Achondroplasia

Achondroplasia is the most common skeletal dysplasia. Although the exact incidence is not known estimates range from 1 in 15,000 to 1 in 26,000 births. The name literally means failure or lack of cartilage formation. This is not strictly true as cartilage formation does occur in the growth plates of patients with achondroplasia.

 
How Achondroplasia Is Inherited
A child with achondroplasia stands next to his brother.

Achondroplasia is inherited in an autosomal dominant manner, but about 75% of patients with achondroplasia represent new mutations. These new mutations typically arise from the father during sperm formation. Paternal age greater than 35 years has been found to be a risk factor (3,4).

 
Causes of Achondroplasia

Achondroplasia is caused by a mutation in the fibroblast growth factor receptor-3 (FGFR-3) gene (3). Mutations which change the amino acid glycine to arginine at position 380 of the FGFR-3 protein account for >97% of all reported cases of achondroplasia. Normally the FGFR-3 protein functions as "brake" for endochondral bone growth. This typical G380R mutation actually increases the ability of the FGFR-3 protein to slow bone growth and causes the features of achondroplasia. This type of change associated with an increased ability is termed a "gain-of-function" mutation (4).

 
Physical Characteristics

Achondroplasia causes disproportionate short stature. Specifically the limbs are disporportionately small when compared to the trunk. Within the limbs the proximal segment is shorter causing rhizomelia. The average adult height is 52" in men and 49" in women with achondroplasia. Achondroplasts have average intelligence and can lead very rich and productive lives.

Face & Skull:
  • The head circumference may be larger than average.
  • The forehead tends to be prominent. This is termed frontal bossing.
  • The nasal bridge tends to be depressed and the nostrils are upturned.
  • The mid-face is underdeveloped, which is termed maxillary hypoplasia.
  • The foramen magnum, which is the opening in the skull base through which the spinal cord passes, is smaller then average.
An infant with achondroplasia.
Trunk, Chest, & Spine:
  • Thoraco-lumbar kyphosis (TLK) is present in most infants with achondroplasia and is a normal finding. It can be seen represented in the drawing on the right as the prominence in the lower back(5).
  • The TLK is replaced in later childhood by lumbar lordosis or sway back.
  • TLK is thought to be caused by the large head size and poor muscular tone in children who are not yet walking. It improves without treatment in 90% of affected children as they begin to walk.
  • The chest usually is broad and flat. The abdomen and buttocks
    are prominent.
  • The spinal canal is smaller than average in achondroplasia.
An infant with achondroplasia.
Arms & Legs:
  • There is marked ligamentous laxity or loose joints.
  • Despite the loose joints, typically the elbows cannot be fully extended. Less commonly the elbow joint may be out of place. This rarely causes symptoms or loss of function.
  • In infancy and early childhood there is extra space between the 3rd and 4th fingers. This is termed trident hand and disappears spontaneously in later childhood. The drawing below demonstrates the trident (5).
  • The fingers are short and broad giving rise to a stubby appearance.
An x-ray showing the characteristics of achondroplasia.
What are the x-ray characteristics?

Long bones are relatively plump and short. Proximal humerus and femur in infancy have distinctive rectangular or translucent ovals that change by 2 years. Fibulas tend to be longer than tibias.

Spacing between vertebral pedicles decreases rather than increases in the lumbar spine as you move from head to pelvis.

The pelvis is short and broad with wide, non-flaring iliac wings.

 
Making the Diagnosis

For parents of average stature, achondroplasia is sometimes detected by the presence of short limbs on routine prenatal ultrasound performed after 22 weeks. In this situation, the diagnosis can then be confirmed by molecular genetic testing techniques using fetal DNA obtained through amniocentesis. Cesarean section is recommended to deliver babies with achondroplasia, due to their large head size and risk of compression of the brain during the course of a vaginal delivery.

For parents who have achondroplasia or average-statured parents with a previously born child with achondroplasia, amniocentesis or chorionic villus sampling (CVS) can be performed. Using cells obtained by these techniques, DNA testing can then be performed and used to identify homozygous/ heterozygous achondroplasia in the pregnancy.

Most neonates with achondroplasia have average lengths and weights at birth. It is our belief that as many as 15% of children with achondroplasia are not recognized at birth.

In the neonate, infant, older child or adult, the diagnosis of achondroplasia can be made by an experienced physician (usually a clinical geneticist) on the basis of physical and radiologic examinations.

Sequencing of the FGFR-3 gene can be done in all patients, but is only required in unusual cases or cases of doubt.

 
Associated Medical Problems
An x-ray shows an achondroplasia patient’s foramen magnum.

Foramen magnum stenosis: As mentioned above, essentially all children with achondroplasia have a smaller than average foramen magnum. The foramen magnum is the opening through which the spinal cord leads the head to travel down the spinal column. For the vast majority of children this does not present a problem. There are, however approximately 5% or fewer of children with achondroplasia in whom this opening is so small that there is not adequate room for the spinal cord to function properly. These children have what is termed cord compression or compressive myelopathy. This is a very serious medical problem and requires surgical correction. Cord compression due to foramen magnum stenosis has been implicated as the cause of sudden death in a very small proportion of infants with achondroplasia. As with all surgeries performed on Little People, we suggest that care be taken to assure that the physician has experience not only with the procedure, but also performing the procedure on Little People.

Hydrocephalus: Enlargement of head circumference occurs invariably in achondroplasia but does not require treatment unless pressure within the skull (intracranial pressure) increases and interferes with brain function. Standard charts for normal head circumference throughout childhood in achondroplasia are available. If there is any deviation from average, an opinion should be obtained from a neurosurgeon regarding the need for a ventriculo-peritoneal shunt (a tube that drains excess fluid from the brain into the abdominal cavity).

Sleep apneas or Sleep-disordered breathing - 2 types: Sleep disordered breathing is common in achondroplasia with studies demonstrating a very wide range of affected children ranging from 22% - 85%. As many as 20% of children could be severely affected (6). There are 2 types of apneas or disordered breathing and they will be discussed separately.

  • Obstructive apnea - results from the blockage of airflow into and out of the lungs with normal respiratory drive. This is the most common type of apnea in achondroplasia because of the mid-face hypoplasia and hypotonia of the pharyngeal muscles. The end result is a "smaller pipe" for the air to travel through. Many children with achondroplasia adopt an open mouth habitus with the tongue resting on the lower lip to create maximum airway space. This commonly manifests as snoring and causes disturbed sleep. Symptoms can include tiredness, irritability, daytime sleeping, etc.Treatment for obstructive apnea can include weight reduction measures, adenoidectomy-tonsillectomy, continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BiPAP) at night by nasal mask to keep the airways open. A tracheostomy may be necessary in the most severe cases.
  • Central apnea - results from failure of the respiratory centers in the brain to properly control the process of breathing. In the brainstem, the respiratory centers are in close proximity to the foramen magnum. Therefore, if the foramen magnum is compressing the spinal cord central apnea can result.
 
Musculoskeletal Problems
An x-ray of the legs of a child with achondroplasia.

Genu Varum is more common than genu valgus in achondroplasia. Knock-knees do not need treatment because they do not progress. Bowlegs however can result in symptoms around the knee such as pain and restricted walking ability. Pain around the knee due to bowing should be distinguished from knee pain due to spinal stenosis. A child with achondroplasia and genu varum with associated x-rays is shown below.

Some experts believed that relative overgrowth of the fibula compared to the tibia causes the knee to bend inwards. Therefore, surgery in the past relied on stopping growth in the fibula (epiphyseodesis) or removing a portion of the fibula.

A more recent analysis of this problem has shown that the bend occurs in the lower part of the femur and the upper part of the tibia. In addition, the tibia is twisted along its axis (internal tibial torsion). A few questions need to be answered through long-term studies before treatment can be advocated for genu varum.

  • Does genu varum in achondroplasia affect long-term function?
  • Does it pose an increased risk for knee arthritis in future?
  • How does surgical correction influence natural history?

We are still in the process of addressing these issues and definite answers may not be available immediately. Symptomatic knee arthritis is not a frequent problem in adults with achondroplasia and this is perhaps a reassuring fact for parents. The current recommendation is to undergo surgery only in the presence of bothersome symptoms or if there is severe deformity. Bracing is not advocated because it is difficult to exert enough corrective forces on the bones in the presence of ligamentous laxity.

Spinal stenosis in the lumbar spine is very common in young adults with achondroplasia, though it can occur at any age. The narrow spinal canal found in achondroplasia and the normal size of the spinal cord and cauda equina (nerve bundle at the base of the spine) mean that there is less room for the spinal cord in the achondroplastic spine. In some patients, this narrowing of the vertebral canal results in compression of the nerves. Symptoms include activity-related leg pain that is relieved on squatting down, tingling, pins and needles, or numbness in the feet (paraesthesias), weakness of the legs or rarely, disturbances in control of bladder or bowel function (incontinence). X-rays, CT and MRI scans of the lower spine, confirm the diagnosis. We believe that obesity greatly increases the risk of this problem developing.

A newborn with muskoskeletal problems due to achondroplasia.

Fixed TLK: As mentioned above, most infants with achondroplasia have a TLK and this is normal. In the vast majority of patients, as the child begins to walk, the TLK will spontaneously resolve without treatment. In some children however, the TLK will become fixed or permanent. Prolonged unsupported sitting likely predisposes this to occur. Bracing can be done to treat this problem and, if severe enough, surgery may be required. Typically, when a child is laid on their belly, the thoraco-lumbar region will flatten and indicate that the TLK is flexible. When, however a child is placed face down and a hump in the spine is seen, as pictured below, the TLK is said to be fixed and treatment will be required (5).

 
Problems Elsewhere in the Body
Obesity

Obesity is a common problem in children and adults of all statures, but especially with achondroplasia. Continuous monitoring for obesity is the first step in maintaining an ideal body weight. The problem is compounded if the weight and height charts which were prepared for average-statured children are used for children with achondroplasia. A weight-for-height chart is available specifically for children with achondroplasia and is a useful guide for weight management. Attention to weight issues in childhood is very important as we believe that obesity will significantly increase the risk for spinal problems in young adults or adults with achondroplasia. Equally important to dietary management is attention to physical activities and appropriate exercise.

Pregnancy

Females with achondroplasia may require a cesarean section for delivery due to the reduced size and shape of the pelvis.

ENT

The mid-face is underdeveloped in achondroplasia. This causes several problems in the ear, nose and throat region.

This hypoplasia can lead to overcrowding of the teeth and malocclusion. These problems may also contribute to articulation/speech defects. Sometimes children may have tongue thrust which affects speech clarity.

The Eustachian tube is a normal connection between the middle ear and the upper throat. In achondroplasia, the anatomy of this tube is distorted and persistent fluid in the middle ear can occur. Over the long term, this leads to conductive hearing loss. Hearing should be checked frequently during the growing years. Deafness can also result from poorly formed middle ear bones or due to compression of the brain stem at the foramen magnum. Ear infections are easily treated, and the use of middle ear tubes is common. Because of anatomical differences, we suggest that care be taken to assure that the physician has experience not only with the procedure, but also performing the procedure on Little People.

 
What to Watch For

Given the differences in head size relative to body size in achondroplasia and average children, it is inappropriate to use the average developmental charts to assess an a child with achondroplasia. There are developmental charts for children with achondroplasia and it is critical that these be used.

We often see children with poor head control at several months of age be referred for physical therapy because this is expected for an average-sized child. This should not be done. Infants with achondroplasia receiving physical therapy will not develop head or trunk control at a more rapid rate. Furthermore, the typical exercises done greatly increase the risk for cord compression related to foramen magnum stenosis.

Extreme care should be taken in the position and handling of infants so as to minimize the occurrence of sudden abnormal head and neck motion. The avoidance of soft swings, umbrella strollers and jumpers is recommended. No backpack carriers or front-pack carriers should be used until the child gains complete and total head control.

Properly installed rear-facing car seats with neck support when traveling in a car are important safety measures. This practice should be continued until the child is 20 pounds regardless of age.

Head size should be monitored carefully at least every three months and at most most, monthly in the first few years of life.

We believe that the parents should become comfortable with feeling the anterior fontanelle or soft spot located on top of the infants skull. The fontanelle should be soft and flat. If the fontanelle becomes hard (like a table top) or bulging when the child is at rest, then this should be brought to immediate medical attention.

Diminishing motor milestones, decreased endurance, apnea or any neurological symptoms should be quickly evaluated by an experienced physician.

Speech delay may indicate underlying conductive hearing loss.

Sleep disturbance may indicate cord compression or obstructive sleep apnea and should be brought to an experienced physicians attention immediately.

 
References
  1. Smith's Recognizable Patterns of Human Malformation. Ed. Jones KL. 6th edition. Elsevier Saunders. 2005.
  2. Hunter AG, Bankier A, Rogers JG, Sillence D, Scott CI Jr. Medical complications of achondroplasia: a multicentre patient review. J Med Genet. 1998 Sep;35(9):705-12.
  3. Trotter TL, Hall JG; American Academy of Pediatrics Committee on Genetics. Health supervision for children with achondroplasia. Pediatrics. 2005 Sep;116(3):771-83.
  4. Wilkin DJ, Szabo JK, Cameron R, Henderson S, Bellus GA, Mack ML, Kaitila I, Loughlin J, Munnich A, Sykes B, Bonaventure J, Francomano CA. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome. Am J Hum Genet. 1998 Sep;63(3):711-6.
  5. Scott, Charles I. Dwarfism. CIBA Clinical Symposia, 1988. All drawings were done by Dr. Frank Netter and are used with permission from Novartis AG.
  6. Mogayzel PJ Jr, Carroll JL, Loughlin GM, Hurko O, Francomano CA, Marcus CL. Sleep-disordered breathing in children with achondroplasia. J Pediatr. 1998 Apr;132(4):667-71.

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All About Genetics

What do you know about your family tree? Have any of your relatives had health problems that tend to run in families? Which of these problems affected your parents or grandparents? Which ones affect you or your brothers or sisters now? Which problems might you pass on to your children?

Thanks to advances in medical research, doctors now have the tools to understand much about how certain illnesses, or increased risks for certain illnesses, pass from generation to generation. Here are some basics about genetics.

Genes and Chromosomes

Each of us has a unique set of chemical blueprints affecting how our body looks and functions. These blueprints are contained in our DNA (deoxyribonucleic acid), long, spiral-shaped molecules found inside every cell. DNA carries the codes for genetic information and is made of linked subunits called nucleotides. Each nucleotide contains a phosphate molecule, a sugar molecule (deoxyribose), and one of four so-called "coding" molecules called bases (adenine, guanine, cytosine, or thymidine). The sequence of these four bases determines each genetic code.

The segments of DNA that contain the instructions for making specific body proteins are called genes. Scientists believe that human DNA carries about 25,000 protein-coding genes. Each gene may be thought of as a "recipe" you'd find in cookbook. Some are recipes for creating physical features, like brown eyes or curly hair. Others are recipes to tell the body how to produce important chemicals called enzymes (which help control the chemical reactions in the body).

Along the segments of our DNA, genes are neatly packaged within structures called chromosomes. Every human cell contains 46 chromosomes, arranged as 23 pairs (called autosomes), with one member of each pair inherited from each parent at the time of conception. After conception, the chromosomes duplicate again and again to pass on the same genetic information to each new cell in the developing child. Twenty-two autosomes are the same in males and females. In addition, females have two X chromosomes and males have one X and one Y chromosome. The X and the Y are known as sex chromosomes.

Human chromosomes are large enough to be seen with a high-powered microscope, and the 23 pairs can be identified according to differences in their size, shape, and the way they pick up special laboratory dyes.

Genetic Problems

Errors to the genetic code or "gene recipe" can happen in a variety of ways. Sometimes information is missing from the code, other times codes have too much information, or have information that's in the wrong order.

These errors can be big (for example, if a recipe is missing many ingredients — or all of them) or small (if just one ingredient is missing). But regardless of whether the error is big or small, the outcome can be significant and cause a person to have a disability or at risk of a shortened life span.

Abnormal Numbers of Chromosomes

When a mistake occurs during cell division, it can cause an error in the number of chromosomes a person has. The developing embryo then grows from cells that have either too many chromosomes or not enough.

In trisomy, for example, there are three copies of one particular chromosome instead of the normal two (one from each parent). Trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), and trisomy 13 (Patau syndrome) are examples of this type of genetic problem.

Trisomy 18 affects 1 out of every 7,500 births. Children with this syndrome have a low birth weight and a small head, mouth, and jaw. Their hands typically form clenched fists with fingers that overlap. They also might have malformations involving the hips and feet, heart and kidney problems, and intellectual disability (also called mental retardation). Only about 5% of these children are expected to live longer than 1 year.

Trisomy 13 affects 1 out of every 15,000 to 25,000 births. Children with this condition often have cleft lip and palate, extra fingers or toes, foot abnormalities, and many different structural abnormalities of the skull and face. This condition also can cause malformations of the ribs, heart, abdominal organs, and sex organs. Long-term survival is unlikely but possible.

In monosomy, another form of numerical error, one member of a chromosome pair is missing. So there are too few chromosomes rather than too many. A baby with a missing autosome has little chance of survival. However, a baby with a missing sex chromosome can survive in certain cases. For example, girls with Turner syndrome — who are born with just one X chromosome — can live normal, productive lives as long as they receive medical care for any health problems associated with their condition.

Deletions, Translocations, and Inversions

Sometimes it's not the number of chromosomes that's the problem, but that the chromosomes have something wrong with them, like an extra or missing part. When a part is missing, it's called a deletion (if it's visible under a microscope) and a microdeletion (if it's not visible). Microdeletions are so small that they may involve only a few genes on a chromosome.

Some genetic disorders caused by deletions and microdeletions include Wolf-Hirschhorn syndrome (affects chromosome 4), Cri-du-chat syndrome (chromosome 5), DiGeorge syndrome (chromosome 22), and Williams syndrome (chromosome 7).

In translocations (which affect about 1 in every 400 newborns), bits of chromosomes shift from one chromosome to another. Most translocations are "balanced," which means there is no gain or loss of genetic material. But some are "unbalanced," which means there may be too much genetic material in some places and not enough in others. With inversions (which affect about 1 in every 100 newborns), small parts of the DNA code seem to be snipped out, flipped over, and reinserted. Translocations may be either inherited from a parent or happen spontaneously in a child's own chromosomes.

Both balanced translocations and inversions typically cause no malformations or developmental problems in the kids who have them. However, those with either translocations or inversions who wish to become parents may have an increased risk of miscarriage or chromosome abnormalities in their own children. Unbalanced translocations or inversions are associated with developmental and/or physical abnormalities.

Sex Chromosomes

Genetic problems also occur when abnormalities affect the sex chromosomes. Normally, a child will be a male if he inherits one X chromosome from his mother and one Y chromosome from his father. A child will be a female if she inherits a double dose of X (one from each parent) and no Y.

Sometimes, however, children are born with only one sex chromosome (usually a single X) or with an extra X or Y. Girls with Turner syndrome are born with only one X chromosome, whereas boys with Klinefelter syndrome are born with 1 or more extra X chromosomes ( XXY or XXXY).

Sometimes, too, a genetic problem is X-linked, meaning that it is associated with an abnormality carried on the X chromosome. Fragile X syndrome, which causes intellectual disability in boys, is one such disorder. Other diseases that are caused by abnormalities on the X chromosome include hemophilia and Duchenne muscular dystrophy.

Females may be carriers of these diseases, but because they also inherit a normal X chromosome, the effects of the gene change on the affected X is minimized. Males, on the other hand, only have one X chromosome and are almost always the ones who have the substantial effects of the X-linked disorder.

Gene Mutations

Some genetic problems are caused by a single gene that is present but altered in some way. Such changes in genes are called mutations. When there is a mutation in a gene, the number and appearance of the chromosomes is usually still normal.

To pinpoint the defective gene, scientists use sophisticated DNA screening techniques. Genetic illnesses caused by a single problem gene include phenylketonuria (PKU), cystic fibrosis, sickle cell disease, Tay-Sachs disease, and achondroplasia (a type of dwarfism).

Although experts used to think that no more than 3% of all human diseases were caused by errors in a single gene, new research shows that this is an underestimate. Within the last few years, scientists have discovered genetic links to many different diseases that weren't originally thought of as genetic, including Parkinson's disease, Alzheimer's disease, heart disease, diabetes, and several different types of cancer. Alterations in these genes are thought to increase one's risk of developing these conditions.

Oncogenes (Cancer-Causing Genes)

Researchers have identified about 50 cancer-causing genes that greatly increase a person's odds of developing cancer. By using sophisticated screening tools, doctors may be able to identify who has these genetic mutations, and determine who is at risk.

For example, scientists have determined that colorectal cancer is sometimes associated with mutations in a gene called APC. They've also discovered that abnormalities in the BRCA1 and BRCA2 gene give women a 50% chance of developing breast cancer and an increased risk for ovarian tumors.

People who are known to have these gene mutations now can be carefully monitored by their doctors. If problems develop, they're more likely to get treated for cancer earlier than if they hadn't known of their risk, and this can increase their odds of survival.

New Discoveries, Better Care

Scientists have made major strides in the field of genetics over the last two decades. The mapping of the human genome and the discovery of many disease-causing genes has led to a better understanding of the human body, enabling doctors to provide better care to their patients and increasing the quality of life for people (and their families) living with genetic conditions.

Reviewed by: Nina Powell-Hamilton, MD
Date reviewed: April 2013