Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.

The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304* ; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027-0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011-0.0047) and zero in ROI (0-0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0-2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275-5,000) years. tMRCA-based simulations predicted 432 (90-5,175) current carriers, including 86 affected (18-1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.

[Consensus on the change of criteria for cure of acromegaly during the last decade]. / Konszenzus a kritériumok változásáról az acromegalia gyógyulásának megítélésében - nemzetközi ajánlás, 2010.

The Acromegaly Consensus Group redefined the consensus criteria for cure of acromegaly. 74 neurosurgeons and experienced endocrinologists summarized the latest results on diagnosis and treatment of acromegaly. In this consensus statement the reliable growth hormone and insulin-like growth factor-1 assays were established. Definition of disease control was discussed based on the available publications and evidence. This short communication summarizes the clinical aspects of consensus criteria for diagnosis and cure of acromegaly based on the original article.

[Growth hormone receptor antagonist in the treatment of acromegaly]. / Növekedésihormonreceptor-antagonista alkalmazásának lehetoségei acromegaliában.

Exploration of construction, function and interaction of human growth hormone and growth hormone receptor in details resulted in the innovation of the new growth hormone receptor antagonist, pegvisomant. Pegvisomant with different mechanism of action extended the tools of medical management of acromegaly. Importance of the novel treatment modality is high. In one hand the necessity of the strict control of growth hormone/insulin-like growth factor-I axis has been proven regarding the mortality of the disease. On the other hand, despite the use of all current modes of treatment (surgery, radiotherapy, dopamine agonists, somatostatin analogs), a significant cohort of patients with acromegaly remains inadequately controlled. Pegvisomant has been registered in 2004. Since 2006, it has been used in Hungary for the treatment of acromegaly in patients who have had an inadequate response to surgery and/or radiation therapy and/or other medical therapies, or for whom these therapies are not appropriate. Clinical use of pegvisomant in the treatment of acromegaly is effective, well tolerated, and safe, based on international Acrostudy database. In order to improve the efficacy of therapy clinical trials started with pegvisomant and somatostatin analog combination treatment. Evidence of several further effects of the growth hormone/insulin-like growth factor-I axis suggests other potential uses of growth hormone receptor antagonists.

[Familial isolated pituitary adenoma syndrome]. / Familiáris izolált hypophysisadenoma.

Familial pituitary adenomas occur in multiple endocrine neoplasia type 1, Carney complex, as well as in familial isolated pituitary adenoma syndrome. Familial isolated pituitary adenoma syndrome is an autosomal dominant disease with incomplete penetrance. Pituitary adenomas occur in familial setting but without any other specific tumors. In 20-40% of families with this syndrome, mutations have been identified in the aryl hydrocarbon receptor interacting protein gene while in the rest of the families the causative gene or genes have not been identified. Families carrying aryl hydrocarbon receptor interacting protein gene mutations have a distinct phenotype with younger age at diagnosis and a predominance of somatotroph and lactotroph adenomas. Germline mutations of the aryl hydrocarbon receptor interacting protein gene can be occasionally identified in usually young-onset seemingly sporadic cases. Genetic and clinical testing of relatives of patients with aryl hydrocarbon receptor interacting protein gene mutations can lead to earlier diagnosis and treatment at an earlier stage of the pituitary tumor.

The clinical aspects of pituitary tumour genetics.

BACKGROUND: Pituitary tumours are usually benign and relatively common intracranial tumours, with under- and overexpression of pituitary hormones and local mass effects causing considerable morbidity and increased mortality. While most pituitary tumours are sporadic, around 5% of the cases arise in a familial setting, either isolated [familial isolated pituitary adenoma, related to AIP or X-linked acrogigantism], or in a syndromic disorder, such as multiple endocrine neoplasia type 1 or 4, Carney complex, McCune-Albright syndrome, phaeochromocytoma/paraganglioma with pituitary adenoma, DICER1 syndrome, Lynch syndrome, and USP8-related syndrome. Genetically determined pituitary tumours usually present at younger age and show aggressive behaviour, and are often resistant to different treatment modalities. SUBJECT: In this practical summary, we take a practical approach: which genetic syndromes should be considered in case of different presentation, such as tumour type, family history, age of onset and additional clinical features of the patient. CONCLUSION: The identification of the causative mutation allows genetic and clinical screening of relatives at risk, resulting in earlier diagnosis, a better therapeutic response and ultimately to better long-term outcomes.

[Treatment of acromegaly]. / Az acromegalia kezelése.

Growth hormone (GH) hypersecretion leads to acromegaly which is associated with several co-morbidities and increased mortality. Despite of the typical clinical features and modern diagnostic tools, it often takes years from the onset of the disease until the diagnosis. The aims of the treatment are to reduce or control the tumor growth, inhibit the GH hypersecretion, normalize the insulin-like growth factor-I (IGF-I) levels, treat the co-morbidities and therefore reduce mortality. There are three approaches for therapy: surgery, medical management (dopamine agonist, somatostatin analogues and GH receptor antagonist), and radiotherapy. Efficient therapy of the disease is based on the appropriate multidisciplinary team management.

Comparison of adipose tissue derived genes in endogenous Cushing's syndrome versus diet-induced obesity.

INTRODUCTION: Dysregulation of adipokine secretion and action is a characteristic feature of obesity and a key clinical feature of Cushing's syndrome (CS). We have investigated whether endogenous glucocorticoid excess influences adipose tissue-derived gene expression. MATERIAL AND METHODS: mRNA expression of adipokines; adiponectin, resistin, tumour necrosis factor-a, interleukin-6 (IL-6), angiotensinogen (AGT), plasminogen activator inhibitor type 1, retinol binding protein 4, visfatin, and cystatin C was assessed by quantitative real-time RT-PCR in visceral adipose tissue removed during abdominal surgery of eight patients with CS, and six control patients. RESULTS: We did not find any significant difference in the investigated genes; however, the almost significant overexpression of AGT and underexpression of IL-6 might be noteworthy (p = 0.06 in both cases). CONCLUSIONS: No significant differences were found in the expression of the investigated genes known as cardiometabolic risk factors. This indicates that there are no major differences between endogenous hypercortisolism or diet-induced obesity regarding the expression of adipokines involved in cardiometabolic disorders. However, the difference in AGT and IL-6 expression might be included in pathways affecting fat distribution in CS.

Subacute thyroiditis associated with COVID-19 infection: a report of an increasing entity

SUMMARY In March 2020, the World Health Organization characterized COVID-19 as a pandemic. By May 2021, 37 cases of subacute thyroiditis (SAT) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) had been reported in the literature. We report a patient diagnosed with SAT associated with COVID-19 and review the previously reported cases. A 31-year-old female with no significant previous history developed SAT 5 weeks after SARS-CoV-2 infection. She presented with anterior neck pain and fever. Thyroid function tests revealed hyperthyroidism with slightly increased inflammatory markers. Thyroid ultrasound showed diffuse hypoechoic left lobe and a hypoechoic area in the right lobe. On the fine-needle-aspiration biopsy, large histiocytes, disrupted and normal follicles, and multinucleated giant cells within colloid were seen. Under oral corticosteroid therapy, clinical progression was rapid. Seven weeks later, all thyroid function tests and inflammatory markers normalized. During the recent viral outbreak, clinicians should keep in mind the possibility of SAT after COVID-19, and patients with symptoms of SAT should be tested for SARS-CoV-2.

Pituitary Carcinoma in a Patient with an SDHB Mutation.

We present the first case of pituitary carcinoma occurring in a patient with a succinate dehydrogenase subunit B (SDHB) mutation and history of paraganglioma. She was initially treated for a glomus tumour with external beam radiotherapy. Twenty-five years later, she was diagnosed with a non-functioning pituitary adenoma, having developed bitemporal hemianopia. Recurrence of the pituitary lesion (Ki-67 10% and p53 overexpressed) occurred 5 years after her transsphenoidal surgery, for which she underwent two further operations followed by radiotherapy. Histology showed large cells with vacuolated clear cytoplasm with positive immunostaining for steroidogenic factor 1 (SF1) and negative staining for pituitary hormones. Four years after the pituitary radiotherapy, two metastatic deposits were identified: a foramen magnum lesion and an intradural extra-medullary cervical lesion at the level of C3/C4. There was also significant growth of the primary pituitary lesion with associated visual deterioration. A biopsy of the foramen magnum lesion, demonstrating cells with vacuolated, clear cytoplasm and positive SF1 staining confirmed a pituitary carcinoma, for which she was commenced on temozolomide chemotherapy. There was dramatic clinical improvement after three cycles and reduction in the size of the lesions was observed following six cycles of temozolomide, and further shrinkage after 10 cycles. The plan is for a total of 12 cycles of temozolomide chemotherapy. SDH mutation-related pituitary tumours have an aggressive phenotype which, in this case, led to metastatic disease. SF1 immunostaining was helpful to identify the tissue origin of the metastatic deposit and to confirm the pituitary carcinoma.

15 YEARS OF PARAGANGLIOMA: The association of pituitary adenomas and phaeochromocytomas or paragangliomas.

The combination of pituitary adenomas (PA) and phaeochromocytomas (phaeo) or paragangliomas (PGL) is a rare event. Although these endocrine tumours may occur together by coincidence, there is mounting evidence that, in at least some cases, classical phaeo/PGL-predisposing genes may also play a role in pituitary tumorigenesis. A new condition that we termed '3Pas' for the association of PA with phaeo and/or PGL was recently described in patients with succinate dehydrogenase mutations and PAs. It should also be noted that the classical tumour suppressor gene, MEN1 that is the archetype of the PA-predisposing genes, is also rarely associated with phaeos in both mice and humans with MEN1 defects. In this report, we review the data leading to the discovery of 3PAs, other associations linking PAs with phaeos and/or PGLs, and the corresponding clinical and molecular genetics.

Regulation of aryl hydrocarbon receptor interacting protein (AIP) protein expression by MiR-34a in sporadic somatotropinomas.

INTRODUCTION: Patients with germline AIP mutations or low AIP protein expression have large, invasive somatotroph adenomas and poor response to somatostatin analogues (SSA). METHODS: To study the mechanism of low AIP protein expression 31 sporadic somatotropinomas with low (n = 13) or high (n = 18) AIP protein expression were analyzed for expression of AIP messenger RNA (mRNA) and 11 microRNAs (miRNAs) predicted to bind the 3'UTR of AIP. Luciferase reporter assays of wild-type and deletion constructs of AIP-3'UTR were used to study the effect of the selected miRNAs in GH3 cells. Endogenous AIP protein and mRNA levels were measured after miRNA over- and underexpression in HEK293 and GH3 cells. RESULTS: No significant difference was observed in AIP mRNA expression between tumors with low or high AIP protein expression suggesting post-transcriptional regulation. miR-34a was highly expressed in low AIP protein samples compared high AIP protein adenomas and miR-34a levels were inversely correlated with response to SSA therapy. miR-34a inhibited the luciferase-AIP-3'UTR construct, suggesting that miR-34a binds to AIP-3'UTR. Deletion mutants of the 3 different predicted binding sites in AIP-3'UTR identified the c.*6-30 site to be involved in miR-34a's activity. miR-34a overexpression in HEK293 and GH3 cells resulted in inhibition of endogenous AIP protein expression. CONCLUSION: Low AIP protein expression is associated with high miR-34a expression. miR-34a can down-regulate AIP-protein but not RNA expression in vitro. miR-34a is a negative regulator of AIP-protein expression and could be responsible for the low AIP expression observed in somatotropinomas with an invasive phenotype and resistance to SSA.

An unusual case of an ACTH-secreting macroadenoma with a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene.

UNLABELLED: A patient of Cushing's disease (CD) characterized by a large tumor and only subtle symptoms of hormonal hypersecretion was examined. The patient had a germline variant in the aryl hydrocarbon receptor-interacting protein (AIP) gene. A 50-year-old male presenting with headache was diagnosed with a large pituitary tumor by magnetic resonance imaging (MRI). His visual fields were intact and he exhibited no features of CD. Owing to an exuberant response to synacthen, an overnight dexamethasone suppression test was performed revealing inadequate suppression of plasma cortisol (419 nmol/l). Owing to tumor growth and visual field impairment, he underwent transsphenoidal surgery and developed hypocortisolemia. The pathology specimen revealed a sparsely granulated corticotrope adenoma. Postoperative MRI showed a large tumor remnant. The patient developed skin hyperpigmentation and a synacthen test demonstrated high basal and stimulated cortisol levels; an overnight dexamethasone suppression test showed no suppression (791 nmol/l) and elevated plasma ACTH levels (135 ng/l). A transcranial operation was performed followed by radiotherapy. Two months after radiotherapy, he developed secondary adrenocortical failure. Genetic testing revealed an AIP variant of unknown significance (p.R16H) without loss of the normal AIP allele in the tumor. A literature review showed ten CD patients with AIP gene variants, of whom five (including our case) were p.R16H. CD is occasionally dominated by pituitary tumor growth rather than symptoms of hypersecretion. The particular AIP gene variant identified in our patient is shared by four other reported cases of CD. Future studies are needed to assess whether the reported AIP gene variant is more than just coincidental. LEARNING POINTS: CD is occasionally dominated by pituitary tumor growth rather than symptoms of hypersecretion.Resolution of both tumor remnant and hormonal hypersecretion may occur within 2 months after postoperative radiotherapy.The particular AIP gene variant identified in our patient is shared by four other reported cases of CD.

Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers.

CONTEXT: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease. OBJECTIVE: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members. DESIGN: This was an observational, longitudinal study conducted over 7 years. SETTING: International collaborative study conducted at referral centers for pituitary diseases. PARTICIPANTS: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study. INTERVENTIONS: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant. MAIN OUTCOME MEASURE(S): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis. RESULTS: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening. CONCLUSIONS: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.

Heterogeneous genetic background of the association of pheochromocytoma/paraganglioma and pituitary adenoma: results from a large patient cohort.

CONTEXT: Pituitary adenomas and pheochromocytomas/paragangliomas (pheo/PGL) can occur in the same patient or in the same family. Coexistence of the two diseases could be due to either a common pathogenic mechanism or a coincidence. OBJECTIVE: The objective of the investigation was to study the possible coexistence of pituitary adenoma and pheo/PGL. DESIGN: Thirty-nine cases of sporadic or familial pheo/PGL and pituitary adenomas were investigated. Known pheo/PGL genes (SDHA-D, SDHAF2, RET, VHL, TMEM127, MAX, FH) and pituitary adenoma genes (MEN1, AIP, CDKN1B) were sequenced using next generation or Sanger sequencing. Loss of heterozygosity study and pathological studies were performed on the available tumor samples. SETTING: The study was conducted at university hospitals. PATIENTS: Thirty-nine patients with sporadic of familial pituitary adenoma and pheo/PGL participated in the study. OUTCOME: Outcomes included genetic screening and clinical characteristics. RESULTS: Eleven germline mutations (five SDHB, one SDHC, one SDHD, two VHL, and two MEN1) and four variants of unknown significance (two SDHA, one SDHB, and one SDHAF2) were identified in the studied genes in our patient cohort. Tumor tissue analysis identified LOH at the SDHB locus in three pituitary adenomas and loss of heterozygosity at the MEN1 locus in two pheochromocytomas. All the pituitary adenomas of patients affected by SDHX alterations have a unique histological feature not previously described in this context. CONCLUSIONS: Mutations in the genes known to cause pheo/PGL can rarely be associated with pituitary adenomas, whereas mutation in a gene predisposing to pituitary adenomas (MEN1) can be associated with pheo/PGL. Our findings suggest that genetic testing should be considered in all patients or families with the constellation of pheo/PGL and a pituitary adenoma.

A comprehensive next generation sequencing-based genetic testing strategy to improve diagnosis of inherited pheochromocytoma and paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas are notable for a high frequency of inherited cases, many of which present as apparently sporadic tumors. OBJECTIVE: The objective of this study was to establish a comprehensive next generation sequencing (NGS)-based strategy for the diagnosis of patients with pheochromocytoma and paraganglioma by testing simultaneously for mutations in MAX, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL. DESIGN: After the methodology for the assay was designed and established, it was validated on DNA samples with known genotype and then patients were studied prospectively. SETTING: The study was performed in a diagnostic genetics laboratory. PATIENTS: DNA samples from 205 individuals affected with adrenal or extraadrenal pheochromocytoma/head and neck paraganglioma (PPGL/HNPGL) were analyzed. A proof-of-principle study was performed using 85 samples known to contain a variant in 1 or more of the genes to be tested, followed by prospective analysis of an additional 120 samples. MAIN OUTCOME MEASURES: We assessed the ability to use an NGS-based method to perform comprehensive analysis of genes implicated in inherited PPGL/HNPGL. RESULTS: The proof-of-principle study showed that the NGS assay and analysis gave a sensitivity of 98.7%. A pathogenic mutation was identified in 16.6% of the prospective analysis cohort of 120 patients. CONCLUSIONS: A comprehensive NGS-based strategy for the analysis of genes associated with predisposition to PPGL and HNPGL was established, validated, and introduced into diagnostic service. The new assay provides simultaneous analysis of 9 genes and allows more rapid and cost-effective mutation detection than the previously used conventional Sanger sequencing-based methodology.

Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma.

We report on an adult woman with rare coexistence of acromegaly, pheochromocytoma (PHEO), gastrointestinal stromal tumor (GIST), intestinal polyposis, and thyroid follicular adenoma. At the age of 56, she was diagnosed with acromegaly caused by a pituitary macroadenoma, treated by transsphenoidal surgery, radiotherapy, and octreotide. During routine colonoscopy, multiple polyps were identified as tubular adenomas with high-grade dysplasia on histology. Years later, an abdominal mass of 8.0 x 6.2 cm was detected by routine ultrasound. Surgical exploration revealed an adrenal mass and another tumor adhered to the lesser gastric curvature, which were removed. Pathology confirmed the diagnosis of PHEO and GIST. PHEO immunohistochemistry was negative for GHRH. During follow-up, nodular goiter was found with normal levels of calcitonin and inconclusive cytology. Near-total thyroidectomy was performed, revealing a follicular adenoma. Her family history was negative for all of these tumor types. Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative. Though the finding of PHEO and acromegaly with multiple other tumors could be a fortuitous coexistence, we suggest that this case may represent a new variant of MEN syndrome with a de novo germline mutation in a not yet identified gene.

Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma / Estudos genéticos na coexistência de acromegalia, feocromocitoma, tumor do estroma gastrointestinal (GIST) e adenoma folicular de tireoide

We report on an adult woman with rare coexistence of acromegaly, pheochromocytoma (PHEO), gastrointestinal stromal tumor (GIST), intestinal polyposis, and thyroid follicular adenoma. At the age of 56, she was diagnosed with acromegaly caused by a pituitary macroadenoma, treated by transsphenoidal surgery, radiotherapy, and octreotide. During routine colonoscopy, multiple polyps were identified as tubular adenomas with high-grade dysplasia on histology. Years later, an abdominal mass of 8.0 x 6.2 cm was detected by routine ultrasound. Surgical exploration revealed an adrenal mass and another tumor adhered to the lesser gastric curvature, which were removed. Pathology confirmed the diagnosis of PHEO and GIST. PHEO immunohistochemistry was negative for GHRH. During follow-up, nodular goiter was found with normal levels of calcitonin and inconclusive cytology. Near-total thyroidectomy was performed, revealing a follicular adenoma. Her family history was negative for all of these tumor types. Genetic analysis for PHEO/paraganglioma genes (SDH A-D, SDHAF2, RET, VHL, TMEM127, and MAX), and pituitary-related genes (AIP, MEN1, and p27) were negative. Though the finding of PHEO and acromegaly with multiple other tumors could be a fortuitous coexistence, we suggest that this case may represent a new variant of MEN syndrome with a de novo germline mutation in a not yet identified gene. Arq Bras Endocrinol Metab. 2012;56(8):507-12.

Relatamos o caso de uma mulher com rara coexistência de acromegalia, feocromocitoma (FEO), tumor do estroma gastrointestinal (GIST), polipose intestinal e adenoma folicular de tireoide. Aos 56 anos, ela foi diagnosticada com acromegalia por um macroadenoma hipofisário, tratado com cirurgia transesfenoidal, radioterapia e octreotide. Uma colonoscopia de rotina detectou múltiplos pólipos, que à histologia eram adenomas tubulares com alto grau de displasia. Anos mais tarde, uma ecografia detectou uma massa abdominal de 8.0 x 6.2 cm, que na exploração cirúrgica era uma lesão adrenal e outro tumor aderido à pequena curvatura gástrica. A patologia confirmou os diagnósticos de FEO e GIST. A imuno-histoquímica do FEO foi negativa para GHRH. No seguimento, encontrou-se um bócio nodular com níveis normais de calcitonina e citologia inconclusiva. Após tireoidectomia total o diagnóstico histológico foi de adenoma folicular. A história familiar era negativa para todos esses tumores. As análises genéticas para genes de síndromes de FEO/paragangliomas (SDH A-D, SDHAF2, RET, VHL, TMEM127 e MAX) e para hipofisárias (AIP, MEN1 e p27) foram todas negativas. Embora a presença de FEO e acromegalia com múltiplos outros tumores possa ser uma coexistência fortuita, acreditamos na possibilidade de uma nova variante de NEM com uma mutação germinativa de novo em um gene ainda não identificado Arq Bras Endocrinol Metab. 2012;56(8):507-12.