Editing MEN syndromes


The Multiple Endocrine Neoplasia syndromes occur as a result of a genetic change leading to the development of both benign and malignant tumours in endocrine organs and tissues

== '''MEN1''' ==

* '''Genetics'''
** Autosomal dominant - phenotypic carriers are heterozygotes - I presume homozygote embryos are non-viable
** Germline, loss-of-function mutation in the ''MEN1'' tumour suppressor gene on 11q13
*** Menin (the protein produced by this gene) is involved in control of G1 to S phase cell cycle progression
*** A 'second hit' is still required - if the other normal copy of the allele is damaged in a cell, loss of function can result, leading to cell proliferation and eventual neoplastic transformation
** 1 in 30,000 in general
** 1-18% of patients with primary hyperparathyroidism have it
** 3% of patients with pituitary adenomas have it
** Commercial testing available since around 1990. 10-20% will not have an identifiable mutation by conventional testing. Genetic testing can't be used to predict clinical course at this time.
* '''Presentation: the ''three p's'''''
** Typically has become evident by age 29
** '''Hyperparathyroidism''' from parathyroid adenomas/hyperplasia - almost all develop primary HPT by 50yo, and are most likely to develop multigland disease
*** 95% penetrance, usually the first manifestation
*** Diagnose biochemically, usually around 20yo
*** Usually have multiglandular disease
*** Affected parathyroids are typically benign
*** Sestamibi is useful to identify ectopic glands prior to exploration
** Microadenoma of anterior '''pituitary'''
*** Penetrance 15-50%, typically occurring age 20-40
*** Symptoms either from hormone secretion (prolactin, growth hormone, corticotropin) or local effects of the tumour resulting in visual field defects
** '''Pancreatic''' NET
*** Penetrance 30-80%
*** Can be functional or non-functional - gastrinoma (50%), insulinoma, VIPoma
*** Chromogranin A or pancreatic polypeptide can be useful as markers even if non-functional
*** Screen biochemically with imaging for further investigation
**** See separate topic under 'pancreas' for more detail on workup
*** 90% of gastrinomas in MEN1 are malignant, and >50% have lymph node metastases. Very good prognosis for isolated tumours, but 52% at five years for those with liver mets.
** Also (less commonly)
*** Adrenocortical and thyroid tumours
*** NET of thymus (most dangerous), bronchus and stomach
**** Preventative trans-cervical thymectomy no longer recommended
*** Meningioma
*** Facial angiofibroma
*** Collagenomas 
*** Multiple lipomas
*** Breast cancer
*** PUD as a complicated of ZES is common
* '''Diagnosis'''
** Positive to genetic testing
** Two MEN1-associated tumours
** One MEN1-associated tumour and a first-degree relative with MEN1
* '''Management'''
** Primary hyperparathyroidism has two treatment options, both reasonable options; however ultimate recurrence is assured if patients are followed long enough
*** Subtotal (3.5) parathyroidectomy 
**** Gives less post-op hypocalcaemia, but 20-30% have recurrent or persistent hypercalcaemia within 10 years
**** 26-45% have hypoparathyroidism
*** Total parathyroidectomy with auto-transplantation into a location outside the neck, typically brachioradialis
**** Recurrence rates 4-20%
**** Hypo-parathyroid rates 40-60%
*** Patients with recurrence and no surgical options can be treated with calcimimetics
*** Don't need pre-op localisation studies
** Enteropancreatic NETs
*** Surgical management is aimed at controlling hormone excess, preventing metastatic progression, and preventing local invasion
*** Manage as per recommendations for sporadic PNETs - see separate topics
** Pituitary adenomas
*** Treat as for sporadic adenomas
* '''Screening''' (offer to anyone with either genetic or clinical diagnosis)
** Pituitary
*** 10+: annual clinical review and prolactin/IGF-1 
*** 20+: add MRI every 4 years
** Parathyroid
*** 10+: annual calcium, phosphate, vit D and PTH
** PNET
*** 15+: annual hormonal testing
*** 20+: MRI every two years
** Thymus
*** 20+: MRI every two years
** ACC
*** 20+: MRI every two years
** Bronchopulmonary NET
*** 30+: chest imaging every two years
* '''Genetic testing indications'''
** Index patients with suspected MEN1
** First-degree relatives
** Can be offered to asymptomatic relatives
* '''Prognosis'''
** Disease-specific survival of 88% at 30 years, mean age at death 50-55 years

== '''MEN2''' ==

* '''Genetics'''
** First described in 1960s
** Gain-of-function germline mutation in the ''RET''  (REarranged during Transfection) proto-oncogene on 10q11.2
** Autosomal dominant
** Codes for a membrane receptor with tyrosine kinase activity which is present in thyroid parafollicular cells, parathyroid glands, enteric ganglia, adrenal chromaffin cells, and peripheral and central neurons
** Distinct genotype-phenotype correlation depending on specific type of ''RET'' gene inherited; thus treatment depends on genetic testing
** Prevalence 1 in 35,000
* '''Diagnosis'''
** Confirmed ''RET'' mutation
** Clinical diagnosis can be made in families with the syndrome but no identifiable ''RET'' mutation
** Offer screening to anyone with MTC, 2 or more typical cancers, or first-degree relatives. Typically do it in infancy.
* '''MEN2A''' (most common subtype)
** Note '''Familial MTC''' which is considered to be an entity within MEN2A, but without potential for other cancers - rely on history of familial MTCs but no other cancers in family. MTC usually develops in mid-40s.
** '''Presentation:'''
*** Medullary thyroid cancer >90% 
**** Hallmark feature
**** Can be multifocal
**** Usually develops in mid-20s
**** 10-year survival 94%
*** Phaeochromocytoma 40-50%
**** Tends to be benign (95%)
*** Primary HPT - penetrance 15-35%. 
**** Single adenoma or diffuse hyperplasia.
**** Management approach similar to sporadic hyperparathyroidism
*** Adrenal medullary hyperplasia
*** Cutaneous lichen amyloidosis - repeated scratching leads to amyloid deposition in dermis
*** Hirschsprung disease
*** Normal physical appearance and body habitus
* '''MEN2B'''
** '''Presentation'''
*** '''MTC'''
**** Hallmark
**** Develops as early as infancy
**** Tends to be aggressive with early metastases
**** 10-year survival 60%
*** '''Phaeochromocytomas''' (50%)
*** Mucosal neuromas of lips and tongue
****
*** Ganglioneuromatosis of the GIT
**** Oesophageal dysmotility
**** Abdominal bloating
**** Intermittent constipation
**** Diarrhoea
*** Marfanoid appearance - elongated facies, Marfinoid habitus, everted eyelids, ophthalmologic abnormalities, skeletal abnormalities including pectus excavatum and scoliosis
*** Adrenal medullary hyperplasia
* '''Management'''
** Screen for phaeo before doing anything - 34% of patients with MTC have phaeo
** Prophylactic thyroidectomy recommended in infants/children/adolescents depending on specific mutation present (see table below)
*** ATA-MOD: start screening at 5yo with 6-12-monthly calcitonin, and use that to determine when to operate
*** ATA-H: operate at 5yo, or earlier if serum calcitonin dictates otherwise
** MTC
*** Total thyroidectomy with central node dissection if localised to neck
*** Require yearly calcitonin for life to detect recurrence
*** Recurrence
**** Re-operate if limited to neck
**** RAI, CTX, RTX are not useful
**** Vandetanib can initiate partial or complete response - tyrosine kinase inhibitor - used for metastatic disease
** Phaeochromocytoma
*** A cortical-sparing or partial adrenalectomy is preferred when possible because of the high likelihood of future contralateral disease
** Hyperparathyroidism
*** Explore and remove abnormal-appearing glands, using pre-operative imaging to guide exploration
* Screening
** MTC
*** Thyroidectomy, not screened
** Phaeochromocytoma:
*** Annual screening (BP and bloods) starting at age 11, or age 16 for ATA-MOD risk
** Parathyroid (MEN2A only):
*** Annual PTH and serum calcium starting at age 11 or 16 depending on risk


== MEN4 ==

* Rare inherited syndrome
* Clinically similar to MEN1 - may account for people meeting clinical criteria for MEN1 without a known MEN1 mutation
* ''CDKN1B'' gene mutation
* Management recommendations
** If primary HPT - subtotal parathyroidectomy and transcervical thymectomy

[[Category:Oncology]]