Genetics

Question 1

Homogentisic oxidase deficiency

Answer 1

aka alkaptonuria

Autosomal recessive alleles on chromosome 3q2

Tissue accumulation of homogentisic acid
- Intermediate in phenylalamine and tyrosine metabolism
- Forms melanin-like polymers leading to deposition of dark material in fibrous tissue and cartilage
- Can also be excreted in urine giving it a dark colour

Features:
- Dark urine on standing
- Ochronosis
- skin pigmentation
- esp. around sweat glands
- Ochronotic arthropathy

Diagnosis:
- Urine chromotography to identify homogentisic acid
- Gene sequencing

Management:
- Screening for cardiovascular, renal, prostate problems
- Dietary resctriction for tyrosine and phenylalanine

Question 2

Hereditary spherocytosis

Answer 2

Most commonly due to alpha-spectrin (SPTA1) deficiency
- Autosomal dominant

Other causes are mutations in SLC4A1, SPTB, ANK1, EPB42

Features:
- Chronic haemolytic anaemia
- Jaundice
- Gallstones
- Splenomegaly
- Aplastic crisis if infected with parvovirus B19

Investigations:
- FBC - haemolytic anaemia, raised MCV
- Blood film = spherocytes, reticulocytosis

Management:
- Supportive - transfusion, EPO
- Folic acid supplements
- Splenectomy

Question 3

Glycogen synthetase deficiency

Answer 3

Type 0 glycogen storage disease
- Impairs liver glycogen synthesis
- Mutation in GYS2 on chr 12

Features:
- Postprandial hyperglycaemia
- Fasting hypoglycaemia + ketosis
- Muscle cramps

Investigations:
- Blood glucose + ketone monitoring
- Genetic sequencing

Management:
- Diet - high protein, complex carbohydrates

Question 4

Hereditary haemorrhagic telangiectasia

Answer 4

aka Osler-Weber-Rendau syndrome

Autosomal dominant

Features:
- Spontaneous and recurrent epistaxis
- Multiple telangiectasias
- Visceral AVMs - most commonly pulmonary and hepatic

Management:
- Oestrogen therapy in women
- Laser treatment of telangiectasias

Question 5

Fragile X Syndrome

Answer 5

The most common hereditary cause of mental disability
- M > F
- X-linked dominant
- Mutation in FMR-1

Often presents later in life
Variable penetrance
50% of female carriers have intellectual impairment

Features:
- Short stature
- Large head circumference
- Pale irises
- Characteristic facies - large forehead, long face and nose, prominent jaw, high-arched palate, large ears.
- Macro-orchidism
- Intellectual impairment
- Mitral valve prolapse
- Strabismus
- Pes planus
- Joint hyperextension

Question 6

DiGeorge Syndrome

Answer 6

Deletion in Chr 22q11
- Leads to failure of neural crest cell migration
- Therefore failure of 3rd + 4th pharyngeal
pouch formation - thymus, parathyroid, aortic
arch, lips, ears

Features:
C - cardiac abnormalities e.g. ToF
A - abnormal facies e.g. micrognethia,
hypertelorism, short philtrum
T - thymic hypoplasia -> low T cells, low IgG/A
C - cleft palate
H - hypocalacaemia from parathyroid hypoplasia
22 - chr 22 deletion

Question 7

Neurofibromatosis type 1

Answer 7

Autosomal dominant mutation in NF1 on chr 17
- 1/2000

Must have 2 or more of the following:
- >=6 cafe au lait macules if pre-pubertal or > 15 if post-pubertal
- Two or more neurofibromas or one plexiform neurofibroma
- Axillary or inguinal freckling
- Optic glioma
- Two or more Lisch nodules (optic hamartomas)
- Distinctive osseous lesion
- A first-degree relative with NF1

Other features:
- Intellectual impairment (50%)
- HTN - from RAS or pheochromocytoma
- Optic gliomas
- Vertebral dysplasia
- Malignant neural sheath tumours

Question 8

Neurofibromatosis type 2

Answer 8

Autosomal dominant or de novo mutation, chr 22
- 1/30,000
- Characterised by multiple CNS tumours

Features:
- Bilateral acoustic neuromas
- Present as deafness in 20s
- Tinnitus
- Vertigo
- Meningiomas
- Glial cell tumours
- Scanty cafe-au-lait spots

Management:
- Annual hearing tests
- MRI screening
- Excision of acoustic neuromas

Question 9

Myotonic dystrophy

Answer 9

Expansion of a CTG repeat in the dystrophia myotonica protein kinase (DMPK) on chr 19
- Autosomal dominant
- Anticipation phenomenon

Features:
- Cataracts
- Frontal balding
- Hypogonadism
- Weakness, wasting, and myotonia of muscles
- Myotonic facies - ptosis, hanging jaw, wasting
- Inability to let go of examiner’s hand
- Percussion myotonia
- Intellectual impairment (30%)

Question 10

Multiple endocrine neoplasia

Answer 10

MEN1
- Parathyroid tumours (90%)
- NETs of the pancreas (75%)
- Anterior pituitary gland tumours (50%)

MEN2a
- Phaeochromocytoma
- Medullary thyroid cancer
- +/- PT gland disease

MEN2b
- Phaeochromocytoma
- Medullary thyroid cancer
- Mucocutaneous neuromas
(absence of PT gland disease)

Question 11

Acute intermittent porphyria

Answer 11

Due to defect in porphobilinogen demaniase
- AD
- Involved in heme synthesis
- Leads to tissue build up of porphyrias
- Multisystem involvement

Triggers:
- Fasting
- Surgery
- Alcohol
- Medications e.g. barbiturates, sulphonylureas, oestrogens

Features:
- GI - bilious vomiting, CIBH, acute abdominal pain
- CNS - neuropathy, seizures, tremor, confusion, muscle weakness, psychiatric sx
- CVD - tachycardia, HTN
- Resp - SOB
- Renal - port-wine urine, bladder distension

Investigations:
- Elevated hepatic aminolevulinate (ALA)
- Elevated serum/urine PBG

Mangement:
- Treat underlying cause
- First 24h
- IV morphine or pethidine
- IV glucose loading - aiming 400g/24-48hr
- If not responding:
- IV haematin for 4-5/7

Complications:
- Liver cirrhosis and HCC
- Permanent neurologial damange
- Misdiagnosis with unnecessary surgery

Question 12

SCID

Answer 12

Mutations in adenosine deaminase (ADA) which degrades deoxyadenosine into inosine
- Product of DNA breakdown
- Deoxyadenosine is toxic to lymphocytes
- Accumulation -> reduced lymophocytes, esp. i
immature ones in the thymus

Question 13

Familial hypercholesterolaemia

Answer 13

LDL receptor dysfunction
- Autosomal dominant
- Heterozygous - 1/250 - 1/500 people
- Homozygous - v. rare, presents in childhood

Features:
- Total cholesterol > 7.5
- Hx of premature cardiovascular diseaes
- Tendon Xanthomata
- Xanthelasma

Management:
- Simon-Broome criteria to diagnosis
- Lipid-lowering therapy, uptitrated until achieve 50% reduction in LDL-C

Question 14

Congenital adrenal hyperplasia

Answer 14

Subdivided in classic (severe) and non-classic (mild) forms
- Non-classic can be revealed via corticotropin
stimulation test
- All autosomal recessive disorders

21-hydroxylase deficiency (90%)
- Cortisol +/- aldosterone deficiency, androgen excess
- Salt-wasting crisis
- Virilisation
- Hypotension
- Raised 17-hydroxyprogesterone is diagnostic

11-hydroxylase deficiency (5%)
- Cortisol deficiency, androgen and aldosterone excess
- Hypokalaemia
- Hypertension
- Virilisation

17-hydroxylase deficiency
- Cortisol and androgen deficiency, mineralocorticoid excess
- Non-virilising
- Intersex males

Question 15

Primary hypertriglyceridaemia

Answer 15

Isolated raised hypertriglyceridaemia
- Number of genetic causes e.g. lipoprotein
lipase deficiency, apoprotein CII deficiency
- Failure to metabolise chylomicrons

Features:
- Presents in childhood
- Eruptive xanthomas
- Lipaemia retinalis
- Retinal vein thrombosis
- Pancreatitis
- Hepatosplenomegaly

Investigations:
- Raised fasting chylomicron levels
- Genetic testing

Management:
- Statins and other lipid-regulating drugs

Question 16

MEN2

Answer 16

Contains MEN2A and 2B
- RET proto-oncogene mutations

Features:
- 2A
- Phaeochromocytoma
- Medullary thyroid cancer
- Cushing’s disease
- Parathyroid hyperplasia
- 2B
- Marfanoid habitus
- Phaeochromocytoma
- Medullary thyroid cancer
- Intestinal and neuronal paragangliomas

Question 17

Hereditary non-polyposis colon cancer (HNPCC)

Answer 17

Autosomal dominant disorder of DNA mismatch repair
- Chr 2 and 3
- Increases risk of multiple cancers
- Colon
- Pancreatic
- Gastric
- Ovarian
- Endometrial

Amsterdam criteria:
- Families with three or more individuals with colon cancer where:
- One affected individual is a first-degree
relative of the other two
- At least one individual diagnosed < 50 yr
- Affected individuals are present in at least 2
generations
- FAP excluded

Management:
- Genetic counselling
- Surveillance colonoscopy
- Every 18-24 months from age 25+
- Prophylactic colectomy once sufficient
polyps seen
- Surveillance OGD
- Every 2 years from age 50+
- Surveillance pelvic examination +/- US
- Every year from age 18+
- Prophylactic hysterectomy/oophorectomy
once children born

Question 18

Kearns-Sayre Syndrome

Answer 18

A mitochondrial disease featuring chronic progressive external ophthalmoplegia (CPEO), pigmentary retinopathy, and onset < 20 yrs
- Variable inheritance patterns

Features:
- CPEO
- Pigmentary retinopathy - incl. retinitis pigmentosa
- Short stature
- Cerebellar ataxia
- Raised CSF protein (>100)
- Conduction blocks
- Anaemia
- Diabetes
- Deafness
- Cognitive defects

Question 19

Oncogenes and disease

Answer 19

KRAS
- Pancreatic adenocarcinoma (80-90%)
- Colon cancer
- Leukaemia
- Ichthyosis

NRAS
- Malignant melanoma (25%)

p16
- Chronic pancreatitis (30%)

p53
- Pancreatic cancer (50%)
- Ovarian cancer (50%)

Rb
- Retinoblastoma
- Bladder cancer

Question 20

Marfan’s syndrome

Answer 20

Autosomal dominant mutations in FBN-1 (fibrillin-1) leading to production of abnormal fibrillin

Features:
- Major
- Pectus carinatum or excavatum
- Thumb and wrist sign
- Aortic root dilatation
- Lens subluxation
- Minor
- Arachnodactyly
- High arched palate
- Joint hypermobility
- Mitral valve prolapse
- Scoliosis

Complications:
- Cardiac murmurs
- Aortic dissection or aneurysm
- Spontaneous pneumothorax
- Vision loss

Question 21

Fanconi syndrome

Answer 21

Aetiology:
- Inherited or acquired

Pathophysiology:
- Inherited or acquired malfunction in NKCC2 transporter in the loop of Henle -> decreased absorption of most electrolytes

Features:
- Failure to thrive
- Hypophosphataemia
- Rickets
- Hypokalaemia
- Type 2 RTA
- Polyuria + polydipsia
- Low Na+, K+, Ca2+, HCO3 - etc.

Management:
- Na+ and K+ supplementation
- Spironolactone/amiloride

Question 22

Barter’s syndrome

Answer 22

Autosomal recessive condition
- Defect in Na + Cl reabsorption in the thick
ascending limb of the loop of Henle

Features:
- Fetal polyhydramnios + polyuria
- Failure to thrive
- Polyuria + polydipsia
- Kidney stones
- Hypokalaemia = muscle cramps, dizziness
- Hypocalcaemia = tetany, spasms

Investigations:
- Bloods:
- Metabolic alkalosis
- Hypokalaemia
- High renin + aldosterone levels
- Urine
- Hypercalciuria
- Hypermagnesuria

Management:
- K+ supplementation
- Spironolactone
- ACEi
- NSAIDs
- GH supplements

Question 23

Gitelman syndrome

Answer 23

Autosomal recessivee
- Dysfunction in thiazide-sensitive NaCl co-
transporter
- Impairment in Na + Cl reabsorption in the
DCT

Features:
- Polyuria + polydipsia
- Kidney stones
- Hypokalaemia = muscle cramps, dizziness
- Hypocalcaemia = tetany, spasms
- Hypomagnesaemia

Investigations:
- Bloods:
- Metabolic alkalosis
- Hypokalaemia
- High renin + aldosterone levels
- Urine
- Hypercalciuria
- Hypermagnesuria

Management:
- Spironolactone if Hypokalaemic
- Mg supplements

Question 24

ADPCKD

Answer 24

Epidemiology:
- Autosomal dominant mutations in PKD 1/2 (chr 16)
- Presents between 30-50 yr

Pathophysiology:
- Polycystin-1/2 mutations lead to dysfunction of cilia and cell junctions
- Form large fluid-filled cysts which cause ischaemic atrophy of surrounding parenchyma as well as obstruction of tubules

Features:
- Polycystic kidneys
- Prone to infection, haemorrhage, etc
- Progressive renal dysfunction - HTN, oedema,
stones
- Liver cysts (33%)
- Berry aneurysms (30%)
- Aortic root dilatation
- With associated MR, TR, etc.
- Increased risk of renal adenomas

Investigations:
- Urinalysis + bloods
- Imaging
- Renal US, CT, MRI
- Genetic testing

Management:
- Early
- Monitoring
- Antihypertensives
- Hydration
- Late
- Requires RRT - dialysis or transplant

Question 25

Von-Hippel Lindau syndrome

Answer 25

An autosomal dominant condition of mutations in the VHL protein leading to neoplasia

Most commonly haemoangiomas with risk of secondary haemorrhage

Features:
- Cerebellar haemangiomas
- Retinal haemangiomas
- Renal and extra-renal cysts
- Phaeochromocytoma
- Clear cell renal cell carcinoma

Question 26

Liddle syndrome

Answer 26

Mutations to ENaC such that excessive sodium reabsorption occurs in the collecting ducts

Features:
- Hypokalaemia
- HTN
- Metabolic alkalosis

Question 27

Barters vs Gitelman vs Liddle

Answer 27

Barters
- Thick loop of Henle
- Impaired Na+/Cl- reabsoprtion
- Normotensive
- Failure to thrive
- Normal magnesium
- Elevated renin + aldosterone
- Hypokalaemia + metabolic alkalosis

Gitelman
- Distal convoluted tubule
- Impaired Na+/Cl- reabsorption
- Normotensive
- Normal development
- Hypomagnesaemia
- Elevated renin + aldosterone

Liddle
- Collecting ducts
- Excessive Na+ reabsorption
- Early-onset hypertension
- Normal development
- Normal magnesium
- ?normal renin + aldosterone

Question 28

Alport syndrome

Answer 28

Inherited disorder of type IV collagen synthesis
- Variable inheritance patterns, majority X-linked
- Most notably affects glomerular basement
membrane
- Also impacts function of inner ear

Features:
- Progressive renal failure
- FSGS with haematuria, proteinuria, HTN
- Sensorineural hearing loss
- High frequency lost first
- Lenticonus

Investigations:
- Bloods
- Echo
- LVH or aortic abnormalities
- Renal biopsy
- Genetic testing

Question 29

Hypokalaemic periodic paralysis

Answer 29

Aetiology:
- Mutations in muscle VGCCs
- AD
- Onset in adolescence

Features:
- Episodic severe muscle weakness
- Triggered by strenuous exercise or high
carbohydrate diet
- Resolve over 24-72hr
- Hypokalaemia

Management:
- Acute
- KCl, although normally self-resolves
- Long-term
- Trigger avoidance
- Acetazolamide or spironolactone

Question 30

Polyglandular syndrome 1

Answer 30

Autosomal recessive

Features:
- Hypoparathyroidism (90%)
- Mucocutaneous candidiasis
- Adrenal insufficiency (60%)
- Primary gonadal failure
- Primary hypothyroidism
- Rarely, hypopituitarism or diabetes insipidus

Question 31

Polyglandular syndrome 2

Answer 31

Autosomal recessive, autosomal dominant, or polygenic

Features:
- Adrenal insufficiency
- Hypothyroidism
- T1DM
- Gonadal failure
- Rarely, diabetes insipidus

Question 32

Inborn errors of metabolism and newborn heelprick screening

Answer 32

Types of error:
- Disorders of carbohydrate metabolism e.g. glycogen storage disease, G6PD deficiency
- Disorders of amino acid metabolism
- Organic acidaemias
- Urea cycle defects
- Disorders of fatty acid oxidation e.g. MCADD
- Disorders of porphyrin metabolism e.g. AIP
- Disorders of purine/pyramidine synthesis e.g. Lesch-Nyhan syndrome
- Peroxisome disorders e.g. Zellweger syndrome
- Mitochondrial disorders
- Lysosomal disorders e.g. Fabry, Gaucher, Niemann-Pick

Heelprick screening
- phenylketonuria (PKU)
- medium-chain acyl-CoA dehydrogenase
deficiency (MCADD)
- maple syrup urine disease (MSUD)
- isovaleric acidaemia (IVA)
- glutaric aciduria type 1 (GA1)
- homocystinuria

Question 33

Homocystinuria

Answer 33

Aetiology:
- Autosomal recessive mutations in cystathione beta synthetase
- involved in conversion of methionine to
cystine + serine, homocystine is intermediate

Features:
- Mental retardation
- Appearance:
- Tall
- Arachnodactyly
- High-arched palate
- Pectus excavatum
- Cardiac:
- AR and MR
- Coronary artery thrombosis
- Vascular
- Increased risk of DVTs
- Ophthalmological:
- myopia
- Lens dislocation
- Retinal detachment
- Osteoporosis

Investigations:
- May be picked-up on neonatal heelprick screening
- Urine
- Positive cyanide nitroprusside test
- Presence of homocysteine

Management:
- Folic acid supplementation
- Pyridoxine
- Low methionine diet

Question 34

Glucose-6-phosphate deficiency

Answer 34

X-linked recessive disorder
- More common in Mediterranean, Middle-Eastern, and African patients

Pathophysiology:
- Involved in the pentose phosphate pathway
- Roles in maintaining red cell membrane flexibility and haem oxygenation
- Deficiency leads to increased rigidity +
methaemoglobinaemia which together
promote haemolysis

Features:
- Acute haemolytic anaemia
- Triggers include infection and medications
e.g. quinines, trimethoprim, fava beans
- Gallstones
- Neonatal jaundice
- Methaemoglobinaemia

Investigations:
- Blood film
- Heinz bodies - denatured haemoglobin
- G6P assay

Management:
- Treat/avoid triggers
- Blood transfusion

Question 35

Alpha-thalassaemia

Answer 35

Mutation of 1-4 of the alpha-haemoglobin chain genes causing inactivation

Phenotypes:
- Single inactivation
- ‘Trait’
- Microcytic hypochromic cells, no anaemia
- Double inactivation
- Microcytic hypochromic cells +/- mild
anaemia
- Triple inactivation
- HbH disease
- Microcytic hypochromic anaemia
- Splenomegaly
- Complete inactivation
- Hydrops fetalis with death in utero

Question 36

Beta-thalassaemia

Answer 36

Mutation in beta-haemoglobin genes leading to inactivation or reduced function

Absence/reduction in beta-chains also leads to overproduction of alpha chains and alternative types of haemoglobin

Phenotypes:
- Major - no functional copies
- Microcytic anaemia beginning at young age
(3-6 months)
- Mild jaundice
- Failure to thrive
- Splenomegaly
- Bone deformities
- Regular transfusions + iron chelation
- Intermedia - reduced function/quantity
- Microcytic anaemia require occasional
transfusions
- Trait
- Mild microcytic anaemia
- Raised HbA2
- Raised red cell count

Management:
- Monitoring
- Hb - need for transfusion
- Ferritin - need for iron chelation
- Blood transfusions
- Prophylactic splenectomy
- Bone marrow transfusion

Question 37

Sickle cell anaemia

Answer 37

Pathophysiology:
- Glu -> Val in the haemoglobin beta-chain
- Causes chain to become insoluble and crystallise whilst in the deoxy state
- Haemolysis
- Cell deposition/entrapment in small blood
vessels

Features:
- Chronic haemolytic anaemia
- Hyposplenism
- Increased infection risk

Management:
- Avoid any triggers for crises
- Vaccination + prophylactic antibiotics if hyposplenic
- Hydroxycarbamide
- Stimulates production of HbF which does not
sickle
- Exchange transfusion
- Bone marrow transplant

Complications:
- Stroke
- Avascular necrosis of the large joints (e.g. hip)
- Pulmonary HTN
- Priapism
- CKD secondary to papillary necrosis
- Retinopathy
- Acute chest crisis
- Acute pain crisis
- Osteomyelitis of the long bones

Question 38

Fanconi anaemia

Answer 38

A rare autosomal recessive disorder of the bone marrow
- Due to mutations in the FA/BRCA DNA repair
pathway

Features:
- Aplastic anaemia
- Presents at c. 5 years
- Short with microcephaly
- Horseshoe kidney
- Abnormal pigmentation

Question 39

Carney complex

Answer 39

Aetiology:
- Autosomal dominant
- Inactivating mutation of protein kinase A (PKA) on Chr 17

Features:
- Spotty skin pigmentation
- Myxoma
- Psammomatous melanotic schwannoma (PMS)
- Endocrine tumours

Diagnosis:
- Two features
- One feature + affected relative