Achondroplasia

 What is achondroplasia?

      In the early stages of development, much of the fetal skeleton is made up of cartilage tissue, which turns into bone. Achondroplasia occurs when cartilage tissue doesn't develop in the bones of your arms and legs. This genetic disorder leads to short-limb dwarfism with the upper parts of arms and legs shorter than the lower portions of those limbs (rhizomelic shortening).

    Causes:

      Achondroplasia is caused by a gene mutation in the receptor that converts cartilage to bone during fetal development.

1. Inherited as an autosomal dominant trait 
2. Father's age is more than 45

Features of Achondroplasia 

 Symptoms of Achondroplasia:

• Bones are shortened (thigh, upper arm).
• Short hands and feet.
• Large separation between third and fourth fingers.
• Maximum height of 4-ft.
• Head larger than normal.
• Prominent forehead.
• Flat nose.
• Delayed development in infants (sitting, crawling, walking).
• Curved lower spine -leading to a hump over the back
• Bowed lower legs
• Normal intelligence
• Poor muscle tone and lose joints
• Crowed or misaligned teeth

 How it affects a child?

         Infants born with achondroplasia normally have weak muscle tone (hypotonia), which could delay motor skill development. There’s is also a high risk of spinal cord compression and upper respiratory blockages among infants, which increases the risk of health complications.

        It is common for people with achondroplasia to have breathing problems, recurrent ear infections and be prone to obesity.

   All children with achondroplasia should be carefully monitored regularly by a healthcare provider to treat or prevent any symptoms that may arise.

 Long term achondroplasia leads to 

• Breathing problems (apnea).
• Obesity
• Recurring ear infection
• Curved spine.
• Bowed legs.
• Excess fluid on your brain (hydrocephalus).
• Obstructive sleep apnea.
• Back pain

Hydrocephalus and sleep apnea

Diagnosis :

     Your child with achondroplasia while you’re pregnant or after your infant is born.

   Diagnosis during pregnancy

       Some characteristics of achondroplasia are detectable during an ultrasound. These include hydrocephalus, or an abnormally large head. If your doctor suspects achondroplasia, genetic tests may be ordered. These tests look for the defective FGFR3 gene in a sample of amniotic fluid, which is the fluid that surrounds the fetus in the womb.

   Diagnosis after your child is born:

           Your doctor can diagnose your child by looking at his or her features. The doctor may also order X-rays to measure the length of your infant’s bones. This can help confirm a diagnosis. Blood tests may also be ordered to look for the defective FGFR3 gene.

What does FGFR3 role in achondroplasia ?

      Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation.

    Achondroplasia (MIM 100800) is the most common form of dwarfism in humans. The disorder is inherited in an autosomal dominant manner, with full penetrance. Two mutations,(G1138A and G1138C) in exon 10 of the FGFR3 gene result in a specific amino acid substitution (G380R).

FGFR3 location :  FGFR3, a tyrosine kinase receptor gene, is located at chromosome 4p16.3 and is composed of 19 exons . The extracellular portion can bind with fibroblast growth factors, initiating cascades of downstream signals that ultimately influence cell growth, migration, angiogenesis, and differentiation.

Full form of FGFR3 :

     Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333 (cluster of differentiation 333).

Treatment of Achondroplasia 

Spinal fusion:

       Some people with achondroplasia develop curvature of the spine. Not all cases of spinal curvature produce symptoms, and not all cases require treatment.

      Spinal fusion is a surgical intervention that involves fusing several vertebrae in the spine. The procedure helps reduce excessive curvature and may help stabilize the spine.

      There are two main reasons that someone with achondroplasia may require spinal fusion:

      Treating lumbar spinal stenosis (LSS):   Some people with achondroplasia may develop LSS, which is a narrowing of the canal that the spinal cord goes through. In people with achondroplasia, LSS is the most common cause of disability in later life.

Treating thoracolumbar kyphosis (TLK):  Some people with achondroplasia may develop TLK, which refers to curvature of the upper spine. Doctors tend to recommend spinal fusion only for extreme cases of TLK, wherein braces and other therapeutic techniques have not worked.

Spinal fusion can cause complications. For example, this surgery can cause  serious short- and long-term pain, both around the spine and in other parts of the body.

Guided growth procedure:

We use a metal plate and screws covering the growth plate to briefly or permanently tether the area. A plate is placed on both sides of the bone to prevent it from growing further. By using guided growth, if the outcome your child needs is reached after months or years, the plate can be removed, and growth often resumes.

Guided growth with a plate can be used for other corrections, such as helping a crooked bone become straight. In this way, a plate and screws are placed on the convex side, restricting it while the concave side grows. With time, the bone straightens.

Timing:

Your health care provider can help you and your child make the decision about when the time is right. Surgeons usually aim to do surgery a year or two before the end of growth. That reduces the risk of overcorrection and, if timed right, growing is complete and the hardware doesn’t need to be removed.

Surgery:

The surgery is generally outpatient, but some may require an overnight stay. The incision is about 1 ½ inches, and surgery takes about 20 minutes for each plate.

Follow-Up:

Your doctor will work with you on the follow-up treatment plan. Usually there are no limitations after surgery. It is moderately painful, since it is right over a joint. Some can kids return to sports within a week; others need weeks of physical therapy to return to normal walking.

We will plan for your child to be inactive for about two weeks, but you should know it could be less or more. The most common location for the surgery is at the knee. A neoprene knee sleeve can maintain gentle compression after the surgery to help with swelling and pain.

Osteotomy:

Osteotomy is the surgical cutting of a bone, to allow for re-alignment. It is a surgical procedure which requires careful planning during recovery period and is done under a general anaesthetic.

Procedure:

     After anesthesia is administered, which may be regional, or general, the surgical team sterilizes the part with antibacterial solution.
      Surgeons map out the exact size of the bone wedge they will remove, either using an X-ray, CT scan, or 3D computer modeling. The surgeon removes a wedge of bone located near the damaged joint. The procedure is supposed to cause a shift of weight from the area where there is cartilage damage to an area where there is more normal or healthy cartilage.The approach is different for different joints.

Ultimately, the procedure allows weight to be distributed more evenly across the joint cartilage. Osteotomy surgically repositions the joint, realigning the mechanical axis away from the damaged cartilage. Once the wedge of bone is removed, the surgeon brings the bones that remain together and uses pins or staples to secure them. An immobilization cast or internal plates may also be used for stability.

Spine osteotomy:

       Spine osteotomies can be broadly divided into three main types. The type of osteotomy used depends on both the location of the spinal deformity and on the amount of correction that is required. A spinal fusion with instrumentation may also be performed along with spine osteotomy to stabilize the spine and prevent further curvature. 

The three main types of osteotomy are:

   Smith-Petersen Osteotomy (SPO): SPO is recommended in patients in whom a relatively small amount of correction (approximately 10-20° for each level) is required. In this procedure, a section of bone is removed from the back of the spine causing the spine to lean more toward the back. The posterior ligament and facet joints are also removed from this area. Anterior bone graft is not used in this procedure as motion through the anterior portion of the spine or the discs is required for correction. SPO may be performed at one or multiple locations along the spine to restore lordosis.

Pedicle Subtraction Osteotomy (PSO): PSO is recommended generally in patients in whom a correction of approximately 30° is required mainly at the lumbar level. PSO involves all three posterior, middle, and anterior columns of the spine. It involves the removal of posterior element and facet joints similar to a SPO and also removal of a portion of the vertebral body along with the pedicles. PSO allows for more correction of the lordosis than SPO.

Vertebral Column Resection Osteotomy (VCR): VCR involves the complete removal of a single or multiple vertebral bodies. It allows for maximum correction that can be achieved with any spinal osteotomy. As VCR introduces a large defect in the spine, spinal fusion is also performed over these levels for reconstruction. Spinal fusion may involve the use of a structural autograft, structural allograft or metal cage. Initially, VCR was performed through a combined anterior and posterior approach but now it can also be performed through only a posterior approach.

Knee osteotomy

Knee osteotomy is commonly used to realign your knee structure if you have arthritic damage on only one side of your knee. The goal is to shift your body weight off the damaged area to the other side of your knee, where the cartilage is still healthy. When surgeons remove a wedge of your shinbone from underneath the healthy side of your knee, the shinbone and thighbone can bend away from the damaged cartilage.

Hip osteotomy :

      It is mainly of 2 types:

1.INNOMINATE OSTEOTOMIES: Osteotomy of the innominate/iliac bone. The following are some of the innominate osteotomies.

Salter's osteotomy: this is an osteotomy of the iliac bone, above the acetabulum. The roof of the acetabulum is rotated with the fulcrum at the pubic symphysis, so that the acetabulum becomes more horizontal, and thus covers the head.

Chiari's pelvic displacement osteotomy: The iliac bone is divided almost tranversely immediately above the acetabulum, and the lower fragment is displaced medially. The margin of the upper fragment provides additional depth to the acetabulum.

Pemberton's pericapsular osteotomy: A curved osteotomy is made and the roof of the acetabulum is deflected downwards over the femoral head, with the fulcrum at the triradiate cartilage of the acetabulum.

2. FEMORAL OSTEOTOMIES: Osteotomy of the femur bone.

Latest treatment for Achondroplasia:

      Today, the U.S. Food and Drug Administration approved Voxzogo (vosoritide) injection to improve growth in children five years of age and older with achondroplasia and open epiphyses (growth plates), meaning these children still have the potential to grow. Achondroplasia is the most common form of dwarfism. 

       “Today’s approval fulfills an unmet medical need for more than 10,000 children in the United States and underscores the FDA’s commitment to help make new therapies available for rare diseases,” said Theresa Kehoe, M.D., director of the Division of General Endocrinology in the FDA’s Center for Drug Evaluation and Research. “With this action, children with short stature due to achondroplasia have a treatment option that targets the underlying cause of their short stature.” 

      Voxzogo’s safety and efficacy in improving growth were evaluated in a year-long, double-blind, placebo-controlled, phase 3 study in participants five years and older with achondroplasia who have open epiphyses. In the study, 121 participants were randomly assigned to receive either Voxzogo injections under the skin or a placebo. Researchers measured the participants’ annualized growth velocity, or rate of height growth, at the end of the year. Participants who received Voxzogo grew an average 1.57 centimeters taller compared to those who received a placebo. 

         The most common side effects of Voxzogo include injection site reactions, vomiting and decreased blood pressure. Voxzogo’s labeling also lists decreased blood pressure as a warning and precaution, which means it is a potentially serious side effect.

         The FDA approved Voxzogo under the accelerated approval pathway, which allows for earlier approval of drugs that treat serious conditions and fill an unmet medical need, based on a surrogate or intermediate clinical endpoint. A condition of this accelerated approval is a post-marketing study that will assess final adult height. This application also received priority, review designation.

      The FDA granted the approval of Voxzogo to BioMarin.