Genetics Flashcards
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.