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Genetic Endocrine disorders

Sub-section: Endocrine other Section: Endocrine

MEN syndromes

MEN 1 syndrome (3P’s)

  • Autosomally dominant inherited mutation in the MEN1 gene which encodes the menin protein– located on chromosome 11.
    • Tumour suppressor gene
  • Manifestations:
    • Pituitary adenomas
    • Parathyroid adenomas
    • Pancreatic tumours

Hyperparathyroidism

  • Usually multiglandular disease.
  • Usually the first manifestation of MEN1
  • 40% of patients develop disease by 20 years old. 100% by 50 years old.
  • Patients with MEN1 associated hyperparathyroidism are more likely to be younger, have 4 gland disease, and have a higher recurrence rate after subtotal parathyroidectomy.
  • Patients need a full neck exploration with a sub-total parathyroidectomy and a thymectomy.
  • If they can’t under go surgery – need bisphosphonates and calcimimetic drugs.

Pituitary adenomas

  • 50% of patients with MEN1 will develop a pituitary adenoma
  • Most are prolactinoma’s – 50%
  • Can also get growth hormone secreting, ACTH secreting, and non-functioning tumours.
  • To screen for pituitary tumours - do a prolactin level, serum IGF-1 (screens for acromegaly), early morning cortisol, TFTs, and LH/FSH levels.

Pancreatic neuroendocrine neoplasms

  • 80% will be non-functional - 50% likelihood of malignancy.
  • The most common functional tumour is a Gastrinoma - Gastrinomas are likely to be malignant.
  • Rarely they can get Insulinoma’s
    • If tumours are < 1cm – usually monitored/surveilled.
    • Once > 2cm in size – managed with resection.
  • Pancreatic tumours are what these patients have the most morbidity and mortality from

Other tumours in MEN1

  • Foregut carcinoids – including tumours in the thymus and bronchus.
  • Can also get angiofibromas, collagenomas, and lipomas (all cutaneous manifestations)
  • Can also get adreno-corticoid tumours but these are usually benign and non-functional.

Indications for testing

  • Family history
    • Germline testing should be offered to the relatives of a patient with MEN1
  • Clinical
    • Young patient presenting with 4 gland hyperplasia
    • Young patient with multi-focal pancreatic NET
    • Patients presenting with 2 manifestations of MEN1

Screening

  • Should be offered a program of clinical, biochemical and radiological screening
  • Parathyroid
    • Annual plasma Ca and PTH
  • Pancreatic NET
    • Annual gastrin, glucagon, VIP, Chromogranin A, insulin levels, and BSL.
    • There hasn’t been an optimal radiological program determined – institution dependent
    • It would be reasonable to perform a CT or MRI pancreas every 1-2 years.
  • Pituitary screening
    • Annual plasma prolactin, IGF-1 levels, Pituitary MRI every 3-5 years.

MEN 2 syndrome

  • Autosomally dominantly inherited mutation in the RET proto-oncogene on chromosome 10

MEN 2A syndrome (2Ps 1M)

  • Manifestations
    • Primary hyperparathyroidism
    • Phaeochromocytoma
    • Medullary thyroid cancer
  • Specifics
    • Medullary thyroid cancer
      • The medullary thyroid cancer patient with 2a get tend to be less aggressive and multifocal.
      • Nearly 100% lifetime penetrance
    • Phaeochromocytoma
      • About 50% of patients with 2a will develop a phaeo.
      • In 60-80% of patients with 2a – the phaeo will be bilateral.
    • Primary hyperparathyroidism
      • Usually hyperplasia thus need to do a multi-gland exploration. Occurs in about 20–30% of patients.
    • Can be born with Hirschsprung’s disease.

MEN 2B syndrome (1P 2M’s)

  • Manifestations
    • Phaeochromocytoma
    • Medullary thyroid cancer
    • Marfan’s habitus
  • Specifics
    • Is more likely to result from a sporadic mutation
    • Medullary thyroid cancer
      • The medullary thyroid cancer is often much more aggressive and often happens earlier in life.
    • Marfan’s habitus
      • They also get a Marfanoid body habitus
    • Mucosal neuromas
      • Neuroma’s on the tongue and lips (has been a spot question
  • Different mutations and different codons on the gene has been associated with different manifestations of the disease (and this can determine at what age they usually get their medullary thyroid cancer)
    • Thus if you diagnose MEN2 you should do this additional testing to determine when they should have thyroidectomy.
  • Other MEN2a subtypes
    • MEN2a with cutaneous lichen amyloidosis.
    • MEN2a with Hirschsprung’s disease
    • Familial medullary thyroid cancer (FMTC) - is a form of MEN2 where the patient only gets medullary thyroid cancer.

Testing for MEN 2

  • RET mutation analysis
  • Indications
    • Anyone that presents with a medullary thyroid cancer
    • Patients with bilateral phaeochromocytoma, phaeochromocytoma in a young patient, or phaeochromocytoma in a patient with a FHx of phaeo.
      • Patients with bilateral phaeochromocytoma should also best tested for NFM1, Von-Hippel Lindau syndrome, SDH mutations
    • Four gland hyperplasia with a family history OR an associated MEN disease

Surveillance

  • Medullary thyroid cancer
    • Need to determine the MEN subtype/codon mutation because if it’s a high risk mutation should have a total thyroidectomy early in life.
      • Both MEN2a and 2b have high risk subtypes.
    • Thyroidectomy for the highest risk groups is recommended in the first few months of life.
    • For the lowest risk groups – surveillance with a calcitonin followed by thyroidectomy in adulthood is reasonable
  • Other surveillance
    • Yearly PTH and calcium levels.
    • Yearly plasma metanephrines and urinary catecholamines.
    • MRI or CT every 4-5 years for image the adrenals looking for phaeo.

Familial hypocalciuric hypercalaemia

  • Overview
    • Causes hyper-calaemia with low urine calcium secretion
    • Autosomally dominantly
      • Mutation for a gene in the calcium sensing receptor expressed in the parathyroid tissue and kidney tissue
        • Leads to higher Ca2+ concentrations being needed to inhibit PTH release than normal
  • Clinical
    • Inappropriately normal or high PTH in the presence of mild hypercalcaemia
    • Low 24 hr urinary Ca2+ (< 5mmol/L)
    • Few, if any signs/symptoms of hypercalcaemia
      • Occasional pancreatitis
  • Diagnosis
    • High serum calcium with inappropriately normal or elevated PTH
    • 24-hour urinary calcium excretion is typically below 200 mg/day (5 mmol/day)
    • Calculation of the Ca/Cr (calcium/creatinine) clearance ratio less than 0.01
    • Check Vitamin D deficient
    • Stop thiazide diuretics
  • Management
    • Calcimimetics – sensitizes the calcium receptor thus reducing PTH excretion and increasing renal calcium excretion
      • Cinacalcet
    • Surgery not indicated unless in the rare event of sequele e.g. pancreatitis

Paraganglioma syndrome (SDH)

  • Overview
    • Genes include SDH A, SDH B, SDH C, and SDH D
      • Tumour suppressor genes
    • Typically autosomal dominant mutations
  • Manifestations
    • Phaeochromocytomas
    • Paragangliomas
    • Also at risk of developing GIST
      • SDH deficient GISTs are less likely to respond to imatinib.
  • Types
    • SDH-A
      • Very rare
    • SDH-B
      • About 80% of patients will develop a tumour by age of 50
      • Usually paraganglionomas
      • Higher likelihood of being malignant
    • SDH-C
      • Rare
      • Usually develop paraganglionomas
      • Low chance of malignancy.
    • SDH-D
      • 90% of patients develop tumour by age of 50
      • Usually para-ganglionomas
      • Higher likelihood of being malignant

SDH-B and D are the bad subtypes with high rates of tumours by aged 50 and also higher rates of the tumours being malignant

Carney-Stratakis dyad

Carney triad

  • Rare
    • These tumours are SDH deficient - although the exact mutation which causes this hasn’t been identified.
  • GIST
  • Paragangliomas
  • Pulmonary chondroma

Surveillance for patients with SDH

  • Should have lifelong screening from aged 10
  • Plasma meta-nephrines and urinary catecholamines.

Von-Hippel-Lindau disease

  • Autosomal-dominant
  • Germline pathogenic variants in the VHL gene
    • tumour suppressor gene

CNS

  • Paragangliomas
  • Hemangioblastomas
    • Retinal, Cerebellar, Brainstem, Spinal cord
  • Endolymphatic sac tumors

Viscera

Diagnosis

  • Established through detection of a germline pathogenic variant in the VHL gene

Surveillance

  • Annual plasma metanephrines and normetanephrines.
  • Regular pancreatic imaging (CT or MRI)

Neurofibromatosis

  • 2 main types – clinically and genetically distinct

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