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Multiple Endocrine Neoplasia Type 2A

MEN2A

Multiple endocrine neoplasia type 2A (MEN 2A) is a hereditary disease that is caused by the mutations of a RET proto-oncogene and is a subtype of MEN syndrome. Pathology arises in endocrine glands, and MEN 2A specifically causes medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism.


Presentation

Multiple endocrine neoplasia type 2A (MEN 2A) is the most frequently occurring form of MEN 2, and many patients have a positive family history of endocrine cancers. Those with MEN 2A characteristically develop medullary thyroid carcinoma (MTC), pheochromocytoma, and parathyroid adenomas or hyperplasia, with a prevalence of up to 95%, 50%, and 30% respectively. Symptoms arise as a result of the tumors present, however, some individuals may remain asymptomatic.

MTC is often the first clinical manifestation of the disease and usually becomes symptomatic by the third decade of life [1]. As MTC results from hyperplasia of the C-cells in the thyroid gland, diarrhea is a common complaint, albeit poor prognostic factor, resulting from hypersecretion of calcitonin [1] [2]. A neck mass is often seen on presentation, with symptoms of local spread such as difficulty swallowing, change in voice, neck pain, and dyspnea. Lymphadenopathy occurs as a result of tumor metastasis to the lymph nodes. The tumor has a propensity to metastasize, often to the liver, bones, and lungs [1]. This usually takes place before patients seek medical attention.

Pheochromocytomas are largely benign, and mainly arise from the adrenal glands and secrete catecholamines, although in MEN 2A they predominantly secrete adrenalin [3]. A minority of patients may present with pheochromocytoma as the first sign of disease, and in contrast to sporadic cases, they are more likely to be bilateral [4]. Furthermore, the symptoms they produce are often insidious and may be paroxysmal [5]. Typical manifestations include palpitations, tachycardia, hypertension, excessive sweating, headaches, anxiety, and hypertensive crisis.

Parathyroid adenomas may cause hypercalcemia, increased calcium excretion in urine, and renal stones. Some patients with MEN 2A additionally present with cutaneous lichen amyloidosis (CLA) often on the upper back, seen as dark itchy desquamating papules [6].

Lymphadenopathy
  • She was clinically asymptomatic, with a normally palpable thyroid and with the cervical region free of lymphadenopathy or other nodules.[ncbi.nlm.nih.gov]
  • A boy had no thyromegaly, thyroidal irregularities or lymphadenopathy and no abnormality on the neck ultrasound examination. The pathology finding of thyroid gland was negative for MTC.[ncbi.nlm.nih.gov]
  • Lymphadenopathy occurs as a result of tumor metastasis to the lymph nodes. The tumor has a propensity to metastasize, often to the liver, bones, and lungs. This usually takes place before patients seek medical attention.[symptoma.com]
  • Then it was noted the persistence of a thyroid stump associated with cervical lymphadenopathy that leads to a third surgical revision that considers a bilateral lymph node cure. Cervical radiotherapy was also performed.[file.scirp.org]
  • The first sign of MTC is often a firm mass in the thyroid or abnormal enlargement of nearby lymph nodes (lymphadenopathy). An MTC mass in the neck may be painful. MTC can spread (metastasize) to other areas of the body.[rarediseases.org]
Cerebral Palsy
  • Each patient underwent total thyroidectomy, with the exception of two children (a 9-year-old child with cerebral palsy and a 12-year-old child with autism) whose parents did not consent to surgery.[nejm.org]
Papule
  • Some patients with MEN 2A additionally present with cutaneous lichen amyloidosis (CLA) often on the upper back, seen as dark itchy desquamating papules.[symptoma.com]
  • Measurements and Main Results: In this family cutaneous lichen amyloidosis presented as multiple infiltrated papules overlying a well-demarcated plaque in the scapular area of the back (right or left).[annals.org]
  • Around 40% of patients with MEN2 develop phaeochromocytoma. [ 7 ] Cutaneous lichen amyloidosis in MEN2A presents with multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back.[patient.info]
Cutaneous Manifestation
  • Cutaneous manifestations of MEN 2A syndrome include macular amyloidosis, whereas MEN 2B syndrome is traditionally linked to multiple mucosal neuromas.[ncbi.nlm.nih.gov]
  • In the contrary, cutaneous manifestations during MEN 2A like lichen amyloid that might be more common on individuals with a mutation of codon 634 were not recorded in our patients [12].[file.scirp.org]
Suggestibility
  • This deletion causes RET loss of heterozygosity exclusively in the metastasis, thus suggesting a role for this second mutational event in tumor progression. No additional mutations were found in the other exons analyzed.[ncbi.nlm.nih.gov]
  • Seven yr after the initial operation, an enhanced urinary excretion-ratio of N-methyladrenaline/adrenalin suggested the possible presence of either persistent or metastatic pheochromocytoma Iodine-123-labeled metaiodobenzylguanidine scintigraphy (I-123[ncbi.nlm.nih.gov]
  • Although the simultaneous occurrence of both MEN2A and sporadic acromegaly may be accidental, there is evidence to suggest a genetic interaction between MEN2 and acromegaly.[ncbi.nlm.nih.gov]
  • Some studies have suggested that the V804L mutation causes the low penetrance multiple endocrine neoplasia type 2 syndrome, with late onset and relatively indolent course, whereas others have reported that V804L and V804M have an aggressive potential.[ncbi.nlm.nih.gov]
  • These variations in phenotypes suggest a role for genetic modifiers, and recently, it has been reported that polymorphisms within RET (G691S/S904S) may have such a modifier effect on the age at onset.[ncbi.nlm.nih.gov]

Workup

Genetic testing is the preferred diagnostic test, performed on patients and their relatives as a screening test. It can also be performed antenatally. The presence of two of the neoplasms belonging to multiple endocrine neoplasia type 2A is enough to make a clinical diagnosis. Depending on the gene mutation found, the finding has a role in management and prognosis of the condition. Other screening tools include screening for MEN 2A characteristic tumors and their biochemical markers in family members yearly.
Laboratory and imaging studies for each of the tumors is as follows:
MTC

  • Measurement of serum calcitonin levels, which may be raised.
  • Imaging studies consist of computerized tomography (CT), magnetic resonance imaging (MRI), and octreotide scanning.

Pheochromocytoma

  • Blood pressure measurements are important as patients may be hypertensive.
  • Elevated levels of urine and serum catecholamines or their products (such as vanillylmandelic acid) are indicators of the tumor [5] [7].
  • Imaging modalities used are CT, MRI, and positron emission tomography (PET) scans. CT is the least sensitive, while PET is the most sensitive test [7]. A metaiodobenzylguanidine (MIBG) scan is also useful [8]. These studies are used to localize the tumor and to check if it is bilateral.

Parathyroid adenoma

  • Serum calcium and phosphate level requests may reveal hypercalcemia, hypophosphatemia. Parathyroid hormone (PTH) levels may be high.
  • Imaging includes the use of single-photon emission CT (SPECT).
Small Bowel Mass
  • Surgical exploration identified a 5-cm pedunculated small-bowel mass approximately 25 cm from the ileocecal junction, as well as bilaterally firm ovaries. Bilateral oophorectomy revealed medullary thyroid cancer in both ovaries and fallopian tubes.[ncbi.nlm.nih.gov]
Pneumoperitoneum
  • After treatment with α-blockers, he underwent a total bilateral laparoscopic adrenalectomy with CO 2 pneumoperitoneum; bilateral PHEO was confirmed by histopathological examination.[journals.plos.org]

Treatment

  • Early detection and treatment are key to successful control. CONCLUSIONS: Identification of kindreds affected by this inherited disorder can result in improved detection and early treatment.[ncbi.nlm.nih.gov]
  • This paper summarizes what is known about the diagnosis, treatment, and follow-care of people with the inherited disorder multiple endocrine neoplasia type 2a (MEN2a).[ncbi.nlm.nih.gov]
  • No subject showed any increase in CT levels after omeprazole treatment. In conclusion, the two most frequent RET proto-oncogene mutations in MEN 2A are present in Brazilian families.[ncbi.nlm.nih.gov]
  • Although this disorder is classified as a rare disease, the patients affected have a low life quality and a very expensive and continuous treatment.[ncbi.nlm.nih.gov]
  • HYPOTHESIS: Adrenal-sparing adrenalectomy is considered the treatment of choice for hereditary bilateral pheochromocytoma in patients with multiple endocrine neoplasia type 2A (MEN 2A).[ncbi.nlm.nih.gov]

Prognosis

  • It is very important to accumulate cases with MEN 2A and investigate the phenotype and the prognosis in each mutation.[ncbi.nlm.nih.gov]
  • If the results verified the mutations of RET gene, thyroidectomy should be undertaken as the guide for better prognosis.[ncbi.nlm.nih.gov]
  • Prognosis of MEN2 is mainly related to the stage-dependant prognosis of MTC indicating the necessity of a complete thyroid surgery for index cases with MTC and the early thyroidectomy for screened at risk subjects.[en.wikipedia.org]
  • Timing of TT could be individualized based on codon-specific prognosis. Until more detailed knowledge is available, consequent genetic and biochemical screening is mandatory for appropriate individual timing of ETT before age of 5 years.[ncbi.nlm.nih.gov]

Etiology

  • (Etiology) MEN 2 Syndrome is caused by the mutation in the RET proto-oncogene on the chromosome 10; the proto-oncogene stimulates the proliferation of cancer cells.[dovemed.com]
  • Lab tests were unremarkable, with the exception of a slightly increased calcium level, elevated PTH values, in a patient who was never investigated for a secondary etiology for hypertension. Calcitonin levels were normal.[journals.lww.com]
  • Etiology Point mutations associated with MEN2A and the FMTC-only subtype have been identified in exons 10 and 11. Evidence of genotype/phenotype correlation exists.[emedicine.com]
  • Immunohistochemistry of the tumor with ACTH confirmed the etiology of the ACTH secretion. Impaired glucose tolerance has been observed in patients with pheochromocytoma with an incidence of from 25 75%.[synapse.koreamed.org]

Epidemiology

  • Approximately 95% of patients with MEN2B have RET germline mutations in exon 16 (codon M918T) and fewer than 5% have RET germline mutations in exon 15 (codon A883F). [1] Epidemiology The overall frequency of MEN2 in the United States is 1 case per 30,000[emedicine.com]
  • Results Epidemiological description of the studied family The family consisted of a sibling of 22 people and 12 children and grand- children ( Figure 1, Figure 2, Figure 3 ) involving 34 people overall. There were three households.[file.scirp.org]
  • Epidemiology and Prevention, Laura Gil, Marina Pollán, Arancha Cebrián, Sergio Ruíz, Marta Azañedo, Javier Benitez, Javier Menárguez and José M.[cancerres.aacrjournals.org]
Sex distribution
Age distribution

Pathophysiology

  • Early total thyroidectomy remains effective in preventing the development of MTC in the long term. [3, 4, 5] Pathophysiology Mutations in RET, a transmembrane proto-oncogene, have been localized to 10q11.2 and are responsible for MEN 2.[emedicine.com]

Prevention

  • Preventive surgery can be performed safely at that age and may be limited to total thyroidectomy when baseline calcitonin levels are normal.[ncbi.nlm.nih.gov]
  • In the present case, prompt sequential dosage of calcium, diagnosis of PHT, and genetic analysis would have resulted in pancreatitis prevention and early MEN2A management.[ncbi.nlm.nih.gov]
  • Clinical recognition and accurate diagnosis of individuals and families who are at risk of harboring a germline RET mutation is critical for the prevention and management of potentially life-threatening neoplasms.[ncbi.nlm.nih.gov]
  • Prophylactic or early total thyroidectomy or pheochromocytoma/parathyroid removal in patients can be preventative or curative and has become standard management.[ncbi.nlm.nih.gov]

References

Article

  1. Cohen MS, Moley JF. Surgical treatment of medullary thyroid carcinoma. J Intern Med. 2003;253(6):616–626.
  2. Callender GG, Rich TA, Perrier ND. Multiple endocrine neoplasia syndromes. Surg Clin North Am. 2008;88(4):863–895.
  3. Modigliani E, Vasen HM, Raue K, et al. Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med. 1995;238(4):363–367.
  4. Rodriguez JM, Balsalobre M, Ponce JL, et al. Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg. 2008;32(11):2520–2526.
  5. Pacak K, Ilias I, Adams KT, Eisenhofer G. Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med. 2005;257(1):60–68.
  6. Seri M, Celli I, Betsos N, Claudiani F, Camera G, Romeo G. A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. Clin Genet. 1997;51(2):86–90.
  7. Ilias I, Pacak K. Diagnosis, localization and treatment of pheochromocytoma in MEN 2 syndrome. Endocr Regul. 2009;43(2):89-93.
  8. Ilias I, Chen CC, Carrasquillo JA, et al. Comparison of 6-18F-fluorodopamine PET with 123I-metaiodobenzylguanidine and 111in-pentetreotide scintigraphy in localization of nonmetastatic and metastatic pheochromocytoma. J Nucl Med. 2008;49(10):1613–1619.

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Last updated: 2019-07-11 20:01