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Last updated: 4/4/2025
Years published: 1993, 2004, 2007, 2017, 2021, 2025
NORD gratefully acknowledges Emily Fishman, NORD Editorial Intern, Stanley Neufeld Phd, MD, Medical Genetics and Genomics Resident, University of Calgary, and A. Micheil Innes, MD, FRCPC, FCCMG, Departments of Medical Genetics and Pediatrics, Cumming School of Medicine University of Calgary, Alberta Children’s Hospital Research Institute for Child and Maternal Health, Calgary, Alberta, Canada and David A Dyment, DPhil, MD, FRCPC, FCCMG, Children’s Hospital of Eastern Ontario Research Institute, for assistance in the preparation of this report.
SHORT syndrome is a rare condition initially 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 (lipoatrophy), diabetes mellitus, hearing loss, intrauterine growth restriction (IUGR-poor fetal growth and low weight) and mild delays in speech.
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, deep set eyes, 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. Some affected individuals have mild 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.
SHORT syndrome is caused by changes (pathogenic variations) in the PIK3R1 gene. This gene is responsible for the 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 a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
SHORT syndrome is a very rare disorder with fewer than 100 reported cases in the literature to date. SHORT syndrome is not known to be more prevalent in a certain ethnic group or geographic location.
The diagnosis of SHORT syndrome is based on physical findings, with the facial features of SHORT syndrome being particularly important, and molecular genetic testing for pathogenic variants in the PIK3R1 gene. The pathogenic variants are seen in a specific domain of PIK3R1 (C-terminal SH2 domain) and 70% are due to a single recurrent variant.
Of note, a PIK3R1 pathogenic variant alone does not result in a diagnosis of SHORT syndrome. There are other disorders that are caused by pathogenic variants in this gene. This includes autosomal dominant immunodeficiency 36 (OMIM 616005), autosomal recessive form of agammaglobulinemia type 7 (OMIM 615214) and emerging evidence of an overgrowth condition associated with gene variants that occur in non-reproductive (somatic) cells after conception.
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 affected individuals and their families.
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/
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, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK201365/ Accessed March 27, 2025.
PIK3R1 gene.MedlinePlus. Updated August 16, 2023. https://ghr.nlm.nih.gov/gene/PIK3R1#conditions. Accessed March 27, 2025.
SHORT syndrome. Genetic and Rare Diseases Information Center. Last updated: 3/7/2016. https://rarediseases.info.nih.gov/diseases/7633/short-syndrome Accessed March 27, 2025.
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 March 27, 2025.
Online Inheritance in Man (OMIM). SHORT Syndrome. Last update: 12/11/2023. https://www.omim.org/entry/269880 Accessed March 27, 2025.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report