Acromesomelic dysplasia

December 31, 2014

Synonyms

Overview

Acromesomelic dysplasia describes a group of extremely rare, inherited, progressive skeletal conditions that result in a particular form of short stature, called short-limb dwarfism. The short stature is the result of unusually short forearms and forelegs (mesomelia) and abnormal shortening of the bones in the hands and feet (acromelia). At birth, the hands and feet may appear abnormally short and broad. Over time, the apparent disproportion becomes even more obvious, especially during the first years of life. Additional features may include: limited extension of the elbows and arms; progressive abnormal curvature of the spine; an enlarged head; and a slightly flattened midface. Acromesomelic dysplasia is inherited as an autosomal recessive trait.

There are different types of acromesomelic dysplasia, which are distinguished by their genetic cause.

Acromesomelic dysplasia, Maroteaux type
Acromesomelic dysplasia, Hunter-Thompson type
Acromesomelic dysplasia, Grebe type
Acromesomelic dysplasia, Osebold-Remondini typ
Acromesomelic dysplasia with genital anomalies
Fibular hypoplasia and complex brachydactyly (Du Pan syndrome)

Symptoms

Affected infants often have a normal birth weight. In most cases, in addition to having unusually short, broad hands and feet, affected infants often have characteristic facial abnormalities that are apparent at birth. Such features may include a relatively enlarged head, unusually prominent forehead, pronounced back portion of the head (occipital prominence), a slightly flattened midface, and/or an abnormally small, pug nose.

During the first years of life, as the forearms, lower legs, hands, and feet do not grow proportionally with the rest of the body, short stature (short-limb dwarfism) begins to become apparent. Over time, affected individuals may be unable to fully extend the arms, rotate the arms inward toward the body with the palms facing down, or rotate the arms outward with the palms facing upward. In some cases, affected individuals may also experience progressive degeneration, stiffness, tenderness, and pain of the elbows (osteoarthritis).

Abnormalities of cartilage and bone development may also cause the bones within the fingers, toes, hands, and feet to become increasingly shorter and broader during the first years of life. During the second year of life, the growing ends of these bones may begin to appear abnormally shaped like a cone or a square and may fuse prematurely. This causes the fingers and toes to appear short and stubby. The hands and feet may seem unusually short, broad, and square; and the feet may appear abnormally flat. In early childhood, extra, loose skin may also develop over the fingers.

During early childhood, affected individuals may also begin to experience progressive, abnormal curvature of the spine. In rare cases, affected individuals can experience delayed puberty and corneal clouding.

Causes

There are thought to be five types of acromesomelic dysplasia. Each is extremely rare, and each is inherited as an autosomal recessive genetic trait, except for AMD Osebold-Remondini type, which appears to be autosomal dominant. The Maroteaux type has been traced to chromosome 9 at gene map locus 9p13-12. Grebe dysplasia (including AMD Hunter-Thompson type) and Du Pan syndrome all have each been mapped to chromosome 20 at gene map locus 20q11.2. Acromesomelic dysplasia with genital anomalies maps to 4q23-24. Osebold-Remondini type has not been genetically mapped yet.

Genetic studies indicate that the change (mutation) at chromosome 9p13-12 (AMD Maroteaux type) is in a gene that codes for a protein the affects bone development, natriuretic peptide receptor B (NPR-B). This is a receptor (a protein that binds another protein) for a hormone called C-type natriuretic peptide, a hormone that is very important for bone growth. The gene located at chromosome 20q11.2 (Grebe dysplasia) codes for a protein known as growth and development factor-5 (GDF5, previously named cartilage-derived morphogenetic protein-1, CDMP1). The gene located at chromosome 4q23-24 (AMD with genital anomalies) codes for a protein known as bone morphogenetic protein receptor, type 1B (BMPR1B). This is a receptor for GDF5.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 9p13-12" refers to a region on the short arm of chromosome 9 between bands 13 and 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females.

Diagnosis

In most cases, acromesomelic dysplasia is diagnosed within the first few years of life based upon a thorough clinical evaluation, detailed patient history, identification of characteristic findings, and advanced imaging techniques. Although the hands and feet may appear unusually short and broad at birth, the progressive abnormalities associated with the disorder (e.g. abnormal shortening of bones in the forearms and lower legs and short stature, further shortening and broadening of bones of the hands and feet, progressive vertebral abnormalities, limited elbow and arm extension, etc.) typically do not become apparent until late infancy or early childhood.

Specialized x-ray studies may confirm the abnormal development and premature fusion of the regions where the shafts (diaphyses) of certain long bones (i.e. bones of the arms and legs) meet their growing ends (epiphyses). In addition, they may reveal abnormal fusion of the growing ends of bones within the fingers, toes, hands, and feet (i.e. phalanges, metacarpals, metatarsals). Such studies may also confirm the presence and/or extent of resulting bone abnormalities (e.g. short, bowed ulna and radius, dislocated or subluxated radial head, short, malformed phalanges, etc.) as well as other skeletal abnormalities that may be associated with acromesomelic dysplasia (e.g. vertebral abnormalities and resulting low thoracic kyphosis and/or lumbar hyperlordosis; hypoplastic ilia; etc.).

Prognosis

Acromesomelic dysplasia is a progressive condition, meaning that signs and symptoms usually become worse over time. However, life expectnacy appears to be normal. Abnormal cartilage and bone development usually affects many bones in the body, particularly those of the hands and feet. Over time, the bones may becomre more disproportionate. The joints may be affected as well. Many affected individuals experience abnormal curvature of the spine.

Treatment

The treatment of acromesomelic dysplasia is directed toward the specific symptoms and physical characteristics that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat skeletal abnormalities (orthopedists), physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

Specific therapies for the treatment of acromesomelic dysplasia are symptomatic and supportive. Abnormal curvature of the spine (i.e. low thoracic kyphosis and/or lumbar hyperlordosis) may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or, in severe cases, corrective surgery. Physical therapy, other supportive techniques, and/or orthopedic surgery may help correct certain specific findings associated with acromesomelic dysplasia.

Early intervention is important to ensure that children with acromesomelic dysplasia reach their potential. Special services that may be beneficial to affected children may include social support and other medical, social, and/or vocational services.

Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.