NORD gratefully acknowledges Philip Vazquez, NORD Editorial Intern from the University of Notre Dame, and Julie Hoover-Fong, MD, PhD, Director, Greenberg Center for Skeletal Dysplasias, Associate Professor, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, for assistance in the preparation of this report.
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 greatly in range and severity, characteristic abnormalities tend to include improper development (dysplasia) of the fingernails and toenails; absence (aplasia) and/or underdevelopment (hypoplasia) of the knee caps (patellae); limited movement of the elbow including extension and rotation caused by underdevelopment or dislocation of the radius (a forearm bone that is part of the elbow) 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 with NPS 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. Another common eye (ocular) difference associated with NPS is an abnormally dark (hyperpigmented) and “cloverleaf” shape discoloration around the inner margin (pupillary margin) of the colored portion of the eyes (irides). This is known as (Lester’s sign) and does not cause any problems with vision.
Approximately 30 -50% of individuals with NPS may also develop abnormalities in kidney function (nephropathy) that may be apparent during childhood or later in life. Kidney failure may occur in up to 5% of all NPS patients.
NPS is an autosomal dominant genetic condition. This means any individual with NPS, regardless of gender, has a 50% chance of passing this condition on to each of his/her offspring.
Nail changes are the most constant feature of NPS (98%). 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, the other fingernails may be more mildly affected or not at all. Typically the severity of the nail dysplasia decreases from the thumb toward the 5th digit. 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 people, the crescent-shaped pale area at the base of the nail (lunula) is malformed and/or triangular. Improper development (dysplasia) of the toenails is usually less common than the fingernails; if the toenails are involved, it is often the little toenail that is affected.
Most individuals with NPS also have abnormalities of certain bones. In most people, one or both knee caps (patellae) may be abnormally small, underdeveloped (hypoplastic), and misshaped (e.g., tripartite, polygonal). In other people, one or both knee caps may be absent. In addition, affected individuals may also demonstrate underdevelopment (hypoplasia) of the two bones that create the outer part of the knee (the top of the fibula in the lower part of the leg and/or the lower, rounded projection of the femur in the upper part of the leg). Due to such abnormalities, individuals with NPS often exhibit partial dislocation (subluxation) of the patella 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).
Most people 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, some 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). Some 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 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’s sign). 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 30-50% 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 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 people, the nephropathy may be relatively benign. However, in about 5% of those affected, progressive kidney failure may result, causing potentially life-threatening complications.
For example, some 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 people, 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 disease with 5% progressing to kidney failure.
NPS is an autosomal dominant genetic condition. 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.
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. Approximately 88% of people with NPS have an affected parent and 12% develop the condition as the result of a new mutation. 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.
LMX1B is the only gene currently known to cause NPS. However, it is likely that one or more genes will be found in the future to cause NPS because there are rare families with all the classic features of NPS but lacking a mutation in the LMX1B gene. The LMX1B gene regulates production of a protein that controls the direction the embryonic structures that become the arms and legs (limb buds) grow relative to the trunk. Mutations of the LMX1B gene result in skeletal defects, including impaired development of the knee caps and elbows, nail dysplasia, and kidney abnormalities.
Many different mutations of the LMX1B gene have been identified in people with NPS. There does not appear to be a correlation between specific LMX1B gene mutations and the range and severity of the condition. However, mutations in one small region of this gene have been found in people with isolated kidney disease. More research is needed to learn more about this unique presentation.
NPS affects males and females in equal numbers and is thought to affect approximately one in 50,000 people. The true prevalence may be higher since mildly affected people may be undiagnosed.
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/horns). 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.
Molecular genetic testing for mutations in the LMX1B gene is available to confirm the diagnosis.
The treatment of 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 (ophthalmologists), 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 stabilization or 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 released to help improve arm extension. However, further surgical manipulation of the elbows may be quite difficult because the internal elbow structures may be misplaced due to its abnormal embryologic development. For this reason, magnetic resonance imaging is recommended prior to undertaking surgery on the elbow (or knee, for that matter). 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 eye drops 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). Blood pressure and kidney function must be monitored closely and treated if abnormal.
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 is recommended 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.
Clinical Testing and Work-Up
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, microcornea, cataracts). For example, in many cases, open-angle glaucoma may initially cause no apparent symptoms and therefore may only be detected during an eye examination, 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 renal insufficiency, such as blood tests to check BUN and creatinine levels. Screening for nephropathy may include urinary analysis which may reveal small traces of blood (hematuria) and/or 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.
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:
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
(Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder [e.g., bone abnormalities, kidney disease etc.].)
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