Nail-patella syndrome (NPS) is a rare genetic disorder that is usually apparent at birth or during early childhood. Although the symptoms and physical characteristics associated with NPS may vary, characteristic abnormalities tend to include improper development (dysplasia) of the fingernails and toenails; absence (aplasia) and/or underdevelopment (hypoplasia) of the knee caps (patellae); underdevelopment of certain bones and/or webbing of skin at the bend of the elbow(s); and/or abnormal projections of bone from the upper (superior) portion of both sides of the hipbone (bilateral iliac horns).
In addition, some individuals within certain families (kindreds) may have abnormally increased fluid pressure of the eyes (glaucoma). The condition results due to progressive blockage of the outflow of fluid (aqueous humor) from the front chamber of the eyes (open-angle glaucoma). Without appropriate treatment, the gradual increase in fluid pressure may cause increased narrowing of visual fields and eventual blindness. Other eye (ocular) abnormalities may also be associated with NPS. For example, in some affected individuals, the inner margin (pupillary margin) of the colored portion of the eyes (irides) may appear abnormally dark (hyperpigmentation) and "cloverleaf shaped" (Lester iris).
Approximately 30 to 40 percent of individuals with NPS may also develop abnormalities in kidney function (nephropathy) that may be apparent during childhood or later in life. Nail-patella Syndrome is inherited as an autosomal dominant trait.
Nail-patella syndrome (NPS), a rare genetic disorder, is usually apparent at birth (congenital) or during early childhood. Although the range and severity of associated symptoms and physical features may vary widely from case to case, characteristic features include improper development (dysplasia) of the fingernails and toenails; bone deformities affecting the knee caps (patellae), elbows, hipbone, and/other areas of the body; distinctive abnormalities of the eyes; and/or kidney disease (nephropathy).
In most individuals with NPS, improper development (dysplasia) of the nails is apparent at birth or early infancy. While the thumbnails are almost always affected, nails on the middle and index fingers are also commonly involved. In some cases, other nails of both the hands and the feet may also be affected. The nails may be abnormally small and narrow (i.e., one half to one third of normal size), split, abnormally thickened, depressed, and/or discolored. In addition, in most cases, the crescent-shaped pale area at the base of the nail (lunula) is malformed and/or triangular.
Most individuals with NPS also have abnormalities of certain bones. In most cases, one or both knee caps (patellae) may be abnormally small, underdeveloped (hypoplastic), and misshaped (e.g., tripartite, polygonal). In other cases, one or both knee caps may be absent. In addition, affected individuals may also demonstrate underdevelopment (hypoplasia) of the upper end of the calf bone (fibula) and/or the rounded projection of the thigh bone (femur) that anchors to the head of the shin bone (lateral femoral condyle). Due to such abnormalities, individuals with NPS often exhibit partial dislocation (subluxation) and a limited range of movements of the knee(s), a deformity in which one or both legs bend outward at the knee (“bow-leg” or genu varum), and/or progressive degeneration, stiffness, tenderness, and pain of the knee(s) (osteoarthritis). In severe cases, osteoarthritis may eventually limit use of the knee(s).
In most cases, individuals with NPS also have abnormalities of the elbows. The portions of bone that meet at the elbow(s) (i.e., capitellum, head of radius) may be abnormally small and underdeveloped (hypoplastic). In addition, in some cases, affected individuals may have abnormal webbing of skin at the bend of the elbow(s) (antecubital pterygium). Due to such abnormalities, affected individuals may be unable to completely extend the arms, rotate the arms inward toward the body with the palms facing down (pronation), or rotate the arms outward with the palms facing upward (supination). In some cases, affected individuals may experience partial dislocation of the elbows (subluxation). Individuals with NPS may also develop progressive osteoarthritis of the elbows that, in severe cases, may eventually limit elbow function.
The majority of individuals with NPS also have abnormal projections of bone from the upper (superior) portion of both sides of the hipbone (bilateral iliac horns). In some cases, additional skeletal abnormalities may be present. These may include underdevelopment (hypoplasia) of the shoulder blades (scapulae) and/or abnormal sideways curvature of the spine (scoliosis).
Some affected individuals within particular families (kindreds) may also have a condition in which fluid pressure of the eyes becomes abnormally increased (glaucoma). The condition results due to progressive blockage of the outflow of fluid (aqueous humor) from the front chamber of the eyes (open-angle glaucoma). Initially, affected individuals may have no apparent symptoms (asymptomatic). As fluid pressure increases, some individuals with the condition may develop mild headaches, blurred vision, and/or the appearance of “halos” around certain lights. Without appropriate treatment, elevated fluid pressure may lead to gradual loss of peripheral vision, increased narrowing of visual fields, and eventual blindness.
Other eye (ocular) abnormalities may also be associated with NPS. In approximately 45 percent of affected individuals, the inner margin (pupillary margin) of the colored portion of the eyes (irides) may appear abnormally dark (hyperpigmentation) and “cloverleaf shaped” (Lester iris). Some individuals may also have abnormal clouding of the lenses of the eyes (cataracts) and/or unusually small corneas (microcornea). The cornea is the front, clear portion of the eye through which light passes. The degree of associated visual impairment depends upon the severity and/or combination of eye abnormalities present.
Approximately 30 to 40 percent of individuals with NPS may also experience abnormalities in kidney function (nephropathy) that may be apparent during childhood or later in life. Such kidney disease may be due to abnormal degeneration of the tiny tubes (renal tubules) that collect, conduct, and secrete urine (nephrotic kidney disease) and/or inflammation and degeneration of the clusters of capillaries (renal glomeruli) that filter the blood passing through the kidneys (glomerular kidney disease).
In most affected individuals, the first apparent signs of nephropathy tend to include the presence of small amounts of blood in the urine (microhematuria); high blood pressure (hypertension); and/or an abnormal accumulation of fluid between layers of tissue under the skin (edema). In most such cases, the nephropathy may be relatively benign. However, in other cases, without appropriate treatment, progressive kidney failure may result, causing potentially life-threatening complications.
For example, in some cases, affected individuals with nephropathy may begin to exhibit a variety of symptoms (nephrotic syndrome) including anemia, edema, and/or other characteristic, abnormal laboratory findings (see “Standard Therapies, Diagnosis” for more information). In some such cases, the kidneys may eventually lose their ability to excrete waste products through the urine, to regulate the balance of salt and water in the body, and to perform their other vital functions (renal failure), resulting in potentially life-threatening complications. Although progressive renal failure has occurred in individuals with NPS during childhood or adolescence, it rarely occurs before the fourth decade of life.
There is confusion in the medical literature concerning the percentage of affected individuals with nephropathy who experience progressive renal failure. It appears that approximately 25 percent of individuals with NPS who exhibit nephropathy may experience nephrotic syndrome and progressive kidney failure.
Nail-patella syndrome (NPS) is inherited as an autosomal dominant trait. Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.
In autosomal dominant disorders, a single copy of the disease gene (received from either the mother or father) will be expressed “dominating” the other normal gene and resulting in the appearance of the disease. The risk of transmitting the disorder from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child. The risk is the same for each pregnancy.
In most cases, individuals with the disease gene for NPS will manifest symptoms associated with the disorder (high penetrance). However, such symptoms and findings may be extremely variable from case to case (variable expressivity).
The gene responsible for NPS* is located on the long arm (q) of chromosome 9 (9q34.1). Research indicates that the locations of the genes for NPS and the ABO blood group are linked, with both being mapped to 9q34.1. 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”. Chromosomes are further subdivided into bands that are numbered. Therefore, chromosome 9q34.1 refers to band 34.1 on the long arm of chromosome 9.
*Evidence suggests that NPS results from changes (mutations) of a gene known as LMX1B (i.e., the LIM-homeodomain gene LMX1B), which has been mapped to chromosome 9q34. The LMX1B gene regulates production of a protein that plays an important role in the growth and development of the embryonic structures that become the arms and legs (limb buds). Investigators suggest that mutations of the LMX1B gene may result in skeletal defects, including impaired development of the knee caps and elbows, nail dysplasia, and kidney abnormalities. In addition, researchers have identified LMX1B gene mutations in members of several families (kindreds) who are affected by open-angle glaucoma in association with NPS.
Many different mutations of the LMX1B gene have been detected during genetic evaluation of kindreds with NPS. Such analysis has revealed no evidence of a correlation between specific LMX1B gene mutations and the range and severity of associated symptoms and findings (NPS phenotype).
Nail-patella syndrome (NPS) affects males and females in equal numbers. A description of the knee cap (patellar) defect in 1897 (Little EM) is thought to be the original report of the disorder in the medical literature, although NPS is also typically associated with nail dysplasia and additional findings as discussed above (see “Symptoms”). Over 400 cases have since been reported, including affected individuals within many multigenerational families (kindreds) as well as apparently isolated (sporadic) cases. NPS is thought to affect approximately one in 50,000 newborns.
In some cases, nail-patella syndrome (NPS) may be detected before birth (prenatally) based upon the results of certain specialized imaging tests, such as ultrasound. During fetal ultrasonography, sound waves are used to develop an image of the developing fetus.
In other cases, NPS may be suspected at birth or early childhood based upon the identification of certain characteristic findings (e.g., nail dysplasia, hypoplastic or absent patellae, antecubital pterygium, bilateral symmetrical iliac spurs). However, in others, the disorder may not be suspected until later in life. NPS may be confirmed based upon a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient and family history, advanced imaging techniques, and laboratory testing.
Specialized imaging techniques such as x-ray studies, computerized tomography (CT) scanning, and/or magnetic resonance imaging (MRI) may confirm the presence and/or extent of certain bone abnormalities characteristically associated with NPS (e.g., patellae hypoplasia and/or aplasia, hypoplastic capitellum and head of radius, bilateral iliac spurs, etc.). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structure. During MRI, a magnetic field and radio waves are used to create cross-sectional images.
Children and adolescents with NPS should be carefully monitored for abnormal sideways curvature of the spine (scoliosis) to ensure prompt detection and appropriate preventive and/or corrective treatment. Affected individuals should also receive thorough eye examinations to confirm and/or detect the presence of certain ocular abnormalities that may be associated with NPS (e.g., open-angle glaucoma, Lester iris, microcornea, cataracts). For example, in many cases, open-angle glaucoma may initially cause no apparent symptoms and therefore may only be detected by routine eye examinations, including specialized testing to measure eye pressure. Early detection of glaucoma is important in ensuring prompt treatment to reduce eye fluid pressure and prevent progressive visual impairment.
In addition, physicians may closely monitor individuals with NPS beginning in early infancy to ensure prompt detection of abnormal kidney function and implementation of immediate, appropriate treatment measures to help prevent potential progressive kidney disease. Laboratory tests may confirm certain findings that may indicate nephropathy. For example, urinary analysis may reveal small traces of blood (hematuria) and abnormally high levels of protein (proteinuria), specifically albumin (albuminuria), in the urine. Additional laboratory studies may reveal unusually low levels of albumin in an affected individual's blood (hypoalbuminemia). Such findings, occurring in association with anemia and edema, may indicate a diagnosis of nephrotic syndrome in some individuals with NPS.
Microscopic examination (e.g., immunofluorescence and electron microscopy) of samples of kidney tissue (renal biopsy) may reveal certain characteristic structural abnormalities that may be present even in some individuals with NPS who may not exhibit observable symptoms or clinical findings indicating renal involvement. For example, in many affected individuals both with and without apparent clinical renal involvement, microscopic examination may reveal certain abnormal changes of the clusters of capillaries (renal glomeruli) that filter blood passing through the kidneys. Such changes may include an increased number of cells (hypercellularity), abnormal thickening of the capillary walls, abnormal deposits of the protein collagen, and/or replacement of normal tissue with scar tissue (focal and segmental sclerosis). In some cases, confirmation of certain glomerular changes may reveal impairment of the glomeruli's filtering ability and may help to confirm a diagnosis of nephrotic syndrome.
The treatment of nail-patella syndrome (NPS) is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, surgeons, physicians who diagnose and treat abnormalities of the bones (orthopedists), specialists who diagnose and treat disorders of the kidneys (nephrologists), eye specialists, physical therapists, dietitians, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
Specific therapies for the treatment of NPS are symptomatic and supportive. In some cases, treatment for associated bone abnormalities may include surgical replacement of knee caps with artificial devices (prosthetics) and/or correction and/or reconstruction of hypoplastic bones within the knee and/or elbow areas. Abnormal webbing at the bend of the elbow (antecubital pterygium) may also be surgically corrected to help improve arm extension. Scoliosis may be treated with a combination of exercises and physical therapy, other supportive techniques, braces, casts, and/or corrective surgery.
In individuals with open-angle glaucoma, treatment measures may include the use of medicated eyedrops to help reduce fluid pressure in the eyes, certain medications by mouth, and/or surgery. In affected children with other ocular abnormalities associated with NPS, corrective glasses, contact lenses, and/or surgery may be used in some cases to help improve vision.
Affected individuals with nephropathy, particularly those who have been diagnosed with nephrotic syndrome, should be referred to physicians who specialize in diseases affecting the kidneys (nephrologists).
Early intervention is important to ensure that children with NPS reach their potential. Special services that may be beneficial to affected children may include physical therapy, special social support, and other medical, social, and/or vocational services.
Genetic counseling will be of benefit for affected individuals and their families. Family members of individuals with NPS should also receive thorough clinical examinations and other appropriate tests to detect certain abnormalities potentially associated with the disorder. Other treatment for this disorder is symptomatic and supportive.
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