disease defined by cervical recurrence and/or slow progression of distant metastasis. Therapies such as chemotherapy, radiotherapy, or inclusion in clinical trials with targeted therapies were not recommended for the latter cases. At the time of interview, only four patients with previous MEN2-related surgeries were still waiting for surgical procedures (MTC 2; Pheo 2). One patient with local recurrence waited for cervical surgery, another for thyroidectomy and parathyroidectomy after subtotal adrenalectomy, and two patients for unilateral adrenalectomy. One patient refused surgery for MTC (Table 1).

Overall, 25 MEN2 patients had uncured MTC (stable 22, recurrent/slowly progressive 3), whereas 16 were biochemically cured patients. Another two patients had no previous treatment for MTC (Table 1).

Psychological profile

Semi-directed interview

In the semi-directed interview, 31 (72%) patients reported fear of dying when they received the genetic diagnosis. At the time of the psychological interview, 30 (70%) MEN2 patients had children, and 24 of them reported that RET genetic testing had been offered to them. All except one agreed with RET genetic testing for their children. Each of the other six (18%) affected parents with children younger than three years of age received genetic counseling based on the recommendations issued in the 2009 ATA Guidelines (14). Seventeen (70%) parents had at least one RET mutation-positive child. One was waiting for the genetic testing result. Six other parents had mutation-negative children. Overall, 46 at-risk children were tested, and half of them were positive RET carriers. Most parents (13/17; 76%) expressed strong feelings of fear of losing their children at the time of genetic testing disclosure. Feelings of guilt of having transmitted the genetic mutation to their children were present in one third of transmitting parents (6/17; 35%; Table 2). At the time of the psychological interview of the 17 MEN2 parents with a RET mutation-positive child, all their children except one had a previous history of at least one MEN2-related surgery.

HADS anxiety scale

High scores for anxiety symptoms, defined as a HADS score ≥8, were present in 18 cases (42%; score 11 ± 2.9; range 8–18): 12 (28%) patients had scores ≥11, indicating the presence of clinically relevant anxiety symptoms, whereas another six (14%) patients exhibited symptoms of anxiety disorders (8 ≤ score <11). In the remaining 25 MEN2 patients, the mean HADS score was 4 ± 2.2 (range 0–7; Table 2).

HADS depression scale

High scores compatible with depression symptoms, defined as a HADS score ≥8, were detected in 11 cases (26%; score 11 ± 3.8; range 8–20). Scores ≥11 were found in five (12%) patients, documenting clinically relevant depression symptoms, whereas symptoms indicative of depression disorders were present in six patients (14%; 8 ≤ score <11). Low score values were documented in the remaining 32 patients (74%; score 3 ± 2.0; range 0–7; Table 2).

Overall, distress (anxiety and/or depression) was present in 20 (46%) cases, taking a HADS score ≥8 as the cutoff, and of these, 13 (30%) had HADS scores ≥11.

MINI-MAC

Mean values of the different types of coping in the 43 MEN2 patients evaluated by MINI-MAC are shown in Table 2. Coping behaviors such as fighting spirit (3.3 ± 0.77), cognitive avoidance (2.56 ± 1.17), and fatalism (3.1 ± 0.90) were higher than weakness-discouragement (1.5 ± 0.84) and anxious preoccupation (1.9 ± 0.95; Table 2). Very high score values (≥3) were more frequent for fighting spirit (86%; 37/43) and fatalism (65%; 28/43) in comparison with cognitive avoidance (42%; 18/43), anxious preoccupation (16%; 7/43), and weakness-discouragement (9%; 4/43). All 13 patients with the maximum score of four for fatalism had high scores (range 3.25–4.0) for fighting spirit.

EORTC QLQ C30

Most of the 43 MEN2 patients were in a satisfactory global state of health (68.1 ± 22.3) when assessed by EORTC QLQ C30, considering both physical and emotional aspects (Table 3). Patients were classified as ECOG 0 (29/43; 67%) or 1 (14/43; 33%).

Table 3.

Quality of Life Results Obtained for 43 MEN2 Patients Using EORTC QLQ C30

EORTC QLQ C30	M ± SD
Global health status/QoL^a	68.1 ± 22.3
Functional scales
Role functioning^a	72.4 ± 32.2
Cognitive functioning^a	57.7 ± 36.1
Physical functioning^a	79.3 ± 21.2
Emotional functioning^a	59.7 ± 32.8
Social functioning^a	81.4 ± 28.9
Symptom scales
Pain^b	35.3 ± 36.6
Fatigue^b	31.3 ± 29.5
Insomnia^b	27.8 ± 35.9
Constipation^b	23.6 ± 36.7
Diarrhea^b	12.7 ± 20.7
Nausea and vomiting^b	12.2 ± 21.2
Dyspnea^b	27.3 ± 35.7
Appetite loss^b	19.7 ± 35
Financial difficulties^b	17.4 ± 30.5

Scores range from 0 to 100, with a higher score representing a higher level of function.

Scores range from 0 to 100, with a higher score representing a higher level of symptoms.

EORTC QLQ C30, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30; QoL, quality of life.

Correlation between psychological assessment instruments

A strong direct correlation between anxiety and depressive symptoms was detected (r = 0.702; p < 0.001). Both symptoms had direct correlations with weakness-discouragement, anxious preoccupation, cognitive avoidance, fatigue, pain, insomnia, and constipation (Supplementary Table S1; Supplementary Data are available online at www.liebertpub.com/thy). Inverse correlations were detected between anxiety/depression symptoms and scales of global health status and functional subscales (role, cognitive, social, and emotional functioning; p < 0.05; Supplementary Table S2). A correlation between fighting spirit and fatalism was also observed (r = 0.369; p = 0.015). However, no correlation between anxiety/depression symptoms and fighting spirit was observed (p > 0.05).

Eleven (25%) patients required individual psychotherapeutic follow-up after the initial evaluation.

Cured versus uncured MTC patients

Higher scores for physical functioning (87 ± 21 versus 77 ± 18; p = 0.021) and cognitive avoidance (odds ratio [OR] = 2.68; p = 0.024) were observed in the cured group compared with uncured cases. Furthermore, a non-significant tendency to a higher prevalence of working activities was observed in cured (81%) compared with uncured (52%) patients (p = 0.054). There was no correlation between ECOG performance and state of cure in the patients (p = 0.084).

Combined or independent analysis of potential factors of psychological effect

Presence of children

Twenty-five patients had children either harboring mutations or waiting for genetic testing disclosure or genetic screening. These affected parents were compared with 18 patients with no children or with RET-negative children. The first group had higher scores for insomnia (p = 0.004), dyspnea (p = 0.005), anxious preoccupation (p = 0.008), and weakness-discouragement (p = 0.049). Furthermore, scores were lower for cognitive (p = 0.001), emotional (p = 0.028), and physical functioning (p = 0.038) in the first subset of cases (Table 4).

Table 4.

Psychological Harm in MEN2 Patients as a Result of the Presence/Absence of Children, Knowledge of RET Genetic Status of the Offspring (RET-Positive Children or RET-Negative Children), and Expectancy for RET Genetic Testing Disclosure

Variable	Children ^a	M	SD	Minimum	Maximum	n	p
Age (years)	Yes	42.56	13.99	22.0	70.0	25	0.083
	No	34.72	14.70	19.0	66.0	18
HADS: anxiety	Yes	8.12	5.00	1.0	18.0	25	0.081
	No	5.39	3.48	0.0	11.0	18
HADS: depression	Yes	5.64	4.95	0.0	20.0	25	0.400
	No	4.11	3.39	0.0	12.0	18
Weakness-discouragement	Yes	1.70	1.01	1.0	4.0	25	0.049
	No	1.19	0.44	1.0	2.8	18
Anxious preoccupation	Yes	2.23	1.03	1.0	4.0	25	0.008
	No	1.49	0.66	1.0	3.0	18
Role functioning	Yes	64.00	36.86	0.0	100.0	25	0.056
	No	86.11	19.17	33.3	100.0	18
Cognitive functioning	Yes	42.00	38.22	0.0	100.0	25	0.001
	No	80.56	19.17	50.0	100.0	18
Fatigue	Yes	38.67	31.61	0.0	100.0	25	0.056
	No	20.99	25.54	0.0	88.9	18
Insomnia	Yes	40.80	39.74	0.0	100.0	25	0.004
	No	9.26	22.30	0.0	66.7	18
Physical functioning	Yes	74.93	21.54	33.3	100.0	25	0.038
	No	88.52	13.30	60.0	100.0	18
Emotional functioning	Yes	50.91	33.63	0.0	100.0	25	0.028
	No	73.38	28.91	4.2	100.0	18
Dyspnea	Yes	40.00	39.67	0.0	100.0	25	0.005
	No	9.26	22.30	0.0	66.7	18

Statistically significant (p < 0.05) values are shown in bold; those in italic bordered statistical significance.

MEN2 patients with children either harboring RET mutations or waiting for genetic testing disclosure or for genetic screening (yes); MEN2 patients with no children or with RET-negative children (no).

Information on disease

Thirty-three MEN2 patients (77%) reported they were well informed on MEN2 by the multidisciplinary team. These patients had lower mean scores for fatigue (p = 0.002), weakness-discouragement (p = 0.012), anxiety (p = 0.022), depression (p = 0.031), anxious preoccupation (p = 0.031), and constipation (p = 0.044), as well as higher scores for role (p = 0.010), cognitive (p = 0.031), and emotional functioning (p = 0.009; Table 5).

Table 5.

Correlations Between Information Degree on MEN2 Disease and Psychometric Indexes of the HADS, MINI-MAC, and EORTC QLQ-C30

Variable	Information degree on MEN2 ^a	M	SD	Minimum	Maximum	n	p
Age (years)	Yes	40.18	14.57	22.0	70.0	33	0.470
	No	36.30	15.32	19.0	68.0	10
HADS: anxiety	Yes	6.03	4.16	0.0	15.0	33	0.022
	No	10.10	4.77	4.0	18.0	10
HADS: depression	Yes	4.15	3.65	0.0	15.0	33	0.031
	No	7.80	5.57	3.0	20.0	10
Weakness-discouragement	Yes	1.33	0.76	1.0	4.0	33	0.012
	No	2.00	0.98	1.0	3.8	10
Anxious preoccupation	Yes	1.75	0.91	1.0	4.0	33	0.031
	No	2.49	0.95	1.0	4.0	10
Role functioning	Yes	80.81	26.39	0.0	100.0	33	0.010
	No	48.33	38.85	0.0	100.0	10
Cognitive functioning	Yes	65.15	33.69	0.0	100.0	33	0.031
	No	35.00	38.85	0.0	83.3	10
Fatigue	Yes	22.90	24.68	0.0	77.8	33	0.002
	No	58.89	31.45	11.1	100.0	10
Constipation	Yes	14.14	27.68	0.0	100.0	33	0.044
	No	53.33	50.18	0.0	100.0	10
Emotional functioning	Yes	67.73	30.51	4.2	100.0	33	0.009
	No	35.83	31.68	0.0	91.7	10

Statistically significant (p < 0.05) values are shown in bold. Preferentially, the correlations with statistical significance were represented in table.

Patients declared, during the semi-directed interview, if they felt satisfied and well-informed (yes) or not (no) about MEN2 disease.

Factors inducing stress

Overall, 30 MEN2 patients presented one or more potential stress-inducing factors: patients (40%; 17/43) with RET mutation-positive children (50%; 23/46), patients waiting for surgery (9%; 4/43) or surgery for their children (2%; 1/43), parents awaiting genetic testing of their children (16%; 7/43), and presence of slowly progressive distant metastasis (5%; 2/43). These stress-inducing factors were absent in 13 subjects (30%; Table 2). Of note, there were no differences in global health status or anxiety/depression scores between these two groups. In patients with stress-inducing factors, scores were higher for fighting spirit (3.6 ± 0.36 vs. 2.9 ± 0.94; p = 0.028), insomnia (36.2 ± 39.2 vs. 7.7 ± 20; p = 0.034), and dyspnea (35.6 ± 39 vs. 7.7 ± 20; p = 0.034), and lower for cognitive functioning (48.9 ± 38.7 vs. 79.5 ± 20.6; p = 0.019). Stress-inducing factors were significantly more frequent in older MEN2 patients and women (67% vs. 33%; p = 0.029; Table 6).

Table 6.

Correlations Between Stressful Factors ^a in MEN2 Patients and Psychometric Indexes of the HADS, MINI-MAC, and EORTC QLQ-C30

Variable	Stressful factors	M	SD	Minimum	Maximum	n	p
Age (years)	Yes	42.40	14.27	22.0	70.0	30	0.032
	No	32.08	13.36	19.0	65.0	13
HADS: anxiety	Yes	7.60	4.87	1.0	18.0	30	0.265
	No	5.54	3.64	0.0	11.0	13
HADS: depression	Yes	5.20	4.77	0.0	20.0	30	0.948
	No	4.54	3.48	0.0	12.0	13
Fighting spirit	Yes	3.60	0.36	3.0	4.0	30	0.028
	No	2.92	0.94	1.0	4.0	13
Cognitive functioning	Yes	48.89	38.64	0.0	100.0	30	0.019
	No	79.49	20.59	50.0	100.0	13
Insomnia	Yes	36.22	39.21	0.0	100.0	30	0.034
	No	7.69	19.97	0.0	66.7	13
Dyspnea	Yes	35.56	39.08	0.0	100.0	30	0.034
	No	7.69	19.97	0.0	66.7	13

Statistically significant (p < 0.05) values are shown in bold. Preferentially, the correlations with statistical significance were represented in table.

Patients with or without potential stressful factors. The following stressful factors were considered: parents with RET mutation-positive children, cases waiting for his own surgery or of their children, short-term expectancy for genetic testing of their children, and presence of slowly progressive distant metastasis.

Treatment-related comorbidities

HADS, EORTC QLQ C30, and MINI-MAC score values did not differ in patients with or without hypoparathyroidism. Fighting spirit was higher in patients who had undergone three or more surgical procedures (3.8 ± 0.4 vs. 3.3 ± 0.71; p = 0.019) or who had clinically controlled chronic adrenal insufficiency secondary to bilateral adrenalectomy (3.6 ± 0.9 vs. 3.3 ± 0.6; p = 0.024; Supplementary Table S3). The presence of treatment-related comorbidities (hypoparathyroidism and adrenal insufficiency) or number of MEN2-related surgical procedures did not interfere with working activities.

Other correlations

Data for demographic profile (age, sex, job, marital status, and education level), patient status (index case or family member), and family size were correlated with results obtained from psychometric scales (HADS, MINI-MAC, and EORTC QLQC 30), disease state (cured or uncured), presence/absence of children, presence/absence of mutation-positive children, ECOG status and presence/absence of MEN2-related stress-inducing factors, number of surgeries, information on disease, and MEN2-related comorbidities (adrenal insufficiency and hypoparathyroidism). Twenty-three (56%) patients were married, 17 (40%) single, one (2%) divorced, and one (2%) widowed. The most frequent non-MEN2-related comorbidities were systemic arterial hypertension (21%; 9/43), dyslipidemia (21%; 9/43), and diabetes (4.7%; 2/43).

Most (24/38; 56%) of the patients were actively working and had higher physical functioning (86 ± 16 vs. 70 ± 23; p = 0.04) than inactive subjects di (unemployed, off work, and not retired). In turn, the latter group (33%; 14/38) presented with a higher scale of pain (57 ± 37 vs. 26 ± 34; p = 0.02). The small group consisting of students (n = 3) or retired individuals (n = 2) were excluded from this analysis.

The global health status (73 ± 22 vs. 59 ± 16; p = 0.04) was lower in the group of index cases (11/43) than it was in family members (32/43).

The mean age of affected members of large MEN2 families was lower than that observed in small families (36 ± 13 years vs. 46 ± 15 years; p = 0.03). Statistically significant correlations were observed in two items of the symptoms scale (EORTC QLQ C30), and they were more prevalent in small families: dyspnea (p = 0.02) and insomnia (p = 0.02). No other correlations were statistically significant.

Qualitative analysis

During the semi-directed interview, qualitative psychologic investigation evaluated the individual experiences of the patients that were consistent with data obtained from psychometric scales. Thus, patients reported daily events and facts associated with anxiety and depression symptoms and insecurity regarding their own future and their children. In addition, diverse attitudes and daily decisions were clearly associated with the different types of coping observed with the MINI-MAC scale. However, most parents (16/17; 94%), during the qualitative interview, revealed documenting feelings of guilt for transmitting the mutation to their children, which contrasted with 35% of them affirming this guilt during the semi-directed interview.

Discussion

Previous psychological studies in MEN2

Available psychological studies in MEN2 patients are scarce and have mostly focused on distress preceding the disclosure of RET genetic testing and reactions of patients and their family members when the mutation-positive carrier status was established (3,4,23 –25). Grosfeld et al. quantitatively and qualitatively documented distress in affected MEN2 family members and partners as result of anticipation of genetic testing disclosure, ambivalent feelings of couples about the decision making for performing genetic testing on their offspring, tackling marital problems and changes in the relationship between parents and children caused for feelings of guilt for genetic transmission, and excessive preoccupation with disease-related signs in mutation-carrying offspring (24,25). In addition, to the authors' knowledge, only two other studies have been published applying psychometric scales in MEN2 patients. The first analyzed distress in 35 MEN2 patients and 40 cases with sporadic MTC applying HADS and HRQoL using the subjective quality of life profile (SQLP) (26). Subsequently, the authors compared HRQoL findings from the same MEN2 cohort with a control population (27).

In contrast, the present cross-sectional study focused on psychological distress (anxiety and depression), HRQoL, and coping in long-standing MEN2 patients using semi-directed interviews and psychometric scales (HADS, EORTC QLQ C30, and MINI-MAC). The MINI-MAC scale has not previously been used to investigate mechanisms of psychological adjustment in MEN2. Furthermore, instead of SQLP, the EORTC QLQ C30 scale was chosen to evaluate HRQoL, as this test is widely applied in cancer patients (29,33,36,37,39 –41). In addition, the EORTC QLQ C30 scale has been considered satisfactory when directed specifically to long-term cancer survivors, such as the present MTC cases (36).

Distress in MEN2 and other inherited cancer patients

Qualitative psychological assessment in MEN2 cases revealed high basal distress indexes (50%) preceding genetic counseling and genetic testing disclosure (3). A lower and variable prevalence of baseline psychological distress (6–39%) was documented in other hereditary cancer syndromes (Von Hippel–Lindau, Li–Fraumeni, hereditary breast and ovarian cancer, hereditary nonpolyposis colon cancer, familial adenomatous polyposis) (5,42,43). A wide variation in the prevalence of psychological distress (anxiety 0.9–49%; depression 0–46%) has been documented in cancer patients. These data may be due to the use of different psychometric scales and study designs (cross-sectional vs. prospective), specific characteristics of each cancer type, sex, age, staging, cultural differences, and time interval since diagnosis (1). Degrees of basal distress could not be approached in the present cases, since in all patients genetic counseling and testing preceded the application of psychometric scales.

Short-term distress outcome in hereditary cancer patients and MEN2

Despite high baseline distress indexes, a significant short-term reduction of symptoms reaching normal levels is typically observed in hereditary cancer syndromes one year after genetic testing disclosure (5,26). Concordantly, a significant distress reduction was reported in MEN2 one year after genetic testing disclosure (3). The short-term distress outcome could not be explored in the present study, as MEN2 patients had long-term follow-up (10.6 ± 8.2 years; range 1–33 years) with genetic testing disclosure several years before the application of the psychometric scales.

Long-term distress outcome in MEN2

Overall, long-term results regarding distress in hereditary cancer syndromes are contradictory (5). Long-term distress rate observed in the MEN2-related MTC patients in this study (anxiety and/or depression: 46%; HAD score ≥8) was definitely more frequent than the short-term distress rate previously reported in MEN2 cases (20%) one year after disclosure of genetic testing results (3). These findings indicate a chronic distress state in the present cases. Using a HADS score >11 as a cutoff, Freyer et al. (26) identified that 48% of their patients with MTC suffered from distress. Changing the HADS score to ≥8 resulted in the distress rate affecting 73% of patients. Formal comparisons with the present study could not be performed, as there were no available data on long-term follow-up in the MEN2 patients reported by Freyer et al. (26). Thus, different from the present study, interferences on short-term distress rate after genetic testing disclosure previously reported by Grosfeld et al. (3) could not be excluded in the study by Freyer et al. (26).

Possible reasons for a high prevalence of long-term distress in the present MEN2 cases may not be fully explained by feeling isolated and a loss of perspective for the future commonly seen in cancer-patient series. This conclusion is supported by the fact that most of patients were actively working, had satisfactory HRQoL patterns, and were biochemically cured or had stable disease. Thus, it is likely that other factors are potentially contributing to the chronic distress state in MEN2, for example the impact of having mutation-positive offspring, the degree of information on the syndromic disease, and influence of MEN2-related comorbidities.

Impact of having children or mutation-positive children

It was found that having a child carrying a RET mutation or expecting results of genetic testing in the offspring are associated with higher scores for weakness-discouragement and anxiety in affected parents. In contrast, patients without children or with non-carrier children were found to have higher HRQoL scores (cognitive, emotional, and physical functioning), an observation that further illustrates the state of high chronic distress in parents with genetically affected children. Consistent with these observations, patients with hereditary MEN2-related MTC present lower levels of satisfaction and HRQoL than sporadic MTC cases and control individuals, documenting a negative psychological impact of harboring a germline RET mutation (27). Additionally, increasing levels of anxiety were reported in parents of at-risk children after the disclosure of positive genetic testing results (24).

Taken together, these data support the findings of a chronic anxiety state in MEN2 patients and lower HRQoL scores in parents who transmitted the RET mutation to their children, contrasting with previous studies showing a gradual and progressive decrease in psychological concerns and better adaptation one year after MEN2 diagnosis and in other familial cancer syndromes such as hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (3,5,26).

Information about MEN2

In the present series, most patients felt they were well informed about MEN2 by medical staff, which probably led to strong compliance with medical management and acceptance of genetic testing (95%) for their children. Of note, a shared decision-making approach has been tentatively used in all cases by the study group in patients affected by genetic syndromes of predisposition to endocrine neoplasia (44 –46). These results reinforce those of Cleiren et al. on the high degree of patient satisfaction obtained with specialized multidisciplinary support (47). The present data indicate less psychological harm, improved psychological adjustments, and better HRQoL scores in well-informed patients. Hence, the importance of offering high-quality information to patients as a potential tool to secure better psychometric indexes must be emphasized.

MEN2-related comorbidities

The impact of MEN2 treatment-related comorbidities such as hypothyroidism, hypoparathyroidism, and adrenal insufficiency have not been analyzed in early psychological studies in MEN2. These conditions can be associated with lower HRQoL patterns, even in patients with adequate hormonal substitution (18 –22). In the present study, patients were only interviewed if their potential comorbidities were well controlled. Thus, all 41 MEN2-related MTC patients operated prior to the psychological interview had compensated post-thyroidectomy hypothyroidism. Moreover, comparing MEN2 subsets with or without hypoparathyroidism and/or adrenal insufficiency, no significant differences were observed, except for a higher fighting spirit in patients with adrenal insufficiency.

Overall, most MEN2-related clinical comorbidities are direct consequences of multiple surgeries and they would have a potential to influence or amplify psychological harm. However, we observed no correlation between the number of MEN2-related surgeries and psychological indexes, except for higher fighting spirit in patients with three or more surgeries.

A previous study documented no influence of thyroidectomy on distress in MEN2-related MTC cases (26). In addition, high levels of frustration and latent dissatisfaction were present in MEN2-related MTC patients with or without thyroidectomy (26). It was not possible to analyze the influence of surgery on psychological concerns because almost all cases underwent thyroidectomy prior to evaluation (41/43; 95%).

QoL in MTC/MEN2

The application of different scales of HRQoL prevented comparisons between the study by Freyer et al. and the present data (26,27).

Cured and uncured patients

MTC/MEN2 is still frequently diagnosed at advanced stages in which cure rates are lower, as seen in many of the present cases (61%). Conversely, cure rates are usually much higher when genetic screening is performed and if at-risk relatives are diagnosed at an early stage, as seen in 16 (39%) of the present patients.

Of note, applying EORTC QLQ C30, the global HRQoL scores for several types of cancer have been reported to be nearly equal to those of the general population. In contrast, markedly worse HRQoL mean scores have been reported in cancer patients or survivors compared with scores for the general population if specific subscales of the EORTC QLQ C30 are considered as functioning scales, symptom scales, and symptom items (39,41).

Despite the lack of healthy unaffected controls, higher physical functioning was documented in the cured patients, while the global HRQoL scores were similar in both groups. These findings are in line with the data of Hinz et al. and support the key role of analyzing specific components of HRQoL as functioning scales (39). Additionally, the higher physical functioning in the cured patients is also illustrated by the tendency to mildly higher frequency of working activities (p = 0.054). Furthermore, cognitive avoidance was most evident in the cured group (p = 0.024). This psychological defense mechanism was appropriate for this subset, as it did not interfere with patient compliance with the offered medical care.

High frequencies of psychological concerns found in patients with persistent disease and cancer survivors (cured patients) may be due to multiple reasons. Among them, patients knew about the low tumor cure rates in older patients, restricted non-surgical therapeutic tools for MTC, frequent requirement for multiple surgeries for disease control, and the fact that MTC can be resistant to chemo- and radiotherapy. Several patients also experienced the death of affected relatives. All these factors could result in disbelief and eventually may explain the high frequency of fatalism in the present patient series. However, the potential negative impact of fatalism probably was counterbalanced by satisfactory QoL, a high physical functioning, and appropriate information on actual disease state favoring strong fighting spirit and, consequently, working activities and excellent compliance with medical care.

The similar frequencies of psychological distress (anxiety and depression) in the cured and uncured MTC patients are likely due to a high prevalence of stable disease in the latter group. Of note, all patients had a satisfactory performance status based on ECOG and HRQoL scales, although HRQoL subscales revealed a higher performance status in the cured group.

Stress-inducing factors

Several potentially stress-inducing factors were identified, alone or in combination, in 30 MEN2 patients, despite similar scores for HRQoL and distress compared with patients without such factors. The finding of higher indexes of insomnia and dyspnea and lower cognitive functioning suggests that these patients are more susceptible to psychological harm. In contrast, higher scores for fighting spirit underscore an appropriate adaptive response mechanism in these patients. The more advanced age associated with increasing stress-inducing factors may be explained at least in part by a high prevalence of parents with RET mutation-positive children or parents expecting genetic screening results for their children.

Some potential stress-inducing factors verified in the MEN2 patients were of limited duration, for example waiting for genetic testing or surgery, while others were persistent such as the presence of RET mutation-positive children and the constant fear of disease recurrence or progression.

The excess of catecholamine secreted by Pheos may be considered an important stress-inducing factor in MEN2, and it could potentially contribute to psychological distress in these patients. Korpershoek et al. (48) reported that adrenal medulla hyperplasia represents micro-Pheos in MEN2, and early surgery should be considered. The impact of Pheos as a stress-inducing factor seems to be minimized in the present cases, as there were only two patients with recently diagnosed Pheos waiting for adrenalectomy and no case with a suspected micro-Pheos.

Prospective studies applying psychometric scales to MEN2 patients are needed to study the impact of stress-inducing factors on psychological distress and HRQoL, and to identify scenarios requiring closer psychological surveillance and attendance. Furthermore, cultural differences and religious and ethical views may also impact psychological scores and should be considered in future investigations.

Guilt

During semi-directed interviews, feelings of guilt were present in 35% of patients with mutation-positive children. However, during qualitative psychological interviews, such feelings were strongly present in most parents with mutation-positive children. Thus, a process of cognitive avoidance, a common coping mechanism in these patients, influenced the answer during the semi-directed questionnaire, obscuring the feelings of guilt of most parents.

RET mutations and psychological profile

The strong genotype–phenotype correlation in MEN2 and its impact on clinical management, early diagnosis, and decisions on surgical procedures, including prophylactic thyroidectomy, is widely known (7,12,14,17,38,49 –56). One may hypothesize that RET mutations in different risk categories may be associated with different psychological outcomes. Most patients harbored exon 10 and 11 RET mutations associated with an earlier onset of MTC. In contrast, nearly half of the patients reported by Freyer et al. harbored RET 804 codon mutations, which are usually associated with a later MTC onset, lower tumor aggressiveness, and a better prognosis (26). The two studies cannot be compared for this reason and because the study by Freyer et al. also included patients with sporadic MTC.

Overall, 175 genetic RET variants have been described so far (57,58). While the clinical impact of many mutations is well established, other sequence variants may be polymorphisms or variants of unknown significance (VUS) (7,17,59,60). A clear distinction of pathogenic and benign variants or VUS is warranted to avoid misclassification, erroneous genetic diagnosis, inappropriate genetic counseling, unnecessary prophylactic thyroidectomies, and undesirable physical and psychological harm.

Brauer et al. stressed the difficulties in dealing with genetic counseling and clinical management of patients harboring the RET^Y791F variant, which was initially classified as having a moderate aggressiveness risk (61). The data (62,63) and other observations (64) support that limited DNA sequencing analysis has led to the misclassification of RET^Y791F as a pathogenic variant and unnecessary thyroidectomies (59,62 –64).

Moreover, recent studies identified peculiarities and difficulties in genetic counseling and the potential for psychological harm in patients harboring VUS in the BRCA genes (65). A growing number of VUS in the RET gene have been documented (7,57,58). However, there is no study on the psychological impact in individuals with identified VUS or misclassified variants in the RET gene.

Considering the present psychological scenario, interventions in patient interest groups and specialized psychologic support would have the potential to reduce the high indexes of chronic distress, feelings of guilt for transmission to offspring, negative coping as fatalism, and amplification of positive coping behaviors as fighting spirit. The value of systematic psychological assessment in MEN2 patients is supported by the need for individual psychotherapy in 25% of the studied patients. The patients were followed for at least six months on a weekly basis for 50-minute sessions, and this support and counseling had a positive impact.

Finally, opportunities for the future should be highlighted. They include the support by patient interest groups that allow individual and social concerns to be addressed. Aside from obtaining general information about the disease, participation in interest groups can decrease patients' feeling of isolation. Furthermore, such groups provide an opportunity to exchange and compare experiences, and they allow complex questions about the disease to be addressed.

In summary, high levels of chronic distress in MEN2 patients are documented, despite a relatively good QoL. This finding is most probably associated with several stress-inducing factors, some of them of a persisting nature, in these patients. In addition, cured cases may have higher physical functioning and higher frequency of working activities.

Conclusion

The psychological assessment protocol developed for and directed to the care of MEN2 patients has proven effective to identify individuals requiring psychological assistance and individual psychotherapeutic treatment. Symptoms of anxiety and depression should be actively investigated and monitored in MEN2 patients, given their high prevalence and long duration. Coping behaviors were frequent in the MEN2 patients studied here, especially fatalism and fighting spirit. The presence of MEN2-related stress-inducing factors may result in the occurrence of adverse psychological effects and may require targeted psychological support. Specialized multidisciplinary teams involving genetic counselors, physicians, surgeons, and psychologists with expertise in MEN2 may improve the quality of medical care of the patients and their family members.

Footnotes

Acknowledgments

We would like to thank all patients and their family's members for agreeing to participate of this study. We also thank Maria G. Cavalcanti (Endocrine Genetics Unit), for providing social support. We are very grateful to Prof. Stephen J. Marx and to the editor of Thyroid for valuable suggestions, commentaries, criticism, and corrections.

K.C.R. is the recipient of a FAPESP fellowship (2012-04698-0). R.A.T. has received a Ciencias Sem Fronteiras CNPq postdoctoral fellowship and is currently at the Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid. S.P.A.T. is presently a CAPES (Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior) National Senior Visiting Professor (PVNS program) at the Federal University of Sao Paulo, Brazil. This investigation was supported by FAPESP (2013/01476-9) and CNPq (401990/2010-9) grants to S.P.A.T. and a FAPESP grant (2013/19810-2) to D.M.L.J.

Author Disclosure Statement

The authors have nothing to declare.

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