Metatropic Dysplasia

The word “Metatropic” is derived from the Greek word “Metatropos”, meaning "changing form." Clinically, this dysplasia is one that progresses over time. Metatropic dysplasia is a rare disorder. Because it is so uncommon, the exact incidence is not known.

 
How Metatropic Dysplasia Is Inherited

Metatropic dysplasia has an autosomal dominant inheritance.
This means that those with metatropic dysplasia have a 50/50 chance of passing this condition on to their children, either males or females. Metatropic dysplasia can also happen for the first time in a child; in cases when both parents are of typical stature, the chance to have another child with metatropic dysplasia is low (2-3%).

 
Causes of Metatropic Dysplasia

A change in a gene called TRPV4.

 
Physical Characteristics

Initially, individuals have shortened limbs with a relatively average-sized trunk (short-limbed dwarfism). As the child gets older and the condition progresses, kyphoscoliosis of the spine develops that decreases trunk height (short-trunk dwarfism). Apparent shortening of the limbs also occurs over time, due to progressive joint contractures.

Face & Skull
Trunk, Chest, & Spine:
  • Small and narrow chest
  • Pectus carinatum (chestbone sticking out more than average) or pectus excavatum (depressed breast bone)
  • Severe kyphoscoliosis
  • In infancy, “coccygeal tail” can be apparent, which is a prolongation of the normal tailbone consisting of cartilage material
Arms & Legs:
  • Signficantly shortened limbs with a characteristic dumbbell shape bone
  • Enlarged joints
  • Progressive joint contractures during childhood
What are the X-ray characteristics?

The radiographic features of Metatropic Dysplasia include small, flat, diamond-shaped vertebral bodies in early infancy due to defective ossification.

Later, platyspondyly and anterior wedging of vertebral bodies are characteristic. Appearance of a hump-like build-up of bone in both the central and posterior portions of vertebral end plates in the lower posterior and upper lumbarspine. The thorax is narrow and ribs are short in both infancy and early childhood. Limbs are also short with marked metaphyseal flare and epiphyseal dysplasia. Deformed capital femoral epiphyses. Hyperplasia of proximal femoral metaphyses. The capital femoral epiphyses are typically deformed. Hyperplasia of proximal femoral metaphyses is usually observed.

Finally, hypoplasia of basilar pelvis with crescent-shaped iliac crests and low-set anteriosuperior iliac spines is characteristic.

 
Making the Diagnosis

Metatropic dysplasia is diagnosed by its characteristic clinical features such as the coccygeal tail, normal facies, spinal issues, and limb shape. Radiographic features help with diagnosis and genetic testing can also help confirm a diagnosis.

Being a rare disorder with few reports in the medical literature, consultation with an experienced clinical geneticist may be required before a diagnosis is made.

 
Musculoskeletal Problems

Metatrophic Dyplasia varies in severity. Some infants die from severe respiratory problems whereas others survive with only minor changes.

Neck

Atlantoaxial instability is almost universally present in metatropic dysplasia. X-rays of the neck should be performed at diagnosis and at periodical intervals thereafter. Progressive instability in this region will lead to spinal cord compression and is potentially life threatening. Signs of cord compression have been listed elsewhere.

If instability is progressive or symptomatic, early surgical fusion of the affected bones is essential. In cases of diagnostic doubt, further information can be obtained by means of an MRI scan (with flexion-extension views and CSF flow studies). It allows accurate determination of the degree of spinal cord compression and space available for the cord.

Spinal fusion may be supplemented by instrumentation (metal implants) to support the bones until the fusion mass consolidates. Usually extra bone is taken from a rib or from the pelvis to help the healing process. Immobilization of the neck is achieved by a halo vest or body cast, for at least 3 months.

Spine

Kyphoscoliosis is commonly seen in early childhood. It is often severe and rapidly progressive. Spinal curves should be diagnosed early and followed-up at regular intervals. Bracing may be of some benefit in younger children with smaller curves (400 to 500).

The timing of spinal decompression and fusion for scoliosis in metatropic dysplasia is dependent upon the severity of the curve, curve progression, age and risk of injury to the spinal cord. Instrumentation of the spinal fusion may not be possible due to the size and structure of the vertebral column. Prolonged immobilization in a halo body cast may be necessary
following surgery.

The status of the respiratory system may dictate the timing of surgery, especially in the younger, more severely affected children. In the lower back, spinal stenosis may occur requiring decompression and spinal fusion.

Limb Deformities

The limbs are short with significant joint contractures. The treatment of bony deformities and joint contractures is dictated by walking ability, amount of functional compromise and symptoms. Common problems include hip and knee flexion contractures and genu valgus. Some individuals may have signs of ligamentous laxity. Premature degenerative arthritis invariably occurs, requiring joint replacement surgery.

 
Problems Elsewhere in the Body
Respiratory Problems

Respiratory problems are the result of a poorly developed, stiff rib cage. Prolonged breathing difficulties may warrant a tracheostomy and long-term ventilatory support. This is a frequent cause of death in infancy.

Other serious but preventable causes of breathing impairity are spinal cord compression and hydrocephalus. Lung function tests and sleep studies are frequently used to diagnose breathing problems in skeletal dysplasias. Regular review by a pulmonologist is recommended.

Hydrocephalus

Hydrocephalus has been reported in metatropic dysplasia. Regular measurement of head circumference will facilitate early diagnosis. Headache, vomiting, visual disturbances, and loss of consciousness are signs of increased pressure around the brain.

 
What to Look For

In metatropic patients, any change in walking ability, endurance or
breathing should merit further assessment by a physician to rule out
spinal cord compression. Specific neurological symptoms such as
tingling or numbness in the arms or legs, weakness, shooting leg or
arm pain, or problems controlling bladder/bowel function should be investigated further.

One should also watch out for progressive curvature of the spine.
Headache, vomiting, visual disturbances, and loss of consciousness
are signs of increased pressure around the brain; possibly due to
worsening hydrocephalus.

 
References
  1. Jones, Kenneth L. Recognizable Patterns of Human Malformation. Philadelphia, PA: Elsevier Saunders. 2006.
  2. Krakow D, Vriens J, Camacho N, Luong P, Deixler H, Funari TL, Bacino CA, Irons MB, Holm IA, Sadler L, Okenfuss EB, Janssens A, Voets T, Rimoin DL, Lachman RS, Nilius B, Cohn DH. Mutations in the gene encoding the calcium-permeable ion channel TRPV4 produce spondylometaphyseal dysplasia, Kozlowski type and metatropic dysplasia. Am J Hum Genet. 2009 Mar;84(3):307-15.
  3. Scott, Charles I. Dwarfism. Clinical Symposium, 1988; 40(1):17-18
  4. Spranger, Jurgen W. Brill, Paula W. Poznanski, Andrew. Bone Dysplasias: An Atlas of Genetic Disorder of Skeletal Development. Oxford: Oxford University Press. 2002.

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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