genetics

Question 1

what are the 6 patterns of inheritance in monogenic disorders?

Answer 1

AD, AR, XLD, XLR, Y-linked, mitochondrial

Question 2

describe MEN1

Answer 2

• multiple endocrine neoplasia type 1
  *Autosomal dominant inheritance
• ‘Classic’ tumour suppressor in endocrine tissues
• Mutations occur throughout MEN1 gene located chromosome 11q13
• Mutations typically result in loss/reduced protein function

Question 3

why is MEN1 important?

Answer 3

→ 50% of affected individuals will die as a direct result of the disease
→ Premature mortality observed in high proportion of affected individuals

Question 4

why is managing MEN1 difficult?

Answer 4

• Lack of genotype-phenotype correlation
• Variable age-related penetrance
• Inability to predict disease course
• Asynchronous/synchronous development of multiple tumours
• Lack of high-quality evidence to guide treatment
• Lack of MEN1-specific or personalised therapies

Question 5

describe MEN2

Answer 5

multiple endocrine neoplasia type 2
* Autosomal dominant
* RET gene – 10q
* Classic proto-oncogene

Question 6

what is more common MEN2A or MEN2B?

Answer 6

MEN2A (90-95% of MEN2 cases)

Question 7

what is typically the first manifestation in MEN2?

Answer 7

medullary thyroid cancer (derived from parafollicular C-cells)

Question 8

what is the diagnosis and treatment of MTC?

Answer 8

Neck USS and FNA
* Measurement basal serum calcitonin (and CEA)
* Imaging to detect localised/advanced disease
* Treatment: Dependent on stage of disease
* Curative surgery for localised disease
* Thyroidectomy with variable extent lymph node dissection
* Mangement of advanced disease – complex – recent advent of tyrosine
kinase inhibitors

Question 9

describe Von Hippel Lidau syndrome

Answer 9

• Mutation in VHL gene
• Autosomal dominant
• Gene mutation leads to accumulation of HIF proteins and stimulation of cellular proliferation
• Range of vascular tumours
• Family screening vital

Question 10

what are the symptoms of neurofibromatosis type 1?

Answer 10

Axillary freckling
* Café-au-lait patches
* Neurofibromas
* Optic gliomas
* Scoliosis
* (learning difficulties in some)
* Phaeochromocytoma (rare)

Question 11

what is the cause of neurofibromatosis type 1?

Answer 11

mutation in NF1 gene

Question 12

what are the symptoms of McCune-Albright syndrome?

Answer 12

• Café-au-lait skin pigmentation (‘Coast of Maine” appearance)
• Polyostotic fibrous dysplasia (bones)
• Precocious puberty (typically females)
• Thyroid nodules
• Pituitary – GH excess
• Cushing’s syndrome (adrenal)

Question 13

what is the cause of McCune-Albright syndrome?

Answer 13

• Post-zygotic somatic GNAS mutation (i.e. not germline)
• Constitutive adenylyl cyclase signaling
• Overproduction of several hormones