Short Stature Homeobox Gene Mutation

Changes in the SHOX gene, located on the sex chromosomes, can lead to a range of conditions affecting growth and bone development, from mild short stature to more severe skeletal abnormalities that impact daily activities.

Table of contents

• What is the SHOX gene and its role
• How SHOX deficiency occurs
• Related health conditions
• Signs and symptoms
• Diagnosis and genetic testing
• How it is inherited
• Treatment and management
• Outlook and prognosis

SHOX deficiency, SHOX haploinsufficiency, short stature homeobox-containing gene mutation

SHOX gene; Dwarfism; Genetic Diseases, X-Linked

What is the SHOX gene and its role

The SHOX gene (short for short stature homeobox-containing gene) provides instructions for making a protein that controls the activity of other genes. Because of this role, the SHOX protein is called a transcription factor, which means it helps regulate how genes work during development^[1].

The SHOX gene belongs to a large family of homeobox genes, which act during early development before birth to control how many body structures form. Specifically, the SHOX gene is essential for skeleton development. It plays a particularly important role in the growth and maturation of bones in the arms and legs^[1].

One copy of the SHOX gene is located on each of the sex chromosomes (the X and Y chromosomes) in an area called the pseudoautosomal region. Although many genes are unique to either the X or Y chromosome, genes in the pseudoautosomal region are present on both chromosomes. As a result, both females (who have two X chromosomes) and males (who have one X and one Y chromosome) have two functional copies of the SHOX gene in each cell^[1][2].

How SHOX deficiency occurs

SHOX deficiency can occur due to several types of genetic changes. The most common cause is a deletion of one copy of the SHOX gene, meaning the gene is completely missing from one chromosome. SHOX deficiency can also result from mutations within the gene itself that prevent it from working properly^[1][4].

Sometimes, deletions occur in genetic material near the SHOX gene that normally helps regulate its activity. These nearby areas contain enhancers, which are sections of DNA that control when and how much of the SHOX protein is produced. When these regulatory regions are deleted, even though the gene itself remains intact, the amount of SHOX protein produced can be significantly reduced^[1][3].

The term haploinsufficiency describes the situation where having only one working copy of the SHOX gene instead of the usual two copies is not enough to produce adequate amounts of SHOX protein. This shortage disrupts normal bone development and growth starting before birth^[3][16].

Related health conditions

The range of conditions caused by SHOX deficiency varies from severe to mild, depending on how many copies of the gene are affected and how much functional SHOX protein is produced^[3].

• Long bones of arms and legs
• Wrist bones
• Forearm bones (radius and ulna)
• Growth plates

Langer mesomelic dysplasia

Langer mesomelic dysplasia is the most severe form of SHOX deficiency. It results from genetic changes involving both copies of the SHOX gene in each cell. This means there is very little or no SHOX protein produced. Deletions of the gene are the most common cause, but mutations in both copies of the gene or deletions of the regulatory regions near both genes can also cause this condition^[1].

The lack of SHOX protein disrupts normal bone development and growth starting before birth. People with this condition have very short stature, extreme shortening of the long bones in the arms and legs (a condition called mesomelia), and an abnormality of the wrist and forearm bones known as Madelung deformity^[1][4].

Léri-Weill dyschondrosteosis

Léri-Weill dyschondrosteosis results from genetic changes involving one copy of the SHOX gene in each cell. Most commonly, this skeletal disorder is caused by a deletion of one SHOX gene. Other genetic changes that can cause the disorder include mutations in one copy of the gene or deletions of nearby genetic material that helps regulate the gene’s activity^[1][3].

In Léri-Weill dyschondrosteosis, the classic clinical features are short stature, mesomelia (shortened middle portions of the limbs), and Madelung deformity. The skeletal abnormalities are similar to those of Langer mesomelic dysplasia but tend to be less severe. Madelung deformity, which is abnormal alignment of the radius, ulna, and carpal bones at the wrist, typically develops in mid-to-late childhood and is more common and severe in females^[3][5].

Idiopathic short stature

Deletions or mutations in the SHOX gene have been identified in some people with short stature that is described as idiopathic, which means it is not associated with the characteristic features of a specific disease or syndrome. However, some people with short stature and changes in the SHOX gene have been found to have subtle skeletal abnormalities^[1][3].

The appearance of short stature caused by SHOX deficiency without mesomelia and Madelung deformity (called SHOX-deficient short stature) is highly variable, even within the same family. This is the mild end of the spectrum of SHOX deficiency disorders^[3].

Turner syndrome

Turner syndrome occurs when one normal X chromosome is present in a female’s cells and the other sex chromosome is missing or structurally altered. Because the SHOX gene is located on the sex chromosomes, most women with Turner syndrome have only one copy of the gene in each cell instead of the usual two copies^[1].

Loss of one copy of this gene reduces the amount of SHOX protein that is produced. A shortage of this protein likely contributes to the short stature and skeletal abnormalities (such as unusual rotation of the wrist and elbow joints) often seen in females with this condition^[1][2].

Signs and symptoms

SHOX deficiency most often results in short stature compared with children of the same age and sex. The severity and range of symptoms depend on the specific condition and how much SHOX protein is being produced^[4].

Common signs and symptoms include shortened forearms and legs, with the middle portion of the limbs being particularly affected. Children may have elbows that turn outward and knees that turn inward. Bowing of the shinbones and short feet are also common findings^[4][5].

Other physical features that may be present include a short neck, a small lower jaw, and unusual curvature of the spine. The roof of the mouth (palate) may be high and narrow. Some individuals have increased muscle mass compared to their height^[4].

Madelung deformity, which affects the bones of the wrists and forearms, can develop in mid-to-late childhood. This abnormality can be evident first in school-aged children and increases with age in both frequency and severity. When present, it may cause wrist pain and limit the range of motion, affecting activities such as lifting, gripping, writing, and typing^[3][5].

In some cases, particularly in severe forms like Langer mesomelic dysplasia, hearing loss has been reported as an accompanying feature^[5].

Diagnosis and genetic testing

The diagnosis of SHOX deficiency is established through genetic testing that identifies either a mutation in the SHOX gene or a deletion, duplication, or insertion that affects the SHOX coding region and the regulatory regions (enhancers) that control SHOX expression^[3].

SHOX gene analysis is typically performed using two main methods. Sanger sequencing examines the DNA sequence of the SHOX gene to identify mutations or changes in the genetic code. Multiplex ligation-dependent probe amplification (MLPA) analysis is used to detect deletions or duplications of the SHOX gene or its regulatory regions^[5].

Healthcare providers may suspect SHOX deficiency based on clinical features such as disproportionate short stature, shortened forearms, or Madelung deformity. When these features are present with or without short stature, genetic testing for SHOX deficiency should be considered^[5].

During evaluation, children with suspected SHOX deficiency undergo measurement of height, weight, arm span, and body proportions. X-rays of the wrists and forearms can reveal characteristic bone abnormalities. Growth patterns are monitored by plotting measurements on growth charts to determine if a child is following their expected growth trajectory^[3][9].

How it is inherited

SHOX deficiency disorders are inherited in a pseudoautosomal dominant manner. In pseudoautosomal dominant inheritance, genes located on both the X and Y chromosomes follow the rules of regular dominant inheritance. This means a SHOX mutation responsible for SHOX deficiency can be located on either the X or the Y chromosome of an affected person^[3].

If a parent has a SHOX deficiency disorder, they have a 50% chance of passing the genetic change to each of their children, regardless of whether the child is male or female^[4].

When both parents have SHOX deficiency (each carrying one affected copy of the gene), their children have specific risks. There is a 50% chance of inheriting one affected copy and developing SHOX deficiency disorder, a 25% chance of inheriting two affected copies and developing the more severe Langer mesomelic dysplasia, and a 25% chance of inheriting two normal copies and not developing either condition^[4].

Family members at risk for SHOX-deficient short stature should undergo presymptomatic diagnosis and evaluation. Identifying affected siblings early is important so that those who would benefit from treatment can begin therapy as soon as possible^[3].

Treatment and management

For prepubertal children with SHOX-deficient short stature, treatment with recombinant human growth hormone (rhGH) should be offered. The recommended dose is 50 micrograms per kilogram of body weight per day. Studies have shown that rhGH therapy can result in a gain in final adult height of 7 to 10 centimeters^[3][7].

Growth hormone therapy has been shown to be effective in improving height outcomes in children with SHOX deficiency. Real-life studies have demonstrated long-term efficacy and safety of this treatment approach^[15].

For individuals with Léri-Weill dyschondrosteosis who develop painful Madelung deformity affecting both wrists, management options include wrist splints and supports during periods of increased discomfort. Ergonomic devices, such as specially designed computer keyboards, can help reduce strain during daily activities^[3].

When Madelung deformity causes significant pain or limits function, different surgical procedures have been attempted to decrease pain and restore wrist function. However, surgery is only considered when symptoms significantly impact quality of life^[3].

Children with SHOX deficiency disorders require regular monitoring. Healthcare providers recommend measuring growth every six months (biannually) to track response to treatment and ensure appropriate growth progression^[3].

If Madelung deformity is present and associated with discomfort, physical activities that strain the wrist should be limited. This includes activities such as lifting, gripping, writing, typing, and sports that put significant pressure on the wrists. Finding ergonomic aids and alternative ways to perform these activities can help maintain function while reducing pain^[3].

Outlook and prognosis

The outlook for individuals with SHOX deficiency varies depending on the severity of the condition. With early diagnosis and appropriate treatment with growth hormone therapy, children with SHOX-deficient short stature can achieve meaningful improvements in their final adult height^[7][15].

While SHOX deficiency primarily affects height and skeletal development, with proper management and support, most individuals can lead healthy, productive lives. The emotional and psychological aspects of being shorter than peers can impact self-esteem, making family support, open communication, and counseling important components of comprehensive care^[14].

Skeletal abnormalities such as Madelung deformity may require ongoing management, but many people learn to adapt their daily activities to minimize discomfort. When wrist pain becomes significant, various treatment options are available to improve comfort and function^[3].

The variability in presentation, even within families, means that not everyone with SHOX deficiency will experience the same degree of symptoms. Some may have only mild short stature without significant skeletal abnormalities, while others may develop more noticeable features. Regular follow-up with healthcare providers helps ensure that any developing issues are identified and addressed promptly^[3].