What is Nail-Patella Syndrome?

Nail-patella syndrome (NPS), also known as Fong disease or hereditary onycho-osteodysplasia, is a rare condition that affects multiple body systems. The typical signs of NPS include abnormal fingernails, underdeveloped or missing kneecaps (patella), bone protrusions (iliac horns) on the hip bone, and unusual elbow joint formation. This condition could also involve the eyes, kidneys, and the nervous system. Dr. E. M. Little first observed and documented NPS’s inherited nature in 1897. But it wasn’t until the mid 20th century that scientists discovered the condition passed from parents to children (autosomal dominant inheritance pattern) and understood its genetic aspect.

Diagnosis of NPS usually involves an examination of the physical symptoms and reviewing X-ray images, although genetic testing and kidney biopsy (a procedure where a small piece of kidney tissue is removed for examination) can help confirm the diagnosis. Even though individuals with NPS usually have a good prognosis, which means they’re likely to have a normal life span, there exist serious complications. Therefore, certain guidelines have been suggested to help manage the condition effectively.

What Causes Nail-Patella Syndrome?

Nail-patella syndrome is an inherited disorder that is passed from parents to children. It is caused by a mutation in a specific gene called LMXB1, which resides on a particular section of chromosome 9. The LMXB1 gene is responsible for creating a protein that plays a critical role in the development of numerous body parts during embryonic stages, including certain parts of limbs, types of brain cells, skull structure, development around the eyes, and specific kidney cells.

It is known that at least 142 types of changes or mutations in the LMXB1 gene can cause this syndrome. There is also evidence of what is known as somatic mosaicism, a condition where some cells have the genetic mutation causing the syndrome, while others do not. This often happens in parents who do not have the syndrome, but have a child who does.

Even though Nail-patella syndrome is likely to appear if the mutation is present, the symptoms can vary a great deal among different family members. This variability may be due to interactions that the LMXB1 gene has with other genes in the body. For example, the PAX2 gene, which also plays a role in kidney and eye development, may interact with the LMXB1 gene. If the LMXB1 gene is mutated, it may interact differently with the PAX2 gene, potentially influencing how Nail-patella syndrome presents. However, more research is needed to fully understand this potential interaction.

Risk Factors and Frequency for Nail-Patella Syndrome

Nail-patella syndrome is quite rare, affecting about 1 in every 50,000 people. Because this syndrome is genetic, it can vary a lot in how it shows up, which might make people doubt the reported rates of this condition. It’s also important to know that even though doctors can diagnose this condition at birth, many families affected by nail-patella syndrome may not receive a diagnosis for many generations. So, we aren’t completely sure about the actual rates of this condition.

Signs and Symptoms of Nail-Patella Syndrome

Nail-patella syndrome is a condition where patients experience reduced muscle mass in their upper and lower body, making it look like there’s a muscular disorder. The main features of this syndrome are changes in the nails and kneecaps. Approximately 98% of patients show different types of nail disorders, including missing, underdeveloped, or damaged fingernails. The toenails are affected to a lesser extent. Interestingly, the fingernails on the side of the little finger are often more affected. One of the signs that doctors look for is a ‘swan-neck’ deformity, where the fingers are hyperextended at certain joints and flexed at others. Another sign is reduced skin creases over certain finger joints, which is quite typical of this syndrome.

Like the nails, the kneecaps of these patients may also be missing, underdeveloped, or irregularly shaped. These kneecaps are often dislocated, although they sometimes are naturally off to one side. Abnormal developments in the lower section of the femur and the primary muscles controlling knee movements can also be observed. Patients may have a limited range of movement in the elbow joints in extension, rotation, and supination techniques. Skin contraction and thin, web-like membranes at the elbow joint are common. Interestingly, they may have symmetrical bone growths on the wide upper end of their hip bones. About 70% of patients with this syndrome have these bone outgrowths, which are characteristic of this condition. These outgrowths are an extension of the tissue that makes up the inner part of the bone, at the level where a muscle (gluteus medius) originates. An intriguing aspect of this syndrome is that although the bone density in the hip and spine area is minimally reduced, patients tend to have a higher risk of fractures in the long bones. The reason for this isn’t well-understood.

Patients with this syndrome may also have other systemic manifestations not related to the skeleton. These can involve the kidneys, eyes, and nervous system. Kidney-related symptoms occur in 30-60% of affected individuals. This aspect of the syndrome significantly influences the patient’s survival rate as it can rapidly progress to kidney failure in about 10% of patients. The most common eye issues are glaucoma and ocular hypertension. Interestingly, individuals with this syndrome often develop these conditions earlier than unaffected individuals, but with regular checks, these issues can be treatable and preventable. A unique symptom related to the eyes is the appearance of a darkened area around the iris, known as Lester’s sign. However, this isn’t a definite indicator of the syndrome. Another symptom experienced by patients includes neurological issues such as numbness, tingling, and pain, which isn’t associated with peripheral nerves but tends to affect extremities more than the upper limb.

Testing for Nail-Patella Syndrome

In simpler terms, when a doctor suspects someone might have Nail-patella syndrome with kidney problems, they may use a routine urine test first. They often look out for protein or blood in the urine, which are usually the first signs. To confirm the diagnosis, a renal biopsy (a test where a small piece of kidney is removed to examine for diseases) might be needed.

Imaging tests, like X-rays and MRI scans, are also crucial in diagnosing Nail-patella syndrome. This is primarily because the condition often results in specific bone and muscle changes that show up these scans. For example, the kneecap can appear small or even absent, along with other changes to specific areas of the thigh bone.

A case has been reported where a specific tissue in the knee was clearly visible on an MRI scan but not on an X-ray. There could also be tell-tale signs in X-rays of the pelvis, like the presence of iliac horns (bony spurs on the pelvis), which is considered a definite sign of Nail-patella syndrome.

X-rays can also highlight radial head dysplasia (a deformity of the head of the radius bone in the forearm) and any complications arising from it, like subluxation (partial dislocation of a joint).

Treatment Options for Nail-Patella Syndrome

Medical Treatment

The main goal of treatment for kidney issues related to this disease is to slow down its development, specifically focusing on reducing the protein in the urine. To do this, certain drugs are used to target the renin-angiotensin-aldosterone system (RAAS), which plays a key role in controlling blood pressure and the balance of fluids and electrolytes. Two types of drugs can be used for this purpose: angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs). However, there isn’t enough data to clearly suggest the best medical treatment. In one specific case, a young girl with kidney disease and high levels of protein in her urine was successfully treated with a combination of ACEi and ARBs. However, it’s important to note that the kidney disease can progress to a severe state requiring a kidney transplant in some cases. Another option that has been suggested for patients who do not respond to ACEi treatment is a drug called cyclosporin, which has been found to reduce protein in the urine in patients with Alport syndrome, another genetic disease affecting the kidneys.

Surgical Treatment

In this disease, knee pain and knee dislocation are common symptoms, which can initially be treated with non-surgical methods. However, several surgical techniques have been developed to fix the instability of the kneecap. Interestingly, one surgical method involves removing a synovial band or plicae, which is thought to contribute to kneecap dislocation. While this method has been reported to improve symptoms, more research is needed to study its long-term outcomes. A survey in the Netherlands indicated that most patients who underwent surgery for their knee symptoms were satisfied, but the rate of continued kneecap instability was the same for patients who had surgery and those who did not.

Patient Management

As of now, no specific guidelines have been proposed by major medical organizations for the management of this disease. A group of researchers has suggested recommendations aiming to maintain the patient’s quality of life, provide genetic counseling for patients and their families, and take preventive measures to avoid complications such as glaucoma and kidney failure that could increase the risk of serious health problems and death.

Nail-patella syndrome is a condition that affects bones, muscles, and nails. However, it can be a bit tricky to diagnose because it shares similar symptoms with other genetic diseases. In order to highlight the similarities and differences with nail-patella syndrome and other conditions, Sweeney and colleagues shared a detailed review. This is important because having clear guidelines helps in making a more accurate diagnosis.

What to expect with Nail-Patella Syndrome

Patients with Nail Patella Syndrome (NPS) usually live as long as others, and any reported links with cancer are thought to be coincidental. There are non-surgical and surgical treatment options available for patients experiencing knee cap related symptoms.

Glaucoma (a condition affecting the eyes, which can lead to blindness) and nephropathy (kidney disease) are two potentially serious health problems associated with NPS. However, these can generally be prevented or managed if they are detected early enough through regular screening.

In terms of kidney disease, patients with signs of protein in their urine (proteinuria) or high blood pressure could be treated with a type of medication called an angiotensin-converting enzyme inhibitor, and in extreme cases, a kidney transplant may be an option.

Possible Complications When Diagnosed with Nail-Patella Syndrome

The most dangerous complications of Nail-Patella Syndrome (NPS) are a type of eye disease called acute open-angle glaucoma and kidney failure. Around 17% of people over 40 with NPS have been found to have glaucoma, but luckily with early detection, it can usually be treated or even prevented.

The scariest thing about NPS, though, is that it can lead to kidney failure, which can often result in death. The progression to kidney failure in Nail-Patella Syndrome can happen very quickly or may take several years, and we don’t fully understand why.

Just like with glaucoma, kidney disease in NPS can usually be treated or even prevented if it’s picked up early through screening.

Common Complications of Nail-Patella Syndrome:

Acute open-angle glaucoma (a type of eye disease)
Kidney failure

Preventing Nail-Patella Syndrome

People who have Nail-Patella Syndrome (NPS), a genetic disorder affecting nails, knees, elbows, and pelvis, can experience a variety of health issues that can be complex and hard to understand. It’s best if a team of different healthcare professionals take care of them. This is called a multidisciplinary approach. Most of the time, these patients are provided care that involves minimal medical interventions, also known as conservative treatment.

It’s recommended that patients with NPS and their families consider genetic counseling. Genetic counseling is a service that provides information and support to people who have, or may be at risk for, genetic disorders. It’s important that they are regularly checked for serious complications that can result from NPS. Specifically, the risk of developing kidney disease (nephropathy) and a serious eye condition that can cause blindness (glaucoma), should be monitored closely.