ENDOCRINOLOGY (WWW.MEDICINENOTES.

IN)

2013

MULTIPLE ENDOCRINE NEOPLASIA & OTHER POLYENDOCRINE SYNDROMES

BY DR. OM LAKHANI , MD
IMPORTANT POINTS These notes are made from Standard Textbook of Medicine The current notes corresponds to Chapter 351 of Harrisons Internal medicine The Yellow shades refer to things you have to revise frequently (atleast once a week) The Blue shades refers to concepts The Pink shades refers to concepts that are not required for undergraduate level but useful for Postgraduate level.

Q. Define Multiple endocrine neoplasia . It is genetic disorder involving Several members of family Involving 2 or more different hormonal tissues

Q. Which is the most common Multiple Endocrine neoplasia ? MEN1 is the most common. It is also known as Wemers syndrome

MEN1 : WERMERS SYNDROME

Q. What is the genetic basis of MEN1 ? MEN1 is caused by defect in MEN1 gene It encodes for a protein known as Menin Menin interacts with JunD causing activation of JunD Q. What are the organs involved in MEN1? MEN1 is associated with 4 Ps Parathyroid involvement Pancreatic neuroendocrine tumor involvement DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in Page 1

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Pituitary involvement Pheochromocytoma (very rare) Q. Which is the most common endocrine organ involvement in MEN1 ?

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Hyperparathyroidism is most common endocrinal manifestation of MEN1 It is also often the first manifestation of MEN1 Prevalence is almost 100 % GI neuroendocrine tumors are second most common

Q. What are the features of Hyperparathyroidism in MEN1 ?

Hyperparathyroidism in MEN1 is often multicentric Parathyroid hyperplasia involving all the parathyroid glands is more common than parathyroid adenoma Hyperplasia is common in younger patients and Adenoma in older patients Clinical features are same as Primary Hyperparathyroidism Q. What % of Enteropancreatic tumors in MEN1 are malignant ? About 1/3rd are malignant Q. Which is the most common Enteropancreatic tumor in MEN1 ?

Gastrinoma is the most common enteropancreatic tumor in MEN1 It is most commonly seen in Dueodenum It is associated with increased gastrin production Fasting gastrin level is >200 pg/ml This leads to Multiple ulcerations throughout GIT along with Diarrhea

Q. Which is the most common Pancreatic tumor in MEN1 ? The most common pancreatic Tumor in MEN1 is Insulinoma Please note- the most common enteropancreatic tumor is Gastrinoma- however it is most commonly seen in Duodenum- so the most common Pancreatic tumor is insulinoma and not gastrinoma Q. Which is the most sensitive test for Diagnosis these Enteropancreatic tumors ?

Intraoprerative ultrasound is the most sensitive test.

DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in

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Q. How are patients with MEN1 screened for Enteropancreatic tumors ?

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Serum gastrin and Pancreatic polypeptide are routinely measured in patients with MEN1 to screen them for possible tumor. Q. Which is the most common Pituitary tumor seen in MEN 1 ?

Prolactinoma is the most common Pituitary tumor in MEN1 o It is associated with Serum prolactin >200 pg/ml o Increase Levels but <200 pg/ml may be associated with Pituitary stalk compression o Concept : The secretion of Prolactin is inhibited by Hypothalamus through Dopamine. If the connection between Hypothalamus and Pituitary is cut off by any tumor it will leads to increase prolactin production by Pituitary Acromegaly due to increase GH production is the second most common Pituitary tumor in MEN1

Q. Do you see carcinoid tumors in MEN1 ?

Yes. Carcinoids are seen in MEN1 However classical features of Carcinoid syndrome like Flushing, Diarrhea etc are rare It is a late manifestation of MEN1 They are often aggressive and more invasive than other carcinoids o Mediastinal carcinoids are more common in Men o Bronchial carcinoid more common in Women

Q. What are the typical skin lesions seen in MEN1 ?

Skin Angiofibromas Collagneomas Lipomas Cutenous Leiomyomas

Q. Which patients with MEN1 should undergo Parathyroid exploration ?

Patients who have Serum calcium >12 mg/dl Renal stones DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in Page 3

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Renal dysfunction Age <50 years Neurological or Muscular manifestations Bone involvement

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Q. What are the approaches to Parathyroid surgery in MEN1 ? There are two approaches 1. To remove all parathyroid tissue and Thymus (it may be the site of Carcinoid in future) and implant parathyroid gland in Non dominant forearm 2. To remove 3-3.5 parathyroid gland and leave about 50 mg of Parathyroid in situ. Intraoperative PTH levels may determine the amount of Parathyroid tissue to remove.

MEN 2A (SIPPLE SYNDROME)

Q. What are the common features of MEN2 ?

Both MEN2A and 2B are associated with o Medullary thyroid carcinoma Most common manifestation o Pheochromocytoma FIGURE WEEKLY REVISE

MEN2 MTC, PHEOCHROMOCYTOMA

MEN2B: MEN2A: Above PlusHyperaparathyroidism Above Plus a) Marfanoid Features b) Mucosal Neuromas c) Intestinal Ganglioneurpmatosis

Type 1: Familal MTC- Only MTC no other features

Type 2 : Above plus Cutenous lichen amyloidosis

Type 3: Above plus Hisrchpung's disease

DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in

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Q. What are the typical features of MEN 2A ? Mneomic (MPH) Medullary thyroid carcinoma Pheochromocytoma Hyperparathyroidism Optional features Cutaneous lichen amyloidosis Hirschsprungs disease

Q. Give an account of MTC in MEN 2A ? It is the most common manifestation It usually develops in Childhood It is hyperplasia of C cell or Calcitonin producing cells It is located in the junction of lower 2/3rd and upper 1/3rd of thyroid gland Size >1 cm- associated with malignancy

Q. What are the features of Pheochromocytoma in MEN 2A ?

It is often bilateral Often associated with more epinephrine secretion than Norepinephrine (unlike Sporadic pheochromocytoma) They are mainly located within Adrenal gland (unlike certain hereditary paraganglioma)

Q. Which is the most common variant of MEN 2A ? The most common variant of MEN 2A is familial MTC This is the autosomal dominant This is associated with just MTC without pheochromocytoma or any other manifestation of MEN 2A Q. What is the Genetic mutation seen in MEN 2A ?

MEN 2A is associated with genetic defect in RET protooncogene o Mutation in Codon 634- associated with classic MEN 2A features

DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in

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o Mutation in Codon 533, 768, 932 associated with familial MTC only- No pheochromocytoma

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MEN 2B
Q. What are the clinical features of MEN 2B ?

Mnemomic M3P Medullary thyroid carcinoma Marfanoid habitus Mucosal Neuromas Pheochromocytoma

Remember there is NO HYPERPARATHYROIDISM IN MEN 2B

MNEMONICS MEN 1- 4 PS MEN 2A- MPH MEN 2B- M3P

Q. What is the difference in MTC of MEN 2A and 2B ?

MTC in MEN2B is more aggressive and more malignant Often associated with Malignancy before age of 1 year

Q. What is the Genetic mutation seen in MEN 2B ?

MEN 2B is associated with genetic defect in RET protooncogene o Mutation in Codon 918- associated with classic MEN 2B features o Others include Codon 883 and 922 mutations DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in Page 6

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Q. How and why is genetic screening done for MEN 2 ?

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As seen earlier MEN 2 may be associated with MTC which may be malignant Hence it is necessary to routinely screen family members of patients with MEN 2 for presence of Mutations If the mutation is found they must undergo early thyroidectomy Ideally two tests should be done and from two labs to exclude MEN 2

Q. What should be the management if a child is found to have mutations in Codon 883, 918 and 922 ? These children may have MEN 2B They must undergo Total thyroidectomy with Central LN dissection (Level IV) in first few months of life Q. What should be the management of Children with Codon 611, 618, 620, 630, 634 and 891 mutation ?

They may have more aggressive Familal MTC They need to undergo Thyroidectomy before age of 6 years Q. What should be the management of Children with Codon 609, 804, 912, 768, 790, 791 mutation ?

They may have less aggressive disease possibility . There are two approaches o a) Thyroidectomy after age of 6 (6-10 years) o b) Screen for pentagastrin stimulated calcitonin test- if found positive- for for thyroidectomy else observe

Q. Which are the other screening tests that must be performed in MEN 2 patients ?

Screen for Pheochromocytoma annually Screen for parathyroid and s. calcium every 2-3 years Q. What is the treatment of the MTC ?

MTC in MEN 2 is treated with total thyroidectomy with Central Lymph node dissection If done early this gives possibility of cure and good prognosis

DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in

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Q. Which are the drugs undergoing trial for use in more extensive MTC ? Some drugs like like Vandetanib Pazopanib Sunitinib Sorafenib

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Are undergoing trial for MTC

POLYGLANDULAR AUTOIMMUNE SYNDROME

Q. What is Polyglandular autoimmune syndrome Type 1 (PGA1) Its mneomic is APECED o APE- Autoimmune polyendocrinopathy in form of Adrenal insufficiency Hypoparathyroidism o C- Candidiasis o ED- Ecodermal dysplasia

It has a childhood onset- Presents with Candidiasis in childhood- difficult to treat Requires 2 of 3 for diagnosis o Hypoparathyroidism o Adrenal insufficiency o Candidiasis Other rarer manifestations include o Hypogonadism o Type 1 Diabetes o Alopecia Hypoparathyroidism appears before Adrenal insufficiency It is autosomal recessive disorder Associated with mutation in AIRE gene

Q. What are the common features of PGA type 2 ? PGA type 2 are associated commonly with o Adrenal insufficiency o Type 1 Diabetes DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in Page 8

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o o o Autoimmune hypothyroidism Graves disease Other autoimmune disorders

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Q. What is the inheritance of PGA type 2 ?

It is autosomal dominant with variable penetrance Associated with HLA DR3 and DR4

Note: PGA 1 Autosomal recessive, Appears in childhood PGA 2- Autosomal dominant , Appears in adulthood

Q. Which are the antibodies found in PGA type 2 ?

1. 2. 3. 4.

Anti TPO antibody Anti TSH antibody GAD 65 antibody Antibody against 21 hydroxylase

Q. What are the Endocrinopathies associated with Congenital rubella syndrome ?

Type 1 Diabetes Hypothyroidism Q. What is IPEX syndrome ? I- Immunedysregulation P- Polyendocriopathy E Enteropathy X- X linked disorder

Q. What should be taken care of before administration of thyroxine in patients with suspected PGA ? DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in Page 9

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Thyroxine given in patient with PGA can unmask an Adrenal insufficiency and precipitate a crisis. Hence it is mandatory to screen for adrenal insufficiency before given thyroxine to a patient with suspected PGA ? Q. What is the earliest clue to development of Adrenal insufficiency in a patient known to have PGA with type 1 Diabetes ? Development of recurrent hypoglycemia and reduced insulin requirement in patient with Type 1 diabetes points towards possible adrenal insufficiency.

OTHER AUTOIMMUNE ENDOCRINE SYNDROMES

Q. Which signs gives an hint about possible autoimmune insulin resistance syndrome ?

Presence of Acanthosis nigricans hints towards insulin resistance. Acanthosis nigricans is velvety skin pigmentation seen in o Axilla o Groin o Dorsum and Side of the neck Q. How do these insulin resistance cause by antibody manifest ? Insulin resistance syndrome associated with antibodies manifests as : 1. Mild glucose intolerance 2. Difficult to treat Diabetes 3. Fasting hypoglycemia- due to inuslinomimetic antibodies

Q. What is the endocrinal abnormality seen in Ataxia Telangiectasia ?

Ataxia telegectasia is associated with anti-insulin antibody leading to development of Insulin resistant diabetes Q. What is Crow Fukase syndrome ?

It is also known as POEMS syndrome DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in Page 10

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It is characterised by o P - Polyneuropathy o O - Organomegaly o E- Endocrinopathy o M- M band o S- skin changes

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DR. OM J LAKHANI, MD For more such notes visit http://www.medicinenotes.in

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