Small patella syndrome (SPS) is a rare syndrome that mainly affects the way certain bones are formed (developed). A person with SPS usually has very small kneecaps (hypoplastic patella) or may have no kneecaps at all (aplastic). The hip (pelvic) bones may be weak, and the bones of the feet may not have formed correctly. Occasionally, bones in the face may also be affected.

Small patella syndrome is caused by a change (pathogenic variant or mutation) in the TBX4 gene. The syndrome is inherited in an autosomal dominant manner. Diagnosis of the syndrome is suspected based on features that can be seen in a physical exam and on imaging tests such as X-rays. Diagnosis of SPS can be confirmed with genetic testing. Treatment of SPS may include pain management with medications, physical and occupational therapies, and surgical treatments.

TBX4 gene. Almost all genes provide instructions to make proteins that help our bodies develop and function properly. While the exact role of the TBX4 gene in humans is not known, it is known that a very similar gene exists in chickens and mice and helps their hind legs develop properly. Therefore, it is thought that the protein made from the TBX4 gene is involved in the development of the legs, but researchers are still trying to understand how changes in the TBX4 gene cause all of the features seen in a person with SPS, as well as why changes in the gene may affect people differently.

TBX4 gene comes in a pair (two copies of the gene). One copy of each gene comes from the mother and one from the father. Since SPS is inherited in an autosomal dominant manner, people with SPS need to have a genetic change (pathogenic variant or mutation) in only one copy of the TBX4 gene in each cell of the body to have SPS.

When a person with SPS has children, each child has a:

• 50% chance to inherit the pathogenic variant in the TBX4 gene, meaning he or she will have SPS
• 50% chance to inherit the working copy of TBX4, meaning he or she will not have SPS

SPS shows a trait called variable expressivity. This means that even people within the same family can have different features of SPS, and the severity of the symptoms may vary. For example, some people with SPS may not notice that they have a small kneecap, while others may have pain or frequent dislocations of the knee.

In some cases, a person with SPS may be the first person diagnosed with the syndrome in their family. This could happen for two reasons. First, it may be that the newly diagnosed person is the first person in the family to have a pathogenic variant in the TBX4 gene. This is called a de novo mutation. In other cases, a person with SPS is the first person diagnosed in the family, but there are other affected family members that were not diagnosed because they only had very mild changes in the size of their kneecaps and other bones.

A person with SPS may have abnormally shaped hip (pelvic) bones which can cause the leg on the affected side to be shorter (coxa vara). The hip bones may also be weak or more likely to break (fracture). Rarely, people with SPS may have changes in the bones of the face (distinctive facial features) including having a very small chin (micrognathia), cleft palate, or flattened nose. Other less common features of the syndrome include having a curved spine (scoliosis) or frequent dental cavities. Some people with SPS have pulmonary arterial hypertension. This means that the blood pressure in the arteries of the lungs is higher than expected.

Genetic testing of the TBX4 gene can be used to confirm the diagnosis of SPS. However, not every person with SPS has a change (mutation or pathogenic variant) in the TBX4 gene that can be detected on genetic testing. It is thought that pathogenic variants in other genes may cause SPS as well.

Other features of SPS may be treated as they would in people who do not have SPS. For example, scoliosis may be treated with bracing or surgery. Pulmonary arterial hypertension may be treated with medications or supplemental oxygen.

Some people with small patella syndrome (SPS) do not have any symptoms due to having only mild features. Other people respond well to treatment options such as physical or occupational therapy and/or pain relievers. However, some people with SPS may struggle from frequent kneecap dislocations and pain caused by the syndrome, and this may limit their activities or otherwise decrease the quality of their life. If the pain is severe, chronic, and disabling, those caring for a person with SPS should watch for signs of depression and/or anxiety.