The SHOX gene, or Short stature homeobox-containing gene, provides instructions for making a protein involved in skeletal development, especially the growth of bones in the arms and legs. This protein is a transcription factor, meaning it controls the activity of other genes active during early embryonic development. Its role in human growth makes it a point of interest for understanding certain types of short stature.
The Role of the SHOX Gene in Development
The protein produced from the SHOX gene is a regulator in the development of the human skeleton. Its highest levels of expression are in the growth plates of long bones, which are areas of new bone growth in children and adolescents. The SHOX protein is active in chondrocytes, the cells that make up cartilage in these growth plates, where it regulates cell proliferation and differentiation to ensure bones in the arms and legs grow to their appropriate length.
The SHOX gene is located within the pseudoautosomal region 1 (PAR1) on the short arms of both the X and Y chromosomes. Unlike most genes on sex chromosomes, this means both males (XY) and females (XX) have two functional copies of the gene in each cell. This dosage is important for normal skeletal growth, and the inheritance pattern is described as pseudoautosomal.
This dual-copy presence ensures that a sufficient amount of the SHOX protein is produced to properly regulate bone development. The gene’s activity helps prevent the premature fusion of the growth plates in the limbs. This function is fundamental for achieving typical adult height and maintaining correct body proportions, particularly the ratio of limb length to trunk height.
Conditions Associated with SHOX Deficiency
When one of two copies of the SHOX gene is altered or missing, it causes SHOX haploinsufficiency, meaning only one gene is functional. The most well-known condition from this deficiency is Leri-Weill dyschondrosteosis (LWD), a skeletal dysplasia with disproportionate short stature and a specific wrist deformity. In about 70% of LWD cases, the cause is SHOX gene haploinsufficiency.
A more severe condition, Langer mesomelic dysplasia (LMD), results from having no functional copies of the SHOX gene, which occurs when an individual inherits an altered gene from both parents. LMD is characterized by extreme short stature and severe shortening of the middle segments of the arms and legs. LWD is caused by one non-functional gene, while LMD results from two.
SHOX gene deficiency also accounts for some cases of idiopathic short stature (ISS), where a child’s height is below the typical range without a clear diagnosis. Mutations or deletions of the SHOX gene are found in approximately 2-15% of individuals with ISS.
SHOX deficiency is also a contributor to the short stature seen in Turner syndrome, a condition in females where one X chromosome is partially or completely missing. Because the SHOX gene is on the X chromosome, most individuals with Turner syndrome have only one copy of the gene, leading to reduced SHOX protein production.
Physical Characteristics and Symptoms
The primary physical manifestation of SHOX deficiency is short stature. This is often disproportionate, where the limbs, particularly the forearms and lower legs (a condition known as mesomelia), are short in relation to the trunk. This disproportion may not be obvious in early childhood but becomes more apparent as a child grows.
A characteristic sign of SHOX deficiency, particularly in Leri-Weill dyschondrosteosis, is the Madelung deformity of the wrist. This deformity develops during mid-to-late childhood or early adolescence and involves an abnormal alignment of the wrist bones. It results from the premature fusion of a part of the growth plate in the radius, leading to a bowed forearm and a prominent ulnar bone at the wrist, which can cause pain and limit movement.
Other physical features can include bowing of the forearm bones, an increased carrying angle at the elbow (cubitus valgus), and a high-arched palate. Some individuals may also show what appears to be muscular hypertrophy, though it is not due to a muscle disorder. The severity of these traits can vary significantly, even among family members with the same gene alteration, and females tend to be more affected than males.
Diagnosis and Management
Diagnosis of a SHOX deficiency-related condition is suspected based on clinical signs like disproportionate short stature or a Madelung deformity. Physicians may use X-rays of the wrist and forearm to identify bone changes. A definitive diagnosis requires genetic analysis, using methods like multiplex ligation-dependent probe amplification (MLPA) to detect deletions or DNA sequencing to find smaller mutations.
Once a SHOX deficiency is confirmed, management focuses on addressing the short stature. Treatment with recombinant human growth hormone (rhGH) is a standard approach for children with this condition. Administered through daily injections, growth hormone increases growth velocity during childhood and can improve final adult height by an average of 7 to 10 cm.
Management may also involve a multidisciplinary team to address specific symptoms. For a painful Madelung deformity, treatment can include wrist splints or supports. In some cases, surgical procedures may be considered to reduce pain and improve wrist function. Regular monitoring by a pediatric endocrinologist is used to manage growth hormone therapy and track overall development.