Week 2 - G - Genetic diseases - N.F type 1 (N.F1 gene ch17), Tuberous Sclerosis (T.S.C.1 - hamartin ch9, T.S.C.2 - tuberin ch16)

Question 1

What are genetic diseases that are expressed as skin conditions known as? What are the 2 most common types?

Answer 1

Genetic diseases that are expressed as skin conditions are known as genodermatoses Most common genodermatoses is neurofibromatosis type 1 (NF1) Second most common is tuberous sclerosis (TS)

Question 2

What is the inheritance of NF1? What is the chance that the child will be affected with the disease should both or a single parent carry one copy of the mutation?

Answer 2

NF1 is an autosomal dominant condition - * 75% chance the child has the condition if both parents carry the mutation * 50% chance the child has the condition if a single parent carries the mutation

Question 3

What is the mutation that occurs causing NF1? What chromsome is the gene located on?

Answer 3

NF1 occurs due to a mutation in the NF1 gene located on chromosome 17

Question 4

What are the two main clinical signs of neurofibromatosis type 1?

Answer 4

Cafe-au lait macules >5 and neurofibromas (soft neural tumours)

Question 5

What are other features of NF1? (these are the diagnostic criterua for the disease)

Answer 5

Diagnosis is made if 2 of the following are found:

Cafe-au lait macules>5

Neurofibromas - 2or more

Axillary/inguinal freckling

Optic glioma

Lisch nodules - 2 or more

Distinctive bony lesions

First degree relative with NF1 according to above criteria

Question 6

What is an optic glioma? What can it cause?

Answer 6

Optic gliomas are tumours that arise from the glial cells of the optic nerve - it can cause compression of the optic nerve leading to vision impairment

Question 7

What is a Lisch nodule?

Answer 7

Lisch nodule, also known as iris hamartoma, is a pigmented nodular aggregate of dendritic melanocytes affecting the iris - appears as small harmless brown/translucent mounds on the iris

Question 8

Neurofibromatosis type 1 is linked to a tumour that may present in a patient with excessive sweating, headaches and elevated heart rate/palpitations What is this tumour known as and why does it cause these symptoms?

Answer 8

This is a phaeochromocytoma This a tumour of the chromaffin cells of the adrenal medulla which stimulates the release of different catecholamines eg adrenaline/noradrenaline resulting in increased sympathetic activity

Question 9

What is the management of neurofibromatosis type 1?

Answer 9

There is no cure for the disorder itself. Instead, people with neurofibromatosis are followed by a team of specialists to manage symptoms or complications Geneticists, neurologists, surgeons physiotherapists all involved

Question 10

Now we discuss tuberous sclerosis - can arise de-novo What is the mode of inheritance of this condition? What are the gene mutation that causes tuberous sclerosis?

Answer 10

Tuberous sclerosis mode of inheritance is autosomal dominant and is caused by a mutation of either of two genes * Tuberous sclerosis 1 (TSC1) which codes for hamartin and is located on chromosome 9 * Tuberous sclerosis 2 (TSC2) which codes for tuberin and is located on chromosome 16

Question 11

What is often the earliest cutaneous sign of tuberous sclerosis? How may the disease intiially present in children?

Answer 11

Earliest cutaneous sign of tuberous sclerosis is usually ash leaf macules (hypomelanic macules) - small white or lighter patches of skin may appear anywhere on the body, and are caused by a lack of melanin Disease may often present in children as infantile seizures

Question 12

What are other presenting cutaneous features of tuberous sclerosis?

Answer 12

Periungual fibromas and longitudinal ridging (image)- around nails (Fibromas are benign tumors that are composed of fibrous or connective tissue) Facial angiofibromas Shagreen patches Enamel pitting Hamartomas - heart, lung kidneys, eyes

Question 13

What are facial angiofibromas and what is the typical distibution of this? What are the facial angiofibromas also known as?

Answer 13

Facial angiofibromas consist of blood vessels and fibrous tissue They are typically reddish spots or bumps on the nose and cheeks in a butterfly distribution Facial angiofibromas also known as adenoma sebaceum

Question 14

What are the shagreen patches that are seen in tuberous sclerosis and the enamel pitting?

Answer 14

Shagreen patches are present in about half of people with TSC, appearing in childhood. They show subepidermal fibrosis. They are areas of thick leathery skin that are dimpled like an orange peel, and pigmented Enamel pitting is present in most adults with TSC - shows small holes in teeth

Question 15

What is a hamartoma? What organs can it affect in tuberous sclerosis?

Answer 15

A hamartoma is a noncancerous tumor made of an abnormal mixture of normal tissues and cells from the area in which it grows In tuberous sclerosis it can affect many different organs such as the hearts, lungs and kidneys

Question 16

Tuberous sclerosis is named after the presence of the cortical tubers that are seen in the disease What is a cortical tuber? Where are they found? What can they cause?

Answer 16

Cortical tubers are a common finding in tuberous sclerosis, present in 95-100% of cases . They are hamartomatous lesions typically located at the gray-white matter interface of the brain, They can cause epilespy and various dregrees of mental impiarment

Question 17

Tuberous sclerosis and NF1 are complex diseases affecting many systems Mnemonic to remember tuberous sclerosis features is EpiLoIA - what does this point to?

Answer 17

EpiLoIA Epi - Epilepsy (eg infantile seizures) LoI - Low Intelligence A - angiofibromas (face) Remember other symptoms * Shagreen patches * Ash-leaf macules * Peringungal fibromas and longitdunal ridging * Enamel pitting * Hamartomas