SHORT syndrome

Alternate names

Short stature, Hyperextensibility, Hernia, Ocular depression, Rieger anomaly and Teething delay; Aarskog-Ose-Pande syndrome; Partial lipodystrophy with Rieger anomaly and short stature

Definition

SHORT syndrome is a medical condition in which affected individuals have multiple birth defects in different organ systems.

Summary

• It was characterized in 1975.
• SHORT syndrome is a condition characterized by multiple abnormalities that affect several parts of the body.
• The term SHORT is an acronym with each letter representing a common feature in affected individuals: (S) short stature; (H) hyperextensibility of joints and/or hernia (inguinal); (O) ocular depression (deep-set eyes); (R) Rieger anomaly (defective development of the anterior chamber of the eye that can lead to glaucoma); and (T) teething delay.
• Other features commonly present include a triangular face, small chin with a dimple, loss of fat under the skin (lipodystrophy), abnormal position of the ears, hearing loss and delayed speech.

Epidemiology

SHORT syndrome is a rare condition; its prevalence is unknown. Only a few affected individuals and families have been reported worldwide.

Cause

• 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 sugar levels.
• PI3K signaling may also play a role in the maturation of fat cells (adipocytes).

Gene mutations

• 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.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

• 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.

Signs and symptoms

• 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 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.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

80%-99% of people have these symptoms

• Deeply set eye(Deep set eye)
• Hypoplasia of the iris(Underdeveloped iris)
• Inguinal hernia
• Joint hyperflexibility(Joints move beyond expected range of motion)
• Sensorineural hearing impairment
• Severe short stature(Dwarfism)

30%-79% of people have these symptoms

• Abnormal pupil morphology(Abnormality of the pupil)
• Abnormality of dental enamel(Abnormal tooth enamel)
• Alopecia(Hair loss)
• Diabetes mellitus
• Excessive wrinkled skin
• Glaucoma
• Insulin resistance(Body fails to respond to insulin)
• Lipodystrophy(Inability to make and keep healthy fat tissue)
• Megalocornea(Enlarged cornea)
• Microdontia(Decreased width of tooth)
• Midface retrusion(Decreased size of midface)
• Neurological speech impairment(Speech disorder)
• Poor appetite(Decreased appetite)
• Sparse hair
• Weight loss

5%-29% of people have these symptoms

• Abnormal anterior chamber morphology
• Abnormality of the mandible(Abnormality of the lower jaw bone)
• Brachydactyly(Short fingers or toes)
• Corneal opacity
• Hypertelorism(Wide-set eyes)
• Malar flattening(Zygomatic flattening)
• Posterior embryotoxon
• Prominent forehead(Pronounced forehead)
• Prominent supraorbital ridges(Prominent brow)
• Short palm
• Telecanthus(Corners of eye widely separated)
• Triangular face(Face with broad temples and narrow chin)
• Wide nasal bridge(Broad nasal bridge)

Diagnosis

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.

Treatment

Treatment of manifestations: Glaucoma: reduce and stabilize intraocular pressure and to preserve vision.

• Sensorineural hearing loss: use of hearing aids.

• Dental anomalies: standard treatment; may include crowns and dental prostheses.

• Glucose intolerance and diabetes mellitus: to be followed by an endocrine specialist.

• Surveillance: Regular monitoring of growth including height, weight, and body mass index. For all individuals with and without apparent anterior chamber anomaly: routine eye examinations to include measurement of intraocular pressure. Hearing assessment every two to three years. Screening for insulin resistance by oral glucose tolerance test every five years in the absence of diabetes. Annual screening lab tests for diabetes mellitus beginning after age ten years.

• Agents/circumstances to avoid: Administration of human growth hormone as it may exacerbate insulin resistance. One individual with SHORT syndrome had worsening insulin resistance when treated with metformin; additional study is needed to determine the effects of this drug.

• Pregnancy management: If present, diabetes mellitus is managed as appropriate.

NIH genetic and rare disease info

• NIH info on SHORT syndrome

SHORT syndrome is a rare disease.

SHORT syndrome Resources
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