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.

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. 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).

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.

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.

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.

Treatment of Manifestations

Surveillance

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.

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:

• If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%.
• If the proband has a known PIK3R1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism [Gorlin et al 1975].
• If the parents have not been tested for the PIK3R1 pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SHORT syndrome because of the possibility of parental germline mosaicism or the theoretic possibility of reduced penetrance in a heterozygous parent.

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, the parent's 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/preimplantation genetic 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. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown).

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.

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.

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 rare genetic diseases and improve the clinical care for patients and families affected by them.

Revision History

• 4 June 2020 (ha) Comprehensive update posted live
• 15 May 2014 (me) Review posted live
• 29 December 2013 (dd) Original submission

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;98:10–8. [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]