Marfan Syndrome

Orthopaedics and Rheumatology: Marfan Syndrome

Marfan Syndrome (sometime Marfan’s Syndrome) is an autosomal dominant connective tissue disorder.

Epidemiology and Aeitiology

-          25% of cases occur without family history

-          Reduced life expectancy – average is around 60

Pathology

-          The result of a mutation in the fibrillin-1 gene (FBN-1) which results in decreased production of extracellular microfibril. Microfibril is involved in the maintenance of elastic fibres, and as a result, there is an alteration in the properties of elastic fibres

Signs and Symptoms

These can be divided into major and minor signs:

-          Major signs – diagnostic is >2 present

o   Long limbs, tall, long, spindly fingers (arachnodactyly)

§ The thumb sign – the distal phalanx of the thumb extends beyond the edge of the clenched fist

o   Arm length height

o   Upwards lens dislocation in the eye (aka ectopia lentis) – the margin of the dislocation lens may been seen through an undilated pupil

o   Pectus deformity (e.g. excavatum or carinatum [outwards])

o   Aortic dissection / dilatiation – particularly at the aortic root. The arotic media is less resistant to stretching, particularly in areas of high pressure – hence the involvement of the aortic root. In severe cases, dissection can occur before the age of 10! Aortic regurg and endocarditis are also common

o   Dural ectasia – widening of the neural canal

-          Minor signs – may support diagnosis

o   Mitral valve prolapse – and accompanying late systolic murmur at the apex

o   High arched palate – can cause altered / unusual voice in some patients

o   Joint Hypermobility

o   Genu recuvatum – hyperextension of the knee, thus is appears to curve backwards

o   Scoliosis

o   Reduced subcutaneous fat

Diagnosis

-          Usually clinical. CT scan may be useful to detect dural ectasia

Treatment

-          The disease is incurable.

-          Treatment aims to minimise the risk of aortic dissection by preventing excessive dilation of the aortic root. This is usually managed with:

o   Β- blockers – e.g. atenolol, propanolol – these reduce the contractility of the heart, and thus reduce the pressure in the aortic root, reducing the risk of dilation and dissection

o   Annual Echocardiogram – dilation of >5cm is repaired surgically

o   Risk in pregnancy – pregnant women are at particularly high risk of cardiac complications.

Homocystinuria

is a disorder that is difficult to distinguish from Marfan Syndrome.

Marfan Syndrome	Homocystinuria
No urinary markers	Homocystine in urine
Heart signs	Heart not usually affected
Upwards lens dislocation	Downwards lens dislocation
Intelligence not affected	Reduced mental ability
Non-reversable changes	Responds to pyridoxine

Notes by Tom Leach

Osteomalacia and Rickets

These are essentially the same disorder. In children, the disease is rickets but after fusion of the epiphyseal plates it is known as osteomalacia.

The most common cause is vitamin D deficiency.

The condition is characterised by normal bone formation with abnormal bone mineralisation, thus there is excess osteoid and cartilage, and insufficient bone.

Causes

-          Vitamin D deficiency – due to lack of sunlight ± insufficient dietary intake. Both often occur simultaneously. Common in the elderly (e.g. often indoors for long periods) and also in dark skinned populations residing in non-native climes (e.g. in the UK) – particularly if they cover up their skin (e.g. common in Inidan Pakistani women and girls in the UK. As a result, chapatti flour is fortified with vitamin D).

-          Renal osteomalacia – resulting in vitamin D deficiency. Often occurs in patients with long-term renal pathologies.

-          Drug Induced – particularly with anticonvulsants

-          Vitamin D resistant rickets / osteomalacia – a collection of inherited diseases, including familial hypophosphataemia, and a disorder where the vitamin D receptor is defective.

o   Type I hereditary vitamin D-dependent rickets – caused by ineffective conversion of vitamin D precursors in the kidneys (25()H)D to 1,25(OH)D. Autosomal recessive

o   Type II hereditary vitamin D-dependent rickets – due to mutations in the 1,25(OH)D receptor, causes end-organ resistance to vitamin D

o   Both are treated with high levels of calcitriol  ( 1,25()H)2vitamin D )

-          Hypoparathyroidism

-          Low dietary calcium / phosphate (rare)

Clinical Features

-          Muscle aches

-          Muscle weakness

-          Bone Pain / pain on walking

-          Predisposition to fractures – especially in the elderly

-          Tetany – parasthesia of the lips, tongue and face, sometimes facial and carpopedal spasm, rarely seizures. May be hard to distinguish from other causes of seizure.

-          In children

o   Generally unwell

o   Delayed walking / crawling / sitting

o   In pregnancy, amy affect the foetus, especially the skull of the newborn (pingpong ball like skull - craniotabes)

§ Craniotabes is also seen in syphilis, and neonates with this are often tested for the disease.

o   Rachitic Rosary – bead like nodules on the ribs

o   Kyphoscoliosis

o   Bowed legs and ‘knock knees’ only occur in severe cases in older children

Investigations

-          Vit D – often ↓

-          Alkaline phosphate: may be ↑ or ↔

-          Parathyroid hormone ↑

-          ↓Calcium

o   Low vitamin D results in low absorption of calcium in the diet, which inturn stimulates increased PTH production. High levels of PTH also increase phosphate excretion, but may normalise serum calcium levels.

-          ↓Phosphate

-          Renal failure (in renal osteomalacia)

-          X-ray – usually of radius / ulnar

o   Diagnosis cannot be made with X-ray alone – also need PHT and 25(OH)D level to rule out other causes of demineralisation.

o    Rickets

§ Changes most easily seen at the ends of the radius and ulnar

§ Ragged bone edges

§ Apparent increased distance from arm bones to carpal bones (Due to demineralisation of this area).

§ Fuzzy, cup-shaped diaphyses (ends of the bone)

§ General increase in radiolucency of the bone

o   Osteomalacia

§ Reduced amount of cortical bone

§ Partial fractures

Treatment

-          Vitamin D supplements + calcium  are first line – 400U tablets, 1-2 times/day

o   After 3 weeks, x-ray improvements can be seen. Typically starting at the very tip of the bone, and continuing down through the affected segment

o   Malapborption might require calciferol (1,25(OH)2D) - 1mg/day (equivalent to 40,000 units of Vit D!)

o   Vit-D resistant rickets should be treated with calciferol 10,000 unites/day

o   Renal osteomalacia is best treated with alfacalcidol

o   Hypercalcaemia is common with all vit D treatments, especially alfacalcidol.

Notes by Tom Leach

Osteomyelitis

Orthopaedics and Rheumatology: Osteomyelitis

Introduction

• Infection of the bone caused by pyogenic organisms
• Can be acute or chronic

Acute Osteomyelitis

Haematogenous osteomyelitis

o Disease of childhood

o Pathogenesis: Organisms (e.g. Staphylococcus Aureus) reach bone via the bloodstream from a septic focus elsewhere (e.g. a boil in the skin). They invade the bone and the body initiates a response but its effectiveness is lessened due to the bones inability to allow swelling so pus collects below the periosteum. The Metaphysis is the major site of infection and the epiphysis acts as a barrier to its spread. If the metaphysis is in the joint capsule (e.g. in the elbow) then acute pyogenic arthritis can occur. Bones most commonly affected are the tibia, femur and humerus

o Symptoms: Acute illness with extreme pain over the affected bone

o Signs: Look for a source of infection (e.g. a boil) and pyrexia with tenderness over the affected bone. There should be a good range of movement unless the infection has spread to the joint

o Investigations: Positive blood cultures and leucocytosis with raised ESR and CRP. Early x-rays will be normal. Later x-rays will show diffuse rarefaction of the metaphyseal area and new bone outlining the raised periosteum

o Treatment: Rest and IV antibiotics (usually flucloxacillin and fusidic acid until the organism is identified) for approximately 4 weeks. Locally, pus can be released to reduce pain and reduce the likelihood of ischaemic necrosis

o Complications: Septicaemia, acute pyogenic arthritis and growth retardation

Osteomyelitis following an open fracture or surgical operation

o Pus discharges through the wound rather than collecting below the periosteum

o There is visible pus and redness with less severe pain (no pressure build up)

o Treatment is to ensure adequate pus drainage and antibiotics but it often becomes chronic

Chronic Osteomyelitis

• Persistence of acute osteomyelitis after treatment
• Pathogenesis: Usually caused by Staphylococcus Aureus but can be Streptococci/Pneumococci. Commonly affects the ends of long bones but can affect the whole length
• Symptoms: Intermittent tenderness over the bone and pyrexia. There may be a sinus track leading to the skin surface
• Investigations: Radiography shows dense bone with patchy sclerosis giving a honeycomb appearance. CT scans can be performed to look for abscess cavities
• Treatment: Surgical drainage of the pus and antibiotics
• Complications: Pathological fractures and amyloid disease

Notes by Natasha Turley 

Osteoporosis

Osteoporosis Notes

Osteoporosis is the most common bone disorder. It is a reduction in bone mass and alteration of bone structure, not just a reduction in bone density. The easiest way to measure the extent of the disease is with bone density scans.

The condition in itself is clinically silent, however, it massively increases the risk of fractures, which increases the risk of mortality.

Epidemiology

-          Most common bone disorder

-          Genetic factors are very important – in twins, concordance is 60-90%. Many genes have been implicated, and it is likely that numerous genes are involved.

o   Osterogenesis imperfecta is a type of monogenic osteoporosis that has been well described, but is rare compared to multigenic and multifactorial causes. OI actually comprises of 4 subtypes, which are classified by the presence of a blue sclera. In some cases, this is apparent in childhood, but may resolve with age. In some cases, affected children are born with multiple fractures. There is also often joint hypermobility, aortic root dilation (causing aortic regurg) and hearing loss. These secondary features are related to defects in collagen.

-          More common in women (4:1)

-          More common in Caucasian population than in other races

-          Affects 35% of the over 50’s in the UK

Causes

-          Post menopausal bone loss is the most common cause – this is related to oestrogen deficiency

-          Hyperparathyroidism

-          Malabsroption (e.g. coeliac’s disease)

-          Osteomalacia

o   Most commonly the result of vitamin D deficiency

-          Multiple myeloma

-          Hypopituitarism

Aetiology

-          Family history

-          Alcohol excess

-          Smoking

-          Amenorrhoea

-          Late menarche

-          Early menopause – including surgical menopause

-          Lack of weight bearing exercise

-          Drugs:

o   Corticosteroids

§ Including Cushing’s disease

o   Anticonvulsants

o   Heparin

o   Thyroxine

o   Extreme alcohol excess

-          Low calcium and/or vitamin D intake

Clinical features

-          Fracture

-          Reduced height (vertebral fracture)

-          Stooping posture – kyphosis, aka dowager’s hump – as a result of wedge shaped fractures of the vertebral bodies.

-           

Pathology

Essentially, there is loss of bone mass, despite normal mineralisation.

-          As opposed to osteomalacia – which occurs when bone is not being properly mineralised, despite the normal production of bone matrix.

Caused by a loss of coupling between bone deposition and bone absorption mechanisms. This can result in excess osetoclast activity, decreased osteoblast activity, or both. The process of mineralisation of new bone matrix remains normal.

Osteoporosis affects both trabecular (long thick bones, e.g. femur) and cortical bone (high surface area, think bones, e.g. spine). When it affects trabecular bones, reabsoprtion of bone is the main mechanism.

Post menopausal osteoporosis

This is the most common type of osteoporosis. Bone mass naturally declines with age. Peak bone mass occurs several years after puberty, and then steadily declines. In women, this decline is increased during and after menopause. This, coupled with the fact that women have a lower peak bone mass than men, means post-menopausal women are at particularly high risk.

Reduced levels of oestrogen mean that normal osteoclast and osteoblast activity is no longer in conjunction, and osteoclast activity slightly exceeds osteoblast activity, so that over time, bone mass is reduced.

Corticosteroid induced osteoporosis

Steroids affect bone density regulatory mechanisms at several places:

-          Decreased absorption of calcium from the gut

-          Decrease muscle mass – which can affect bone remodelling by altering the normal weight bearing stressors normally exerted on bone

-          Increasing osteoclast activity

Diagnosis

-          Bone mineral density two standard deviation BELOW the mean value for young adults of the same sex. This is assessed using a DEXA scan.

o   More mild reduction in bone density are classed as osteopenia. This is likely to progress to osteoporosis, so preventative measures may be initiated at this stage.

o   The BMD is assessed on a scale relative to 0.

§ >0 – better BMD than the reference

§ 0 to -1 – in the top 84% of the population

§ -1 to -2.5 – osteopenia

§ <-2.g - osteoporosis

-          Thyroid Function Test

-          Vitamin D levels

-          Myeloma screen

o   ESR

o   Serum immunoglobulins / electrophoresis

o   Urinary Bence Jones Protein

-          X-ray – not very sensitive or specific. Often osteoporosis only presents with a fracture, so you will end up doing one anyway!

-          Screening programs are not widely undertaken, as their efficacy is not proven

Complications

Fractures mainly depend on the type of bone affected by the osteoporosis. The lumbar vertebrae, wrist and the hip are the most commonly affected bones.

-          Vertebral fractures.

o   This can present ‘silently’, perhaps as an exaggerated kyphosis – Dowager’s Hump. This is particularly common in elderly women, and can also cause a reduction in height.

§ Only 30% of vertebral fractures are symptomatic

o   It may also present as acutely, especially when the nerves and nerve roots are involved.

§ Thoracic spine – pain radiates around the front of the torso

§ Lumbar spine – sciatic and femoral nerves may be involved.

§ Sudden onset back pain

§ 25% may feel nauseous and/or vomit

§ Localised tenderness

o   Management

§ Bed rest (1-2 weeks) may be helpful

§ TENS can relieve pain

§ Diazepam (muscle relaxant) may also be helpful

§ Initiate preventative treatments (calcitonin, bisphosphonates)

§ Physiotherapy

-          Non-spinal fractures

o   Managed in the standard way

Treatment

The aim of treatment is to reduce the risk of fracture.

Lifestyle changes

May be sufficient for some patients. Measures include:

-          Sufficient daily calcium intake – the equivalent to 1 pink of milk per day (1200-1500mg)

-          Smoking cessation

-          Reduction in alcohol intake

-          Increase weight bearing exercise

o   Not only increases bone density, but also helps to prevent falls.

o   At least 30 minutes weight bearing exercise 3x per week is needed to increase bone density

Drug treatments

-          NICE guidlines:

o   1^st line – use a bisphosphonate

o   2^nd line – if no improvement, try a different bisphosphonate

o   3^rd line – if no improvement, try strontium

Drug treatments can reduce the risk of fracture by up to 50%

Supplements

Many patients also receive dietary supplements as adjuncts to their pharmacological therapy:

-          Calcium

-          Vitamin D

Used alone, they reduce the risk of fracture only by 4%! In very elderly patients, for whom vit D deficiency is the main mechanism of bone density loss, they may be sufficient

  

Bisphosphonates – e.g. risedronate, clodronate, pamidronate, etidronate

The different drugs have similar mechanisms, but different efficacy. The most effective is usually pamidronate given IV. Etidronate is the least effective, and has to be given in higher doses, which increase the side effects.

The drugs are essentially analogues of pyrophosphate.

Mechanism

-          Bind to hydroxyapatite crystals in the bone, and are then taken up by osteoclasts – resulting in a high concentration of the drugs in these particular cells. Once within the cell they:

o   Cause apoptosis – by acting as analogues to ATP

o   Inhibit cholesterol synthesis mechanisms – which eventually results in apoptosis

o   Inhibit binding of the osteoclasts ruffled border to the bone surface – and thus the osteoclast cannot resorb the bone.

Pharmacokinetics

-          Poorly absorbed from the gut

-          Should be taken on an empty stomach – as they can bind to calcium in food, after which, the drug cannot be absorbed.

o   Only about 10% of the oral dose is absorbed under normal circumstances

o   Usually taken weekly, and with plenty of water.

-          Pamidronate is only available IV, all other agents only available as oral preparations

-          They are rapidly removed from the blood by the kidney, but as they bind to salts, they stay deposited in bone for long periods

Unwanted effects

-          GI upset – which can be severe!

-          Bone pain

-          Oesophagitis – to reduce the risk, the patient should take the drug:

o   With a full glass of water

o   At least 30 minutes before food

o   And stay stood or sat upright for at least 30 minutes after the tablet is taken

-          Headache

Uses

As well as osteoporosis, bisphosphonates are used in Paget’s disease, and sometimes used against bone metastases.

HRT

No longer used as mainstream treatment, but if other treatments are not tolerated or effective, then it may be useful in women in post-menopausal osteoporosis.

-          Most effective when started early in menopause, and continued for >5 years

-          Bone loss continues, and is possibly increased upon stopping HRT

-          Also increases the risks of cardiovascular disease and stroke

Strontium

Sometimes used as an alternative to bisphosphonates

Calcitonin

Sometimes used in those for whom bisphosphonates are not very effective

Notes by Tom Leach

Paget's Disease of the Bone

Paget's Disease of the Bone

Along with osteoporosis, this is a common degenerative bone disease

Epidemiology and Aetiology

This is the second most common bone disorder (after osteoporosis), and affects >5% of the over 55’s in the UK. The prevalence varies between countries and races. The UK has the highest incidence. It is rare in Scandinavia, China and Japan.

-          Increased incidence in Pet Owners

-          Genetic susceptibility

-          Essentially unknown aetiology; environmental factors in a predisposed individual (possibly viral infection is the environmental factor)

-          Incidence increases with age

o   Rare under 50

-          Slight male predominance

Clinical features

-          Chronic progressive disease

-          Often asymptomatic, and discovered incidentally with a raised ALP in the blood, or discovered incidentally on x-ray

-          Only 15-30% of cases have symptoms

-          Bone pain! – the most common symptom

-          May affect bones anywhere in the skeleton, but common sites include; pelvis, lumbar spine, femur, thoracic spine, sacrum, skull, tibia, humerus

-          Usually only affects one site! – it is not ‘systemic’ like osteoporosis, and does not spread to other sites.

-          Osteoarthritis

-          Fractures – bones are prone to fracture because they become more brittle

-          Deafness / Headaches – occurs in some patients due to compression of the vestibulocochlear nerve, when the skull is affected

-          Osteosarcoma – used to be more common, now only affects 1% of patients.

Pathology

-          Increased number of osteoclasts. Osteoclasts also often larger. The osteoblasts are normal, but are often over active, due to increased factors released by osteoclasts.

-          Essentially, an accelerated rate of bone turnover – with subsequent rapid new bone formation – and this new bone does not have a normal bone matrix – the matrix is disorganised

-          The bones increase in size, but become more brittle, and thus more prone to fracture.

Investigations

-          Blood tests

o   Raised ALP – ALP can be an indicator of osteoblastic activity

§ Also check γ-GT – to rule out a liver cause!

o   Serum calcium and phosphates will be normal

-          X-ray

o   Widening of the cortical region – i.e. the hollow cortex at the centre of the bone (where marrow is produced) is wider

o   Mixed areas of sclerosis and lysis – on the x-ray will look like lots of opaque dark splodges in the bone

o   Bone deformities

§ Bone bends anteriorly in the tibia

§ Bone bends laterally in the femur

o   May also show what appears to be localised osteoporosis in areas of very high osteoclast activity – called osteoporosis circumscripta – this is particularly apparent in the skull

-          Bone scan – increased isotope uptake in affected bones

-          Urine – may contain collagen due to very high bone resorption

Treatment

Knowing who and when to treat is the biggest problem. It is essentially based on symptoms severity. Reasons to treat include:

-          Severe pain

-          Nerve compression from expanding bone

-          Fractures

Other management options include:

-          Orthoses – braces, usually plastic that support and protect a bone

-          Analgesia

-          Education

-          Treat the complications – e.g. joint replacement

-          Bisphosphonates

o   These are the ‘mainstay’ of treatment. They inhibit osteoclast activity, and cause osteoclast apoptosis. they damage the cytoskeleton of the osteoclast, so the cell is then unable to bind to bone, and to perform its bone resorption duties.

o   Are often able to induce disease remission. Typical regimen will last 2 months.

Notes by Tom Leach