POLYGLANDULAR ENDOCRINOPATHY DR.IBRAHIM MOKHTAR MD CONSULTANT ENDOCRINOLOGY
Oct 27, 2014
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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