polyglandular endocrinopathy final
TRANSCRIPT
POLYGLANDULAR ENDOCRINOPATHY
DR.IBRAHIM MOKHTAR MDCONSULTANT 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 -1DEFINITION
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 -1GENETICES
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 -1EPIDEMIOLOGY
The prevalence of the condition has estimated at
1/10000.
MEN -1FEATURES
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 -1SCREENING
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 -1PROGNOSIS
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-2DEFINITION
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-2GENETICS
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 hirschsprung’s disease .
MEN-2aFEATURES
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-2aFEATURES (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-2aFEATURES (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-2bFEATURES
Many patients don’t 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 MANAGEMENTMEDULLARY 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 MANAGEMENTPHAEOCHROMOCYTOMA
Treatment should precede that of MTC 1/3 of patients develop a second adrenal
tumour after removal of the first
MEN-2 MANAGEMENTHYPERPARATHYROIDISM
3 Options : 1- Surgery 2-Observation 3-Medical management
MEN-2 MANAGEMENTHYPERPARATHYROIDISM
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 MANAGEMENTHYPERPARATHYROIDISM
Surgery: Indications: 2-Relative
Concomitant illness Difficulty of follow up Younger ( < 50 ) patients Patient preference
MEN-2 MANAGEMENTHYPERPARATHYROIDISM
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 MANAGEMENTHYPERPARATHYROIDISM
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 MANAGEMENTHYPERPARATHYROIDISM
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-2SCREENING
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-2PROGNOSIS
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 COMPLEXGENETICS
Autosomal dominant In activating mutation of PRKARIA on 17q in
approximately 40% families .
CARNEY COMPLEXCLINICAL 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 COMPLEXDIAGNOSTIC CRITERIA
2 of the clinical features or 1 feature and an affected first degree
AUTOIMMUNEAUTOIMMUNE 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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