Tag Archives: Dominance (genetics)

Wilson’s Disease

Definition :

Wilson’s disease is an inherited disorder that causes too much copper to accumulate in your liver, brain and other vital organs. Another term for Wilson’s disease is hepatolenticular degeneration.

Copper plays a key role in the development of healthy nerves, bones, collagen and the skin pigment melanin. Normally, copper is absorbed from your food, and any excess is excreted through bile — a substance produced in your liver.

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Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.

But in people with Wilson’s disease, copper isn’t eliminated properly and instead accumulates, possibly to a life-threatening level. Left untreated, Wilson’s disease is fatal. When diagnosed early, Wilson’s disease is treatable, and many people with the disorder live normal lives.

The excess copper can build up in the liver and/or brain causing liver damage and/or neurological problems. It can also collect in other parts of the body including the eyes and the kidneys.
Copper begins to accumulate immediately after birth but the symptoms usually appear in the 2nd to 3rd decade. The first signs are hepatic (liver) in about 40% of cases, neurological (brain) in about 35% of cases and psychiatric, renal (kidney), haematological (blood), or endocrine (glands) in the remainder.

The condition is due to mutations in the Wilson disease protein (ATP7B) gene. A single abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms (they are carriers). If a child inherits the gene from both parents, they may develop Wilson’s disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older people have been described. Wilson’s disease occurs in 1 to 4 per 100,000 people.  Wilson’s disease is named after Samuel Alexander Kinnier Wilson (1878–1937), the British neurologist who first described the condition in 1912


Symptoms:
The most pathognomonic sign of Wilson’s disease results from a buildup of copper in the eyes. These rings are
called Kayser – Fleischer rings. Rings are brownish, visible aroound the corneo – scleral junction (limbus).
95% of Wilson’ s disease patients presenting with neurological signs will have Kayser – Fleischer rings and 65% of Wilson’s disease patients presenting with hepatic signs will present a ring.

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Wilson’s disease causes a wide variety of signs and symptoms that are often mistaken for other diseases and conditions. Signs and symptoms vary depending on what parts of your body are affected by Wilson’s disease.
Signs and symptoms of Wilson’s disease include:

*Clumsiness
*Depression
*Difficulty speaking
*Difficulty swallowing
*Difficulty walking
*Drooling
*Easy bruising
*Fatigue
*Involuntary shaking
*Joint pain
*Loss of appetite
*Nausea
*Skin rash
*Swelling of arms and legs
*Yellowing of the skin and eyes (jaundice)

The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis.  People with liver problems tend to come to medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilson’s disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but haven’t received a diagnosis.:

Causes:
Wilson’s disease occurs when a genetic mutation leads to an accumulation of copper in  one’s body.

How the genetic mutation occurs
The genetic mutation that causes Wilson’s disease is most commonly passed from one generation to the next. Wilson’s disease is inherited as an autosomal recessive trait, which means that to develop the disease you must inherit two copies of the defective gene, one from each parent. If you receive only one abnormal gene, you won’t become ill yourself, but you’re considered a carrier and can pass the gene to your children.

How the genetic mutation causes Wilson’s disease
The mutation that causes Wilson’s disease occurs in a gene called ATP7B. When a mutation occurs on this gene, it leads to problems with a protein that’s responsible for moving excess copper out of your liver.

Your body collects copper from the food you eat during the digestive process. The copper is transported to your liver where liver cells use it for everyday tasks. Most people eat more copper than they need. In these cases, the liver takes what it needs and excretes the rest in bile, a digestive juice made by the liver.

But in people with Wilson’s disease, the extra copper doesn’t leave your body. Instead, copper builds up in the liver, where it can cause serious and sometimes irreversible damage. In time, excess copper leaves the liver and begins accumulating in and harming other organs, especially the brain, eyes and kidneys.

Complications:
Wilson’s disease can cause serious complications such as:

*Scarring of the liver (cirrhosis). As liver cells try to make repairs to damage done by excess copper, scar tissue forms in the liver. The scar tissue makes it more difficult for the liver to function.

*Liver failure. Liver failure can occur suddenly (acute liver failure), or it can develop slowly over many years. If liver function progresses, a liver transplant may be a treatment option.

*Liver cancer. Damage to the liver caused by Wilson’s disease may increase the risk of liver cancer.

*Persistent neurological problems. Neurological problems usually improve with treatment for Wilson’s disease. However, some people may experience persistent neurological difficulty, despite treatment.
*Kidney problems. Wilson’s disease can damage the kidneys, leading to kidney problems, such as kidney stones and an abnormal number of amino acids excreted in the urine (aminoaciduria).

Diagnosis:
Wilson’s disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson’s. Most have slightly abnormal liver function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin level. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors. Alkaline phosphatase levels are relatively low in those with Wilson’s-related acute liver failure. If there are neurological symptoms, magnetic resonance imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting.  MRI may also demonstrate the characteristic “face of the giant panda” pattern.

There is no totally reliable test for Wilson’s disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard or most ideal test is a liver biopsy

Ceruloplasmin
Levels of ceruloplasmin are abnormally low (<0.2 g/L) in 80–95% of cases. It can, however, be present at normal levels in people with ongoing inflammation as it is an acute phase protein. Low ceruloplasmin is also found in Menkes disease and aceruloplasminemia, which are related to, but much rarer than Wilson’s disease.

The combination of neurological symptoms, Kayser–Fleisher rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson’s disease. In many cases, however, further tests are needed.
Serum and urine copper
Serum copper is paradoxically low but urine copper is elevated in Wilson’s disease. Urine is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 ?g/24h (1.6 ?mol/24h) confirm Wilson’s disease, and levels above 40 ?g/24h (0.6 ?mol/24h) are strongly indicative.[1] High urine copper levels are not unique to Wilson’s disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).

In children, the penicillamine test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 ?g (25 ?mol), it is a reliable indicator of Wilson’s disease. This test has not been validated in adults.

Liver biopsy
Once other investigations have indicated Wilson’s disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. This is assessed microscopically for the degree of steatosis and cirrhosis, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250 ?g of copper per gram of dried liver tissue confirms Wilson’s disease. Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson’s.

In the earlier stages of the disease, the biopsy typically shows steatosis (deposition of fatty material), increased glycogen in the nucleus, and areas of necrosis (cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory cells, piecemeal necrosis and fibrosis (scar tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis.

Genetic testing
Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counselling

Treatment:
DietaryIn general, a diet low in copper-containing foods is recommended, with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.

Medication
Various treatments are available for Wilson’s disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet.

Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is also observed in other treatments for Wilson’s, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment.  Intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.  A further agent with known activity in Wilson’s disease is tetrathiomolybdate. This is still regarded as experimental,  although some studies have shown a beneficial effect.

Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur, or if the urinary excretion of copper increases.

In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-Lewisite) is still occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks, and has a number of unpleasant side effects such as pain.

People who are asymptomatic (for instance those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.

Physical therapy
Physiotherapy is beneficial for those patients with the neurologic form of the disease. The copper chelating treatment may take up to six months to start working, and physical therapy can assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of contractures that can result from dystonia.

Transplantation
Liver transplantation is an effective cure for Wilson’s disease, but is used only in particular scenarios because of the numerous risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment, or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated
Lifestyle and home remedies:

Doctors sometimes recommend limiting the amount of copper you consume in your diet during the first year of your treatment for Wilson’s disease. As your signs and symptoms recede and the copper levels in your body drop, you may be able to include copper-containing foods in your diet.

Copper-containing foods
Foods that contain high levels of copper include:

*Copper-containing vitamin and mineral supplements
*Liver
*Shellfish
*Mushrooms
*Nuts
*Chocolate
*Dried fruit
*Dried peas, beans and lentils
*Avocados
*Bran products

Copper in tap water
Have your tap water’s copper levels tested if you have copper pipes in your home or if your water comes from a well. Most municipal water systems don’t contain high levels of copper.

If you have copper pipes, run the tap for several seconds before collecting water for drinking or cooking. Water that sits in the copper pipes can pick up copper particles. Running the water flushes that contaminated water out of the pipes.

Copper pots and pans
Don’t use copper pots, pans or storage containers for your food or drinks.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose

Resources:
http://en.wikipedia.org/wiki/Wilson’s_disease
http://www.eurowilson.org/en/living/guide/what/index.phtml
http://www.mayoclinic.com/health/wilsons-disease/DS00411

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Acrodysostosis

Alternative Names  :Arkless-Graham; Acrodysplasia; Maroteaux-Malamut

Definition:
Acrodysostosis is an extremely rare  genetic disorder that is present at birth. It is a rare congenital malformation syndrome which involves shortening of the interphalangeal joints of the hands and feet, mental deficiency in approximately 90% of affected children, and peculiar facies. Other common abnormalities include short head (as measured front to back i.e. [[ ]]), small broad upturned nose with flat nasal bridge, protruding jaw, increased bone age, Intrauterine growth retardation, juvenile arthritis and short stature. Further abnormalities of the skin, genitals, teeth, and skeleton may occur.

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Most reported cases have been sporadic, but it has been suggested that the condition might be genetically related i.e. in a autosomal dominant mode of transmission. Both males and females are affected. The disorder has been associated with older parental age.

Symptoms:
•Growth problems, short arms and legs
•Frequent middle ear infections
•Hearing problems
•Unusual looking face
•Mental deficiency

People with acrodysostosis have certain bones that mature rapidly, before they’ve had enough time to grow fully. The bones most often affected are those of the nose and jaw, and the long tubular bones of the hands and feet.

This abnormal bone development results in a collection of characteristic features, including a typical facial appearance (short nose, open mouth and prominent jaw), small hands and feet.

Those with acrodysostosis often have some degree of mental retardation and learning difficulties.

Causes:
The gene responsible for acrodysostosis has not yet been identified and the condition may result from different genetic problems rather than one specific condition.

Most patients with acrodysostosis have no family history of the disease. However, sometimes the condition is passed down from parent to child.

It appears to be inherited in an autosomal dominant fashion. This means that if one parent is carrying the gene, they will be normal but there is a one in two chance that any child of theirs will have the condition and seems to be more common among older parents.

There is a slightly greater risk with fathers who are older.

Diagnosis:
Exams and Tests
A physical exam confirms this disorder.

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Findings may include:

•Advanced bone age
•Bone deformities in hands and feet
•Delays in growth
•Problems with the skin, genitals, teeth, and skeleton
•Short arms and legs with small hands and feet
•Short head, measured front to back (brachycephaly)
•Short height
•Small, upturned broad nose with flat bridge
•Unusual features of the face (short nose, open mouth, jaw that sticks out)
•Unusual head
•Wide-spaced eyes (hypertelorism), sometimes with extra skin fold at corner of eye
In the first months of life, x-rays may show spotty calcium deposits, called stippling, in bones (especially the nose). Infants may also have:

•Abnormally short fingers and toes (brachydactyly)
•Early growth of bones in the hands and feet
•Short bones
•Shortening of the forearm bones near the wrist

Treatment:
There’s no cure for acrodysostosis but appropriate support by orthopaedic surgeons and paediatricians is important.

Treatment depends on the physical and mental problems that occur.

Antenatal diagnosis may be made by ultrasound examination of the bones in babies whose mother has the condition, but routine screening isn’t done.

Possible Complications:
•Arthritis
•Carpal tunnel syndrome
•Worsening range of movement in the spine, elbows, and hands

Prognosis ;
Problems depend on the degree of skeletal involvement and mental retardation. In general, patients do relatively well.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:
http://www.nlm.nih.gov/medlineplus/ency/article/001248.htm
http://www.bbc.co.uk/health/physical_health/conditions/acrodysostosis1.shtml
http://en.wikipedia.org/wiki/Acrodysostosis

http://www.gfmer.ch/genetic_diseases_v2/gendis_detail_list.php?cat3=1098

http://health.allrefer.com/health/acrodysostosis-info.html

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Achondroplasia

Definition:
Achondroplasia is a genetic (inherited) bone disorder that occurs in one in 25,000 live births. Achondroplasia is the most common type of dwarfism, in which the child’s arms and legs are short in proportion to body length. Further, the head is often large and the trunk is normal size. The average height of adult males with achondroplasia is 52 inches (or 4 feet, 4 inches). The average height of adult females with achondroplasia is 49 inches (or 4 feet, 1 inch).

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When a baby is developing in the womb, the skeleton first forms out of cartilage, which then this develops into bone (except in certain areas such as the nose or ears where cartilage remains).

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In achondroplasia, this process doesn’t happen as it should, especially in the long bones of the arms and legs. Instead, the cartilage cells in the growth plates turn only very slowly into bone.


Symptoms:

The following are the most common symptoms of achondroplasia. However, each child may experience symptoms differently. Symptoms may include:

*shortened arms and legs, with the upper arms and thighs more shortened than the forearms and lower legs

*large head size with prominent forehead and a flattened nasal bridge

*crowded or misaligned teeth

*curved lower spine – a condition also called lordosis (or “sway-back”) which may lead to kyphosis, or the development of a small hump near the shoulders that usually goes away after the child begins walking.

*small vertebral canals (back bones) – may lead to spinal cord compression in adolescence. Occasionally children with achondroplasia may die suddenly in infancy or early childhood in their sleep due to compression of the upper end of the spinal cord, which interferes with breathing.

*bowed lower legs

*flat feet that are short and broad

*extra space between the middle and ring fingers (Also called a trident hand.)

*poor muscle tone and loose joints

*frequent middle ear infections which may lead to hearing loss

*normal intelligence

*delayed developmental milestones such as walking (which may occur between 18 to 24 months instead of around one year of age)

These bone abnormalities can lead to a range of health problems, as well as psychological trauma caused by the stigma of looking different from the crowd. Most children with achondroplasia have normal intelligence.

Babies with achondroplasia may have poor muscle tone and be slow to stand and walk. Spinal problems can develop, and the lower part of the legs may become bowed. There may be dental problems because teeth are often crowded and poorly aligned. Middle ear infections occur frequently and can cause mild to moderate hearing loss.

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Causes:
Achondroplasia is inherited by an autosomal dominant gene that causes abnormal cartilage formation. Autosomal dominant inheritance means that the gene is located on one of the autosomes (chromosome pairs 1 through 22). This means that males and females are equally affected. Dominant means that only one gene is necessary to have the trait. When a parent has a dominant trait, there is a 50 percent chance that any child they have will also inherit the trait. So, in some cases, the child inherits the achondroplasia from a parent with achondroplasia. The majority of achondroplasia cases (80 percent), however, are the result of a new mutation in the family – the parents are of average height and do not have the abnormal gene.

As mentioned, persons with achondroplasia have a 50 percent chance to pass the gene to a child, resulting in the condition. If both parents have achondroplasia, with each pregnancy, there is a 50 percent chance to have a child with achondroplasia, a 25 percent chance that the child will not inherit the gene and be of average height, and a 25 percent chance that the child will inherit one abnormal gene from each parent, which can lead to severe skeletal problems that often result in early death.

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Geneticists have found that fathers who are older than 45 have a higher chance of having children with certain autosomal dominant conditions such as achondroplasia, but no cause for the new mutations in sperm has been discovered at this time.

The gene responsible for achondroplasia was discovered in 1994 making accurate prenatal diagnosis available, in most cases.

There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia.

In approximately 75 per cent of cases the problem results from a new mutation of a gene (that is, neither parent carries the faulty gene), but in some cases a child inherits achondroplasia from a parent who also has the condition. There is also a link with older fathers, over the age of 40.

Diagnosis:

Achondroplasia can be diagnosed before birth by fetal ultrasound or after birth by complete medical history and physical examination. DNA testing is now available before birth to confirm fetal ultrasound findings for parents who are at increased risk for having a child with achondroplasia.A DNA test can be performed before birth to detect homozygosity, wherein two copies of the mutant gene are inherited, a lethal condition leading to stillbirths.
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Radiologic findings:
A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow foramen magnum, and relatively small skull base. The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. The iliac wings are small and squared,[4] with a narrow sciatic notch and horizontal acetabular roof. The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates. Fibular overgrowth is present. The hand is broad with short metacarpals and phalanges, and a trident configuration. The ribs are short with cupped anterior ends. If the radiographic features are not classic, a search for a different diagnosis should be entertained. Because of the extremely deformed bone structure, people with achondroplasia are often double jointed.

The diagnosis can be made by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended.

Another distinct characteristic of the syndrome is thoracolumbar gibbus in infancy.


Treatment :

Currently, there is no way to prevent or treat achondroplasia, since the majority of cases result from unexpected new mutations. Treatment with growth hormone does not substantially affect the height of an individual with achondroplasia. Leg-lengthening surgeries may be considered in some very specialized cases.

Detection of bone abnormalities, particularly in the back, are important to prevent breathing difficulties and leg pain or loss of function. Kyphosis (or hunch-back) may need to be surgically corrected if it does not disappear when the child begins walking. Surgery may also help bowing of the legs. Ear infections need to be treated immediately to avoid the risk of hearing loss. Dental problems may need to be addressed by an orthodontist (dentist with special training in the alignment of teeth).

There is research into the family of genes called fibroblast growth factors, in which the gene that causes achondroplasia is included. The goal is to understand how the faulty gene causes the features seen in achondroplasia, in order to lead to improved treatment. These genes have been linked to many heritable skeletal disorders.

However, if desired, the controversial surgery of limb-lengthening will lengthen the legs and arms of someone with achondroplasia.

Usually, the best results appear within the first and second year of therapy.  After the second year of GH therapy, beneficial bone growth decreases. Therefore, GH therapy is not a satisfactory long term treatment.

Prognosis:
People with achondroplasia seldom reach 5 feet in height. Intelligence is in the normal range. Infants who receives the abnormal gene from both parents do not often live beyond a few months.

Complications:
* Clubbed feet
* Fluid build up in the brain (hydrocephalus)

Epidemiology:

Achondroplasia and is one of several congenital conditions with similar presentations, such as osteogenesis imperfecta, multiple epiphyseal dysplasia tarda, achondrogenesis, osteopetrosis, and thanatophoric dysplasia. This makes estimates of prevalence difficult, with changing and subjective diagnostic criteria over time. One detailed and long-running study in the Netherlands found that the prevalence determined at birth was only 1.3 per 100,000 live births.  However, another study at the same time found a rate of 1 per 10,000.


Prevention:

Genetic counseling may be helpful for prospective parents when one or both have achondroplasia. However, because achondroplasia most often develops spontaneously, prevention is not always possible.

* Reviewed last on: 11/2/2009
* Neil K. Kaneshiro, MD, MHA, Clinical Assistant Professor of Pediatrics, University of Washington School of Medicine. Also reviewed by David Zieve, MD, MHA, Medical Director, A.D.A.M., Inc.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose.

Resources:
http://www.yalemedicalgroup.org/stw/Page.asp?PageID=STW026342
http://en.wikipedia.org/wiki/Achondroplasia
http://www.bbc.co.uk/health/physical_health/conditions/achondroplasia1.shtml
http://www.umm.edu/ency/article/001577all.htm

http://wikis.lib.ncsu.edu/index.php/Group_6_HYALOS_(hyaline_cartilage)

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