Nail-patella syndrome

The symptoms of nail-patella syndrome most commonly affect the way the nails, kneecaps (patellae), elbows, and hip bone form. Almost all people with nail-patella syndrome have nails that are missing, underdeveloped, discolored, split, or ridged. The fingernails are more likely to be affected than the toenails. The thumbnails tend to be the most severely affected.^[1][2][3] 

Most people who have nail-patella syndrome have kneecaps that are small, absent, or irregularly shaped. This can cause problems such as frequent kneecap dislocation or early-onset arthritis. One kneecap may be affected more than the other. Most people with the syndrome also have problems with one or both of their elbows because different parts of the elbow did not develop correctly. Some people are not able to fully extend their elbows or may have a hard time turning (rotating) the lower part of the arm when their arm is straight. The elbow may dislocate easily.^[1][2][3] 

Changes in the pelvic bones called iliac horns can often be seen on x-ray and are found in 70% of people with nail-patella syndrome. Iliac horns are small pointy growths of bone (bony projections) that are not normally found on people's hip bones.  Although these changes do not cause any health problems, iliac horns, if present, can be used to diagnose nail-patella syndrome.^[1][2][3]

Other less common symptoms may include gastrointestinal problems such as constipation or irritable bowel syndrome. There may be nerve (neurological) problems affecting the hands and feet, such as reduced sensitivity to pain and temperature, numbness, tingling, or burning sensations. The hands and feet may be unusually cold, even in warm weather. Dental problems may include weak, crumbling teeth and thin dental enamel.^[2][4]

People with nail-patella syndrome are at a higher risk to develop increased pressure in the eye (glaucoma). About 30-50% of people with nail-patella syndrome have kidney disease. The most common feature of kidney disease is having high levels of protein in the urine (proteinuria). High blood pressure (hypertension) is also common in people with kidney disease. In about 5% of people with nail-patella syndrome, the kidney disease may progress to kidney failure.^[2][3] 

The symptoms associated with nail-patella syndrome can vary widely, even among people in the same family. This concept is called variable expressivity.^[1] 

Nail-patella syndrome is caused by genetic changes (pathogenic variants or mutations) in the LMX1B gene in about 95% of people with the syndrome. The LMX1B gene gives the body instructions to make a protein that is thought to control when other genes are "turned on." These other genes make proteins important for the development of the nails, kneecaps, elbows, kidneys, and eyes. However, the exact function of the LMX1B gene, and the effect of pathogenic variants on its function, are not completely understood.^[1][2]

In rare cases, people who have symptoms of nail-patella syndrome do not have a pathogenic variant in the LMX1B gene. Therefore it is thought that there may be other genes in which pathogenic variants cause nail-patella syndrome.^[3]

Nail-patella syndrome is inherited in an autosomal dominant manner.^[1] Like most genes, the LMX1B gene comes in a pair (two copies). One copy of the gene is inherited from each parent. When a syndrome is inherited in an autosomal dominant manner, a person must only have a pathogenic variant in one copy of the gene to have the syndrome. 

When a person who has a genetic change in the LMX1B gene has children, for each child there is a:

• 50% chance to inherit the changed copy of the LMX1B gene, meaning he or she will have nail-patella syndrome
• 50% chance to inherit the working copy of the LMX1B gene, meaning he or she will not have nail-patella syndrome

About 88% of people with nail-patella syndrome have a genetic change in the LMX1B gene that is inherited from a parent. In some cases, the parent may not have been previously diagnosed with nail-patella syndrome because the symptoms were mild.^[2] In about 12% of people with nail-patella syndrome, the genetic change in the LMX1B gene was not inherited from either parent. Instead, the genetic change was new in the person diagnosed with nail-patella syndrome. Genetic changes that are new in a person are called de novo.^[2] 

Nail-patella syndrome is diagnosed based on the signs and symptoms present (this is called a "clinical diagnosis" and means that laboratory or genetic testing is not necessary for the diagnosis). The diagnosis may be made when a person has a thorough clinical exam and/or imaging studies that identify symptoms such as fingernail or toenail abnormalities (present in 98% of people with the syndrome), small or absent kneecaps, elbow abnormalities, and/or iliac horns (a bone finding common in people with this syndrome but uncommon in people who do not have the syndrome). The diagnosis can be made when a person has at least one (but usually more than one) characteristic symptom.^[1][2] Because about 95% of people with this syndrome have a mutation in the LMX1B gene, genetic testing that identifies a mutation in this gene can confirm the diagnosis both in people with a clinical diagnosis, and in cases where the clinical diagnosis is uncertain.^[2]

After a diagnosis of nail-patella syndrome, a person may be recommended to undergo screening for health problems that are more common in people with the syndrome. This may include having regular blood pressure checks, urine tests to watch for the development of kidney problems, and examinations by a medical eye doctor (ophthalmologist) to check for signs of glaucoma.^[2]

Symptoms of nail-patella syndrome affecting the knee and elbow (orthopedic problems) may be treated with physical therapy, braces, splints, or surgeries. Before a person with nail-patella syndrome has surgery for orthopedic problems, an MRI is recommended to make sure the doctors understand the unique anatomy of the joint or body part. Other symptoms of the syndrome, such as glaucoma or high blood pressure (hypertension), can be treated with medications as the medical problem would in people who do not have the syndrome. In some cases, people with nail-patella syndrome may require a kidney transplant.^[2] It is recommended that people with the syndrome avoid non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, due to their increased risk of kidney problems.^[2]

While many people with nail-patella syndrome do not have serious medical problems, many people have medical complications, including frequent kneecap dislocations, the development of early-onset arthritis, glaucoma, or kidney problems. About 5% of people with nail-patella syndrome develop end-stage kidney disease, meaning that the kidneys stop working and the person may require a kidney transplant. In general, people with the syndrome do well after kidney transplants.^[2] Whether or not a person has kidney disease may be the best indicator of the long-term outlook for people with nail-patella syndrome.^[4]