SHORT syndrome

Actionability Adult Summary Report

Gene: PIK3R1 (HGNC:8979)
Literature Search: 10/12/2020
Curation Status: Released (1.0.2)
Release History
Related Reports
Pediatric Summary Report: (1.0.2)

Secondary Findings in Adult Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

Actionability Assertions

Gene Condition (MONDO ID) OMIM ID Final Assertion
PIK3R1 SHORT syndrome (0010026) 269880 Moderate Actionability

Actionability Assertion Rationale

  • There was not consensus, but the majority agreed on a moderate assertion, based on extrapolation from treatment of related symptomology. We recognize very limited disease-specific evidence for this ultra-rare condition.

Actionability Scores

Outcome / Intervention Pair Severity Likelihood Effectiveness Nature of Intervention Total Score
Morbidity due to underlying lipodystrophy-related disorders of glucose and lipid metabolism / Optimal metabolic control (including management of hyperglycemia, hyperlipidemia, and lipodystrophy) 1 3C 2C 3 9CC
View scoring key
Domain of Actionability Scoring Metric State of the Knowledgebase
Severity: What is the nature of the threat to health to an individual? 3 = Sudden death as a reasonably possible outcome
2 = Reasonable possibility of death or major morbidity
1 = Modest morbidity
0 = Minimal or no morbidity 		N/A
Likelihood: What is the chance that the outcome will occur? 3 = >40% chance
2 = 5%-39% chance
1 = 1%-4% chance
0 = <1% chance 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Effectiveness: What is the effectiveness of a specific intervention in preventing or diminishing the risk of harm? 3 = Highly effective
2 = Moderately effective
1 = Minimally effective
0 = Controversial or unknown effectiveness
IN = Ineffective/No interventiona 		A = Substantial evidence or evidence from a high tier (tier 1)
B = Moderate evidence or evidence from a moderate tier (tier 2)
C = Minimal evidence or evidence from a lower tier (tier 3 or 4)
D = Poor evidence or evidence not provided in the report
N = Evidence based on expert contributions (tier 5)
Nature of intervention: How risky, medically burdensome, or intensive is the intervention? 3 = Low risk, or medically acceptable and low intensity
2 = Moderate risk, moderately acceptable or intensive
1 = Greater risk, less acceptable and substantial intensity
0 = High risk, poorly acceptable or intensive 		N/A
a Do not score the remaining categories

Prevalence of the Genetic Condition

The prevalence of SHORT syndrome is unknown. SHORT syndrome is very rare; with fewer than 50 cases reported in the literature. No ethnic predilection is known.
View Citations

Adam MP, et al. (1993) PMID: 24830046, SHORT syndrome. Orphanet encyclopedia, ORPHA: 3163.

Clinical Features (Signs / symptoms)

SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deeply set eyes), Rieger anomaly, and teething delay, which reflects the most striking clinical features of the original reported cases. However, these five features are neither required to make the diagnosis nor the most specific features of SHORT syndrome. The post-natal features most consistently observed in SHORT syndrome are mild to moderate short stature; partial lipodystrophy (evident in the face, chest, and upper extremities, often sparing the buttocks and legs); and a characteristic facial gestalt (triangular face with a prominent forehead and deep-set eyes, nose with thin nasal alae and a low-hanging columella, relatively small lower face, downturned mouth, dimpled chin, and prominent ears). Generalized lipodystrophy has also been reported. Patients are sometimes described as having a progeroid appearance, thin body habitus, hands lacking subcutaneous fat, and skin with an aged translucent appearance. Other frequent features include insulin resistance and diabetes mellitus, Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis (including glaucoma), delayed dentition and other dental issues (hypodontia, enamel hypoplasia, malocclusion, multiple dental caries), and sensorineural hearing loss. Variable clinical characteristics may include mild speech delay, hyperextensible joints, inguinal hernias, frequent minor infections in the absence of clinical immunodeficiency, nephrocalcinosis, pulmonic stenosis, ectopic kidney, ovarian cysts, advanced bone age, metabolic complications, micrognathia, heart malformations, and cataracts.
View Citations

Adam MP, et al. (1993) PMID: 24830046, SHORT syndrome. Orphanet encyclopedia, ORPHA: 3163., Brown RJ, et al. (2016) PMID: 27710244, Online Medelian Inheritance in Man. (2017) OMIM: 269880, Avila M, et al. (2016) PMID: 26497935, Online Medelian Inheritance in Man. (2019) OMIM: 171833

Natural History (Important subgroups & survival / recovery)

Lack of subcutaneous fat may be evident in the face at birth, as the first presenting feature of partial lipodystrophy, which later becomes more readily apparent in the chest and upper extremities. The characteristic facial features of SHORT syndrome are present at birth and become increasingly apparent with age. Heart malformations (particularly pulmonary stenosis), if present, can be detected in infancy. There have been reports of lipodystrophy and nephrocalcinosis in infancy. Feeding difficulties and/or failure to thrive despite adequate caloric intake are commonly reported in early childhood. Glaucoma has been reported at or soon after birth but can also develop later. Sensorineural hearing loss has been diagnosed within the first year of life. Speech delay may develop during childhood. Mild-to-moderate short stature is usually present throughout childhood and has been observed in most adults reported to date. Insulin resistance has a highly variable age at diagnosis ranging from 7-49 years. Though insulin resistance may be evident in mid-childhood or adolescence, diabetes mellitus typically does not develop until early adulthood. Individuals with SHORT syndrome are considered to have a normal life expectancy. Male and female patients appear to be equally affected.
View Citations

Adam MP, et al. (1993) PMID: 24830046, SHORT syndrome. Orphanet encyclopedia, ORPHA: 3163., Online Medelian Inheritance in Man. (2017) OMIM: 269880, Avila M, et al. (2016) PMID: 26497935

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Prevalence of Genetic Variants

The population prevalence of PIK3R1 pathogenic variants was not available.
To date, pathogenic variants in PIK3R1 have been identified in 40 affected individuals from 31 families.
Tier 3 View Citations

Adam MP, et al. (1993) PMID: 24830046

Penetrance (Includes any high-risk racial or ethnic subgroups)

The penetrance of SHORT syndrome appears complete in all individuals undergoing molecular genetic testing to date.
Tier 4 View Citations

Adam MP, et al. (1993) PMID: 24830046

The following description of the phenotypic features associated with this condition is based on data compiled from 40 genetically confirmed affected individuals from 31 families:

- Short stature (≤-2 standard deviations): 30/38 (79%)

- Partial lipodystrophy: 31/35 (89%)

- Insulin resistance: 18/23 (78%)

- Diabetes: 11/18 (61%)

- Anterior chamber ocular defects: 6/20 (30%)

Tier 3 View Citations

Adam MP, et al. (1993) PMID: 24830046

Glaucoma, which has been reported in at least 4 pediatric patients.
Tier 3 View Citations

Adam MP, et al. (1993) PMID: 24830046, Online Medelian Inheritance in Man. (2017) OMIM: 269880

The following phenotypes are based on a single study of 8 newly ascertained individuals and 24 previously reported patients with SHORT syndrome with causal PIK3R1 pathogenic variants (mean age at last follow-up was 21 years):

- Ocular depression (deep-set eyes): 27/27 cases (100%)

- Rieger abnormality: 13/30 cases (43%)

- Refractive errors: 12/24 (50%)

- Other abnormalities of the anterior chamber of eye: 5/16 cases (31%)

- Hyperopia, astigmatism, or myopia: 12/24 cases (50%)

- Insulin resistant diabetes with high insulin requirements: 9/14 cases (≥ 15 years) (64%)

- Deafness: 5/32 (16%)

Tier 5 View Citations

Avila M, et al. (2016) PMID: 26497935

In a small study of 8 patients (7 adults) genetically confirmed with SHORT in 2 unrelated families, the following laboratory values appeared to be elevated compared to BMI- and age-matched controls and reference values:

- Fasting plasma glucose: 3 adults/7 total (43%)

- HbA1c: 2 adults/6 total (33%)

- Leptin: 1 adult/5 total (20%)

- Total cholesterol: 0 adults/6 total (0%)

- HDL cholesterol: 1 adult/6 total (17%)

- LDL cholesterol: 0 adults/6 total (0%)

- Triglycerides: 0 adults/6 total (0%)

Tier 5 View Citations

Chudasama KK, et al. (2013) PMID: 23810379

Expressivity

The features of the SHORT syndrome acronym vary between patients. One case series found that only 11 of 21 patients (52%) presented at least 4 of 5 signs of this acronym.
Tier 5 View Citations

Avila M, et al. (2016) PMID: 26497935

Variable expression of many of the features has been observed multiple members of the same family.
Tier 3 View Citations

Brown RJ, et al. (2016) PMID: 27710244, Online Medelian Inheritance in Man. (2017) OMIM: 269880

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Patient Management

At diagnosis, the following evaluations should be completed:

- Ophthalmological exam

- Screening for hearing loss

- Fasting glucose and insulin, with or without oral glucose tolerance test (depending on age)

- Cardiac ultrasound

- Abdominal ultrasound for renal anomalies

- Lipid blood test (triglyceride).

Tier 2 View Citations

Avila M, et al. (2016) PMID: 26497935

Additional tests to consider at diagnosis include:

- Measuring length and weight

- Assessing speech and language in those with evidence of developmental delay

- Dental exam

- Genetic counseling.

Tier 4 View Citations

Adam MP, et al. (1993) PMID: 24830046

Guidelines general to lipodystrophies, but not specific to SHORT syndrome, indicate that current therapeutic options for metabolic management consist of lifestyle modifications (diet and exercise) and conventional antihyperglycemic and lipid-lowering medications. Metformin, sulfonylureas, thiazolidinediones, and insulin can be used to manage hyperglycemia, while fibrates and statins can be used to manage hypertriglyceridemia. When metabolic abnormalities associated with lipodystrophies are particularly severe, conventional treatments are likely to be inadequate at re-establishing metabolic control. Plasmapheresis may be an option to lower dangerously high triglyceride levels. Patients may require very high doses of insulin and will benefit from highly concentrated (e.g., U-500) insulin. However, very few studies were identified reporting on the effectiveness of these medications in lipodystrophies. One study of 5 nondiabetic type 2 familial partial lipodystrophy adult patients (LMNA-positive) were treated with the thiazolidinedione, rosiglitazone. Within 12 months of treatment, hip circumference significantly increased from 93.6 ± 2.78 cm to 96.2 ± 2.3 cm (p < 0.05) and there were significant reductions in fasting glucose levels, liver transaminases, and baseline and postprandial free fatty acids. However, other measures of body composition (e.g., weight, BMI) and glycemic control (e.g., insulin levels) were not improved, nor were any measures of lipid metabolism (e.g., total cholesterol, triglycerides).
Tier 2 View Citations

Handelsman Y, et al. PMID: 23435042, Vatier C, et al. (2019) PMID: 30296183

Another source that provides clinical management recommendations specific to SHORT syndrome, provides similar guidance regarding treatment with lifestyle and medication for glucose intolerance and diabetes. However, this source noted that metformin worsened insulin resistance in one case of SHORT syndrome and should be used with caution.
Tier 3 View Citations

Adam MP, et al. (1993) PMID: 24830046

Leptin replacement therapy (LRT) (metreleptin) can be useful to manage lipodystrophy-related metabolic complications.
Tier 2 View Citations

Handelsman Y, et al. PMID: 23435042, Vatier C, et al. (2019) PMID: 30296183

No studies were identified that reported on the management of SHORT syndrome-associated lipodystrophy. However, a systematic review of 12 prospective cohort studies and clinical case series assessed the effect of LRT in 226 patients (50% males; average age: 26.5 [SD=10] years; follow-up time range: 3-100 months) with several lipodystrophy syndromes (generalized and partial; congenital and acquired) on various clinical endpoints. Meta-analyses including patients with congenital and acquired generalized lipodystrophies, and partial lipodystrophies, found that LRT decreased fasting glucose (p = 0.0001), HbA1c (p = 0.003), triglycerides (p < 0.00001), total cholesterol (p = 0.003), liver volume (p = 0.0002) and aspartate aminotransferase (p = 0.01). Other outcomes of insulin, alanine aminotransferase, and LDL and HDL cholesterol were not significantly improved. Subgroup analysis found that patients with congenital lipodystrophies (n=21) had smaller decreases in glucose, HbA1c, and triglycerides compared to those with acquired lipodystrophies (n=5).
Tier 1 View Citations

Rodríguez AJ, et al. (2014) PMID: 25465598

Additional clinical studies on lipodystrophies (ranging from 6-86 patients predominantly diagnosed with congenital lipodystrophy, treated for 6-12 months, ranging in age from 10-68 years,) found that treatment with metreleptin was associated with markedly reduced hepatic and muscular lipid content, and improved insulin sensitivity, insulin secretion, hyperglycemia, and dyslipidemia, in part independently of reduced caloric intake.
Tier 2 View Citations

Handelsman Y, et al. PMID: 23435042, Vatier C, et al. (2019) PMID: 30296183

General guidelines for communication deficits include referral to a multidisciplinary care center, when available. A team approach that includes otolaryngologists, clinical geneticists, genetic counselors, audiologists, speech and ASL therapists, early hearing intervention and family support specialists (which may include other individuals who are deaf or hard of hearing or other parents of deaf or hard-of-hearing children), and other appropriate specialists offer optimal opportunity to provide ongoing management and support of deaf and hard-of-hearing individuals and their families as their needs change over time.
Tier 2 View Citations

Joint Committee on Infant Hearing (JCIH). (2016) URL: digitalcommons.usu.edu., Alford RL, et al. (2014) PMID: 24651602, New York State Department of Health. (2007) URL: www.health.ny.gov., Trinidad-Ramos G, et al. PMID: 19962682

Early intervention (EI) should begin as soon as possible after confirming hearing loss, regardless of age of identification or the type of hearing loss. When possible, it is recommended that intervention begin within the first year, optimally by the age of 6 months. EI comprises evaluation for amplification or sensory devices, surgical and medical evaluation, communication assessment and therapy, and access to education and support resources. The purpose of early intervention is to meet the individualized needs of the child and family, including acquisition of communication competence, social skills, emotional well-being and positive self-esteem. All children who are deaf from birth to 3 years of age and their families should have EI providers who have the qualifications, knowledge, and skills (e.g. educational strategies for infants/toddlers who are deaf), to optimize the child’s development and child/family well-being.
Tier 2 View Citations

Joint Committee on Infant Hearing (JCIH). (2016) URL: digitalcommons.usu.edu., New York State Department of Health. (2007) URL: www.health.ny.gov., American Academy of Pediatrics (AAP) / Joint Committee on Infant Hearing (JCIH). (2013) URL: pediatrics.aappublications.org., US Preventive Services Task Force, et al. (2008) PMID: 18595997

Shorter duration of hearing loss was associated with better outcomes, as it meant upon detection of hearing loss children and families could be provided with intervention services. Eleven research studies reported on the influence of duration of hearing loss on outcomes for children with hearing loss. A wide range of speech and language measures were captured using different methodologies. Almost all studies included children who used cochlear implants. Children who had a shorter duration of hearing loss tended to do better in terms of speech and language measures compared to their peers with a longer duration of hearing loss. The impact of duration of hearing loss on other outcomes such as reading ability and play were poorly represented in the literature. The evidence indicates that a composite of interrelated constructs of a habilitation methodology contribute to optimal outcomes for children with hearing loss.
Tier 1 View Citations

Kumar et al., Centre for Allied Health Evidence. (2008) URL: www.unisa.edu.au.

If the family chooses, fitting of hearing aid amplification no later than four months of age (or as soon as there is confirmation that the child is deaf or hard of hearing) is optimal, if not medically contraindicated (e.g., draining ear, local skin or ear canal condition, absent auditory nerves). The purpose of hearing aid amplification in infants who are deaf or hard of hearing is to facilitate timely and optimal auditory development as a precursor to development of spoken language.
Tier 2 View Citations

Joint Committee on Infant Hearing (JCIH). (2016) URL: digitalcommons.usu.edu., New York State Department of Health. (2007) URL: www.health.ny.gov.

Age at fitting of hearing aids may influence outcomes for children who have hearing loss. Timely access to audition is likely to support the development of speech and language skills. Age at fitting of hearing aids interacts with other variables (such as age at diagnosis and commencement of intervention programs). This finding highlights the complex inter-relationship between variables and their influence on outcomes.
Tier 1 View Citations

Kumar et al., Centre for Allied Health Evidence. (2008) URL: www.unisa.edu.au.

If the family’s goals for their child include development of spoken language, cochlear implants are the mainstay of treatment for most children with severe to profound hearing loss. Cochlear implants should only be considered after an assessment by a multidisciplinary team. As part of the assessment, children should also have had a valid trial of an acoustic hearing aid for at least 3 months (unless contraindicated or inappropriate). If there is failure to make expected progress with appropriately fitted amplification in those with severe to profound hearing loss, cochlear implants are indicated. Timing of the intervention remains critical, with better outcomes achieved for those receiving an implant by two years of age. Outcomes following cochlear implantation can be impacted by a number of variables that include: age at implantation, progression of hearing loss, duration of device use, cochlear morphology and cranial nerve VIII integrity, electrode placement, high qualify mapping of speech processor, parental educational level, and involvement in family centered, intensive-auditory based intervention. In general, device failure rates after successful implantation are low (less than 5% over 15 years).
Tier 2 View Citations

Joint Committee on Infant Hearing (JCIH). (2016) URL: digitalcommons.usu.edu., New York State Department of Health. (2007) URL: www.health.ny.gov., US Preventive Services Task Force, et al. (2008) PMID: 18595997, National Institute for Health and Care Excellence (NICE). (2019) URL: www.nice.org.uk.

A child’s age at the time of cochlear implantation does influence outcomes for children who have hearing loss. The younger a child is when they receive a cochlear implant, the better the outcomes. However, there is no consensus regarding a minimum age or an optimum age for implantation. Success following implantation is dependent upon high quality intervention services.
Tier 1 View Citations

Kumar et al., Centre for Allied Health Evidence. (2008) URL: www.unisa.edu.au.

Treatment of additional manifestations in individuals with SHORT syndrome is symptomatic, requires a multidisciplinary team, and include the following:

- Ocular anomalies should be treated by an ophthalmologist to decrease and stabilize ocular pressure, and preserve vision.

- Standard dental treatment, which may include crowns and dental prostheses, for dental anomalies.

Tier 4 View Citations

Adam MP, et al. (1993) PMID: 24830046, SHORT syndrome. Orphanet encyclopedia, ORPHA: 3163.

If lipodystrophic or insulin-resistant phenotypes are present, blood glucose and lipid levels should be checked carefully before first prescription of a contraceptive pill.
Tier 2 View Citations

Vatier C, et al. (2019) PMID: 30296183

Surveillance

Recommended follow-up for individuals with SHORT syndrome includes:

- Monitor growth

- In childhood follow developmental milestones, particularly speech and language

- Fasting glucose and insulin, and HbA1C annually (potentially starting later in childhood)

- Oral glucose tolerance tests every 5 years in absence of diabetes

- In women, gynecological ultrasound to search for polycystic ovaries.

Tier 2 View Citations

Avila M, et al. (2016) PMID: 26497935

Regular surveillance of hearing status is recommended for all children with hearing levels that fall outside the range of normal in one or both ears. Regular assessment of progress of communication development (receptive and expressive language, speech, and auditory skills) through appropriate protocols is recommended every 6 months in the infant/toddler period and annually thereafter.
Tier 2 View Citations

Joint Committee on Infant Hearing (JCIH). (2016) URL: digitalcommons.usu.edu., American Academy of Pediatrics (AAP) / Joint Committee on Infant Hearing (JCIH). (2013) URL: pediatrics.aappublications.org.

Additional regular monitoring includes annual eye exams, including measurement of intraocular pressure.
Tier 4 View Citations

Adam MP, et al. (1993) PMID: 24830046, SHORT syndrome. Orphanet encyclopedia, ORPHA: 3163.

Circumstances to Avoid

Because growth hormone treatment could aggravate pre-existing insulin resistance and accelerate the onset of diabetes mellitus, its use in patients with SHORT syndrome should be evaluated with caution.
Tier 2 View Citations

Avila M, et al. (2016) PMID: 26497935

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.

Nature of Intervention

Interventions for SHORT syndrome include invasive and non-invasive imaging, clinical monitoring, routine blood tests, and medication. Treatment with oral sulfonylureas is associated with possible side effects of weight gain and hypoglycemia. Statins are generally well-tolerated. Adverse effects are rare even at standard doses, but include elevated liver enzymes, muscle symptoms (the most severe of which is rhabdomyolysis, which can be fatal), new onset diabetes, potential fetal teratogenicity, and impacts on sexual and physical maturation.
Context: Adult Pediatric
View Citations

Rosenson RS, et al. PMID: 24793443, Grundy SM, et al. (2019) PMID: 30423393, National Institute for Health and Care Excellence (NICE). (2019) URL: www.nice.org.uk.

Services for people who are deaf aim to improve their quality of life by maximizing their ability to communicate, using the means most appropriate for the person and their environment, and to enable the person to move safely within their environment. General risks and complications of cochlear implantation include risk of meningitis, infection, facial nerve paralysis, electrode migration and anesthesia risk; however, the overall risks of complications of screening and treatment are estimated to be small (less than 1%). Cerebral spinal fluid (CSF) outflow is another risk of cochlear implantation, particularly in patients with EVA with and without cochlear hypoplasia. Patients who experience rapid CSF outflow (known as a CSF gusher) may be at higher risk of developing postoperative otogenic meningitis.
Context: Pediatric
View Citations

Joint Committee on Infant Hearing (JCIH). (2016) URL: digitalcommons.usu.edu., New York State Department of Health. (2007) URL: www.health.ny.gov., US Preventive Services Task Force, et al. (2008) PMID: 18595997, National Institute for Health and Care Excellence (NICE). (2019) URL: www.nice.org.uk.

LRT is typically administered as a subcutaneous injection once or twice daily, and treatment is lifelong. However, it appears to be well-tolerated. Anti-metreleptin antibodies with neutralizing activity have been identified in patients treated with MYALEPT and could inhibit endogenous leptin action and/or result in loss of MYALEPT efficacy. Worsening metabolic control and/or severe infection have been reported. Treatment with metreleptin is also associated with possible weight gain and hypoglycemia.
Context: Adult Pediatric
View Citations

Vatier C, et al. (2019) PMID: 30296183, Rodríguez AJ, et al. (2014) PMID: 25465598, U.S. Food and Drug Administration. (1997) URL: www.accessdata.fda.gov.

Chance to Escape Clinical Detection

Diagnosis of lipodystrophy is frequently challenging and may easily be confused with common central obesity, metabolic syndrome, and other metabolic disorders.
Context: Adult Pediatric
Tier 3 View Citations

Handelsman Y, et al. PMID: 23435042, Vatier C, et al. (2019) PMID: 30296183

The relatively mild clinical presentation of several of the subjects suggests that SHORT syndrome may be underdiagnosed.
Context: Adult Pediatric
Tier 3 View Citations

Adam MP, et al. (1993) PMID: 24830046, Avila M, et al. (2016) PMID: 26497935

Some individuals lack the distinctive and recognizable facial features of SHORT syndrome, having a less-specific phenotype indistinguishable from many other inherited disorders with short stature and/or partial lipodystrophy.
Context: Adult Pediatric
Tier 4 View Citations

Adam MP, et al. (1993) PMID: 24830046

Description of sources of evidence:

Tier 1: Evidence from a systematic review or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Gene Condition Associations
OMIM Identifier Primary MONDO Identifier Additional MONDO Identifiers
PIK3R1 269880 0010026

References List

Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A. (1993) SHORT Syndrome. GeneReviews®.

Alford RL, Arnos KS, Fox M, Lin JW, Palmer CG, Pandya A, Rehm HL, Robin NH, Scott DA, Yoshinaga-Itano C. (2014) American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genetics in medicine : official journal of the American College of Medical Genetics. 16(1530-0366):347-55.

American Academy of Pediatrics (AAP) / Joint Committee on Infant Hearing (JCIH). Supplement to JCIH 2007 Position Statement: Principles and Guidelines for Early Intervention After Confirmation That a Child Is Deaf or Hard of Hearing. (2013) Accessed: 2021-02-04. URL: https://pediatrics.aappublications.org/content/pediatrics/131/4/e1324.full.pdf

Avila M, Dyment DA, Sagen JV, St-Onge J, Moog U, Chung BHY, Mo S, Mansour S, Albanese A, Garcia S, Martin DO, Lopez AA, Claudi T, König R, White SM, Sawyer SL, Bernstein JA, Slattery L, Jobling RK, Yoon G, Curry CJ, Merrer ML, Luyer BL, Héron D, Mathieu-Dramard M, Bitoun P, Odent S, Amiel J, Kuentz P, Thevenon J, Laville M, Reznik Y, Fagour C, Nunes ML, Delesalle D, Manouvrier S, Lascols O, Huet F, Binquet C, Faivre L, Rivière JB, Vigouroux C, Njølstad PR, Innes AM, Thauvin-Robinet C. (2016) Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management. Clinical genetics. 89(1399-0004):501-506.

Brown RJ, Araujo-Vilar D, Cheung PT, Dunger D, Garg A, Jack M, Mungai L, Oral EA, Patni N, Rother KI, von Schnurbein J, Sorkina E, Stanley T, Vigouroux C, Wabitsch M, Williams R, Yorifuji T. (2016) The Diagnosis and Management of Lipodystrophy Syndromes: A Multi-Society Practice Guideline. The Journal of clinical endocrinology and metabolism. 101(1945-7197):4500-4511.

Chudasama KK, Winnay J, Johansson S, Claudi T, König R, Haldorsen I, Johansson B, Woo JR, Aarskog D, Sagen JV, Kahn CR, Molven A, Njølstad PR. (2013) SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. American journal of human genetics. 93(1537-6605):150-7.

Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, Braun LT, de Ferranti S, Faiella-Tommasino J, Forman DE, Goldberg R, Heidenreich PA, Hlatky MA, Jones DW, Lloyd-Jones D, Lopez-Pajares N, Ndumele CE, Orringer CE, Peralta CA, Saseen JJ, Smith SC, Sperling L, Virani SS, Yeboah J. (2019) 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 73(1558-3597):e285-e350.

Handelsman Y, Oral EA, Bloomgarden ZT, Brown RJ, Chan JL, Einhorn D, Garber AJ, Garg A, Garvey WT, Grunberger G, Henry RR, Lavin N, Tapiador CD, Weyer C. The clinical approach to the detection of lipodystrophy - an AACE consensus statement. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 19(1934-2403):107-16.

Joint Committee on Infant Hearing (JCIH). Year 2019 Position Statement: Principles and Guidelines for Early Hearing Detection and Intervention Programs. (2016) URL: https://digitalcommons.usu.edu/cgi/viewcontent.cgi?article=1104&context=jehdi

Kumar et al., Centre for Allied Health Evidence. A systematic review of the literature on early intervention for children with permanent hearing loss. Volumes 1 and 2.. (2008) URL: https://www.unisa.edu.au/cahe

National Institute for Health and Care Excellence (NICE). Cochlear implants for children and adults with severe to profound deafness. Technology appraisal guidance [TA566].. (2019) URL: https://www.nice.org.uk/guidance/ta566

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Early Rule-Out Summary

This topic passed the early rule out stage

Findings of Early Rule-Out Assessment

  1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition?
  2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways?

    3. a. Patient Management

    b. Surveillance or Screening

    c. Circumstances to Avoid

  3. Is it actionable in an undiagnosed adult with the condition?
  4. Is this condition an important health problem?
  5. Is there at least on known pathogenic variant with at least moderate penetrance (≥40%) or moderate relative risk (≥2) in any population?