NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

SHORT Syndrome

, MD, FRCPC, FCCMG and , DPhil, MD, FRCPC, FCCMG.

Author Information

Initial Posting: ; Last Update: June 4, 2020.

Estimated reading time: 20 minutes

Summary

Clinical characteristics.

SHORT syndrome is a mnemonic for short stature, hyperextensibility, ocular depression (deeply set eyes), Rieger anomaly, and teething delay. It is now recognized that the features most consistently observed in SHORT syndrome are mild intrauterine growth restriction (IUGR); mild to moderate short stature; partial lipodystrophy (evident in the face, and later in the chest and upper extremities, often sparing the buttocks and legs); and a characteristic facial gestalt. Insulin resistance may be evident in mid-childhood or adolescence, although diabetes mellitus typically does not develop until early adulthood. Other frequent features include Axenfeld-Rieger anomaly or related ocular anterior chamber dysgenesis, delayed dentition and other dental issues, and sensorineural hearing loss.

Diagnosis/testing.

The diagnosis of SHORT syndrome is established in a proband with compatible clinical features (with emphasis on the facial gestalt) and a heterozygous pathogenic variant in PIK3R1 identified by molecular genetic testing.

Management.

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.

Genetic counseling.

SHORT syndrome is inherited in an autosomal dominant manner. The proportion of individuals with SHORT syndrome caused by a de novo pathogenic variant is unknown but appears to be significant. Each child of an individual with SHORT syndrome has a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk and preimplantation genetic testing are possible if the pathogenic variant has been identified in an affected family member.

Diagnosis

The designation SHORT syndrome was coined by Gorlin et al [1975] to reflect several of the most striking clinical 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 these five features are neither required to make the diagnosis nor necessarily the most specific features of SHORT syndrome.

Suggestive Findings

SHORT syndrome should be suspected in individuals with some combination of the following findings:

  • Intrauterine growth restriction
  • Short stature
  • Partial lipodystrophy
  • Characteristic facial gestalt (see Figure 1). The face has a triangular appearance. The forehead is broad and the eyes are deep-set. The nose has a narrow tip and thin nasal alae. The columella is low-hanging. The middle and lower thirds of the face are relatively small. The corners of the mouth are downturned and the chin can be dimpled. The ears are often prominent but not low-set or posteriorly rotated.
  • Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies
  • Delayed dentition
  • Insulin resistance / diabetes mellitus
Figure 1. . Facial features of SHORT syndrome.

Figure 1.

Facial features of SHORT syndrome. The face has a triangular appearance with a prominent forehead and deep-set eyes. The nose has characteristic thin nasal alae and a low-hanging columella. The corners of the mouth can be downturned and the chin can be (more...)

No formal diagnostic criteria have been published for SHORT syndrome; however, to date the presence of characteristic facial features is highly predictive for identifying a heterozygous PIK3R1 pathogenic variant.

Establishing the Diagnosis

The diagnosis of SHORT syndrome is established in a proband with compatible clinical features (with emphasis on the facial gestalt) and a heterozygous pathogenic variant in PIK3R1 identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive and recognizable facial features of SHORT syndrome described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a less-specific phenotype indistinguishable from many other inherited disorders with short stature and/or partial lipodystrophy are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of SHORT syndrome, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of PIK3R1 is performed first to detect missense, frameshift, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications may be considered. However, to date such variants have not been identified as a cause of SHORT syndrome.
  • A multigene panel that includes PIK3R1 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the phenotype is indistinguishable from many other inherited disorders characterized by short stature or partial lipodystrophy, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible.

If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis. Note: To date such variants have not been identified as a cause of SHORT syndrome.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in SHORT Syndrome

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
PIK3R1Sequence analysis 331/31 probands 4
Gene-targeted deletion/duplication analysis 5None reported 4
Unknown 6NA
1.
2.

See Molecular Genetics for information on allelic variants detected in this gene.

3.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4.

To date, a PIK3R1 pathogenic variant has been identified in 40 individuals from 31 families with SHORT syndrome (reviewed in Avila et al [2016], Huang-Doran et al [2016], Klatka et al [2017], Hamaguchi et al [2018]). Of these, 22/31 families have the recurrent pathogenic variant c.1945C>T.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

PIK3R1 is currently the only gene in which pathogenic variants are known to cause SHORT syndrome. Of note, an individual reported by Reardon & Temple [2008] had a clinical diagnosis of SHORT syndrome, but subsequent testing failed to identify a PIK3R1 pathogenic variant, suggesting the possibility of genetic heterogeneity. However, in retrospect, the classic facial gestalt of SHORT syndrome was not present [Dyment et al 2013]. There has been a single report of an individual with a de novo variant in PRKCE and a SHORT-like presentation; however, this has not been replicated [Alcantara et al 2017]. A homozygous variant in IGF1R has also been reported to cause a SHORT-like syndrome; however, the child presented with developmental delay, multiple malformations, and a facies that differed from that seen in others with a diagnosis of PIK3R1-related SHORT syndrome [Prontera et al 2015].

Clinical Characteristics

Clinical Description

To date, a pathogenic variant in PIK3R1 has been identified in 40 affected individuals from 31 families [Avila et al 2016, Huang-Doran et al 2016, Klatka et al 2017, Hamaguchi et al 2018]. The following description of the phenotypic features associated with this condition is based on these reports.

Table 2.

Select Features of SHORT Syndrome

FeatureNumber of Persons with Feature
Intrauterine growth restriction30/34
Short stature30/38 1
Partial lipodystrophy31/35
Facial gestalt40/40
Insulin resistance18/23
Diabetes11/18
Anterior chamber ocular defects6/20
Delayed dentition22/23
1.

The remaining 8/40 individuals are described as short but with height between -2 SD and -1 SD.

Intrauterine growth restriction (IUGR). Infants with SHORT syndrome are usually born at or slightly before term and typically exhibit mild IUGR [Lipson et al 1989].

Short stature. Feeding difficulties and/or failure to thrive despite adequate caloric intake are commonly reported in young children.

  • Mild-to-moderate short stature is usually present throughout childhood. Bone age may or may not be delayed. Other skeletal changes include gracile diaphyses and large and coned-shaped epiphyses [Haan & Morris 1998].
  • Mild short stature has been seen in most adults reported to date. Adult height in males with a molecularly confirmed diagnosis of SHORT syndrome was between 155 and 163 cm and in females between 143 and 160 cm [Chudasama et al 2013, Dyment et al 2013, Thauvin-Robinet et al 2013].

Partial lipodystrophy. Partial lipodystrophy is very common in SHORT syndrome [Koenig et al 2003]. Lack of subcutaneous fat is evident in the face and later becomes more readily apparent in the chest and upper extremities. Although the buttocks and legs are often spared, localized regions of lipoatrophy at the elbows and buttocks have been reported [Aarskog et al 1983, Koenig et al 2003]. The hands also lack subcutaneous fat, and the skin has an aged, translucent appearance.

The body habitus is described as thin. All four adult males reported to date with a molecularly confirmed diagnosis had a body mass index (BMI) below 18.5 (range 13.5-17.9); four of eight adult females also had a BMI below 18.5 (range 15.1-22.5) [Chudasama et al 2013, Dyment et al 2013, Thauvin-Robinet et al 2013].

Characteristic facial gestalt. The characteristic facial features of SHORT syndrome – sometimes described as having an "aged" or "progeroid" appearance [Koenig et al 2003] – are present at birth and become increasingly apparent with age. Head shape is normal and occipital-frontal circumference is proportionate with other growth parameters. The vasculature of the scalp is prominent. The forehead is broad, palpebral fissures are deep-set, and alae nasi are thin with a low-hanging columella. The chin is small and can be dimpled. (See Figure 1.)

Insulin resistance / diabetes mellitus. Although insulin resistance may be evident in mid-childhood or adolescence, diabetes mellitus typically does not develop until early adulthood [Aarskog et al 1983, Schwingshandl et al 1993].

Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies – also referred to as anterior chamber dysgenesis – have been reported in the majority of individuals with SHORT syndrome. Glaucoma, which has been reported in at least one individual at birth [Brodsky et al 1996], can also develop later [Bankier et al 1995]. Glaucoma is thought to be the result of poorly developed aqueous humor drainage structures of the anterior chamber of the eye.

The majority of individuals with a PIK3R1 pathogenic variant have at least some ocular involvement including myopia, hyperopia, and/or astigmatism, and half have Rieger anomaly or related anterior chamber defects [Chudasama et al 2013, Dyment et al 2013, Thauvin-Robinet et al 2013, Schroeder et al 2014].

Delayed dentition. Delayed dentition is common in individuals with a molecularly confirmed diagnosis of SHORT syndrome. Other dental issues include hypodontia, enamel hypoplasia, and malocclusion. Multiple dental caries have also been reported [Koenig et al 2003].

Other

  • Sensorineural hearing loss of 80-90 dB has been diagnosed within the first year of life. Among individuals with a molecularly confirmed diagnosis of SHORT syndrome, six have been reported with hearing loss [Avila et al 2016].
  • While cognition is not affected in SHORT syndrome, some affected children have mild speech delay.
  • Some, but not all, affected individuals exhibit hyperextensible joints and/or inguinal hernias.
  • Although there does not appear to be an increased risk for life-threatening infections or evidence of clinical immunodeficiency, there have been reports of a nonspecific history of frequent infections [Koenig et al 2003].
  • Nephrocalcinosis has been reported in a mother-son pair with a molecularly confirmed diagnosis [Reardon & Temple 2008]. Nephrocalcinosis was identified incidentally in the son at age two months (on an abdominal US examination performed for follow up of anorectal atresia); the nephrocalcinosis was stable when reassessed at age two years. The mother also developed nephrocalcinosis as an adult.
  • Pulmonic stenosis and ectopic kidney have also been reported [Koenig et al 2003, Schroeder et al 2014, Bárcena et al 2014].
  • Fertility is generally preserved in SHORT syndrome; ovarian cysts are commonly reported in affected females.

Genotype-Phenotype Correlations

To date no clear genotype-phenotype correlation is evident; however, pathogenic variants appear to cluster in the C-terminal SH2 domain of PIK3R1.

The recurrent missense pathogenic variant c.1945C>T has been identified in 22 of 31 families with SHORT syndrome. While individuals with this specific variant usually have typical SHORT syndrome, to date the numbers are too small to determine whether the phenotype observed with this pathogenic variant differs from that observed with other pathogenic variants.

Penetrance

The penetrance of SHORT syndrome appears complete in all individuals undergoing molecular genetic testing to date: all simplex cases (i.e., a single occurrence in a family) with parents available for testing have had a de novo PIK3R1 pathogenic variant, and all familial cases have inherited the pathogenic variant from an affected parent.

Nomenclature

Since it was first described in the early 1970s, what appears to be SHORT syndrome has been described by different terms, including:

  • Low-birthweight Rieger syndrome
  • Autosomal partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes *
  • Absent iris stroma, narrow body build, and small facial bones *

* Individuals with the latter two disorders have subsequently been demonstrated to have a PIK3R1 pathogenic variant and SHORT syndrome.

Prevalence

SHORT syndrome is very rare; fewer than 50 cases have been reported in the literature.

No ethnic predilection is known.

Differential Diagnosis

Table 3 provides a comparative analysis of disorders with some clinical similarities to SHORT syndrome.

Table 3.

Genes of Interest in the Differential Diagnosis of SHORT Syndrome

Gene(s) / Genetic MechanismDifferential DisorderMOIFeatures of Differential Disorder
Overlapping w/ SHORT syndromeDistinguishing from SHORT syndrome
11p15.5 hypomethylation
mUPD7
CDKN1C
HMGA2
IGF2
PLAG1 1
Silver-Russell syndrome (SRS)See footnote 2.
  • IUGR & postnatal growth deficiency
  • Nonspecific facial features incl triangular-shaped face 3
  • More significiant short stature in SRS than in SHORT syndrome
  • No eye anomalies or lipodystrophy in SRS
AGPAT2
BSCL2
Berardinelli-Seip congenital lipodystrophy (BSCL)AR
  • BSCL is usually diagnosed at birth or shortly thereafter; severe BSCL may have prenatal-onset w/IUGR.
  • All children w/neonatal or infantile presentation demonstrate lipoatrophy in 1st yr of life.
  • Insulin resistance & subsequent diabetes mellitus become common in late adolescence & early adulthood.
Hepatomegaly, severe generalized lipodystrophy, & acromegaloid facial features in BSCL
FOXC1
PITX2
Nonsyndromic anterior chamber eye anomalies (OMIM 137600, 601631)ADAnterior chamber eye anomaliesAbsence of other features assoc w/SHORT syndrome
IGF1RNonsyndromic IUGR 4ADIUGR, short stature, glucose intolerance
  • Absence of facial features of SHORT syndrome
  • ↑ IGF1
JAG1
NOTCH2
Alagille syndrome 5ADOcular & dental findings may be similar.Liver disease in Alagille syndrome
LMNAHutchinson-Gilford progeria syndrome (HGPS)ADMicrognathia, short stature, absence of subcutaneous fat
  • Clinical features of HGPS develop in childhood (vs typically evident at birth in SHORT syndrome).
  • Some features of accelerated aging w/disease progression in HGPS are distinct from those in SHORT syndrome.
PTPN11SHORT-like syndrome 6ADIUGR, short stature, lipoatrophy, & metabolic abnormalitiesFacial features not characteristic of SHORT syndrome
UBR1Johansson-Blizzard syndrome (OMIM 243800)ARIUGR, short stature, hypoplastic alae nasi, hypodontia, & hearing lossHeart & genitourinary malformations, aplasia cutis congenital, pancreatic insufficiency

AD = autosomal dominant; AR = autosomal recessive; IGF1 = insulin-like growth factor 1; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mUPD = maternal uniparental disomy

1.

Silver-Russell syndrome (SRS) is genetically heterogeneous. Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35%-50% of individuals, and mUPD7 causes SRS in 7%-10% of individuals. A small number of individuals with SRS have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in CDKN1C, IGF2, PLAG1, and HMGA2 have been described.

2.

Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband.

3.

Since it is possible that some individuals with a clinical diagnosis of SRS and normal molecular studies have a diagnosis of SHORT syndrome, careful consideration of the facial phenotype in these individuals is warranted.

4.
5.

Alagille syndrome is a complex multisystem disorder involving the liver, heart, eyes, face, and skeleton.

6.

Hallerman-Streiff syndrome. The facial features of SHORT syndrome can also be similar to those seen in Hallerman-Streiff syndrome in early life. The molecular basis of Hallerman-Streiff syndrome is unknown (OMIM 234100).

Note: Copy number variations at several loci including PITX2 (4q25) and BMP4 (14q22.2) (which are frequently detected by chromosomal microarray analysis) can lead to syndromic anterior-chamber eye anomalies with phenotypes that to date have been clinically distinct from those of SHORT syndrome [Karadeniz et al 2004, Lines et al 2004, Reis et al 2011].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SHORT syndrome, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with SHORT Syndrome

System/ConcernEvaluationComment
Short statureMeasure length & weight.
Mild speech delayAssess speech & language in those w/evidence of DD.
Axenfeld-Rieger anomaly or related anterior chamber ocular anomaliesExam by ophthalmologist experienced in management of developmental eye disorders or glaucoma
Hearing lossHearing assessment
Delayed dentitionDental exam
Insulin resistance / diabetes mellitusAssessment by endocrinologist & consideration of fasting glucose & oral glucose tolerance testThis is important in the individual diagnosed w/SHORT syndrome as an older child (age >10 yrs) or later as an adult.
Pulmonary stenosisEchocardiogram
NephrocalcinosisAbdominal US
Genetic counselingBy genetics professionals 1To inform patients & families re nature, MOI, & implications of SHORT syndrome to facilitate medical & personal decision making

DD = developmental delay; MOI = mode of inheritance; US = ultrasound

1.

Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Table 5.

Treatment of Manifestations in Individuals with SHORT Syndrome

Manifestation/ConcernTreatmentConsiderations/Other
Axenfeld-Rieger anomaly or related anterior chamber ocular anomaliesTreatment by ophthalmologist experienced in management of developmental eye disorders or glaucomaImportant to ↓ & stabilize ocular pressures & to preserve vision
Hearing lossSee Hereditary Hearing Loss and Deafness.
Dental anomaliesStandard treatment & may incl crowns & dental prostheses.
Insulin resistance / Diabetes mellitusStandard treatment for glucose intolerance & diabetes mellitus w/diet, lifestyle, oral medication, & insulin under supervision of a specialist in diabetes care is recommended.1 report found that treatment w/metformin → worsening of insulin resistance in 1 person w/SHORT syndrome, suggesting need for caution in use of metformin & further study [Lewandowski et al 2019].

Surveillance

Table 6.

Recommended Surveillance for Individuals with SHORT Syndrome

System/ConcernEvaluationFrequency
Short statureMonitor growth incl height, weight, & body mass indexEvery 6-12 mos
Eye abnormalityEye exams to incl measurement of intraocular pressureAnnually
Hearing lossHearing assessmentEvery 2-3 yrs
Insulin resistanceOral glucose tolerance testEvery 5 yrs in absence of diabetes
DiabetesFasting glucose, insulin, & HBA1cAnnually starting in later childhood (age >10 yrs)

Agents/Circumstances to Avoid

Given the increased risk for insulin resistance in individuals taking growth hormone, it has been suggested that growth hormone be contraindicated in individuals with SHORT syndrome [Thauvin-Robinet et al 2013].

One report observed a worsening of insulin resistance in a child with SHORT syndrome treated with metformin [Lewandowski et al 2019]. The report was limited to a single individual; as such, further study is needed to determine the effects of this drug.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Successful pregnancies have occurred in women with SHORT syndrome. If present, diabetes mellitus is managed as appropriate.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SHORT syndrome is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with SHORT syndrome have an affected parent.
  • Twelve of the 40 individuals with SHORT syndrome diagnosed to date were found to have a de novo PIK3R1 pathogenic variant; however, this is likely an underestimate as the parents of individuals representing simplex cases of SHORT syndrome have not been evaluated sufficiently to determine if the pathogenic variant occurred de novo.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant.
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a de novo pathogenic variant in the proband.* Although no instances of confirmed germline mosaicism have been reported, the occurrence of SHORT syndrome in a sib pair reported in Gorlin et al [1975] appears to have been due to germline mosaicism.
    * Misattributed parentage can also be explored as an alternative explanation for an apparent de novo pathogenic variant.
  • The family history of some individuals diagnosed with SHORT syndrome may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. Note: To date, all parents found to be heterozygous for a PIK3R1 pathogenic variant have had clinical manifestations of SHORT syndrome apparent on physical examination (primarily presence of short stature, lipodystrophy, and characteristic facial features).

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with SHORT syndrome has a 50% chance of inheriting the PIK3R1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the PIK3R1 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

SHORT Syndrome: Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SHORT Syndrome (View All in OMIM)

171833PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 1; PIK3R1
269880SHORT SYNDROME

Molecular Pathogenesis

PIK3R1 encodes the regulatory subunit (p85α) of the PI3K holoenzyme. The subunit p85α stabilizes the catalytic subunit (p110α) that regulates the AKT/mTOR pathway. This pathway is critical to proper cell proliferation and growth. When p85α binds to p110α, phosphatidylinositol (3,4) bisphosphate is converted to phosphoinositol (3,4,5) triphosphate, which thereby recruits AKT and initiates the downstream effectors of cellular growth.

Studies of fibroblasts and lymphoblasts of individuals with SHORT syndrome show a diminished capacity to activate the AKT pathway and downstream targets. Reduced p85α results in p110α not being available for downstream effects.

Mechanism of disease causation. Pathogenic variants are thought to cause SHORT syndrome via haploinsufficiency; however, few studies have investigated its underlying mechanism.

Table 7.

Notable PIK3R1 Pathogenic Variants

Reference SequencesDNA Nucleotide
Change
Predicted
Protein Change
Comment [Reference]
NM_181523​.2
NP_852664​.1
c.1945C>Tp.Arg649TrpRecurrent variant [Chudasama et al 2013, Dyment et al 2013]

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Cancer and Benign Tumors

Sporadic tumors (including glioblastomas, breast, endometrial, bladder, uroepithelial, ovarian, colorectal, and gastric) occurring as single tumors in the absence of any other findings of SHORT syndrome may harbor somatic PIK3R1 variants that are not present in the germline; thus, predisposition to these tumors is not heritable.

References

Literature Cited

  • Aarskog D, Ose L, Pande H, Eide N. Autosomal dominant partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes. Am J Med Genet. 1983;15:29–38. [PubMed: 6407320]
  • Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfäffle R, Raile K, Seidel B, Smith RJ, Chernausek SD, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003;349:2211–22. [PubMed: 14657428]
  • Alcantara D, Elmslie F, Tetreault M, Bareke E, Hartley T. Care4Rare Consortium, Majewski J, Boycott K, Innes AM, Dyment DA, O'Driscoll M. SHORT syndrome due to a novel de novo mutation in PRKCE (protein kinase Cɛ) impairing TORC2-dependent AKT activation. Hum Mol Genet. 2017;26:3713–21. [PubMed: 28934384]
  • 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. Clinical reappraisal of SHORT syndrome with PIK3R1 mutations: toward recommendation for molecular testing and management. Clin Genet. 2016;89:501–6. [PubMed: 26497935]
  • Bankier A, Keith CG, Temple IK. Absent iris stroma, narrow body build and small facial bones: a new association or variant of SHORT syndrome? Clin Dysmorphol. 1995;4:304–12. [PubMed: 8574420]
  • Bárcena C, Quesada V, De Sandre-Giovannoli A, Puente DA, Fernández-Toral J, Sigaudy S, Baban A, Lévy N, Velasco G, López-Otín C. Exome sequencing identifies a novel mutation in PIK3R1 as the cause of SHORT syndrome. BMC Med Genet. 2014;15:51. [PMC free article: PMC4022398] [PubMed: 24886349]
  • Baynes KC, Beeton CA, Panayotou G, Stein R, Soos M, Hansen T, Simpson H, O'Rahilly S, Shepherd PR, Whitehead JP. Natural variants of human p85 alpha phosphoinositide 3-kinase in severe insulin resistance: a novel variant with impaired insulin-stimulated lipid kinase activity. Diabetologia. 2000;43:321–31. [PubMed: 10768093]
  • Bravo García-Morato M, García-Miñaúr S, Molina Garicano J, Santos Simarro F, Del Pino Molina L, López-Granados E, Ferreira Cerdán A, Rodríguez Pena R. Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. Clin Immunol. 2017;179:77–80. [PubMed: 28302518]
  • Brodsky MC, Whiteside-Michel J, Merin LM. Rieger anomaly and congenital glaucoma in the SHORT syndrome. Arch Ophthalmol. 1996;114:1146–7. [PubMed: 8790109]
  • 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. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet. 2013;93:150–7. [PMC free article: PMC3710758] [PubMed: 23810379]
  • Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E, Smith AM, Perez EE, Murray PJ. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J Exp Med. 2012;209:463–70. [PMC free article: PMC3302225] [PubMed: 22351933]
  • Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, Temple IK, Reardon W, Mansour S, Haq MR, Gilbert R, Lehmann OJ, Vanstone MR, Beaulieu CL., FORGE Canada Consortium. Majewski J, Bulman DE, O'Driscoll M, Boycott KM, Innes AM. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013;93:158–66. [PMC free article: PMC3710754] [PubMed: 23810382]
  • Gorlin RJ, Cervenka J, Moller K, Horrobin M, Witkop CJ Jr. Malformation syndromes. A selected miscellany. Birth Defects Orig Artic Ser. 1975;11:39–50. [PubMed: 819054]
  • Haan E, Morris L. SHORT syndrome: distinctive radiographic features. Clin Dysmorphol. 1998;7:103–7. [PubMed: 9571279]
  • Hamaguchi T, Hirota Y, Takeuchi T, Nakagawa Y, Matsuoka A, Matsumoto M, Awano H, Iijima K, Cha PC, Satake W, Toda T, Ogawa W. Treatment of a case of severe insulin resistance as a result of a PIK3R1 mutation with a sodium-glucose cotransporter 2 inhibitor. J Diabetes Investig. 2018;9:1224–7. [PMC free article: PMC6123033] [PubMed: 29476696]
  • Huang-Doran I, Tomlinson P, Payne F, Gast A, Sleigh A, Bottomley W, Harris J, Daly A, Rocha N, Rudge S, Clark J, Kwok A, Romeo S, McCann E, Müksch B, Dattani M, Zucchini S, Wakelam M, Foukas LC, Savage DB, Murphy R, O'Rahilly S, Barroso I, Semple RK. Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations. JCI Insight. 2016;1:e88766 [PMC free article: PMC5070960] [PubMed: 27766312]
  • Karadeniz NN, Kocak-Midillioglu I, Erdogan D, Bökesoy I. Is SHORT syndrome another phenotypic variation of PITX2? Am J Med Genet A. 2004;130A:406–9. [PubMed: 15481036]
  • Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J, Ohtsuka Y, Hisatome I, Ninomoya H, Nanba E, Fukushima T, Takahashi S. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab. 2005;90:4679–87. [PubMed: 15928254]
  • Klatka M, Rysz I, Kozyra K, Polak A, Kołłątaj W. SHORT syndrome in a two-year-old girl - case report. Ital J Pediatr. 2017;43:44. [PMC free article: PMC5418728] [PubMed: 28472977]
  • Koenig R, Brendel L, Fuchs S. SHORT syndrome. Clin Dysmorphol. 2003;12:45–9. [PubMed: 12514365]
  • Lewandowski KC, Dąbrowska K, Brzozowska M, Kawalec J, Lewiński A. Metformin paradoxically worsens insulin resistance in SHORT syndrome. Diabetol Metab Syndr. 2019;11:81. [PMC free article: PMC6771105] [PubMed: 31583022]
  • Lines MA, Kozlowski K, Kulak SC, Allingham RR, Héon E, Ritch R, Levin AV, Shields MB, Damji KF, Newlin A, Walter MA. Characterization and prevalence of PITX2 microdeletions and mutations in Axenfeld-Rieger malformations. Invest Ophthalmol Vis Sci. 2004;45:828–33. [PubMed: 14985297]
  • Lipson AH, Cowell C, Gorlin RJ. The SHORT syndrome: further delineation and natural history. J Med Genet. 1989;26:473–5. [PMC free article: PMC1015656] [PubMed: 2664179]
  • Petrovski S, Parrott RE, Roberts JL, Huang H, Yang J, Gorentla B, Mousallem T, Wang E, Armstrong M, McHale D, MacIver NJ, Goldstein DB, Zhong XP, Buckley RH. Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature. J Clin Immunol. 2016;36:462–71. [PMC free article: PMC5690581] [PubMed: 27076228]
  • Prontera P, Micale L, Verrotti A, Napolioni V, Stangoni G, Merla G. A new homozygous IGF1R variant defines a clinically recognizable incomplete dominant form of SHORT syndrome. Hum Mutat. 2015;36:1043–7. [PubMed: 26252249]
  • Ranza E, Guimier A, Verloes A, Capri Y, Marques C, Auclair M, Mathieu-Dramard M, Morin G, Thevenon J, Faivre L, Thauvin-Robinet C, Innes AM, Dyment DA, Vigouroux C, Amiel J. Overlapping phenotypes between SHORT and Noonan syndromes in patients with PTPN11 pathogenic variants. Clin Genet. 2020. Epub ahead of print. [PubMed: 32233106]
  • Reardon W, Temple IK. Nephrocalcinosis and disordered calcium metabolism in two children with SHORT syndrome. Am J Med Genet A. 2008;146A:1296–8. [PubMed: 18384141]
  • Reis LM, Tyler RC, Schilter KF, Abdul-Rahman O, Innis JW, Kozel BA, Schneider AS, Bardakjian TM, Lose EJ, Martin DM, Broeckel U, Semina EV. BMP4 loss-of-function mutations in developmental eye disorders including SHORT syndrome. Hum Genet. 2011;130:495–504. [PMC free article: PMC3178759] [PubMed: 21340693]
  • Schroeder C, Riess A, Bonin M, Bauer P, Riess O, Döbler-Neumann M, Wieser S, Moog U, Tzschach A. PIK3R1 mutations in SHORT syndrome. Clin Genet. 2014;86:292–4. [PubMed: 23980586]
  • Schwingshandl J, Mache CJ, Rath K, Borkenstein MH. SHORT syndrome and insulin resistance. Am J Med Genet. 1993;47:907–9. [PubMed: 8279490]
  • Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, Le Merrer M, Le Luyer B, Héron D, Mathieu-Dramard M, Bitoun P, Petit JM, Odent S, Amiel J, Picot D, Carmignac V, Thevenon J, Callier P, Laville M, Reznik Y, Fagour C, Nunes ML, Capeau J, Lascols O, Huet F, Faivre L, Vigouroux C, Rivière JB. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet. 2013;93:141–9. [PMC free article: PMC3710759] [PubMed: 23810378]

Chapter Notes

Author Notes

Dr A Micheil Innes's research is focused on both the clinical delineation and the identification of the molecular basis of rare genetic conditions.

Dr David Dyment's research interests are the identification of the molecular causes of rare syndromic and neurogenetic diseases.

Both Dr Innes and Dr Dyment are investigators with Care for Rare – SOLVE, a pan Canadian collaboration to investigate the causes of and improve the clinical care for patients and families affected by rare genetic diseases.

Revision History

  • 4 June 2020 (ha) Comprehensive update posted live
  • 15 May 2014 (me) Review posted live
  • 29 December 2013 (dd) Original submission
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2020 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK201365PMID: 24830046

Views

Tests in GTR by Gene

Related information

  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...