Autosomal Dominant Flashcards
Protein C Deficiency
Protein C deficiency is an autosomal codominant condition which causes an increased risk of thrombosis
Features:
- VTE
- Skin necrosis following the commencement of warfarin: when warfarin is first started biosynthesis of protein C is reduced. This results in a temporary procoagulant state after initially starting warfarin, normally avoided by concurrent heparin administration. Thrombosis may occur in venules leading to skin necrosis
Hereditary Angioedema
Hereditary angioedema is an autosomal dominant condition associated with low plasma levels of the C1 inhibitor (C1-INH) protein. C1-INH is a multifunctional serine protease inhibitor - the probable mechanism behind attacks is uncontrolled release of bradykinin resulting in oedema of tissues.
Ix:
- C1-INH level is low during an attack
- Low C2 and C4 levels are seen, even between attacks. - - Serum C4 is the most reliable and widely used screening tool
Sx:
- Attacks may be proceeded by painful macular rash
- Painless, non-pruritic swelling of subcutaneous/submucosal tissues
- May affect upper airways, skin or abdominal organs (can occasionally present as abdominal pain due to visceral oedema)
NB: urticaria is not usually a feature
Mx of Acute attack:
Acute: IV C1-inhibitor concentrate
A C1-esterase inhibitor can be used for short-term prophylaxis before procedures or to terminate acute attacks of hereditary angioedema. Conestat alfa and icatibant are licensed for the treatment of acute attacks of hereditary angioedema in adults with C1-esterase inhibitor deficiency
If this isn’t available, use fresh frozen plasma (FFP)
Prophylaxis:
Tranexamic acid and anabolic steroid Danazol are used for short-term and long-term prophylaxis
Von Hippel-Lindau (VHL) Syndrome = HHT
Von Hippel-Lindau (VHL) syndrome is an autosomal dominant condition predisposing to neoplasia. It is due to an abnormality in the VHL gene located on short arm of chromosome 3
Features
cerebellar haemangiomas
retinal haemangiomas: vitreous haemorrhage
renal cysts (premalignant)
phaeochromocytoma
extra-renal cysts: epididymal, pancreatic, hepatic
endolymphatic sac tumours
Von Hippel Lindau disease is a rare autosomal dominant condition which is associated with many tumour types including haemangioblastomas, neuroendocrine tumours and renal cell carcinoma. It can present with walking difficulties, headaches and hypertension in addition to other symptoms and signs however nosebleeds are not a commonly recognised feature of this disease.
Retinal + Cerebellar Haemorrhages > THINK VON HIPPEL LINDAU
Spinocerebellar Ataxis
Spinocerebellar ataxias are a group of autosomal dominant disorders which are associated with the progressive development of ataxic features such as gait disturbance, nystagmus and tremor. The majority of affected patients develop symptoms within the 3rd and 4th decade.
CADASIL
CADASIL
Overview
Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)
rare cause of multi-infarct dementia
patients often present with migraine
Example Question:A 42 year-old man presents with an acute of onset of weakness in the left face, arm, and leg, which has not resolved. On examination there is upper motor neuron facial weakness on the left, with dense weakness of the left arm and leg. There is no evidence of sensory neglect, hemianopia, or dysphasia.
He past medical history includes migraine with visual aura, for which he takes propranolol and sumatriptan. His last migraine attack was a month ago. He has suffered two transient ischaemic attacks in the last year, and now also takes clopidogrel. His father also suffered from migraine with aura and died in his 50s after suffering a series of strokes.
Plain computed tomography shows multiple round lesions in the white matter, which appear the same density as cerebrospinal fluid. Magnetic resonance imaging shows scattered well-circumscribed lesions in the subcortical white matter which appear hypointense on T1 and hyperintense on T2-weighted sequences. On DWI (diffusion-weighted imaging) there is a hyperintense lesion in the right internal capsule, with a corresponding hypointense area on the ADC (apparent diffusion coefficient) map.
What is the most likely underlying diagnosis?
Patent foramen ovale Progressive multifocal leukoencephalopathy Migrainous infarction Cerebral amyloid angiopathy > CADASIL
The clinical and radiological description fits with a lacunar infarction in the right internal capsule resulting in a pure motor hemiparesis. The area of acute infarction is not visible on the CT in the hyperacute phase, but is visible on the diffusion-weighted MR as described. The other white matter lesions are most likely old lacunar infarcts which may have been clinically silent.
The personal history of migraine with aura coupled with the family history make this most likely CADASIL (cerebral autosominal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The conditions results from mutations in the NOTCH3 gene on chromosome 19. Individuals typically develop migraine with aura around age 30, transient ischaemic attacks and ischaemic strokes in their 40s, and dementia around the 50s. Strokes are typically lacunar.
There is an association between patent foramen ovale, migraine with aura, and stroke.
Stroke in this context is embolic, which characteristically produces wedge-shaped infarcts involving cortex and white matter, rather than the small lesions seen in lacunar stroke. Emboli may arise in the venous circulation and cross over into the arterial circulation via the shunt (paradoxical embolism).
Progressive multifocal leukoencephalopthy is a demyelinating disease of the central nervous system caused by reactivation of the JC virus, most typically seen in patients with AIDS and low CD4 counts.
In migranous infarction the neurological deficit develops during an attack of migraine.
Cerebral amyloid angiopathy is an important cause of primary lobar intracerebral haemhorrage in the elderly.
Acute Intermittent Porphyria
Acute intermittent porphyria (AIP) is a rare autosomal dominant condition caused by a defect in porphobilinogen deaminase, an enzyme involved in the biosynthesis of haem. The results in the toxic accumulation of delta aminolaevulinic acid and porphobilinogen. It characteristically presents with abdominal and neuropsychiatric symptoms in 20-40 year olds. AIP is more common in females (5:1)
Features abdominal: abdominal pain, vomiting neurological: motor neuropathy psychiatric: e.g. depression hypertension and tachycardia common
Diagnosis
classically urine turns deep red on standing
raised urinary porphobilinogen (elevated between attacks and to a greater extent during acute attacks)
assay of red cells for porphobilinogen deaminase
raised serum levels of delta aminolaevulinic acid and porphobilinogen
Hereditary Haemorrhagic Telangiectasia
Also known as Osler-Weber-Rendu syndrome, hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant condition characterised by (as the name suggests) multiple telangiectasia over the skin and mucous membranes. Twenty percent of cases occur spontaneously without prior family history.
There are 4 main diagnostic criteria. If the patient has 2 then they are said to have a possible diagnosis of HHT. If they meet 3 or more of the criteria they are said to have a definite diagnosis of HHT:
- epistaxis : spontaneous, recurrent nosebleeds
- telangiectases: multiple at characteristic sites (lips, oral cavity, fingers, nose)
- visceral lesions: for example gastrointestinal telangiectasia (with or without bleeding), pulmonary arteriovenous malformations (AVM), hepatic AVM, cerebral AVM, spinal AVM
- family history: a first-degree relative with HHT
There are 4 main diagnostic criteria. If the patient has 2 then they are said to have a possible diagnosis of HHT. If they meet 3 or more of the criteria they are said to have a definite diagnosis of HHT:
- epistaxis : spontaneous, recurrent nosebleeds
- telangiectases: multiple at characteristic sites (lips, oral cavity, fingers, nose)
- visceral lesions: for example gastrointestinal telangiectasia (with or without bleeding), pulmonary arteriovenous malformations (AVM), hepatic AVM, cerebral AVM, spinal AVM
- family history: a first-degree relative with HHT
Neurofibromatosis
There are two types of neurofibromatosis, NF1 and NF2. Both are inherited in an autosomal dominant fashion
NF1 is also known as von Recklinghausen’s syndrome. It is caused by a gene mutation on chromosome 17 (Neurofibromatosis has 17 characters) which encodes neurofibromin and affects around 1 in 4,000
Café-au-lait spots (>= 6, 15 mm in diameter) Axillary/groin freckles Peripheral neurofibromas Iris hamatomas (Lisch nodules) in > 90% Scoliosis Phaeochromocytoma's
NF2 is caused by gene mutation on chromosome 22 (NF2 all the 2s) and affects around 1 in 100,000
Bilateral acoustic neuromas
Multiple intracranial schwannomas, mengiomas and ependymomas
Neurofibromatosis patients can develop HTN for 3 main reasons:
1) Co-existant essential HTN
2) Phaeochromocytoma
3) Renal Vascular Stenosis 2dry to Fibromuscular dysplasia
Hereditary Neuropathy with Liability to Pressure Palsy (HNPP)
Hereditary Neuropathy with Liability to Pressure Palsy (HNPP). This is a neurological syndrome in which trivial trauma to a peripheral nerve e.g. sleeping on a limb, results in a mononeuropathy which may take weeks to resolve. It usually presents in second or third decade of life. The condition is most common in families with Dutch or German ancestry. It is caused by a deletion in the peripheral myelin protein 22 gene on chromosome 17. It is an autosomal dominant condition.
Nerve conduction studies in HNPP are characteristic of a demyelinating neuropathy: conduction is slow and action potentials are small. Nerve biopsy may show a predominance of smaller fibres and localised thickening of the myelin sheath. These investigations are helpful in supporting the diagnosis although gene testing, if positive, is confirmatory.
Management is conservative with e.g. wrist splints, ankle-foot orthoses, and protective padding.
Example Question
A 28-year-old gentleman student from Germany presents to you with right foot drop ongoing for two weeks with some numbness and tingling of the foot. These symptoms developed after he knelt down to pick something up from the floor. Three years ago he woke up from sleep with clawing of his fourth and fifth digit after having been asleep in a prone position and this lasted a week. Eight years ago he also had a left wrist and finger drop lasting three weeks after he sat on the couch with his left arm draped over the back of the couch for ten minutes. He denies falling asleep or remaining on the couch for a prolonged period. He has no other past medical history of note and has never sought medical advice for his problems. On examination, there is right foot drop (2/5 power) and similar weakness of dorsiflexion and eversion of the right foot. There is also sensory loss over the lower lateral part of the right leg and dorsum of the right foot in all modalities. Reflexes are intact. Neurological examination and general examination are otherwise unremarkable. Which of the following tests would confirm the suspected diagnosis?
Nerve conduction studies Electromyography Nerve biopsy > PMP22 gene testing HBA1C
The diagnosis is Hereditary Neuropathy with Liability to Pressure Palsy (HNPP).
The patient’s presenting mononeuropathy is a common peroneal nerve palsy. Three years ago he had an ulnar nerve palsy and eight years ago he had a radial nerve palsy (also called Saturday night palsy).
Neurofibromatosis - Diagnosis
Diagnostic Criteria NF1:
The NIH consensus development group published some criteria to aid diagnosis of neurofibromatosis type 1 in 1988, as neurocutaneous disorders can be difficult to distinguish.
It is important to note that these criteria focus on cafe au lait macule size in adults and children.
A child with 6 or more cafe au lait macules larger than 0.5 cm would fit one of the criteria but they would need to be 1.5 cm or larger in an adult.
Other criteria include:
- axillary freckling
- 2 or more cutaneous/subcutaneous neurofibromas or one plexiform neurofibroma, optic pathway glioma, bony dysplasia
- 2 or more Lisch nodules
- or a 1st-degree relative with neurofibromatosis type 1. At least two of these criteria are required to reach clinical diagnosis.
Diagnostic criteria for NF2 are:
Bilateral vestibular schwannomas
A first degree relative with NF2 AND
Unilateral vestibular schwannoma OR
Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
Unilateral vestibular schwannoma AND
Any two of: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
Multiple meningiomas AND
Unilateral vestibular schwannoma OR
Any two of: schwannoma, glioma, neurofibroma, cataract
Tuberous Sclerosis
Genetic condition of autosomal dominant inheritance
Neuro and Cutaneous Features
Neuro Features:
- Developmental Delay
- Epilepsy (Infantile, partial)
- Intellectual Impairment
Cutaneous Features:
- Depigmented ‘ash leaf’ spots > fluorescent under UV light
- Roughened skin over lumbar spine = SHAGREEN PATCHES
- Adenoma sebaceum = angiofibromas over nose in butterfly distribution
- Fibromata beneath nails = Sublingual fibromata
- Can also have cafe au lait spots
ALSO:
- Retinal haemorrhages (white areas on retina)
- Rhabdomyomas of the heart
- Gliomatous changes can occur in brain lesions
- Polycystic kidneys and renal angiomyolipomata
- Lymphangioleiomyomatosis - multiple lung cysts
DIFFERENTIAL = Neurofibromatosis
Neurofibromatosis vs Tuberous Sclerosis
BOTH:
- Neurocutaneous Fx
- Autosomal dominant
- Ocular Haemtomas (however NF has IRIS haemartomas = LISCH nodules, TS has RETINAL Haemartomas = Phakomata)
SEE PASSMED VENN DIAGRAM
Gardner’s Syndrome
Gardener’s syndrome is a condition that is inherited in an autosomal dominant fashion. It’s main clinical features include adenomatous intestinal polyposis, which can present with changes in bowel habit and rectal bleeding, osteomas and fibromas. 50% of patients with Gardener’s syndrome have colon cancer by the age of 39.
Questions = combination of colorectal polyps with extracolonic manifestations.
Presence of classically osteomas with a familial polyposis syndrome, sometimes also with cutaenous, adrenal or nasal lesions, is diagnostic of Gardners syndrome, a variant of familial adenomatous polyposis.
Peutz-Jeghers is a reasonable differential but its polyps are more frequently associated with pigmented lesions instead of boney outgrowths
Hypokalaemic Periodic Paralysis
Hypokalaemic periodic paralysis
Hypokalaemic periodic paralysis is a rare autosomal dominant disorder characterised by episodes of paralysis, typically occur at night. The underlying defect is a mutation in muscle voltage-gated calcium channels. Attacks may be precipitated by carbohydrate meals
Management
lifelong potassium supplementation
Example Question:
A 17 year old girl is brought into A&E by her mother. The patient appears terrified after she experienced an episode on waking earlier in the morning when she could not move at all for 2 hours. This was her second episode. She reports no loss of consciousness and was aware throughout the episode. She has no other past medical history documented. She is not aware of a previous episode of epilepsy. On examination, her heart sounds and breath sounds are unremarkable. Neurological examination demonstrated no abnormalities. She normal dentition and her BMI is 19.5. A 12 lead ECG demonstrated a jerky baseline with flat T waves. What is the diagnosis?
Partial or absence seizures Guillain Barre syndrome Botulinum toxicity Myasthenia gravis > Hypokalaemia
The patient describes episode of periodic paralysis and the ECG characteristics are consistent with that of hypokaelamia. The underlying diagnosis is a rare familial condition of skeletal muscle ion channels called hypokaelamc periodic paralysis, onset most commonly in childhood and adolescents. Attacks last hours and neurological examination is normally unremarkable in between attacks. The average K+ on diagnosis is 2.4 mmol/L1. Diagnosis is often made clinically in association with low potassium but genetic testing can help if known mutations are present.
- Miller TM, Dias da Silva MR, Miller HA et al. Correlating phenotype and genotype in the periodic paralyses. Neurology. 2004;63(9):1647.
Pseudohyperparathyroidism
Pseudohypoparathyroidism
Pseudohypoparathyroidism is caused by target cell insensitivity to parathyroid hormone (PTH) due to a mutation in a G-protein. In type I pseudohypoparathyroidism
there is a complete receptor defect whereas in type II the cell receptor is intact. Pseudohypoparathyroidism is typically inherited in an autosomal dominant fashion*
Bloods
PTH: high
calcium: low
phosphate: high
Features short fourth and fifth metacarpals short stature cognitive impairment obesity round face
Investigation
infusion of PTH followed by measurement of urinary phosphate and cAMP measurement - this can help differentiate between type I (neither phosphate or cAMP levels rise) and II (cAMP rises but phosphate levels do not change)
*it was previously thought to be an X-linked dominant condition
Liddle’s Syndrome
Liddle’s syndrome
Liddle’s syndrome is a rare autosomal dominant condition that causes hypertension and hypokalaemic alkalosis. It is thought to be caused by disordered sodium channels in the distal tubules leading to increased reabsorption of sodium.
Treatment is with either amiloride or triamterene
Multiple Endocrine Neoplasia
Multiple endocrine neoplasia
The table below summarises the three main types of multiple endocrine neoplasia (MEN). MEN is inherited as an autosomal dominant disorder.
MEN type I
3 P’s
Parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia
Pituitary (70%)
Pancreas (50%): e.g. insulinoma, gastrinoma (leading to recurrent peptic ulceration)
Also: adrenal and thyroid
Most common presentation = hypercalcaemia
MEN type IIa Medullary thyroid cancer (70%) 2 P's Parathyroid (60%) Pheochromocytoma MEN type IIb Medullary Thyroid Cancer RET oncogene
MEN type IIb 1 P Phaeochromocytoma Marfanoid body habitus Neuromas MEN1 gene RET oncogene
MODY
MODY
Maturity-onset diabetes of the young (MODY) is characterised by the development of type 2 diabetes mellitus in patients < 25 years old. It is typically inherited as an autosomal dominant condition. Over six different genetic mutations have so far been identified as leading to MODY.
It is thought that around 1-2% of patients with diabetes mellitus have MODY, and around 90% are misclassified as having either type 1 or type 2 diabetes mellitus.
MODY 3
60% of cases
due to a defect in the HNF-1 alpha gene
MODY 2
20% of cases
due to a defect in the glucokinase gene
Features of MODY
typically develops in patients < 25 years
a family history of early onset diabetes is often present
ketosis is not a feature at presentation
patients with the most common form are very sensitive to sulfonylureas, insulin is not usually necessary
Familial Hypercholesterolaemia
Familial hypercholesterolaemia
Familial hypercholesterolaemia (FH) is an autosomal dominant condition that is thought to affect around 1 in 500 people. It results in high levels of LDL-cholesterol which, if untreated, may cause early cardiovascular disease (CVD). FH is caused by mutations in the gene which encodes the LDL-receptor protein.
Clinical diagnosis is now based on the Simon Broome criteria:
in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l or children TC > 6.7 mmol/l and LDL-C > 4.0 mmol/l, plus:
for definite FH: tendon xanthoma in patients or 1st or 2nd degree relatives or DNA-based evidence of FH
for possible FH: family history of myocardial infarction below age 50 years in 2nd degree relative, below age 60 in 1st degree relative, or a family history of raised cholesterol levels
Management
the use of CVD risk estimation using standard tables is not appropriate in FH as they do not accurately reflect the risk of CVD
referral to a specialist lipid clinic is usually required
the maximum dose of potent statins are usually required
first-degree relatives have a 50% chance of having the disorder and should therefore be offered screening. This includes children who should be screened by the age of 10 years if there is one affected parent
statins should be discontinued in women 3 months before conception due to the risk of congenital defects
Peutz-Jeghers Syndrome
- autosomal dominant condition characterised by numerous Haemartomatous polyps in GI tract
Also assoc with pigmented freckles on lips face, palms and soles
Around 50% of patients will have died from GI tract cancer by age 60
Genetics:
- autosomal dominant
- responsible gene encodes serine threonine kinase LKB1 or STK11
Features:
- Haemarthromatous polyps in GI tract (mainly Sm bowel)
- Pigmented lesions on lips, oral mucosa, face, palms, soles
- Intestinal obstruction eg Intussusception
- GI Bleeding
Mx:
- Conservative unless Cx develop
Marfan’s Syndrome - Associations
Ophthalmology:
Superotemporal Ectopia Lentis
(upwards lens dislocation)
Seen in 50% of patients
(NB Inferonasal ectopia lentis is characteristic of Homocystinuria)
Glaucoma and Retinal detachment also seen
Dural ectasia:
Ballooning of the dural sac at the lumbosacral level
Sx:
- lower back pain assoc w neural Cx e.g. bladder and bowel dysfunction
- headaches
- leg pain
- intermittent episodes of urinary incontinent
- can also cause bowel dysfunction
Associations = Marfans
Affects 60% of patients with Marfans (autosomal dominant CTD)
Cardiac:
Most common = Dilation of aortic sinuses
Also seen = Mitral Valve prolapse
Beckwith-Widerman Syndrome
Inherited condition assoc with
- Organomegaly
- Macroglossia
- Abdominal wall defects
- Wilm’s tumour
- Neonatal hypoglycaemia
Rarely can result from changes in structure of chromosome 11 rather than inherited pattern of autosomal dominance
Achondroplasia
= autosomal dominant disorder assoc with short stature
Caused by a mutation in the fibroblast growth factor receptor 3 gene (FGFR-3 gene)
This results in abnormal cartilage giving rise to:
- short limbs (rhizomelia) w shortened fingers (brachydactly)
- large head w frontal bossing
- midface hypoplasia w a flattened nasal bridge
- ‘Trident’ hands
- lumber lordosis
NB With achondroplasia, both parents are often affected which can make the interpretation slightly trickier. Homozygous achondroplasia children unfortunately don’t live past first few days of life
Autosomal Dominant
In autosomal dominant diseases:
- both homozygotes and heterozygotes manifest disease (there is no carrier state)
- both M + F affected
- only affected individuals can pass on disease
- disease is passed onto 50% of children
- appears in every generation
- risk remains the same for each successive pregnancy
Cx Factors:
- NON -PENETRANCE - Lack of clinical signs and Sx (N phenotype) despite abnormal gene
Eg 40% of otosclerosis
- SPONTANEOUS MUTATION - New mutation in one of the gametes
Eg 80% of individuals with achondroplasia have unaffected parents
Autosomal Dominant vs Autosomal Recessive
Autosomal recessive disorders are often metabolic in nature (autosomal dominant = structural) and are generally more life-threatening
Autosomal recessive = METABOLIC (exception = Inherteid ataxias)
Autosomal dominant = STRUCTURAL (exception = Hyperlipidaemia type II, Hypokalaemic Periodic Paralysis)
Metabolic conditions which are not autosomal recessive
- Hunters and G6PD = X-linked recessive
Structural conditions which are not autosomal dominant
- Ataxia telangiectasia and Friedrichs ataxia = autosomal recessive
Marfan’s Syndrome
= autosomal dominant connective tissue disorder
Defect in fibrillin-1 gene on chromosome 15 Affects 1 in 3000 Features: - tall stature with arm span to heigh ratio >1.05 - high arched palate - arachnodactyly - pectus excavaum - pes planus - scoliosis of >20 degrees
Heart:
- dilation of aortic sinuses (seen in 90%) which may lead to aortic aneurysm, aortic dissection, aortic regurgitation, mitral valve prolapse (75%)
Eyes:
- upward lens dislocation, blue sclera, myopia
Dural Ectasia
Life expectancy used to be around 40-50 but w advent of regular echocardiography monitoring and beta-blocker/ACEi therapy this has improved significantly
Osteogenesis Imperfecta
More commonly known as BRITTLE BONE DISEASE
= a group of disorders of collagen metabolism > bone fragility and fractures
The most common and milder form of Osteogenesis Imperfecta = Type 1
- autosomal dominant
- abnormality in type 1 collagen due to decreased synthesis of pro-alpha 1 or pro-alpha 2 collagen polypeptides
Features:
- presents in childhood
- fractures following minor trauma
- blue sclera
- deafness 2dry to otosclerosis
- dental imperfections are common
Familial Benign Hypocalciuric Hypercalcaemia
Familial benign hypocalciuric hypercalcaemia
Familial benign hypocalciuric hypercalcaemia is a rare autosomal dominant disorder characterised by asymptomatic hypercalcaemia. It is due to a defect in the calcium sensing receptor
Brugada
Brugada syndrome is a form of inherited cardiovascular disease with may present with sudden cardiac death. It is inherited in an autosomal dominant fashion and has an estimated prevalence of 1:5,000-10,000. Brugada syndrome is more common in Asians.
Pathophysiology
- a large number of variants exist
- around 20-40% of cases are caused by a mutation in the SCN5A gene which encodes the myocardial sodium ion channel protein
Antithrombin III Deficiency
= inherited cause of thrombophilia - occurring in approx 1: 3000 of the population
= AUTOSOMAL DOMINANT
= Heterogenous group of disorders as some patients have deficiency of normal antithrombin III and others have abnormal antithrombin III
Antithrombin III inhibits several clotting factors: Thrombin, Factors 9a, 10a, 11a and 12a
Antithrombin III also mediates effect of heparin
Features:
- recurrent venous thrombosis
- arterial thromboses do occur but uncommon
Mx:
- LIFELONG WARFARIN
- Heparinisation during pregnancy (NB as patients with antithrombin III deficiency will have a degree of resistance to heparin, anti-Xa levels should be monitored to ensure adequate anticoagulation
- Antithrombin III concentrates (often used during surgery or childbirth)
Hereditary Spherocytosis
Basics:
- Most common hereditary haemolytic anaemia in people of Northern European Descent
- Autosomal dominant defect of RBC cytoskeleton
- Normal biconcave disc is replaced by sphere shape
- RBC survival reduced as destroyed by spleen
Presentation:
- FTT
- Jaundice/gallstones
- Splenomegaly
- Aplastic crisis (precipitated by Parvovirus infection)
- MCHC elevated
Diagnosis:
- Osmotic Fragility Test
Mx:
- Folate replacement
- Splenectomy
Alzheimer’s Disease
- 5% of cases are inherited as an autosomal dominant trait
- mutations in the amyloid precursor protein (chromosome 21), presenilin 1 (chromosome 14) and presenilin 2 (chromosome 1) genes are thought to cause the inherited form
Osteogenesis Imperfecta
More commonly known as BRITTLE BONE DISEASE
= a group of disorders of collagen metabolism > bone fragility and fractures
The most common and milder form of Osteogenesis Imperfecta = Type 1
- autosomal dominant
- abnormality in type 1 collagen due to decreased synthesis of pro-alpha 1 or pro-alpha 2 collagen polypeptides
Features:
- presents in childhood
- fractures following minor trauma
- blue sclera
- deafness 2dry to otosclerosis
- dental imperfections are common
Von Willebrand’s Disease
Von Willebrand’s disease is the most common inherited bleeding disorder. The majority of cases are inherited in an autosomal dominant fashion* and characteristically behaves like a platelet disorder i.e. epistaxis and menorrhagia are common whilst haemoarthroses and muscle haematomas are rare
*type 3 von Willebrand’s disease (most severe form) is inherited as an autosomal recessive trait. Around 80% of patients have type 1 disease
Role of von Willebrand factor
large glycoprotein which forms massive multimers up to 1,000,000 Da in size
promotes platelet adhesion to damaged endothelium
carrier molecule for factor VIII
Types
type 1: partial reduction in vWF (80% of patients)
type 2: abnormal form of vWF
type 3: total lack of vWF (autosomal recessive)
Investigation
prolonged bleeding time
APTT may be prolonged
factor VIII levels may be moderately reduced
defective platelet aggregation with ristocetin
Management
tranexamic acid for mild bleeding
desmopressin (DDAVP): raises levels of vWF by inducing release of vWF from Weibel-Palade bodies in endothelial cells
factor VIII concentrate
Hereditary Sensorimotor Neuropathy I
HSMN type I
autosomal dominant
due to defect in PMP-22 gene (which codes for myelin)
features often start at puberty
motor symptoms predominate
distal muscle wasting, pes cavus, clawed toes
foot drop, leg weakness often first features
HNPP
Hereditary Neuropathy with Liability to Pressure Palsy (HNPP). This is a neurological syndrome in which trivial trauma to a peripheral nerve e.g. sleeping on a limb, results in a mononeuropathy which may take weeks to resolve. It usually presents in second or third decade of life. The condition is most common in families with Dutch or German ancestry. It is caused by a deletion in the peripheral myelin protein 22 gene on chromosome 17. It is an autosomal dominant condition.
Nerve conduction studies in HNPP are characteristic of a demyelinating neuropathy: conduction is slow and action potentials are small. Nerve biopsy may show a predominance of smaller fibres and localised thickening of the myelin sheath. These investigations are helpful in supporting the diagnosis although gene testing, if positive, is confirmatory.
Management is conservative with e.g. wrist splints, ankle-foot orthoses, and protective padding.
Example Question
A 28-year-old gentleman student from Germany presents to you with right foot drop ongoing for two weeks with some numbness and tingling of the foot. These symptoms developed after he knelt down to pick something up from the floor. Three years ago he woke up from sleep with clawing of his fourth and fifth digit after having been asleep in a prone position and this lasted a week. Eight years ago he also had a left wrist and finger drop lasting three weeks after he sat on the couch with his left arm draped over the back of the couch for ten minutes. He denies falling asleep or remaining on the couch for a prolonged period. He has no other past medical history of note and has never sought medical advice for his problems. On examination, there is right foot drop (2/5 power) and similar weakness of dorsiflexion and eversion of the right foot. There is also sensory loss over the lower lateral part of the right leg and dorsum of the right foot in all modalities. Reflexes are intact. Neurological examination and general examination are otherwise unremarkable. Which of the following tests would confirm the suspected diagnosis?
Nerve conduction studies Electromyography Nerve biopsy > PMP22 gene testing HBA1C
The diagnosis is Hereditary Neuropathy with Liability to Pressure Palsy (HNPP).
The patient’s presenting mononeuropathy is a common peroneal nerve palsy. Three years ago he had an ulnar nerve palsy and eight years ago he had a radial nerve palsy (also called Saturday night palsy).
FSHMD
Facioscapulohumeral muscular dystrophy (FSHMD) is an autosomal dominant form of muscular dystrophy. As the name suggests it stypically affects the face, scapula and upper arms first. Symptoms typically presents by the age of 20 years
Essential Tremor
Essential tremor (previously called benign essential tremor) is an autosomal dominant condition which usually affects both upper limbs
Features
postural tremor: worse if arms outstretched
improved by alcohol and rest
most common cause of titubation (head tremor)
Management
propranolol is first-line
primidone is sometimes used
Example Question:
You are the medical registrar on call. While reviewing another patient, you notice an 82-year-old female inpatient on the same ward, currently treated for community-acquired pneumonia sitting in a chair. You notice a persistent movement of her head, in a nodding motion, associated with a tremor of both hands, worse in the left than the right. Reading through her notes, she has previously been treated for epilepsy and was started on oral phenytoin by her GP 4 months ago. On examination, the hand tremor appears to worsen when her arms are outstretched. She performs finger-nose dysmetria testing without difficulty with no speech. She demonstrates no cogwheeling. The patient appears unconcerned by the symptoms ‘I have learned to live with it for years doctors!’ she tells you. What is the most likely diagnosis?
Tremor-predominant Parkinson's disease Phenytoin induced cerebellar tremor > Essential tremor Physiological tremor Orthostatic tremor
The patient’s examination is one of isolated tremor with no other cerebellar or neurological features. The clinical features of worsening on posture, head nodding and lack of cerebellar symptoms suggest a diagnosis of essential tremor. She demonstrates no signs of Parkinson’s disease, a tremor that does not alleviate with movement and the history describes onset beyond the start of phenytoin. Orthostatic tremor onsets in the trunk and legs when the patient stands. The described features are perhaps too severe for a physiological tremor, which is typically low in amplitude and barely visible. It is unlikely the patient would have received a beta agonist for a community-acquired pneumonia in the absence of obstructive airways disease, hence a drug-induced tremor is also unlikely.
HOCM
Hypertrophic obstructive cardiomyopathy (HOCM) is an autosomal dominant disorder of muscle tissue caused by defects in the genes encoding contractile proteins. The most common defects involve a mutation in the gene encoding β-myosin heavy chain protein or myosin binding protein C. The estimated prevalence is 1 in 500.
Features
- often asymptomatic
- dyspnoea, angina, syncope
- sudden death (most commonly due to ventricular arrhythmias), arrhythmias, heart failure
- jerky pulse, large ‘a’ waves, double apex beat
- ejection systolic murmur: increases with Valsalva manoeuvre and decreases on squatting
Associations:
- Friedreich’s ataxia
- Wolff-Parkinson White
Inherited Dilated Cardiomyopathy
Inherited dilated cardiomyopathy
around a third of patients with DCM are thought to have a genetic predisposition
a large number of heterogeneous defects have been identified
the majority of defects are inherited in an autosomal dominant fashion although other patterns of inheritance are seen
Brugada Syndrome
Brugada syndrome
Brugada syndrome is a form of inherited cardiovascular disease with may present with sudden cardiac death. It is inherited in an autosomal dominant fashion and has an estimated prevalence of 1:5,000-10,000. Brugada syndrome is more common in Asians.
Pathophysiology
a large number of variants exist
around 20-40% of cases are caused by a mutation in the SCN5A gene which encodes the myocardial sodium ion channel protein
ECG changes
convex ST segment elevation > 2mm in > 1 of V1-V3 followed by a negative T wave
partial right bundle branch block
changes may be more apparent following flecainide
ECG showing Brugada pattern, most marked in V1, which has an incomplete RBBB, a downsloping ST segment and an inverted T wave
Management
implantable cardioverter-defibrillator
Familial Hypercholesterolaemia
Familial hypercholesterolaemia (FH) is an autosomal dominant condition that is thought to affect around 1 in 500 people. It results in high levels of LDL-cholesterol which, if untreated, may cause early cardiovascular disease (CVD). FH is caused by mutations in the gene which encodes the LDL-receptor protein.
Clinical diagnosis is now based on the Simon Broome criteria:
- in adults total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l or children TC > 6.7 mmol/l and LDL-C > 4.0 mmol/l, plus:
- for definite FH: tendon xanthoma in patients or 1st or 2nd degree relatives or DNA-based evidence of FH
- for possible FH: family history of myocardial infarction below age 50 years in 2nd degree relative, below age 60 in 1st degree relative, or a family history of raised cholesterol levels
NB Other causes of significant hypercholesterolaemia (Nephrotic syndrome, Cholestasis, Hypothyroidism)
Management
the use of CVD risk estimation using standard tables is not appropriate in FH as they do not accurately reflect the risk of CVD
referral to a specialist lipid clinic is usually required
the maximum dose of potent statins are usually required
first-degree relatives have a 50% chance of having the disorder and should therefore be offered screening. This includes children who should be screened by the age of 10 years if there is one affected parent
statins should be discontinued in women 3 months before conception due to the risk of congenital defects
CPVT Catecholaminergic Polymorphic VT
CPVT Catecholaminergic Polymorphic VT
- a form of inherited cardiac disease assoc w sudden cardiac death
- autosomal dominant
- prevalence 1: 10,000
Pathophysiology
> defect in ryanodine receptor found in myocardial sarcoplasmic reticulum
Features
> exercise or emotion induced polymorphic VT resulting in syncope
> sudden cardiac death
> Sx develop before age 20
Mx:
> Beta blockers
> ICD
Arrhythmic Right Ventricular Cardiomyopathy ARVC
- a form of inherited CVD which may present with syncope or sudden death (Generally regarded as second most common cause of sudden death in the young after HOCM)
- inherited autosomal dominant
- R ventricular myocardium is replaced with fatty and fibrofatty tissue
- 50% patients have a mutation of one of the several genes which encodes components of a desmosome
Sx:
- palpitations
- syncope
- sudden cardiac death
ECG:
- abnormalities in V1-3
- TWI
- Epsilon wave in 50% (terminal notch after QRS)
Echo:
- subtle in early stages but may show enlarged, hypo kinetic R ventricle with a free wall
MRI:
- May show fibrofatty tissue
Mx:
- DRUGS - Sotalol
- Catheter Ablation to prevent VT
- ICD
NB Naxos disease is the autosomal recessive variant of ARVC = TRIAD of ARVC + Palmoplantar keratosis + Woolly hair
ADPKD
ADPKD Type 1 = Mutation in PKD1 gene on chromosome 16 = 85% cases
ADPKD Type 2 = Mutation in PKD2 gene on chromosome 4 = 15% cases
Features hypertension recurrent UTIs abdominal pain renal stones haematuria (presentation can be confused with renal colic!) chronic kidney disease
Extra-renal manifestations
liver cysts (70%)
berry aneurysms (8%)
cardiovascular system: mitral valve prolapse, mitral/tricuspid incompetence, aortic root dilation, aortic dissection
cysts in other organs: pancreas, spleen; very rarely: thyroid, oesophagus, ovary
Screening Ix for relatives = Abdom US
US Diagnostic Criteria (in patients with positive FHx)
- 2 cysts, unilateral or bilateral if aged <30
- 2 cysts in both kidneys if aged 30-59
- 4 cysts in both kidneys if aged >60
HNPCC
HNPCC, an autosomal dominant condition, is the most common form of inherited colon cancer. Around 90% of patients develop cancers, often of the proximal colon, which are usually poorly differentiated and highly aggressive. Currently seven mutations have been identified, which affect genes involved in DNA mismatch repair leading to microsatellite instability. The most common genes involved are:
MSH2 (60% of cases)
MLH1 (30%)
Patients with HNPCC are also at a higher risk of other cancers, with endometrial cancer being the next most common association, after colon cancer.
The Amsterdam criteria are sometimes used to aid diagnosis:
at least 3 family members with colon cancer
the cases span at least two generations
at least one case diagnosed before the age of 50 years
FAP
FAP is a rare autosomal dominant condition which leads to the formation of hundreds of polyps by the age of 30-40 years. Patients inevitably develop carcinoma. It is due to a mutation in a tumour suppressor gene called adenomatous polyposis coli gene (APC), located on chromosome 5. Genetic testing can be done by analysing DNA from a patients white blood cells. Patients generally have a total colectomy with ileo-anal pouch formation in their twenties.
Patients with FAP are also at risk from duodenal tumours. A variant of FAP called Gardner’s syndrome can also feature osteomas of the skull and mandible, retinal pigmentation, thyroid carcinoma and epidermoid cysts on the skin
MEN
Multiple endocrine neoplasia
The table below summarises the three main types of multiple endocrine neoplasia (MEN). MEN is inherited as an autosomal dominant disorder.
MEN type I
3 P’s
Parathyroid (95%): hyperparathyroidism due to parathyroid hyperplasia
Pituitary (70%)
Pancreas (50%): e.g. insulinoma, gastrinoma (leading to recurrent peptic ulceration)
Also: adrenal and thyroid
Most common presentation = hypercalcaemia
MEN type IIa Medullary thyroid cancer (70%) 2 P's Parathyroid (60%) Pheochromocytoma MEN type IIb Medullary Thyroid Cancer RET oncogene
MEN type IIb 1 P Phaeochromocytoma Marfanoid body habitus Neuromas MEN1 gene RET oncogene
Pseudohypoparathyroidism
Pseudohypoparathyroidism
target cells being insensitive to PTH
due to abnormality in a G protein
Typically inherited in autosomal dominant fashion
T1 pseudohypoparathyroidism = Complete receptor defect
T2 pseudohypoparathyroidism = Cell receptor is intact
associated with low IQ/cognitive impairment short stature shortened 4th and 5th metacarpals obesity round face
Bloods: low calcium, high phosphate, high PTH
Ix: diagnosis is made by measuring urinary cAMP and phosphate levels following an infusion of PTH. In hypoparathyroidism this will cause an increase in both cAMP and phosphate levels.
In pseudohypoparathyroidism type I neither cAMP nor phosphate levels are increased whilst in pseudohypoparathyroidism type II only cAMP rises, phosphate levels don’t change
Pseudopseudohypoparathyroidism
similar phenotype to pseudohypoparathyroidism but normal biochemistry
Spinocerebellar Ataxias
Spinocerebellar ataxias are a group of autosomal dominant disorders which are associated with the progressive development of ataxic features such as gait disturbance, nystagmus and tremor. The majority of affected patients develop symptoms within the 3rd and 4th decade.
