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NORD is very grateful to Ernestina Schipani, MD, PhD, Associate Professor of Medicine, Massachusetts General Hospital, Harvard Medical School, for assistance in the preparation of this report.
Jansen type metaphyseal chondrodysplasia is an extremely rare progressive disorder in which 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 early childhood. Abnormal cartilage and bone development may also affect other bones of the body, particularly those of the hands and feet (i.e., metacarpals and metatarsals). Infants with Jansen type metaphyseal chondrodysplasia may also have characteristic facial abnormalities and additional skeletal malformations. During childhood, affected individuals may begin to exhibit progressive stiffening and swelling of many joints and/or an unusual "waddling gait" and squatting stance. In addition, affected adults may eventually develop abnormally hardened (sclerotic) bones especially in the back of the head (cranial bones), which, in some cases, may lead to blindness and/or deafness. In addition, affected individuals have abnormally high levels of calcium in the blood (hypercalcemia). The range and severity of symptoms may vary from case to case. Most cases of Jansen type metaphyseal chondrodysplasia occur randomly as the result of a spontaneous genetic change (i.e., new genetic mutation).
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 hypercalcemi 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.
Symptoms of the following disorders can be similar to those of Jansen type metaphyseal chondrodysplasia. Comparisons may be useful for a differential diagnosis:
Hypochondroplasia is a rare inherited skeletal disorder characterized by short stature with abnormally short arms and legs (short-limbed dwarfism) and an unusually long trunk (thorax and abdomen). Major symptoms may include bowing of the legs, abnormally short, broad fingers and toes (brachydactyly), mild limitation of elbow movements, and/or abnormal backward curvature of the spine (lordosis). In addition, affected infants may exhibit abnormalities of the head and face (craniofacial) area including drooping of the upper eyelids (ptosis), an abnormally prominent forehead (frontal bossing), and/or an unusually large head (macrocephaly). Hypochondroplasia is inherited as an autosomal dominant genetic trait. (For more information on this disorder, choose "Hypochondroplasia" as your search term in the Rare Disease Database.)
McKusick type metaphyseal chondrodysplasia, also known as cartilage-hair hypoplasia, is an extremely rare inherited disorder characterized by unusually fine, sparse hair and abnormal development of the cartilage and subsequent bone formation in the long bones of the arms and legs (metaphyseal chondrodysplasia), resulting in unusually short arms and legs and short stature (short-limbed dwarfism). Most affected individuals exhibit impairment of certain white blood cells (T-cells) that play an important role in helping the body's immune system fight certain infections (cellular immunodeficiency). In addition, affected individuals may also exhibit impaired absorption of certain necessary nutrients (malabsorption); abnormally low levels of certain white blood cells in the body (neutropenia and lymphocytopenia); low levels of circulating red blood cells (anemia); increased susceptibility to repeated infections, such as chickenpox; abnormalities of the teeth; and/or other physical findings. The range and severity of symptoms vary widely from case to case. McKusick type metaphyseal chondrodysplasia is inherited as an autosomal recessive trait. (For more information on this disorder, choose "McKusick Type Metaphyseal Chondrodysplasia" as your search term in the Rare Disease Database.)
Schmid type metaphyseal chondrodysplasia is a rare inherited disorder characterized by short stature with abnormally short arms and legs (short-limbed dwarfism). Additional physical characteristics may include outward "flaring" of the bones of the lower rib cage, bowed legs (genu varum), pain in the legs, and/or hip deformities in which the thigh bone is angled toward the center of the body (coxa vara). Such abnormalities of the legs and hips typically result in an unusual "waddling" walk (gait). Schmid type metaphyseal chondrodysplasia is thought to be inherited as an autosomal dominant trait. (For more information on this disorder, choose "Schmid Type Metaphyseal Chondrodysplasia" as your search term in the Rare Disease Database.)
Spahr type metaphyseal chondrodysplasia is an extremely rare inherited disorder characterized by abnormal development of the cartilage and subsequent bone formation in the long bones of the arms and legs (metaphyseal chondrodysplasia), resulting in severely bowed legs and short stature (short-limbed dwarfism). This disorder is similar to Schmid type metaphyseal chondrodysplasia except Spahr type metaphyseal chondrodysplasia is thought to be inherited as an autosomal recessive genetic trait.
Vitamin D deficiency rickets is a rare inherited disorder characterized by skeletal abnormalities due, in most cases, to a deficiency in vitamin D levels (Type I) or inability to properly utilize vitamin D (Type II). Skeletal abnormalities may include bowed legs; abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis); malformations of the bones of the spine, pelvis, and legs; and/or, in severe cases, abnormal side-to-side (horizontal) depression of the lower portion of the chest cavity (Harrison groove). In most cases, affected infants will exhibit abnormally low levels of calcium in the blood (hypocalcemia). (For more information on this disorder, choose "Rickets, Vitamin D Deficiency" as your search term in the Rare Disease Database.)
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:
Contact for additional information about Jansen type metaphyseal chondrodysplasia:
Ernestina Schipani, M.D., Ph.D.
Professor of Medicine and
Anatomy and Cell Biology
980 W. Walnut Street
R3 Rm C110
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., short stature, craniofacial abnormalities, deafness, etc.].)
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Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Metaphyseal Chondrodysplasia, Jansen Type. Entry No: 156400. Last Edited March 1, 2012. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed May 7, 2012.
Report last updated: 2012/05/08 00:00:00 GMT+0