Short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay, commonly known by the acronym SHORT syndrome, is a rare disorder that affects many parts of the body.

Most people with SHORT syndrome are small at birth and gain weight slowly in childhood. Affected adults tend to have short stature compared with others in their family. Many have a lack of fatty tissue under the skin (lipoatrophy), primarily in the face, arms, and chest. This lack of fat, together with thin, wrinkled skin and veins visible beneath the skin, makes affected individuals look older than their biological age. This appearance of premature aging is sometimes described as progeroid.

Most people with SHORT syndrome have distinctive facial features. These include a triangular face shape with a prominent forehead and deep-set eyes (ocular depression), thin nostrils, a downturned mouth, and a small chin. Eye abnormalities are common in affected individuals, particularly Rieger anomaly, which affects structures at the front of the eye. Rieger anomaly can be associated with increased pressure in the eye (glaucoma) and vision loss. Some people with SHORT syndrome also have dental abnormalities such as delayed appearance (eruption) of teeth in early childhood, small teeth, fewer teeth than normal (hypodontia), and a lack of protective covering (enamel) on the surface of the teeth.

Other signs and symptoms that have been reported in people with SHORT syndrome include immune system abnormalities, a kidney disorder known as nephrocalcinosis, hearing loss, loose (hyperextensible) joints, and a soft out-pouching in the lower abdomen called an inguinal hernia. A few affected individuals have developed problems with blood sugar (glucose) regulation including insulin resistance and diabetes. Most people with SHORT syndrome have normal intelligence, although a few have been reported with mild cognitive impairment or delayed development of speech in childhood.

SHORT syndrome results from mutations in the PIK3R1 gene. This gene provides instructions for making one part (subunit) of an enzyme called PI3K, which plays a role in chemical signaling within cells. PI3K signaling is important for many cell activities, including cell growth and division, movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival. Studies suggest that PI3K signaling may be involved in the regulation of several hormones, including insulin, which helps control blood glucose levels. PI3K signaling may also play a role in the maturation of fat cells (adipocytes).

Mutations in the PIK3R1 gene alter the structure of the subunit, which reduces the ability of PI3K to participate in cell signaling. Researchers are working to determine how these changes lead to the specific features of SHORT syndrome. PI3K's role in insulin activity may be related to the development of insulin resistance and diabetes, and problems with adipocyte maturation might contribute to lipoatrophy in affected individuals. It is unclear how reduced PI3K signaling is associated with the other features of the condition.

Normal Function

The PIK3R1 gene provides instructions for making a part (subunit) of an enzyme called phosphatidylinositol 3-kinase (PI3K). The primary function of the subunit is to regulate the enzyme's activity. Several slightly different versions of this regulatory subunit are produced from the PIK3R1 gene; the most abundant of these is called p85 alpha (p85α).

PI3K is a kinase, which means that it adds a cluster of oxygen and phosphorus atoms (a phosphate group) to other proteins through a process called phosphorylation. PI3K phosphorylates certain signaling molecules, which triggers a series of additional reactions that transmit chemical signals within cells. PI3K signaling is important for many cell activities, including cell growth and division (proliferation), movement (migration) of cells, production of new proteins, transport of materials within cells, and cell survival.

Studies suggest that PI3K signaling may be involved in how cells regulate several hormones. One of these hormones is insulin, which helps control levels of blood glucose, also called blood sugar. PI3K signaling may also play a role in the maturation of fat cells (adipocytes).

Health Conditions Related to Genetic Changes

Activated PI3K-delta syndrome

Variants (also called mutations) in the PIK3R1 gene have been found to cause an immune disorder called activated PI3K-delta syndrome. PIK3R1 gene variants cause a form of the condition called activated PI3K-delta syndrome type 2. People with activated PI3K-delta syndrome type 2 typically have recurrent bacterial infections of the respiratory tract and chronic viral infections.

PIK3R1 gene variants lead to an altered p85α protein, sometimes causing it to be abnormally short. These variants are classified as gain-of-function variants because a PI3K-delta enzyme that contains the altered subunit is frequently turned on (overactive).

Studies indicate that overactive PI3K-delta signaling alters the growth of certain immune system cells known as B cells and T cells. T cells mature and die too quickly, and B cells are blocked from maturing at an early stage. The immature B cells cannot respond to foreign invaders and likely self-destruct. The lack of B cells and T cells makes it difficult for people with this disorder to fight off bacterial and viral infections. Overactive PI3K-delta signaling can also stimulate the abnormal proliferation of white blood cells in some affected individuals. Activated PI3K-delta syndrome type 2 is also associated with an increased risk of developing a form of blood cell cancer called lymphoma.

Short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay

Variants in the PIK3R1 gene have also been reported to cause a condition known as short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay (often called SHORT syndrome). This condition is characterized by signs and symptoms affecting many parts of the body, including the skin, eyes, teeth, and joints.

The most common PIK3R1 gene variant changes a single protein building block (amino acid) in the regulatory subunit of PI3K. Variants in the PIK3R1 gene alter the structure of the subunit, which reduces the ability of PI3K to participate in cell signaling. Because the variants reduce the enzyme's activity, they are described as loss-of-function variants.

Researchers are working to determine how PIK3R1 gene variants lead to the specific features of SHORT syndrome. PI3K's role in insulin activity may be related to insulin resistance and diabetes, which are problems with blood glucose regulation that are found in some people with SHORT syndrome. Abnormal adipocyte maturation might contribute to a lack of fatty tissue under the skin (lipoatrophy), which is another common feature of the condition. It is unclear how reduced PI3K signaling is associated with the other signs and symptoms of SHORT syndrome.

Cancers

Some gene variants, called somatic variants, are not inherited and are present only in certain cells. Somatic PIK3R1 gene variants have been identified in some cancers of the uterine lining (endometrial cancers) and in a form of brain cancer called glioblastoma. Less commonly, somatic variants in the PIK3R1 gene have been found in cancers of the colon, ovary, and breast.

Cancer-associated changes in the PIK3R1 gene alter the regulatory subunit such that it can no longer control the activity of PI3K, which increases PI3K signaling dramatically. Because the genetic changes enhance the activity of the enzyme, they are classified as gain-of-function variants. Increased PI3K signaling appears to promote the uncontrolled cell growth and division that is characteristic of cancerous tumors. It is unclear why these variants seem to be more common in some types of cancer than in others.

Other Names for This Gene

• p85
• p85-ALPHA
• P85A_HUMAN
• phosphatidylinositol 3-kinase 85 kDa regulatory subunit alpha
• phosphatidylinositol 3-kinase regulatory subunit alpha
• phosphatidylinositol 3-kinase-associated p-85 alpha
• phosphoinositide-3-kinase regulatory subunit
• PI3-kinase subunit p85-alpha
• PI3K regulatory subunit alpha

Genomic Location

SHORT syndrome has an autosomal dominant pattern of inheritance, which means one copy of the altered PIK3R1 gene in each cell is sufficient to cause the disorder. In most cases, the condition results from a new mutation in the gene and occurs in people with no history of the disorder in their family. In other cases, an affected person inherits the mutation from one affected parent.

There is no formal criteria for diagnosis yet. The term “SHORT syndrome” was first created to reflect several of the features of the original reported cases: Short stature, Hyperextensibility, Ocular depression (deeply set eyes), Rieger anomaly, and Teething delay. However, it is now recognized that all of these five features are neither required to make the diagnosis nor necessarily the most specific features of SHORT syndrome.

The features most consistently observed in SHORT syndrome include:

• Intrauterine growth restriction (IUGR)
• Short stature
• Partial lipodystrophy
• Facial characteristics: Face with triangular shape, prominent forehead, deep-set eyes, nose with a narrow low-hanging tip and thin nasal alae, small chin with a central dimple and large ears that are low-set.

Other frequent features include:

• Axenfeld-Rieger anomaly or related eye anomalies
• Delayed dentition
• Diabetes.

In general, the facial features allow to make a suspicion of the diagnosis. Diagnosis is confirmed with the genetic testing showing a mutation in the PIK3R1 gene.