SHORT Syndrome

Disease Overview

SHORT syndrome is a rare condition described by RJ Gorlin et al in 1975 based on the striking physical features of two infants born to unaffected parents. Over time, additional individuals have been described and the clinical definition of SHORT syndrome has been expanded. Each letter of SHORT syndrome represents one of the common findings in affected persons:

(S) = short stature

(H) = hyperextensibility of joints and/or hernia (inguinal)

(O) = ocular depression (deep-set eyes)

(R) = Rieger anomaly (defective development of the eye that often leads to glaucoma)

(T) = teething delay

Not all of these five features are required for diagnosis of SHORT syndrome.
Other characteristics common in SHORT syndrome are a triangular face, small chin with a dimple, a loss of fat under the skin (lipodystrophy), hearing loss, intrauterine growth restriction (IUGR) (poor fetal growth and low weight) and delayed speech.

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Synonyms

• Aarskog-Ose-Pande syndrome
• lipodystrophy-Rieger anomaly-diabetes syndrome
• Rieger anomaly-partial lipodystrophy syndrome
• PIK3R1-associated syndromic insulin resistance with lipoatrophy

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Signs & Symptoms

SHORT syndrome is a disorder that affects multiple organ systems. This condition was initially characterized by short stature, joints that stretch more than usual (hyperextensibility), a particular type of hernia in which the intestine protrudes through a weak spot in the abdominal muscles (inguinal hernia), deep set eyes (ocular depression), defective development of the anterior chamber of the eye that can lead to glaucoma (Rieger anomaly) and delayed eruption of teeth.

In addition to the classic features, other characteristics that are common in SHORT syndrome include a triangular face, small chin with a dimple, abnormal position of the ears and hearing loss. Loss of fat under the skin (lipodystrophy) is also common, causing difficulty gaining weight and a translucent appearance to the skin. This typically presents first in the face followed by the chest and upper extremities in the first few years of development. Often, the lower extremities are spared from lipodystrophy, but overall body appearance is thin with low body mass index (BMI). Some affected individuals have speech delay and other developmental delays but intelligence is normal. In addition to teething delay, development of further dental issues is likely. Insulin resistance is common in mid-childhood to adolescence, often progressing into diabetes mellitus by early adulthood. Babies with SHORT syndrome are usually born at or slightly before term, but often have low birth weight, small head circumference and shortened length. Individuals with SHORT syndrome are thought to have a normal life-expectancy.

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Causes

SHORT syndrome is caused by changes (pathogenic variations) in the PIK3R1 gene. This gene is responsible for proper function of the enzyme PI3K. Enzymes are proteins that are required for cellular reactions. Specifically, PI3K is involved in cell growth and division, transport of materials within cells, movement of cells and regulation of the hormone insulin.

SHORT syndrome is inherited in an autosomal dominant manner. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The pathogenic variant can be inherited from either parent if affected or can be the result of a new (de novo) variant in the affected individual. The risk of passing the pathogenic variant from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

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Affected populations

SHORT syndrome is a very rare disorder with fewer than 50 reported cases in the literature to date. SHORT syndrome is not known to be more prevalent in a certain ethnic group or geographic location.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of SHORT syndrome. Comparisons may be useful for a differential diagnosis:

Rieger syndrome: a rare disorder inherited in an autosomal dominant pattern. The main characteristics are facial, dental and eye abnormalities. Facial characteristics include a small jaw, broad nasal bridge and/or a protruding lower lip. Although Rieger anomaly is a classic feature of SHORT syndrome, an individual may have Rieger syndrome alone without the other clinical features of SHORT syndrome. (For more information on this disorder choose “Rieger” as your search term in the Rare Disease Database.)

Russell-Silver syndrome: a rare disorder characterized by intrauterine growth restriction (IUGR) and growth deficiency after birth. This can also be characterized by short stature, a small triangular-shaped face, short arms and light brown spots on the skin (cafe-au-lait spots). The corners of the mouth turn downward and short incurved fifth fingers are apparent. Intelligence is often normal although in some children intellectual disability may occur. (For more information on this disorder, choose “Russell-Silver” as your search term in the Rare Disease Database.)

Alagille syndrome: a rare genetic disorder that can affect multiple organ systems of the body including the liver, heart, skeleton, eyes and kidneys. Common symptoms, which often develop during the first three months of life include blockage of the flow of bile from the liver (cholestasis), yellowing of the skin and mucous membranes (jaundice), poor weight gain and growth, severe itching and pale, loose stools. The eye and dental features of Alagille syndrome are similar to those of SHORT syndrome, but the liver abnormalities of Alagille syndrome are not seen in SHORT syndrome. (For more information on this disorder, choose “Alagille” as your search term in the Rare Disease Database.)

Congenital generalized lipodystrophy (Berardinelli-Seip syndrome): a rare genetic disorder characterized by the near total loss of body fat (adipose tissue) and extreme muscularity that is often present at birth or soon thereafter. Insulin resistance and diabetes mellitus are also common later in life. The degree of lipodystrophy is much more severe in congenital generalized lipodystrophy compared to SHORT syndrome. (For more information on this disorder, choose “congenital generalized lipodystrophy” as your search term in the Rare Disease Database.)

Hutchinson-Gilford progeria syndrome: a rare, fatal, genetic condition of childhood with striking features resembling premature aging. Individuals develop a distinctive facial appearance characterized by a disproportionately small face in comparison to the head; an underdeveloped jaw (micrognathia); malformation and crowding of the teeth; abnormally prominent eyes; a small nose; prominent eyes and a subtle blueness around the mouth. These features are similar to those of SHORT syndrome, but individuals with SHORT syndrome do not have the features associated with accelerated aging. (For more information on this disorder, choose “Hutchinson-Gilford progeria” as your search term in the Rare Disease Database.)

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Diagnosis

The diagnosis of SHORT syndrome is based on physical findings, with facial features being particularly important, and molecular genetic testing for pathogenic variants in the PIK3R1 gene.

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Standard Therapies

No specific treatment exists for SHORT syndrome. Treatment is symptomatic and supportive based on the features present in each patient. Rieger anomaly/glaucoma, dental anomalies, insulin resistance/diabetes mellitus and hearing loss can often be treated by appropriate medical specialists. Given the increased risk for insulin resistance, it is generally advisable to avoid growth hormone treatments.

Genetic counseling is recommended for patients and their families.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Raygada M and Rennert O. SHORT Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:250.

JOURNAL ARTICLES
Avila A, Dyment DA, Dagen JV, et al. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management. Clin Genet. 2016 Apr;89(4):501-506.  doi: 10.1111/cge.12688. Epub 2015 Nov 27.

Koenig R, Brendel L and Fuchs S. SHORT syndrome. Clin Dysmorph. 2003;12:45-49.

INTERNET
Innes AM, Dyment DA. SHORT Syndrome. 2014 May 15 [Updated 2020 Jun 4]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK201365/  Accessed May 5, 2021.

PIK3R1 gene.MedlinePlus. https://ghr.nlm.nih.gov/gene/PIK3R1#conditions. Reviewed: December 2013. Accessed May 5, 2021.

SHORT syndrome. Genetic and Rare Diseases Information Center. National Institutes of Health. Last updated: 3/7/2016. https://rarediseases.info.nih.gov/diseases/7633/short-syndrome  Accessed May 5, 2021.

Dyment D, Innes AM. SHORT syndrome. Orphanet. Last Update:June 2019. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=3163  Accessed May 6, 2021.

McKusick VA. SHORT SYNDROME. Online Inheritance in Man (OMIM). Last update: 12/14/2017. https://www.omim.org/entry/269880. Accessed May 5, 2021

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