Dwarfism and genetics

ALSO KNOWN AS: Short stature; little person; achondroplasia; ACH; achondroplastic dwarfism

DEFINITION: “Dwarfism” in humans is a term used to describe adults who are less than 4 feet, 10 inches in height. More than three hundred conditions are known to cause dwarfism, or short stature. Dwarfism is most often caused by genetic conditions, but it can also be related to endocrine malfunction, acquired conditions, or growth hormone deficiency. Individuals with dwarfism usually have normal intelligence and have an average lifespan. Little people can also give birth to children with normal stature. Dwarfism may result in multiple medical problems that can lead to death. The term “dwarf” is socially unacceptable by most people. Those with dwarfism prefer to be referred to as "little people" or as having short stature.

Risk Factors

Having a parent with a form of dwarfism, such as achondroplasia, a parent who carries a mutated FGFR3 gene, or parents of advanced age can increase the risk of inheriting dwarfism. Other abnormalities such as damage or conditions of the pituitary gland, hormonal disorders, problems with absorption, malnutrition, kidney disease, or extreme emotional distress can increase the risk of developing dwarfism.

Etiology and Genetics

Dwarfism, of which there are several hundred forms, occurs in approximately one in every ten thousand births. Approximately 85 percent of little people are born to parents of average height. The most common type of dwarfism, achondroplasia, is an autosomal dominant trait, but in 80 percent of cases, it appears in children born to normal parents as a result of mutations in the sperm or egg.

Dwarfisms in which body proportions are normal usually result from metabolic or hormonal disorders in infancy or childhood. Chromosomal abnormalities, pituitary gland disorders, problems with absorption, malnutrition, kidney disease, and extreme emotional distress can also interfere with normal growth. When body parts are disproportioned, the is usually due to a genetic defect.

Skeletal dysplasias are the most common causes of dwarfism and are the major cause of disproportionate types of dwarfism. More than five hundred skeletal dysplasias have been identified. Chondrodystrophic dwarfism occurs when cartilage cells do not grow and divide as they should and cause defective cartilage cells. Most chondrodystrophic little people have abnormal body proportions. The defective cells occur only in the spine or only in the arms and legs. Short-limb dwarfism includes individuals with achondroplasia, diastropic dysplasia, and Hunter-Thompson chondrodysplasia.

Achondroplasia is the most common skeletal dysplasia. It occurs in every fifteen thousand to forty thousand babies born of all races and ethnicities and in both males and females. Achondroplasia is caused by an and is identified by a disproportionate short stature consisting of a long trunk and short upper arms and legs. Eighty percent of all cases of achondroplasia result from a mutation on chromosome 4 in a gene that codes for the fibroblast growth factor receptor 3, FGFR3. If one parent has achondroplasia and the other does not, then a child born to them would have a 50-percent chance of inheriting achondroplasia. On the other hand, if both parents have achondroplasia, their offspring have a 50 percent chance of inheriting achondroplasia, a 25-percent chance of being of average stature, and a 25-percent chance of inheriting the abnormal allele from each parent and suffering often-fatal skeletal abnormalities. Children who do not inherit the mutation will never have achondroplasia and cannot pass it on to their offspring, unless a spontaneous mutation occurs in the sperm or egg of the parents. Geneticists have observed that fathers who are thirty-five years of age or older are more likely to have children with achondroplasia as a result of mutations in their sperm.

Diastrophic dysplasia is a relatively common form of short-limb dwarfism that occurs in an estimated one in 500,000 US births and one in 33,000 in Finland. It is identified by the presence of short arms and calves, clubfeet, and short, broad fingers with a thumb that has a hitchhiker-type appearance. Infant mortality can be high as a result of respiratory complications, but if they survive infancy, short-limbed dwarfs have a normal lifespan. Orthopedic dislocations of joints are common. Scoliosis is seen especially in the early teens, and progressive cervical kyphosis and partial dislocation of the cervical spine eventually cause compression of the spinal cord. Diastrophic dysplasia is an inherited autosomal recessive condition linked to the SLC26A2 gene, which is responsible for cartilage and bone formation. Parents have a 25-percent chance that each additional child will get diastrophic dysplasia.

Short-trunk dwarfism includes individuals with spondyloepiphyseal dysplasia (SED), which results from abnormal growth in the spine and long bones that leads to a shortened trunk. In spondyloepiphyseal dysplasia tarda, the lack of growth may not be recognized until six to ten years of age. Those affected have progressive joint and back pain and eventually develop osteoarthritis. About 90 percent of SED tarda cases occur because of TRAPPC2 gene mutations, and the X-linked condition affects some one in 150,000 to 200,000 people. Spondyloepiphyseal dysplasia congenita is caused by autosomal dominant gene mutations in the COL2A1 gene, responsible for type II collagen, and is evidenced by a short neck and trunk, and barrel chest at birth. It is not uncommon for cleft palate, hearing loss, myopia, and retinal detachment to be present. This rare condition is known to have affected about 175 people.

Morquio syndrome, which was first described in 1929, is classified as a mucopolysaccharidosis (MPS) disease caused by the body’s inability to produce lysomes, enzymes that help to break down and recycle dead cells. Consequently, wastes are stored in the body’s cells. Morquio syndrome occurs in one in two hundred to three hundred thousand people.

Hunter-Thompson chondrodysplasia is a rare form of dwarfism caused by a mutation in growth factor genes. Affected individuals have shortened and misshapen bones in the lower arms, the legs, and the joints of the hands and feet. Fingers are shortened and toes are ball-shaped.

Growth hormone, a protein that is produced by the pituitary (“master”) gland, is vital for normal growth. Isolated growth hormone deficiencies affect between one in four thousand and ten thousand people. These deficiencies arise from mutations to the GH1, GHRHR, or BTK genes, which control growth hormone production and reception and antibody production, respectively.. In panhypopituitarism, the gland does not produce any hormones. The pituitary gland shuts down and growth is stunted.

Turner syndrome affects one in every 2,500 female infants and is characterized by the absence of or damage to one of the X chromosomes in most of the cells in the body. Short stature and the failure to develop sexually are hallmarks of Turner syndrome. Learning difficulties, skeletal abnormalities, heart and kidney problems, infertility, and thyroid dysfunction may also occur. can be treated with human growth hormones and by replacing sex hormones.

Symptoms

For inherited disorders at birth, a long trunk and shortened limbs will be noticeable. A child born with dwarfism may go on to exhibit delayed gross motor development and skills, breathing and neurologic problems, hydrocephalus (water on the brain), increased susceptibility to ear infections and hearing loss, weight problems, curvature of the spine (scoliosis), bowed legs, stiff arms, joint and back pain or numbness, and crowding of teeth. Portions of the face may be underdeveloped. Sleep apnea can develop as a result of compression of the spine. Adult height will be stunted (usually reaching 42-52 inches). Seeking proper medical care can help to relieve some of these symptoms and complications.

Screening and Diagnosis

Close monitoring by parents and doctors is necessary to record the constellation of symptoms for each unique case of dwarfism. Often an initial diagnosis can be made by observing physical characteristics. Magnetic resonance imaging (MRI) and computed tomography (CT) scans can illustrate spinal and other structural abnormalities before serious complications arise. Imaging techniques can also help to determine the type of dwarfism present. Molecular genetic testing can be done to detect a FGFR3 mutation. Genetic testing is 99-percent sensitive and available in clinical laboratories. The continues to investigate genetic links to dwarfism. Prenatal counseling and screening for traits of dwarfism, along with genetic counseling and support groups, are avenues to pursue for family and individual physical, psychological, and social well-being and to make informed choices.

Treatment and Therapy

Some forms of dwarfism can be treated through state-of-the-art surgical and medical interventions such as bone-lengthening procedures, reconstructive surgery, and growth and sex hormone replacement.

Short stature is the one quality all people with dwarfism have in common. After that, each of the many conditions that cause dwarfism has its own set of characteristics and possible complications. Fortunately, many of these complications are treatable, so that people of short stature can lead healthy, active lives. Continued follow-up with the physician team is essential.

For example, some babies with achondroplasia may experience hydrocephalus (excess fluid around the brain). They may also have a greater risk of developing sleep apnea—a temporary stop in breathing during sleep—because of abnormally small or misshapen airways or, more likely, because of airway obstruction by the adenoids or the tonsils. Occasionally, a part of the brain or spinal cord is compressed. With close monitoring by doctors, however, these potentially serious problems can be detected early and surgically corrected.

Prevention and Outcomes

Genetic counseling as well as family and public education regarding dwarfism and growth problems can bring greater awareness of dwarfism to communities and allow parents to make good choices. Inherited dwarfism is not preventable, but some cases caused by malnutrition, injury, absorption, or kidney conditions may be prevented. The use of preimplantation genetic diagnosis to select for dwarfism has become a topic of intense debate around medical ethics and reproductive liberty, as some prospective parents want their children to share their traits.

The type, symptoms, and severity of complications vary from person to person, but most little people have an average lifespan. With a sense of support, self-esteem, and independence, a person with dwarfism can lead a very satisfying and productive life.

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