Multiple Endocrine Neoplasia (MEN) Syndromes Lecture (Dr. Lopez) Flashcards
Overview of the Multiple Endocrine Neoplasia (MEN) Syndromes
- Multiple Endocrine Neoplasia (MEN) Syndromes is a group of Disorders that affect the Endocrine System
- MEN typically involves Tumors (Neoplasia) in at least two Endocrine Glands
- ** Tumors can be Noncancerous (Benign) or Cancerous (Malignant)
- Clinical features depend on the Endocrine Glands involved
- Each Syndrome is inherited as an Autosomal Dominant Trait with a High Degree of Penetrance and Variable Expressivity
- The major forms of MEN Syndromes are called Type I, Type 2 (Type 2A and Type 2B) and Type 4 (not discussed today)
Whats the Prevalence of MEN Syndromes?
- MEN1: Prevalence is estimated to vary between 2 to 20 per 100,000 population
- MEN 2: less common than MEN 1
a) Type 2A is the MOST COMMON FORM
b) Type 2B is a relatively UNCOMMON, accounting for about 5% of all cases of Type 2
How can so many various Endocrine Organs be affected in these Syndromes?
- In terms of Biochemical features, MEN tumors arise from the so called “AMINE Precursor Uptake and Decarboxylation” (APUD) group of cells, which constitute the diffuse System of NEUROENDOCRINE Cells distributed throughout the Body
- The “APUD” acronym denotes the Capacity of these cells to Synthesize and/ or Secrete Biogenic Amines formed through activity of the Enzyme L-DOPA DECARBOXYLASE
- Inherited Genetic defects affect different groups of APUD cells and lead to Neoplastic Development of related Cell types in Diverse Anatomic Regions
Common Features of Amino Precursor, Uptake, and Decarboxylation (APUD) Cell:
- Biogenic Amine Synthesis
- Amine Precursor Uptake
- Amine (DOPA) Decarboxylase
- Small Polypeptide Hormone Synthesis
- Membrane Bound Neurosecretory Granules
Summary of the conditions associated with MEN Syndromes
MEN I
MEN I:
- Pancreas/ GI Endocrine
- Pituitary
- PARATHYROID*
Symptoms:
- Hyperparathyroidism
- Hypercalcemia
- POSSIBLE ZE Syndrome
- VARIOUS PITUITARY PATH:
a) Acromegaly
b) Cushing Syndrome
c) Galactorrhea
Summary of the conditions associated with MEN Syndromes
MEN IIA
MEN IIA:
- Pheochromocytoma
- Medullary Thyroid Cancer (Mutation fo RET Proto-Oncogene)
- Parathyroid
Symptoms:
- Hyperparathyroidism
- Hypercalcemia
- Medullary Carcinoma
- Increased Calcitonin
- Increased Catecholamines
Summary of the conditions associated with MEN Syndromes
MEN IIB
MEN IIB:
- Pheochromocytoma
- Medullary Thyroid Cancer (Mutation of RET Proto-Oncogene)
- MUCOSAL NEUROMAS!!!!!!
Symptoms:
- MUCOSAL NODULES
- MARFANOID BODY HABITUS
- Medullary Carcinoma
- Increased Calcitonin
- Increased Catecholamines
MEN Type 1 or WERMER Syndrome
1) Caused by Mutations in the MEN 1 Gene, which encodes a protein known as MENIN
- Menin functionally acts as a TUMOR SUPPRESSOR
* *** Mutations in MENIN causes unregulated Cell Division that leads to Tumor Formation
2) Tumors in the 3 P’s: Parathyroid, Pancreas (Endocrine), and Pituitary
3) Carcinoid Tumors have also been reported frequently in MEN 1 Patients
- MALE patients appear to have a Predilection for developing CARCINOID Tumors within the Thymus, whereas BRONCHIAL Carcinoids occur almost exclusively in WOMEN
3) Three means of Diagnosing MEN 1:
a) CLINICAL: Two or more MEN 1-associated Tumors
b) FAMILIAL: Patient with one MEN 1-associated Tumor and a first degree relative with MEN 1
c) GENETIC: An asymptomatic carrier of MEN 1 Mutation (No biochemical Manifestations)
MEN Type 1: Parathyroid Glands
- Although the Parathyroid Glands are the most frequently involved organs (95%) and HYPERPARATHYROIDISM is usually the FIRST MANIFESTATION of the Syndrome, its presence may not be detected until Clinical Disease of the Pituitary or Pancreas has brought the patient to Medical Attention
- HYPERPARATHYRODISIM associated with MEN 1 results from HYPERPLASIA of all FOUR Glands (Although it might be Gradual)
MEN Type 1: Endocrine Pancreas
- NEOPALSTIC transformation of the Pancreatic Islet Cells is the SEOND MOST COMMON Manifestation of MEN 1
- Tumors that develop in the Pancreas can be Benign or Malignant
- The most frequent Manifestation of MEN 1 Pancreatic involvement is GASTRONOMA
- Approximately One-Third of Patients with Gastronomes are associated with MEN 1
- Insulinomas are the second most Common Type of FUNCTIONAL Pancreatic Tumor in MEN 1
- Other Pancreatic Tumors include: Glucagonomas, Somatostatinomas, and Vasoactive Intestinal Polypeptide Secreting Tumors (VIPomas)
MEN Type 1: Pituitary Gland
- Pituitary Tumors occur in 50% to 42% with MEN 1
- Most Tumors are functionally Active and Secrete PROLACTIN
- The symptoms of HYPERPROLACTINEMIA (Galactorrhea and Amenorrhea in Women; impotence in Men) are the THIRD MOST COMMON Manifestation of MEN 1
- MEN 1 patients may develop TUMOR-Secreting ACTH or GROWTH HORMONE and present with CUSHING Syndrome or Acromegaly, respectively
- Patients with MEN 1 Syndrome have an INCREASED Frequency of BOTH Functional and Non-functional Adrenal Cortical HYPERPLASIA or ADENOMAS
MEN Type 1: Treatment
Therapy Includes:
1) Surgical RESECTION of Hyperplastic PARATHYROID Tissue
2) Surgical RESECTION of PITUITARY Adenomas or Pharmacological Management of Pituitary Adenomas with BROMOCRIPTINE for Prolactinomas and OCTREOTIDE for Acromegaly
***Bromocriptine = Prolactinomas
***Octreotide = Acromegaly
3) Subtotal PANCREATECTOMY (Removing as many Multifocal Tumors as possible in Patients with Endocrine Pancreatic Tumors)
* * Surgical cure for the associated Pancreatic Tumors is NOT USUALY POSSIBLE
MEN Type 2
1) Caused by an ACTIVATING Mutation of the RET Protooncogene
- RET Gene codes for a Receptor TYROSINE KINASE that Phosphorylates and activates Enzymes CRITICAL to CELLULAR DEVELOPMENT
2) The MOST COMMON Sign of MEN 2 is MALIGNANT Transformation of the PARAFOLLICULAR CELLS (or C Cells) = MEDULLARY THYROID CARCINOMA (MTC)!!!!!!!!!!!!!
- C Cells normally ELABORATE CALCITONIN and are Scattered throughout the Thyroid Gland
3) Some people (~50%) with this disorder also develop a PHEOCHROMOCYTOMA (Adrenal Gland Tumor)
- MEN 2 is divided into: Type 2A and Type 2B
- Overal Mortality of MEN 2B is more Severe; average age of death for patients with MEN 2A is 60 Years, whereas in patients with MEN 2B, average age of death is 30 years
MEN Type 2A or Sipple Syndrome
1) MEN 2A consists of Neoplastic Transformation of PARATHYROIDS, THYROID Parafollicular C Cells, and ADRENAL MEDULLA
2) Parafollicular Cells in patients with MEN 2A characteristically progress through a state of C-CELL HYPERPLASIA to NODULAR HYPERPLASIA to MALIGNANT DEGENERATION over a Variable Period
- MTC also expresses Peptides and Hormones not COMMONLY elaborated by C Cells, including Somatostatin, TRH, VIP, POMC, Carcinoembryonic Antigen, and Neurotensin
3) Pheochromocytomas associated with MEN 2A secrete GREATER amounts of EPINEPHRINE than SPORADIC PHEOCHROMOCYTOMA
4) Hyperparathyroidism associated with MEN-2A is similar to that found in MEN-1 but is LESS FREQUENT than in MEN 1 (10 to 20% vs 95% in MEN 1)
5) Cutaneous LICHEM AMYLOIDOSIS, is an Itchy Skin Condition, might be present in some cases
MEN Type 2B
- MEN 2B syndrome is the association of MTC and Pheochromocytoma with Multiple Mucosal Neuromas in an affected Individual
- MTC associated with this Syndrome is MORE AGGRESSIVE than other forms; Metastatic Lesions have been Described in INFANCY
- HYPERPARATHYROIDISM is NOT ASSOCIATED with MEN 2B!!!!!!!!!!!!!!!!!!!!!
Pheochromocytoma
*** Tumor of the Chromaffin Tissue
- Produces EXCESS CATECHOLAMINES
-
**Symptoms SPORADIC:
1) HYPERTENSION (reported that
