SHOX syndrome is a genetic condition that influences bone growth and physical development, primarily manifesting as differences in height and limb proportion. The condition arises from alterations to a specific gene responsible for skeletal formation, leading to a range of characteristics that vary among those affected.
Genetic Origins of SHOX Syndrome
The root of SHOX syndrome lies in the short stature homeobox-containing (SHOX) gene. This gene provides instructions for a protein active within the growth plates, which are areas of cartilage near the ends of long bones. The SHOX protein plays a part in the development of cartilage cells called chondrocytes. Proper function of this gene ensures bones grow to their appropriate length and shape.
A deficiency in the functional SHOX protein disrupts bone growth, leading to the skeletal abnormalities seen in the syndrome. This can be caused by a deletion of the entire gene or a mutation within its DNA sequence. About 80-90% of cases are due to deletions, while the remaining 10-20% result from mutations that impair the protein’s function.
The SHOX gene is located on the sex chromosomes. It resides in the pseudoautosomal region of both the X and Y chromosomes. Genes in this region behave like those on non-sex chromosomes (autosomes), meaning both males (XY) and females (XX) have two functional copies in each cell. Because of this, SHOX syndrome is inherited in a pseudoautosomal dominant pattern, and a parent with the condition has a 50% chance of passing the genetic variant to each child.
Physical Characteristics
The most consistent feature of SHOX syndrome is short stature, often accompanied by disproportionate growth where the limbs are unusually short compared to the trunk. The shortening is most pronounced in the middle segments of the limbs (mesomelia), affecting the forearms and lower legs. This disproportion can become more apparent as a child grows.
A common skeletal sign of SHOX syndrome is the Madelung deformity of the wrist. This condition involves an abnormal alignment of the radius and ulna—the two bones of the forearm—causing a bend and partial dislocation of the wrist joint. This can result in a visible bump on the outside of the wrist, limited range of motion, and sometimes pain, typically developing during mid-to-late childhood.
Other physical traits can also be present, though their prevalence and severity vary. Some may have a high-arched palate or an unusually small jaw. Another finding is an increased carrying angle at the elbow (cubitus valgus), where the forearms angle away from the body. Additionally, some individuals may display well-developed calf muscles.
The Diagnostic Process
Diagnosis often begins with a clinical evaluation. A doctor will assess the individual’s growth patterns, noting a height below the third percentile for their age, and look for distinctive physical features. The physician will also take detailed measurements of limb segments to identify any disproportionate shortening.
Following the physical examination, radiological studies are ordered. X-rays of the wrists and forearms are particularly useful for identifying skeletal abnormalities. These images can reveal the signs of Madelung deformity, such as the bowing of the radius and changes in the alignment of the small carpal bones in the wrist.
The definitive step to confirm a diagnosis is molecular genetic testing of a blood sample to look for changes in the SHOX gene. The testing can detect if the gene has been deleted or if it has specific mutations. This analysis confirms SHOX deficiency as the cause of the skeletal features.
Management and Treatment Approaches
The primary medical intervention for short stature in SHOX syndrome is growth hormone (GH) therapy, which aims to increase the growth rate during childhood and improve final adult height. GH therapy is initiated once growth failure is identified and continues until the child’s growth plates have closed, signaling the end of bone growth.
For skeletal issues like the Madelung deformity, orthopedic management is a component of care. In milder cases where the deformity causes minimal pain or functional limitation, treatment may involve observation or the use of wrist splints to provide support and alleviate discomfort.
In more severe instances with significant pain, loss of wrist function, or progressive worsening, surgical correction may be necessary. These surgeries aim to improve the alignment of the wrist bones to reduce pain, increase range of motion, and improve the function of the wrist and hand.