In Jansen type metaphyseal chondrodysplasia, an extremely rare progressive disorder, portions of the bones of the arms and legs develop abnormally with unusual cartilage formations and subsequent abnormal bone formation at the large (bulbous) end portions (metaphyses) of these long bones (metaphyseal chondrodysplasia). As a result, affected individuals exhibit unusually short arms and legs and short stature (short-limbed dwarfism), findings that typically become apparent during childhood. Abnormal cartilage development and bone formation may also affect other bones of the body, including those of the hands and feet (i.e., metacarpals and metatarsals). As affected individuals age, abnormal cartilage formations in affected areas may harden into rounded (bulbous) masses of bone, which may become prominent.
In most cases, infants with Jansen type metaphyseal chondrodysplasia have characteristic facial abnormalities that are present at birth (congenital) including an unusually small jaw (micrognathia); receding chin; highly-arched roof of the mouth (palate); unusually wide fibrous joints between bones of the skull (cranial sutures); and/or prominent, widely spaced eyes (ocular hypertelorism).
During childhood, it may become apparent that affected individuals have additional skeletal abnormalities such as unusually short, clubbed fingers (brachydactyly) with permanent fixation of the fifth finger in a bent position (clinodactyly); an abnormally small lower rib cage; fractured ribs; and/or malformations of the spine and pelvis. As affected children age, they may eventually develop abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) and/or bowing of the legs. In addition, short stature becomes more obvious as affected children age; the torso grows longer, but the arms and legs do not grow proportionally.
Children with Jansen type metaphyseal chondrodysplasia may also experience diminished muscle mass and gradual swelling of certain joints, particularly the hips and knees. Affected joints may become stiff and painful and certain movements, particularly bending (flexion), may become limited. Most affected children develop an unusual semi-squatting stance and a “waddling” walk (gait). Eventually, certain joints may become fixed in a permanently bent (flexed) position (joint contractures).
Intellectual disability and a delay in the acquisition of skills requiring coordination of muscular and mental activity (psychomotor retardation) have not been reported in patients with Jansen metapyseal chondrodysplasia.
In some cases, adults with Jansen type metaphyseal chondrodysplasia may eventually exhibit overgrowth of the bones above the eyes and those of the forehead (supraorbital and frontonasal hyperplasia), an unusually thickened base of the skull, and/or abnormal hardening (sclerosis) of certain cranial bones. In some cases, sclerosis of certain cranial bones may eventually result in blindness and/or deafness. Affected adults may also exhibit additional joint contractures. In addition, affected individuals have abnormally high levels of calcium in the blood (hypercalcemia).
Most cases of Jansen type metaphyseal chondrodysplasia occur randomly as the result of a spontaneous genetic change (i.e., new mutation). Inheritance is autosomal dominant.
Genetic diseases are determined by two genes, one received from the father and one from the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the 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 regardless of the sex of the resulting child.
The gene that is probably involved in most cases of Jansen type metaphyseal chondrodysplasia associated with hypercalcemia is located on the short arm (p) of chromosome 3 (3p21.1-p22). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” In order for researchers to clearly refer to the thousands of genes that may be present on one chromosome, both the long arm and short arm of each chromosome are divided into many bands that are numbered.
Jansen type metaphyseal chondrodysplasia is caused by genetic change(s) (mutation[s]) of a gene that encodes for a specific protein (i.e., PTH/PTHrP receptor). Parathyroid hormone helps to regulate the levels of calcium in the blood.
The degree of hypercalcemia may vary in different patients. At least one mild form of Jansen type metaphyseal chondrodysplasia has been identified in which affected family members had less-pronounced skeletal abnormalities.
Jansen type metaphyseal chondrodysplasia is an extremely rare disorder that affects males and females in equal numbers. Approximately 20 cases have been reported in the medical literature.
In most cases, the diagnosis of Jansen type metaphyseal chondrodysplasia may be suspected during infancy or early childhood. The diagnosis may be confirmed by a thorough clinical evaluation, identification of characteristic physical findings, and a variety of specialized tests, particularly advanced imaging techniques. These techniques include x-ray studies that may reveal abnormal development of the large (bulbous) ends (metaphyses) of certain bones of the body, particularly those of the arms and legs. Laboratory tests that detect abnormally high levels of calcium in the urine (hypercalciuria) and blood (hypercalcemia) are helpful in confirming the diagnosis.
The treatment of Jansen type metaphyseal chondrodysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedic surgeons, dental specialists, speech pathologists, specialists who assess and treat hearing problems (audiologists), physical therapists, and other health care professionals may need to systematically and comprehensively plan an affected child’s treatment.
Physical therapy and/or orthopedic surgery may help correct certain specific findings associated with Jansen type metaphyseal chondrodysplasia, such as deformities of the joints.
Early intervention is important to ensure that children with Jansen type metaphyseal chondrodysplasia reach their highest potential. Special services that may be beneficial to affected children may include speech therapy, special social support, physical therapy, 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.
Researchers are studying the use of bisphosphonates for the treatment of individuals with Jansen type metaphyseal chondrodysplasia. More research is necessary to determine the long-term safety and effectiveness of bisphosphonates as a potential treatment for this disorder.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
Contact for additional information about Jansen type metaphyseal hondrodysplasia:
Ernestina Schipani, M.D., Ph.D.
Professor of Orthopedic Surgery, Medicine, and
and Cell and Developmental Biology
University of Michigan-Medical School
109 Zina Pitcher
Ann Arbor, MI 48104
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