Acromesomelic Dysplasia

Acromesomelic dysplasia is an extremely rare, inherited, progressive skeletal disorder that results in a particular form of short stature known as short-limb dwarfism. The disorder is characterized by Macromedia and mesomelia. Mesomelia describes the shortening of the bones of the forearms and lower legs relative to the upper parts of those limbs. Acromelia is the shortening of the bones of the hands and feet. Thus, the short stature of affected individuals is the result of unusually short forearms and abnormal shortening of bones of the lower legs. The very shorthands, fingers, feet, and toes are characteristic. These findings are apparent during the first years of life.

Acromesomelic dysplasia is a rare skeletal disorder that causes the abnormal bone and cartilage development, leading to shortening of the forearms, lower legs, hands, feet, fingers, and toes.^[rx] Five different genetic mutations have been implicated in the disorder. Treatment is individualized but is generally aimed at palliating symptoms, for example, treatment of kyphosis and lumbar hyperlordosis.

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 the 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 that affects bone development, natriuretic peptide receptor B (NPR-B). This is a receptor (a protein that binds to 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 a 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 is 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 of 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.

Related Disorders

Achondroplasia is the most common disorder of short-limbed dwarfism. Affected individuals have arms and legs that are very short, while the torso is more nearly normal in size. During fetal development and childhood, cartilage normally develops into bone, except in a few places, such as the nose and ears. In individuals with achondroplasia, something goes wrong during this process, especially in the long bones (such as those of the upper arms and thighs). The rate at which cartilage cells in the growth plates of the long bones turn into bone is slow, leading to short bones and reduced height. This syndrome is caused by specific mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Achondroplasia differs from AMD in that the upper bones of the arms and legs (the humerus and femur) are the most affected in achondroplasia, while it is the lower bones (radius and ulna in the arm, tibia, and fibula in the leg) and the hands and the feet that are the most affected in AMD. (For more information on this disorder, choose “ Achondroplasia ” as your search term in the Rare Disease Database.)

Acrodysostosis is an extremely rare disorder characterized by abnormally short, malformed bones of the hands and feet (peripheral dysostosis), abnormally short fingers and toes (brachydactyly), malformation, and shortening of the forearm bones (radius and ulna), and progressive growth retardation, resulting in short-limbed dwarfism. As children with the disorder grow older, they may experience progressively impaired and limited movements of the hands, feet, and/or elbows as well as pain and swelling in various joints (arthritis) of the body. Affected individuals also exhibit characteristic malformations of the head and facial (craniofacial) area including an abnormally flat, underdeveloped (hypoplastic) “pug” nose, an underdeveloped upper jaw bone (maxillary hypoplasia), widely spaced eyes (ocular hypertelorism), and/or extra folds of skin that may partially cover the eyes’ inner corners (epicanthal folds). Intellectual disability may also be present. In most cases, acrodysostosis is thought to occur randomly, for unknown reasons (sporadic). (For more information on this disorder, choose “Acrodysostosis” as your search term in the Rare Disease Database.)

Acromicric dysplasia is another extremely rare inherited disorder characterized by abnormally short hands and feet, growth retardation, and delayed bone maturation leading to short-limbed dwarfism, and mild facial abnormalities. Craniofacial malformations may include an abnormally narrow opening between the upper and lower eyelids (palpebral fissures) and a short nose with upturned (anteverted) nostrils. In most cases, acromicric dysplasia appears to occur randomly, for unknown reasons (sporadically). However, autosomal dominant inheritance has not been ruled out. (For more information on this disorder, choose “Acromicric Dysplasia” as your search term in the Rare Disease Database.)

There are several syndromes of isolated shortening of the bones in the hands and feet, known as brachydactyly. Two of these syndromes, brachydactyly types A2 and C are also caused by mutations in the GDF5 gene.

Short stature may be the normal expression of genetic potential, in which case the growth rate is normal, or it may be the result of a condition causing growth failure with a lower-than-normal growth rate. Growth failure is the term that describes a growth rate below the appropriate growth velocity for age.

A child is considered short if he or she has a height that is below the fifth percentile; alternatively, some define short stature as a height less than 2 standard deviations below the mean, which is near the third percentile. Thus, 3-5% of all children are considered short. Many of these children have normal growth velocity. These short children include those with familial short stature or constitutional delay in growth and maturation. To maintain the same height percentile on the growth chart, growth velocity must be at least at the 25th percentile. When considering all children with short stature, only a few have a specific treatable diagnosis, such as growth hormone deficiency or hypothyroidism. Most of these are children with a slow growth velocity.

Symptoms

Acromesomelic dysplasia (AMD) is characterized by the inhibition of the growth of certain long bones (i.e. bones of the forearms and lower legs). As a result, affected individuals exhibit unusually short forearms and lower legs and short stature (short-limbed dwarfism). These findings typically become apparent during the first years of life. Abnormal cartilage and bone development also affect other bones, particularly those of the hands and feet (i.e. metacarpals, phalanges, metatarsals).

Infants with acromesomelic dysplasia 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 (macrocephaly), unusually prominent forehead (frontal bossing), and 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-limbed dwarfism) begins to become apparent. Due to abnormal development and premature fusion (ossification) of the growth portions and the shafts of the long bones of the arm, the bones on the outer aspect and the thumb side of the forearm (ulna and radius, respectively) may be markedly shortened (hypoplastic) and abnormally curved. In addition, the end portion of the radius (that normally meets with the bone of the upper arm [humerus] to form part of the elbow joint) may be completely or partially dislocated (subluxation). This is known as Madelung deformity. As a result, affected individuals may be unable to fully extend their arms, rotate the arms so the palms face down (pronation), or rotate their arms so the palms face upward (supination). Some affected individuals may also experience progressive degeneration, stiffness, tenderness, and pain of the elbows (osteoarthritis).

The hands and feet appear unusually short and broad at birth. Because the abnormalities of cartilage and bone development in the hands and feet are also progressive, the bones within the fingers and toes (phalanges), as well as in the body of the hands (metacarpals) and feet (metatarsals), become increasingly shorter and broader during the first years of life. During the second year of life, the growing ends of these bones (epiphyses) may begin to appear abnormally shaped like a cone or a square and may fuse prematurely. Thus, the fingers and toes appear short and stubby (brachydactyly); the hands and feet may seem unusually short, broad, and square; and the feet may appear abnormally flat. In many individuals, the great toes may appear relatively large in comparison to the other toes. In addition, the fingernails and toenails may also appear abnormally short and broad, though they are otherwise normal. In early childhood, extra, loose (redundant) skin may develop over the fingers.

During early childhood, individuals with AMD may also begin to demonstrate abnormalities of bones of the spinal column (vertebrae) and to experience progressive, abnormal curvature of the spine. Affected children may demonstrate unusual front-to-back curvature of the central portion of the spine (low thoracic kyphosis) and/or abnormally exaggerated inward curvature of the lower spine (lumbar hyperlordosis).

Common symptoms include:

Short stature
Progressive degeneration
Stiffness
Tenderness
Osteoarthritis
Abnormal bone shape
Macrocephayl
Frontal bossing
Occipital prominence
Slightly flattened midface
Abnormally small, pug nose

In rare cases, additional abnormalities may be present. For example, some individuals with AMD experience delayed puberty and, in a few reported cases, affected children have demonstrated corneal clouding.

Diagnosis

In most patients, 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.).

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 is recommended for affected individuals and their families. Another treatment for this disorder is symptomatic and supportive.

Acromesomelic Dysplasia

Causes

Diagnosis

Treatment

Acrodysostosis

Acromicric Dysplasia

4-Layered Lissencephaly

Classic Lissencephaly

Hyperhomocysteinemic Syndrome

Homocystinuria due to Cystathionine Beta-synthase (CBS) Deficiency