Nail-Patella Syndrome (NPS) is a rare, inherited condition that affects connective tissues throughout the body, primarily manifesting in the nails, bones, and kidneys. It is a multisystem disorder, and its severity can differ significantly among affected individuals, even within the same family. NPS is estimated to affect approximately one in 50,000 people globally. While physical symptoms are present from birth, the diagnosis may sometimes be delayed due to the variability of the signs. The condition is also sometimes referred to as Hereditary Onychoosteodysplasia.
The Underlying Genetic Cause
Nail-Patella Syndrome is caused by a mutation in the LMX1B gene (LIM homeobox transcription factor 1 beta), located on chromosome 9. This gene provides instructions for making a protein that acts as a transcription factor, regulating the activity of other genes.
The LMX1B protein is important for the normal development of several body structures during the embryonic stage, including the dorsal parts of the limbs, the eyes, and specialized kidney cells called podocytes. The mutation typically results in a non-functional or poorly functioning protein. This loss-of-function mutation causes the disease through haploinsufficiency, where having only one working copy of the gene is not enough for normal development.
NPS follows an Autosomal Dominant pattern of inheritance. A person only needs to inherit one copy of the altered LMX1B gene from a single parent to develop the condition. Consequently, an affected parent has a 50% chance of passing the syndrome on to any child. In a small percentage of cases, the condition can arise spontaneously due to a new, non-inherited mutation.
Primary Musculoskeletal Manifestations
The most visible characteristics of Nail-Patella Syndrome involve the nails and the skeletal system. Nail dysplasia, or abnormal nail development, is present in nearly all affected individuals, typically affecting the fingernails more severely than the toenails. The nails may be small, thin, ridged, pitted, split, or completely absent. The thumb and index finger nails are often the most noticeably affected. A distinctive feature is the presence of a triangular-shaped lunula—the white half-moon area at the base of the nail.
Skeletal abnormalities are also common, particularly involving the knee, elbow, and hip joints. The patellae (kneecaps) are frequently underdeveloped (hypoplastic), irregularly shaped, or entirely absent (aplastic) in about 75% of patients. This patellar involvement can lead to joint instability, frequent kneecap dislocations, and chronic pain. The elbows often show limited range of motion, making it difficult to fully extend the arm or rotate the forearm.
A unique bony feature associated with NPS is the presence of bilateral posterior iliac horns, which are symmetrical, cone-shaped bone projections on the back of the pelvis. These iliac horns are considered pathognomonic, meaning their presence is sufficient to diagnose NPS. They usually do not cause symptoms and are discovered incidentally through X-ray imaging. Other potential skeletal issues include scoliosis and generalized joint laxity.
Systemic Involvement and Associated Risks
Beyond the musculoskeletal features, Nail-Patella Syndrome can affect other organ systems, most notably the kidneys and eyes, which presents the most significant health risks. Kidney disease, known as NPS nephropathy, occurs in approximately 30% to 50% of patients. This involvement is a direct consequence of the LMX1B mutation affecting the podocytes, specialized cells that form the filtration barrier within the kidneys’ glomeruli.
The earliest sign of kidney involvement is often the presence of protein (proteinuria) and sometimes blood (hematuria) in the urine. While many individuals with NPS nephropathy experience a slow, non-progressive course, up to 15% of those with kidney involvement may progress to End-Stage Renal Disease (ESRD). The pathology is characterized by the accumulation of collagen fibrils within the glomerular basement membrane, which can only be confirmed through a kidney biopsy.
Ocular complications are also a concern, with glaucoma—increased pressure within the eye—being the most common. Glaucoma in NPS can appear earlier in life than in the general population, necessitating proactive eye monitoring. Less frequently, individuals may experience peripheral neuropathy, which affects the nerves outside of the brain and spinal cord.
Diagnosis and Lifetime Management
The diagnosis of Nail-Patella Syndrome is often made based on a clinical examination that identifies the classic features, such as the characteristic nail changes and skeletal abnormalities. Imaging studies, particularly X-rays, are used to confirm the presence of hypoplastic patellae, elbow deformities, and the unique iliac horns. Definitive confirmation is achieved through genetic testing, which identifies the specific mutation in the LMX1B gene.
There is currently no cure for NPS, so management focuses on treating symptoms and preventing complications. Orthopedic management includes physical therapy to strengthen muscles around unstable joints and, in severe cases of patellar instability or joint degeneration, surgical intervention.
The most important aspect of lifetime management is the regular, proactive monitoring of kidney function, due to the risk of nephropathy. This involves annual checks of blood pressure and regular urinalysis to screen for proteinuria and hematuria. If signs of kidney disease are found, medications like Angiotensin-Converting Enzyme (ACE) inhibitors may be prescribed to reduce protein loss and control blood pressure, helping slow the progression of renal damage. Regular eye examinations are also necessary to monitor for and promptly treat glaucoma.