NF1 and NF2
NF-1 is AD, caused by a mutation in the NF-1 tumour suppressor gene on chromosome 17q. Results in loss of function of protein neurofibromin –> unopposed RAS activity and dysregulated cell proliferatoin. Usually 100% penetrant by age 5 with 50% of the mutations being sporadic. NF-1 is characterised by neurofibromas, Lisch nodules (iris hamartomas), bony lesions, optic glioma, cafe-au-lait spots, axillary/inguinal freckling. Associated conditions include short stature, intellectual impairment, HTN (renal artery stenosis) and GIST. 1% have a phaeo.
NF-2 is caused by a mutation of the Merlin gene on chromosome 22. This is also a tumour suppressor gene and results in benign CNS tumours, most commonly acoustic neuromas. Other lesions include meningiomas, spinal ependymomas, and neurofibromas.
What are the diagnostic criteria for NF-1 and NF-2?
NF-1 (von Recklinghausen’s disease)
Two or more of the following: (neuroFIBROMA)
- Fibroma: 2 or more neurofibroma of any type or 1 plexiform fibroma
- Iris hamartoma (Lisch nodules) - 2 or more
- Bony lesion - such as sphenoid dysplasia, thinning of long bone cortex w or w/o pseudoarthrosis
- Relative of the first-degree with NF-1
- Optic glioma
- Macules - 6 or more cafe au lait macules >5mm in greatest diameter in prepubertal individuals and >15mm in greatest diameter in postpubertal individuals
- Axillary/Inguinal freckling
- NF-2
Either one of:
- Bilateral masses of the CN VIII
- Unilateral masses or other peripheral nerve cell tumour with family history of NF-2.
Outline the congenital causes of increased VTE risk.
- Antithrombin III deficiency
- AT inactivates thrombin
- Required for Heparin to be therapeutic
- 2-4% of VTE <45
- Protein C deficiency
- 1:200 - 1:300
- 4% of VTE <45
- Protein S deficiency
- 8% of VTE <45
- Factor V Leiden mutation
- Protein C cannot inactivate Factor V
- 20-40% of VTE
- Homocysteinuria
- Rare
- Treat with folate and B12
Which syndromes are associated with adrenocortical carcinoma?
How do adrenocortical carcinomas present?
- MEN 1
- Li Fraumeni
- Beckwith-Weidemann
The majority of ACCs are hormonally functional and present with Cushing’s syndrome, primary hyperaldosteronism, virilisation or feminisation.
Secretion of multiple hormones is characteristic.
Which syndromes are associated with Phaeochromocytomas?
- MEN-2 (RET oncogene)
- von Hippel Lindau (vHL tumour suppressor gene)
- Neurofibromatosis-1 (NF-1 gene)
- Carney’s syndrome
- SDH enzyme mutations (Succinate Dehydrogenase)
NB - Patients with SDH mutations commonly present with paragangliomas
Von Hippel Lindau disease
- AD syndrome caused by a germline mutation in the VHL tumour suppressor gene on chromosome 3. Characterised by metachronous development of multiple benign & malignant tumours which are vascular with pronounced angiogenesis - their cells exhibit overproduction of VEGF
H.I.P.P.E.L
H = Haemangioblastoma of CNS (cerebellar, brainstem, spinal cord)
I = Increased risk RCC
P = Pancreatic tumours (NETs)
P = Phaemochromocytoma
E = Eye; retinal haemangioblastoma
L = Liver, renal, and pancreatic cysts
What hereditary syndrome is associated with GIST?
Carney’s triad
Carney triad (CT) is characterized by the coexistence of three types of neoplasms, mainly in young women, including gastric GIST, pulmonary chondroma, and extra-adrenal paraganglioma. The underlying genetic defect remains elusive.
Neurofibromatosis-1 also predisposes to GIST formation.
What is Riley-Banayan-Ruvalcaba syndrome?
What is Cowden syndrome?
What do they have in common?
- Cowden’s syndrome is the commonest presentation of PTEN hamartoma tumour syndorme; an AD condition characterised by multiple hamartomas of tissue derived of all three germ-cell layers. 3 main groups of abnormalities
- multiple benign tumours: hamartomatous GI polyps, benign thyroid disease (adenomatous nodules and follicular adenomas in addition to hypothyroidism and hyperthyroidism), benign breast disease, orofacial skin lesions (incl tricholemmomas, acral keratosis, papillomatous papules, mucosal lesions)
- Predisposition to breast adenca, thryoid ca (espec follicular) and endometrial adenocarcinoma
- Other features incl macrocephaly, mild-mod learning difficulties and occasionally Lhermitte-Duclos disease (LDD), an unusual condition of cerebella ganglion cell hypertrophy that causes ataxia & seizure
- Riley-Banayan-Ruvalcaba syndrome is a rarer AD manifestation of PTEN mutation, described in kids. Characterised by intestinal polyps, haemangiomas, lipomas, penile cafe-au-lait spots, and macrocephaly. Patients with this are at risk of breast cancer, thyroid disease, and protein losing enteropathy.
Both are due to mutations in the PTEN (phosphate and tensin homologue) gene on chromosome 10q22. This is a tumour suppressor gene. Mutations in PTEN gene cause a number of phenotypes that are collectively known as the PTEN hamartoma tumour syndrome
What is Castleman’s disease?
Castleman disease is a group of uncommon lymphoproliferative disorders characterized by lymph node enlargement, characteristic features on microscopic analysis of enlarged lymph node tissue, and a range of symptoms and clinical findings.
It can be unicentric (possible cured by surgical resection) or multicentric (harder to treat).
What is Carney’s triad?
What is Carney complex?
Carney’s triad consists of GIST, Pulmonary chondroma, and extra-adrenal paraganglionoma (mutations in SDHA, B, C and D genes have been excluded & molecular mechanism currently unknown.
Carney complex, and its subsets LAMB syndrome and NAME syndrome, are autosomal dominant conditions comprising myxomas of the heart and skin, hyperpigmentation of the skin (lentiginosis), and endocrine overactivity. The LAMB acronym refers to lentigines, atrial myxomas, and blue nevi. NAME refers to nevi, atrial myxoma, myxoid neurofibromas, and ephelides. Follicular thyroid cancer is common in Carney complex.
What is this?
Chilaiditi’s syndrome; the hepatic flexure is above the liver and below the diaphragm. It may be mistaken for free air.
What is Li-Fraumeni syndrome?
Li Fraumeni is an inherited AD condition due to mutations of the p53 gene on chromosome 17p. This results in loss of p53 tumour suppression and resultant increased risk of multiple cancers.
The classical LFS malignancies - breast ca, soft tissue sarcomas (espec rhabdomyosarcoma, undiff pleomorphic sarcoma, pleomorphic sarcoma), adrenocortical carcinoma, brain ca, osteosarcoma, haematological malignant neoplasms
Used to be called SBLA syndrome; sarcoma, breast, leukaemia, adrenal.
?annual whole body MRI + dedicated breast imaging + colonscopy?
What is Plummer-Vinson syndrome?
A syndromic triad of Iron-deficiency anaemia, oesophageal webs, and post-cricoid dysphagia.
Associated with glossitis, angular cheilosis, and stomatitis.
At risk of post-cricoid/oesophageal cancer.
Rare, occurs mostly in females.
What is Gorlin-Goltz syndrome?
Gorlin-Goltz, aka Gorlin, aka Naevoid BCC syndrome is an AD condition due to mutations in the PTCH (patched) gene on Ch 9q.
It results in multiple BCCs, characteristic asymmetrical facies, keratocystic jaw tumours, and skeletal abnormalities.
What is Leriche’s syndrome?
Buttock and thigh pain with loss of erectile function in the male. Signifies aorto-iliac occlusion.
What is Klippel-Trenaunay syndrome?
Why is it important to know about?
A congenital disorder characterized by a triad of:
Varicose veins
Bony and soft tissue hypertrophy affecting a limb (leg)
Port-wine stain
Patients with Klippel Trenaunay syndrome often have anomalous or absent deep veins so GSV stripping can be devastating to the limb.
What is Paget-Schrotter syndrome?
DVT of the subclavian +/- axillary vein that typically occurs in young males in the dominant arm. Also known as “effort-induced thrombosis”.
May be associated with thoracic outlet obstruction.
What is the VACTERL association?
The VACTERL association (also VATER association) refers to a recognized group of birth defects which tend to co-occur. Note that this pattern is a recognized association, as opposed to a syndrome, because there is no known pathogenetic cause to explain the grouped incidence.
Vertebral defects
Anal defects
Cardiac defects
Tracheoesophageal defects
Renal defects
Limb growth defects
What is Peutz Jeghers syndrome?
Peutz-Jeghers syndrome is an AD condition characterized by the development of intestinal hamartomatous polyps in association with mucocutaneous melanocytic macules.
It is associated with a mutation in the STK11 gene on chromosome 19.
Although the polyps are not malignant, patients are at risk of developing GIT malignancy, also pancreatic, lung, breast, uterine, ovarian, cervical testicular
Most common GIT malignancy = colon and pancreas; extraintestinal = breast.
90% lifetime cancer risk altogether at av age 42
Familial hypocalciuric hypercalcaemia
AD, loss of function mutation in CASR gene (encodes clacium-sensing receptor)
Mild to mod hypercalcaemia that is generally asymptomatic and normal PTH
Renal excretion of calcium & Mg characteristically decreased & urine calcium:creat ratio <0.01 in 80%
MEN1
- Pituitary adenoma (10-60%)
- prolactinoma (20%), NF (6%), GHoma (5%), ACTHoma (2%)
- Pancreatic NET (30-80%)
- NF (80%), gastrinoma (40%; 50% metastatic at time of dx), pancreatic polypeptidoma (20%), insulinoma (10%), glucagonoma, VIPoma, somatostatinoma
- Primary hyperparathyroidism (90%)
- generally have asymmetric/asynchronous, independent PT adenomas in 3 or 4 glands
- others: foregut NETs, adrenocortical tumour (mostly non-functioning adenoma, rarely ACC or hyperaldosteronism, cutaneous manifestations (lipoma, angiofibroma, collagenoma)
- Autosomal dominant, MEN1 tumour suppressor gene on chromosome 11 - encodes menin (a protein that can influence a number of key cellular processes incl transcription, DNA repair & cytosekeltal function
- consider screening all gastrinoma pts since 25% have MEN1
- if first-degree relative w lesion typical of MEN1, consider in presence of a single lesion
- exclude in pts w recurrent PHP, espec multiglandular disease
Management
- PHP - debate re type & time of surgery - subtotal parathyroidectomy (60% cure rate at 10yrs, 51% at 15 yrs); vis total parathyroidectomy w or w/o autograft - assoc w post-op hypoparathyroidesm and lifelong vit D tx (transcervical thymectomy recommended at time of parathyroidectomy
- Panc - insulinoma = surgery; other syndromes respond to medical therapy and timing of surgery debated
- gastrinomas often multifocal and small and can be in duo - morbid & surgery in MEN1 frequently not curative, in part bc multifocal and often metastatic; surgery still beneficial for DFS and decreasing advanced disease in ZES
- nonfunctioning and those secreting panc polypeptide = generally clincially silent - no consensus re best treatment
- Pit - prolactinomas treated w dopamine agonists, nonfunctioning adneomas - surgery, GH-secreting adenomas - surgery +/- rad
Surveillance
- ant pit: prolactin, IGF-1 and MRI yearly from age 5
- PTs: calcium, PTH yearly from age 8
- Pancreas: glucose & insulin annually from age 5; VIP, glucagon, somatostatin yearly from age 20; MRI 3-5yrly from age 20
- Foregut carcinonoid: chromogranin A yearly from age 20 (and MRI as above)
MEN2
- MEN2A = Hyperparathyroidism (20-30%), Phaeo (50%), MTC (90%)
- PHP mostly asymptomatic; often less severe than in MEN1 and synchronous involvement of all 3 glands less common; 30-50% have single adenoma; others diffuse hyperplasia
- MEN2B = MTC (nearly all), Phaeo (?50%), Marfanoid habitus, mucosal/GI neuroma
- MTC usually first manifestation in MEN2
- Autosomal dominant, gain of function mutation in RET gene on chromosome 10
- Partial genotype-phenotype correlation; different types of RET mutations seen in MEN2A, MEN2B, FMTC
- offer testing to
- new pts w 2 synchronous or metachronous features of MEN2
- pts presenting w single manifestation of MEN2 who have first-degree relative w endocrine features of MEN2
- infants presenting w GI or mucosal features of MEN2B
- pts w MTC
- infants presenting w Hirschsprung’s & fhx suggestive of MTC
- management
- total thyroidectomy with timing depending on particular RET mutation; all MEN2B in first year of life; if calcitonin still elevated post-op then stage
- if diagnosed MTC or not before recommended cut-off do central neck dissection
- PHP - surgical mx challenging due to heterogeneity of PT glands & frequently more difficult ops related to prior thyroidectomy & central neck dissection for MTC; options include
- resection of visibly enlarged PT glands
- subtotal parathyroidectomy
- total parathyroidectomy w immediate heterotopic autotransplantation
- AAES recommends resection of only visibly enlarged glands in MEN2-assoc HPT
- total thyroidectomy with timing depending on particular RET mutation; all MEN2B in first year of life; if calcitonin still elevated post-op then stage
- surveillance
- all pts w MEN2 or those identified as RET mutation carriers but yet to express disease should have annual biochem screening for:
- MTC - plasma calcitonin, CEA
- Phaeo - urine and plasma metanephrines
- PHP - ionised Ca, parathyroid hormone
- in high risk groups, start screening at time of planning thyroidectomy; in others start at age 5-7
- all pts w MEN2 or those identified as RET mutation carriers but yet to express disease should have annual biochem screening for:
Genetics of pancreatic cancer
- 5-10% of all pancreatic ca is due to inherited risk factors
- Pts w known genetic syndromes are responsible for ~20% of hereditary cases of panc ca; term familial pancreatic cancer applies to remaining 80% of pts w an inherited predisposition but who don’t have an identifiable genetic syndrome
- 5.2% of pts harbour a pancreatic cancer-predisposing genetic alteration (cf 7.9% w positive fhx)
- Peutz-Jeghers (STK11, 35% increased risk)
- BRCA1/2
- FAMMM (CDKN2A, 17% increased risk)
- Lynch (MLH1, MSH2, MSH6, 8.6x increased risk) —> MSI-H PDAC –> ?immune therapy candidates
- APC/FAP
- PALB2 (familial breast ca syndrome)
- ATM (familial breast ca syndrome)
- Genes associated with hereditary pancreatitis – pts w hereditary pancreatitis have >50x increased risk of panc ca
- PRSS1
- SPINK1
- CFTR
- First degree relatives w panc ca have at least 2x increased risk
- Familial pancreatic cancer defined by families w 2 or more first-degree relatives w panc adenocarcinoma that don’t fulfill the criteria of other inherited tumour syndromes w ed risk for development of panc adenocarcinoma
- 18fold increased risk for development of panc ca cf general pop & this s w ing no of first-degree rels w panc ca & if one of affected individuals is dx <50yrs
- Pathogenesis of pancreatic cancer = stepwise progression from normal -> pancreatic intraepithelial neoplasma (PanIN-1A, PanIN-1B, PainIN-2, PanIN-3) -> invasive carcinoma - with early KRAS mutation in >90%, followed later by P16/CDKN2A loss and later again TP53 (30-50%) and SMAD4 (30%)
FAP
- AD disorder caused by mutations in APC gene on chromosome 5
- 1 in 10,000; accounts for <1% all CRC
- 25% have de novo mutation thus no fhx
- absence of functional APC protein –> aberrant accumulation of beta-catenin –> transcriptional activation of the Wnt signallingn pathway and its target genes that control cell growth
- clinical features (polyps of GI tract (colon, duo, stomach, SB) + A DOPE CD)
- nearly complete penetrance of colonic polyposis but variable penetrance of extracolonic manifestations of the disease
- hundreds of CR adenomatous polyps at young age (2nd/3rd decade), CRC av age 39 if not treated
- severe FAP = thousands of colorectal adenomas
- classical FAP = 100-1000 adenomas, risk of CRC nearly 100%
- attenuated FAP = <100 adenomas
- duodenal adenomatous polyps (30-70%; lifetime risk duo ca 4-10%)
- non-neoplastic gastric fundic gland polyps (50-80%)
- gastric adenomas (10%, risk of gastric ca low)
- SB polyps w ca
- less common pancreatic adenoca, hepatoblastoma
- adrenocortical adenoma
- desmoids
- osteomas
- papillary thyroid ca (2%) - espec in women
- epidermoid cysts
- CHRPE (congenital hyperplasia of the retinal pigment epithelium)
- dental anomalies incl supranumerary teeth
- diagnosis can be genetic or clinical (>100 CR adenomas)
- who to test
- children or other relevant family of affected at age 12-14
- mutation carriers –> colonoscopy q1yr from 14
- if no specific mutation found in index should still have colonoscopies from teenage years; if no polyps by age 50 can stop
- surveillance
- colonoscopy q1yr from age 14
- gastroscopy q1-5yrs from age 25-30 - frequency depends on Spigelman (polyp number, size, histo, dysplasia)
- annual thyroid USS from 20
- intervention
- sulindac (NSAID) - but side effects so weigh up
- colectomy before cancer develops - if symptomatic or polyps large/dense - ASAP
- otherwise at socially acceptable time - usu in late teens after finishing school
- restorative proctocolectomy w IPAA OR colectomy + IRA w rectal surveillance OR total proctocolectomy and end ileostomy
- after IRA or RPC, flexi sig q12mo
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Anatomy - Jon66
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Examinations - Jon13
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