POLYGLANDULAR ENDOCRINOPATHY

DR.IBRAHIM MOKHTAR MD
CONSULTANT ENDOCRINOLOGY

INTRODUCTION

Polyglandular endocrinopathies includes different syndromes with affection of multiple endocrine glands in variable ,although predictable , combinations. Non-endocrine manifestations may be present in some of these syndromes ,which may be the first clue to its presence.

INTRODUCTION

The mechanism of polyglandular endocrinopathies may be either :

1-Neoplastic :
A-Multiple Endocrine Neoplasia Syndromes (MEN) B -Carney Syndrome OR

2-Autoimmune :
Autoimmune Polyglndular Syndromes (APS)

MULTIPLE ENDOCRINE NEOPLASIA (MEN)

MEN includes : 1-MEN -1 2-MEN -2a and MEN -2b

MEN -1
DEFINITION
MEN-1 describes the association of the occurrences of tumours involving two or more endocrine glands: Parathyroid adenoma or hyperplasia Pancreatic endocrine adenoma or hyperplasia Pituitary adenomas.

MEN -1 GENETICES
MEN-1 is an autosomal dominant condition with high penetrance. The gene on chromosome 11q 13 has recently been described. . The gene product is menin, a protooncogene . In contrast to MEN-2 , a large number of different mutations can occur and a substantial proportion are sporadic.

MEN -1 EPIDEMIOLOGY
The prevalence of the condition has estimated at 1/10000.

MEN -1 FEATURES

Parathyroid hyperplasia and adenoma the usual presenting feature ;occurs in nearly all cases. Pancreatic endocrine tumours occur in 70% of patients presenting between age 15 and 50 ,if not screened. Different secreting types are seen . Diffuse pancreatic hyperplasia is usual , as are multiple adenomata . Multiple duodenal micro gastrinomas account for half of those seen in MEN-1. Pituitary adenomas clinically apparent in 30% . Unlike the parathyroid and pancreases there is no pituitary hyperplasia . Different types occur.

MANAGEMENT

Parathyroid hyperplasia and adenoma the timing of operation can be difficult if hypercalcaemia is mild. Operation is indicated for most patients and if there are complications . Usually total parathyroidectomy is performed with autotransplantation of one gland into the forearm and immediate replacement calcitriol .

MANAGEMENT (CONT)

Pancreatic endocrine tumours the surgical approach is controversial and an experienced surgeon is essential . For kindreds with aggressive disease , the pancreas and duodenum with adjacent lymph nodes should be removed . An alternative is enucleation of the palpable lesions and duodenal resection if indicated . Medical therapy can be used for gastrinomas (omerpazole) but medical therapy is less successful with insulinomas so a more aggressive surgical approach is important . For the treatment of metastatic disease.

MANEGEMENT (CONT)

Pituitary adenomas these are managed with surgery , drug treatment or radiotherapy.

MEN -1 SCREENING
because so many different mutations have been described, widespread genetic screening of probands and relatives is not currently feasible . First and second-degree relatives of affected individuals should be screened biochemically . Screening allows the detection of malignant kindreds and lowers the age of detection of the syndrome by 20 years.

MEN -1 PROGNOSIS
Malignant pancreatic tumours are the major cause of mortality . Those in MEN-1 appear less malignant than sporadic malignant pancreatic tumours and carry a better prognosis , with a median survival of 15 vs 5 years (MEN-1 vs sporadic) . This may reflect diagnosis.

MEN-2 DEFINITION
MEN-2 includes two forms plus familial medullary thyroid cancer: MEN-2a familial medullary thyroid carcinoma in combination with pheochromocytoma and parathyroid tumours. MEN-2b familial medullary thyroid cancer associated with pheochromocytoma , ganglionearomatosis (mucosal) , and marfanoid habitus . Familial medullary thyroid carcinoma may also occur in isolation.

MEN-2 GENETICS
These are autosomal dominant conditions . The MEN2 gene is on the long arm of chromosome 10 (10q11.2). Mutations affect the protooncogene ret, which is a transmembrane receptor with an extracellular cysteine rich domain and intracellular tyrosine kinase domain . Different germline mutations cause different familial syndromes . The c-ret protooncogene is also involved in the aetiology of papillary thyroid carcinoma and hirschsprungs disease .

MEN-2a FEATURES

30% of gene carriers never manifest clinically significant diseases . Medullary thyroid cancer (MTC) often the initial presentation . Pheochromocytoma and parathyroid disease develop later . There may be a nodule diagnosable by FNAC ,but the diagnosis may be made only in histology which shows the tumours often multifocal with C cell hyperplasia and stromal amyloid . Circulating calcitonin is elevated . With metastatic disease , diarrhoea is common (30%) . Hypocalcaemia is not seen .

MEN-2a FEATURES (CONT)

Occasional tumours secrete ACTH, and MTC is a rare cause of ectopic ACTH secretion (Cushing's) . Pheochromocytoma present later in 20-50% of affected individuals who may develop unilateral or bilateral (50%) tumours . They are multicentric , but malignancy is rare (0-8%) . They must be ruled out before any surgery .

MEN-2a FEATURES (CONT)

Hyperparathyroidism occurs in 10-25% of affected individuals . Usually chief hyperplasia is found and hypercalcaemia is mild . Cutaneous lichen amyloidosis seen in some affected patients .there is a pruritic and lichenoid lesion over the upper back .

MEN-2b FEATURES

Many patients dont have a family history and the syndrome is due to a new mutation . There are a mucosal neuromas on the distal tongue and conjunctiva , thickened lips , a marfanoid habitus (with slipped femoral epiphysis and pectus excavatum) , and mucosal neuromas through out the GI tract . MTC presents earlier and mucosal neuromas pathognomonic.

MEN-2 MANAGEMENT MEDULLARY THYROID CANCER(MTC)

Total thyroidectomy and careful lymph node dissection Postoperative thyroxine Regular postoperative calcitonin measurement every 6-12 months to detect early recurrence with surgical treatment Responds poorly to radiotherapy and chemotherapy

MEN-2 MANAGEMENT PHAEOCHROMOCYTOMA

Treatment should precede that of MTC 1/3 of patients develop a second adrenal tumour after removal of the first

MEN-2 MANAGEMENT HYPERPARATHYROIDISM

3 Options : 1- Surgery 2-Observation 3-Medical management

MEN-2 MANAGEMENT HYPERPARATHYROIDISM

Surgery: Indications:
1-Definite
Markedly elevated serum calcium(>3mmol/L) Impaired renal function Renal stones Nephrocalcinosis Markedly elevated urinary calcium(>10mmol/24h) Reduced BMD Disequilibrium hypercalcaemia ( confusion, lethargy, depresssion)

MEN-2 MANAGEMENT HYPERPARATHYROIDISM

Surgery: Indications:
2-Relative
Concomitant illness Difficulty of follow up Younger ( < 50 ) patients Patient preference

MEN-2 MANAGEMENT HYPERPARATHYROIDISM

Surgery: Procedure 1-Adenoma :remove affected gland 2-Hyperplasia : either -Total parathyroidectomy with medical treatment for
hypocalcaemia OR -Partial parathyroidectomy (perhaps with reimplantation of tissue in more accessible site

Only by experienced surgeons

MEN-2 MANAGEMENT HYPERPARATHYROIDISM

Medical management :
Only indicated if patient not suitable for surgery

1-Hormone replacement therapy

-Reduce serum and urine calcium -Preserve bone mass

2-Bisphosphonates
-Only transient effect on serum and urine calcium -Preserve bone mass

3-Oral phosphate
-Sustained reduction in plasma calcium -Increased ectopic calcification (particularly kidney -Increased PTH -Cannot be recommended

MEN-2 MANAGEMENT HYPERPARATHYROIDISM

Observation
- Suitable for patients with mild disease with no evidence of en d organ damage -They require regular follow up 1-Annual plasma ca. renal function , blood pressure 2-Every 2-3 years BMD ,renal ultrasound -Any significant deterioration indicates surgery

MEN-2 SCREENING

Most gene mutations are detectable(80%) All first and second degree relatives should be screened with : 1-Genetic analysis ,as soon as possible after age of 3 2-Biochemical screening (calcitonin ,calcium)

MEN-2 PROGNOSIS

The prognosis for patients with MEN-2a is significantly better than for patients with MEN-2b (80% v.65% 10 year survival ) Residual disease may be dormant over years Early surgery beneficially affects prognosis ,which may explain the better prognosis for MEN-2a

CARNEY COMPLEX GENETICS

Autosomal dominant In activating mutation of PRKARIA on 17q in approximately 40% families .

CARNEY COMPLEX CLINICAL FEATURES

Spotty skin pigmentation . Myxomas - Heart - Skin - Mucosal Endocrine tumours (commonest is primary pigmented nodular adrenocortical disease (PPNAD ) causing Cushing's) Psammomatous melanotic schwannoma (PMS) .

CARNEY COMPLEX DIAGNOSTIC CRITERIA

2 of the clinical features or 1 feature and an affected first degree

AUTOIMMUNE POLYGLANDULAR SYNDROME (APS)

APGS includes 1-APS type 1 2-APS type 2

APS TYPE 1

Autosomal recessive Hypoparathyroidism (90%) Primary adrenal insufficiency (60%) Primary gonadal failure Primary hypothyroidism Rarely hypopitutrism ,diabetes inspidus

APS TYPE 1 (ASSOCIATIONS)

Chronic mucocutaneous candidiasis Vitiligo Chronic active hepatitis Pernicious anaemia Malabsorption

APS TYPE 2

Autosomal recessive ,autosomal dominant , or polygenic Adrenal insufficiency (100%) Primary hypothyroidism Primary gonadal failure Type1 DM Rarely diabetes inspidus

APS TYPE 2 (ASSOCIATIONS)

Vitiligo Alopecia Myasthenia gravis Pernicious anemia Immune thrombocytopenic purpura

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