Nail-Patella syndrome (NPS) is a rare, inherited disorder that affects the body’s connective tissue, impacting several systems including the skeletal structure, nails, kidneys, and eyes. This condition typically presents from birth or early childhood and has a wide range of symptom severity among affected individuals. NPS affects approximately one in 50,000 people. The syndrome is defined by a characteristic set of physical findings related to the development of the limbs and other tissues.
Defining Physical Manifestations
The most consistent feature of NPS is nail dysplasia, observed in nearly all affected individuals, often more severely on the fingernails than the toenails. These nails are frequently small, underdeveloped (hypoplastic), or completely absent. The thumbnails and index fingernails usually show the most pronounced changes. The nail surface may also exhibit pitting, ridges, or splits, and the pale, half-moon-shaped area at the base of the nail, known as the lunula, can appear triangular instead of crescent-shaped.
Skeletal abnormalities are also a defining characteristic, most notably involving the kneecaps, or patellae. The patellae are often underdeveloped (hypoplastic), irregularly shaped, or entirely missing (aplasia) in about 75% of patients. This malformation can lead to the kneecap being positioned higher and farther to the side than normal, resulting in joint instability and frequent dislocation.
Other joints are also commonly affected, particularly the elbows, with about 75% of individuals experiencing some degree of elbow abnormality. This can manifest as limited mobility, specifically difficulty with full extension or rotation of the forearm. A unique bony projection known as an iliac horn can be present on the back of the pelvic bone (ilium). While these iliac horns are considered a pathognomonic sign of NPS, they are typically asymptomatic.
The Genetic Cause
Nail-Patella syndrome is caused by a change, or mutation, in the LMX1B gene, which is located on chromosome 9. This gene provides instructions for making a protein that functions as a transcription factor, meaning it regulates the activity of numerous other genes. The LMX1B protein plays a formative role in the embryonic development of the limbs, kidneys, and eyes.
The inheritance pattern for NPS is autosomal dominant, meaning that a person only needs to inherit one copy of the altered gene from either parent to develop the condition. An individual with NPS has a 50% chance of passing the gene change on to each of their children. This pattern explains why the condition often appears across multiple generations in a family.
While most cases are inherited, approximately 10% of NPS diagnoses result from a spontaneous mutation in the LMX1B gene, occurring in individuals with no family history of the disorder. The wide variation in symptoms seen in NPS, even among family members with the same gene change, is due to the condition’s highly variable expressivity.
Diagnosis and Ongoing Management
Diagnosis is often initiated clinically by observing the characteristic physical findings, particularly the combination of nail and skeletal changes. Imaging tests, such as X-rays, confirm skeletal abnormalities like patellar underdevelopment and the presence of iliac horns. A definitive diagnosis is typically made through genetic testing, which identifies a mutation in the LMX1B gene.
Since there is no treatment that corrects the underlying genetic cause, management focuses on addressing specific symptoms and monitoring for potential complications. Orthopedic issues, such as joint instability and pain, are often managed with physical therapy, bracing, or corrective surgery. Magnetic resonance imaging (MRI) may be used before surgical intervention to map the abnormal joint anatomy.
A serious concern in NPS is the involvement of the kidneys, known as NPS nephropathy, which occurs in about 30% to 50% of affected individuals. The first indication of kidney involvement is often proteinuria. Regular monitoring with urine tests and blood pressure checks is necessary to detect early signs of kidney issues. Medications like angiotensin-converting enzyme (ACE) inhibitors may be prescribed to manage high blood pressure and potentially slow the progression of kidney disease. Periodic eye examinations are also recommended to screen for ocular involvement, specifically the increased risk of developing glaucoma at a younger age.