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Hartsfield Syndrome

, MD, FAAP and , MD.

Author Information

Initial Posting: .

Summary

Clinical characteristics.

Hartsfield syndrome comprises two core features: holoprosencephaly (HPE) spectrum disorders and ectrodactyly spectrum disorders.

  • HPE spectrum disorders, resulting from failed or incomplete forebrain division early in gestation, include alobar, semilobar, or lobar HPE. Other brain malformations observed in persons with Hartsfield syndrome include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Varying degrees of developmental delay are observed. Microcephaly, spasticity, seizures, and feeding difficulties are common. Hypothalamic dysfunction (manifest as temperature dysregulation and erratic sleep patterns) can occur, as well as hypogonadotropic hypogonadism and central insipidus diabetes.
  • Ectrodactyly spectrum disorders are unilateral or bilateral malformations of the hands and/or feet characterized by a median cleft of hand or foot due to absence of the longitudinal central rays (also called split hand/foot malformation). The number of digits on the right and left can vary. Polydactyly and syndactyly can also be seen.

Diagnosis/testing.

The diagnosis is established in a proband with the two core features: an HPE spectrum disorder and an ectrodactyly spectrum disorder. It can be confirmed by identification of either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance).

Management.

Treatment of manifestations: Medically refractory epilepsy typically requires multiple antiepileptic drugs. Spasticity can be treated with physical and occupational therapy and bracing, as well as muscle relaxants (when moderate or severe). Sometimes surgery may be required. Diabetes insipidus may need treatment with desmopressin; temperature dysregulation can be managed by modifying the environment; disturbance of sleep-wake cycles can be managed with good sleep hygiene and, if needed, with use of melatonin or other sleep aids such as clonidine. Some children may require a gastrostomy and/or a tracheostomy.

Genetic counseling.

Hartsfield syndrome is inherited most commonly in an autosomal dominant (AD) and less commonly in an autosomal recessive (AR) manner.

  • AD inheritance: Most probands have a de novo FGFR1 pathogenic variant. Germline mosaicism has been observed in two unrelated families.
  • AR inheritance: At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once the FGFR1 pathogenic variant(s) have been identified in an affected family member, prenatal testing or preimplantation genetic diagnosis for a pregnancy at increased risk is possible.

Diagnosis

Suggestive Findings

Hartsfield syndrome should be suspected in individuals with the following core features:

  • Holoprosencephaly (HPE) spectrum disorders. The spectrum results from failed or incomplete forebrain division early in gestation and includes alobar, semilobar, or lobar HPE. Other brain malformations can include corpus callosum agenesis, absent septum pellucidum, absent olfactory bulbs and tracts, and vermian hypoplasia. Microcephaly is common.
  • Ectrodactyly spectrum disorders. These unilateral or bilateral malformations of the hands and/or feet are characterized by a median cleft of hand or foot due to absence of longitudinal central rays (also called split hand/foot malformation). The number of digits on the right and left hand/foot can vary. Polydactyly and syndactyly can be part of the spectrum.

Additional features that may be present [Imaizumi et al 1998, Abdel-Meguid & Ashour 2001, Keaton et al 2010, Simonis et al 2013]:

  • Facial dysmorphism (hypertelorism or hypotelorism)
  • Cleft lip and/or palate (midline or bilateral)
  • Malformed ears
  • Cardiac defects
  • Abnormal genitalia (micropenis, cryptorchidism)
  • Vertebral anomalies
  • Radial or ulnar defects
  • Central diabetes insipidus
  • Growth hormone deficiency, hypogonadotropic hypogonadism, central diabetes insipidus
  • Varying degrees of developmental delay, seizures

Establishing the Diagnosis

The diagnosis of Hartsfield syndrome is established clinically in a proband with the two core features of a holoprosencephaly (HPE) spectrum disorder and an ectrodactyly spectrum disorder and can be confirmed on molecular genetic testing by identification of either an FGFR1 heterozygous pathogenic variant (in those with autosomal dominant inheritance) or FGFR1 biallelic pathogenic variants (in those with autosomal recessive inheritance) (see Table 1) [Simonis et al 2013, Dhamija et al 2014].

Molecular testing approaches can include single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Single-gene testing. Sequence analysis of FGFR1 is performed first and followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found [Simonis et al 2013, Dhamija et al 2014].
  • A multigene panel that includes FGFR1 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing, mitochondrial sequencing, and genome sequencing may be considered if serial single-gene testing (and/or use of a multigene panel that includes FGFR1) fails to confirm a diagnosis in an individual with features of Hartsfield syndrome. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene that results in a similar clinical presentation). 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 Hartsfield Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant 2 Detectable by This Method
FGFR1Sequence analysis 36/7, 1/1, 3/3 4
Gene-targeted deletion/duplication analysis 5Unknown 6
Unknown 7NA
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.

Simonis et al [2013]; Dhamija et al [2014]; C Vilain and G Smits, unpublished data

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used can 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.

No data on detection rate of gene-targeted deletion/duplication analysis are available.

7.

Clinical Characteristics

Clinical Description

Hartsfield syndrome, comprising malformations of the two major groups holoprosencephaly (HPE) spectrum malformations and ectrodactyly spectrum malformations, has been reported to date in fewer than 20 individuals [Keaton et al 2010, Simonis et al 2013]. Among the individuals reported, all but two were males.

Following discovery of the genetic basis of Hartsfield syndrome, the diagnosis has been molecularly confirmed in ten probands: 6/7 reported by Simonis et al [2013], 1/1 reported by Dhamija et al [2014], and 3/3 unreported cases [C Vilain and G Smits, unpublished data].

In addition to HPE spectrum malformations and ectrodactyly spectrum malformations, Hartsfield syndrome may include the following features:

Craniofacial dysmorphism

  • Hypotelorism or hypertelorism; malformed, low-set and posteriorly rotated ears; eye anomalies; and cleft lip and or palate (median or bilateral) are common.
  • Craniosynostosis (metopic and coronal) has been reported.

Central nervous system

  • HPE is associated with varying degrees of developmental delay.
  • Spasticity is common.
  • Seizures are common, and may be difficult to control.
  • Hypothalamic dysfunction, manifest as temperature dysregulation and erratic sleep patterns, can occur.
  • Microphthalmia and coloboma have been reported as a part of the HPE spectrum of malformations.
  • Tethered cord has been seen in a few patients.

Skeletal anomalies. Other skeletal anomalies include vertebral anomalies and radial and ulnar aplasia.

Gastrointestinal. Feeding difficulties due to axial hypotonia, gastrointestinal reflux, and oro-motor dysfunction may be a major problem and result in failure to thrive.

Respiratory. Aspiration pneumonia can result from poorly coordinated suck and swallow.

Endocrine. Due to midline brain defects that involve the pituitary, central endocrine disorders are common (including growth hormone deficiency, central diabetes insipidus, and hypogonadotropic hypogonadism).

Genitourinary. Some males have micropenis, cryptorchidism (due to hypogonadotropic hypogonadism) and hypospadias.

Cardiovascular. One individual had coarctation of the aorta.

Phenotype of Autosomal Recessive Hartsfield Syndrome

Compared with four individuals with a heterozygous FGFR1 pathogenic variant, the two with biallelic FGFR1 pathogenic variants had a more severe phenotype [Simonis et al 2013]:

  • HPE spectrum:
    • Alobar holoprosencephaly (1/2)
    • Diminished cortical thickening (2/2)
    • Absent corpus callosum (2/2)
  • Median cleft (1/2)
  • Hypotelorism (2/2)
  • Severe developmental delay and growth retardation (2/2)
  • Ectrodactyly spectrum: split hand/foot malformation of both hands and feet, and fewer than three digits bilaterally (2/2)
  • Death before age five years (2/2)

Nomenclature

In the older literature, Harstfield syndrome has been referred to as:

  • Holoprosencephaly and split hand/foot syndrome
  • Holoprosencephaly, hypertelorism, and ectrodactyly syndrome (HHES)

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been established among the small number of affected individuals with a molecularly confirmed diagnosis of Hartsfield syndrome reported to date.

FGFR1 pathogenic variants described to date in individuals with Hartsfield syndrome cluster in specific domains of the receptor [Simonis et al 2013; C Vilain and G Smits, unpublished data]:

  • A heterozygous pathogenic variant affecting amino acid residues located in the ATP binding pocket of the intracellular tyrosine kinase domain (TKD) is found in most affected individuals with variable phenotypes.
  • Biallelic pathogenic variants affecting amino acid residues located in the extracellular ligand binding domain D2 of FGFR1 have been found in two individuals with a severe phenotype.
  • A heterozygous pathogenic variant in the intracellular C-terminal loop of the TKD was found in one individual with a mild phenotype.

Prevalence

Hartsfield syndrome is very rare: of the fewer than 20 individuals reported in the medical literature only 13 (from 10 families) have been confirmed to have loss-of-function variants in FGFR1.

Differential Diagnosis

Holoprosencephaly (HPE). See Holoprosencephaly Overview.

Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3). Ectrodactyly with or without syndactyly is present in approximately 70% of all affected individuals and ranges widely in severity and location of the digital abnormalities. Ectodermal defects typically manifest as silvery-blond, sparse fine hair; dry skin and unique pigmentary skin changes; nail changes; dental changes including oligodontia and enamel defects; and xerostomia and subjective decrease in sweating capacity. Cleft lip/palate is present in approximately 40% of affected individuals; the spectrum includes submucous cleft palate only, cleft of the soft and/or the hard palate only, cleft lip only, and the combination of cleft lip and cleft palate. EEC3 is caused by mutation of TP63 and inherited in an autosomal dominant manner.

Overexpression of KAL1. One male with hyperosmia, ectrodactyly, genital anomalies, and mild intellectual disability had partial duplication of the X-linked gene KAL1. KAL1 protein at high levels may interfere with FGFR1 signaling activity, leading to an overlapping phenotype [Sowińska-Seidler et al 2015].

Microduplication of Xq24. One individual with duplication of Xq24 and Hartsfield syndrome phenotype has been reported [Takenouchi et al 2012].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Hartsfield syndrome, the following evaluations are recommended:

  • Determine the type of holoprosencephaly (alobar, semilobar, or lobar) by neuroimaging, preferably a brain MRI.
  • Assess development including evidence of spasticity.
  • Evaluate suspicious activity for evidence of seizures.
  • Evaluate nutritional status and feeding for evidence of problems that may result from cleft lip/palate and/or oromotor dysfunction and other problems that may result from gastrointestinal involvement (e.g., slow gastric emptying, gastroesophageal reflux, constipation).
  • Evaluate for evidence of diabetes insipidus, temperature dysregulation, and/or disturbance of sleep-wake cycles.
  • Evaluate for evidence of endocrine deficiency (growth hormone deficiency, hypogonadotropic hypogonadism, central diabetes insipidus).
  • Consult with a clinical geneticist and/or genetic counselor.

Treatment of Manifestations

Neurologic. Medically refractory epilepsy typically requires multiple antiepileptic drugs (AEDs).

Spasticity can be treated with physical and occupational therapy and bracing. Muscle relaxants may be used to treat moderate or severe spasticity. Surgery may be required.

Hypothalamic involvement

  • Central diabetes insipidus may require treatment with desmopressin.
  • Temperature dysregulation can be managed by modifying the environment.
  • Disturbance of sleep-wake cycles can be managed with good sleep hygiene and, if needed, with use of melatonin or other sleep aids such as clonidine.

Skeletal. Surgery of hand and foot defects can improve dexterity.

Other

  • Tethered cord may require surgical intervention.
  • Cleft lip and palate: reparative surgery is needed in most.
  • Some children may require a gastrostomy and/or tracheostomy.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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

Hartsfield syndrome is inherited in an autosomal dominant (most commonly) or autosomal recessive manner.

Risk to Family Members ‒ Autosomal Dominant Inheritance

Parents of a proband

Sibs of a proband

Offspring of a proband. To date, no individual with Hartsfield syndrome has been known to reproduce.

Other family members. Given that most probands with Hartsfield syndrome reported to date have the disorder as a result of a de novo FGFR1 pathogenic variant, the risk to other family members is presumed to be low.

Risk to Family Members ‒ Autosomal Recessive Inheritance

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one FGFR1 pathogenic variant).
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.

Offspring of a proband. To date, no individual diagnosed with Hartsfield syndrome has been known to reproduce.

Other family members. Each sib of the proband’s parents is at a 50% risk of being a carrier of a FGFR1 pathogenic variant.

Carrier (Heterozygote) Detection

Carrier testing for at-risk relatives requires prior identification of the FGFR1 pathogenic variants in the family.

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 parents of affected individuals.

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 Diagnosis

Once the FGFR1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for Hartsfield syndrome are possible.

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.

  • Carter Centers for Brain Research in Holoprosencephaly and Related Malformations
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

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.

Hartsfield Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
FGFR18p11​.23Fibroblast growth factor receptor 1FGFR1 databaseFGFR1FGFR1

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 Hartsfield Syndrome (View All in OMIM)

136350FIBROBLAST GROWTH FACTOR RECEPTOR 1; FGFR1
615465HARTSFIELD SYNDROME; HRTFDS

Molecular Genetic Pathogenesis

FGFR1 is a member of the receptor tyrosine kinase superfamily. The fibroblast growth factor (FGF) signalling pathway is a major factor in embryonic development. A full-length representative protein consists of an extracellular region, comprising three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member binds both acidic and basic fibroblast growth factors and is involved in limb induction [Groth & Lardelli 2002, Tole et al 2006].

Gene structure. FGFR1 has a genomic size of approximately 58 kb. Transcript splice variants produce multiple protein isoforms. The longest transcript variant NM_023110.2 contains 18 total exons (17 coding exons). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Seven single-nucleotide variants in FGFR1 have been reported to date in persons with Hartsfield syndrome [Simonis et al 2013, Dhamija et al 2014].

Table 2.

FGFR1 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.494T>Cp.Leu165SerNM_023110​.2
NP_075598​.2
c.572T>Cp.Leu191Ser
c.1468G>Cp.Gly490Arg
c.1867G>Tp.Asp623Tyr
c.1880G>Cp.Arg627Thr
c.1884T>Gp.Asn628Lys
c.2174G>Ap.Cys725Tyr

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

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

Normal gene product. The longest transcript variant, NM_023110.2, encodes the longest protein isoform (NP_075598.2), of 822 amino acids. It is composed of an extracellular ligand-binding domain that contains three immunoglobulin (Ig)-like domains, a single transmembrane helix, and a cytoplasmic domain responsible for tyrosine kinase activity

Abnormal gene product. Hartsfield syndrome results from loss-of-function variants of FGFR1 [Simonis et al 2013, Dhamija et al 2014].

Cancer and Benign Tumors

Sporadic tumors occurring as single tumors in the absence of any other findings of Hartsfield syndrome may harbor somatic variants and/or copy number changes in FGFR1 that are not present in the germline; thus, predisposition to these tumors is not heritable [Ahmad et al 2012].

References

Literature Cited

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  • Ahmad I, Iwata T, Leung HY. Mechanisms of FGFR-mediated carcinogenesis. Biochim Biophys Acta. 2012;1823:850-60. [PubMed: 22273505]
  • Dhamija R, Kirmani S, Wang X, Ferber MJ, Wieben ED, Lazaridis KN, Babovic-Vuksanovic D. Novel de novo heterozygous FGFR1 mutation in two siblings with Hartsfield syndrome: a case of gonadal mosaicism. Am J Med Genet A. 2014;164A:2356–9. [PubMed: 24888332]
  • Farrow EG, Davis SI, Mooney SD, Beighton P, Mascarenhas L, Gutierrez YR, Pitukcheewanont P, White KE. Extended mutational analyses of FGFR1 in osteoglophonic dysplasia. Am J Med Genet A. 2006;140:537–9. [PubMed: 16470795]
  • Groth C, Lardelli M. The structure and function of vertebrate fibroblast growth factor receptor 1. Int J Dev Biol. 2002;46:393–400. [PubMed: 12141425]
  • Imaizumi K, Ishii T, Masuno M, Kuroki Y. Association of holoprosencephaly, ectrodactyly, cleft lip/cleft palate and hypertelorism: a possible third case. Clin Dysmorphol. 1998;7:213–6. [PubMed: 9689997]
  • Jarzabek K, Wolczynski S, Lesniewicz R, Plessis G, Kottler ML. Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome. Adv Med Sci. 2012;57:314–21. [PubMed: 23154428]
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  • Sarfati J, Bouvattier C, Bry-Gauillard H, Cartes A, Bouligand J, Young J. Kallmann syndrome with FGFR1 and KAL1 mutations detected during fetal life. Orphanet J Rare Dis. 2015;10:71. [PMC free article: PMC4469106] [PubMed: 26051373]
  • Schell U, Hehr A, Feldman GJ, Robin NH, Zackai EH, de Die-Smulders C, Viskochil DH, Stewart JM, Wolff G, Ohashi H, Price RA, Cohen MM, Muenke M. Mutations in FGFR1 and FGFR2 cause familial and sporadic Pfeiffer syndrome. Hum Mol Genet. 1995;4:323–8. [PubMed: 7795583]
  • Shi Y, Wren C, Wang X, Babovic-Vuksanovic D, Spector E. Detection of gonadal mosaicism in Hartsfield syndrome by next generation sequencing. Abstract #396. Salt Lake City, UT: ACMG Annual Clinical Genetics Meeting. 2015. Available online. Accessed 10-16-17.
  • Simonis N, Migeotte I, Lambert N, Perazzolo C, de Silva DC, Dimitrov B, Heinrichs C, Janssens S, Kerr B, Mortier G, Van Vliet G, Lepage P, Casimir G, Abramowicz M, Smits G, Vilain C. FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly. J Med Genet. 2013;50:585–92. [PMC free article: PMC3756455] [PubMed: 23812909]
  • Sowińska-Seidler A, Piwecka M, Olech E, Socha M, Latos-Bieleńska A, Jamsheer A. Hyperosmia, ectrodactyly, mild intellectual disability, and other defects in a male patient with an X-linked partial microduplication and overexpression of the KAL1 gene. J Appl Genet. 2015;56:177–84. [PMC free article: PMC4412513] [PubMed: 25339597]
  • Takenouchi T, Okuno H, Kosaki R, Ariyasu D, Torii C, Momoshima S, Harada N, Yoshihashi H, Takahashi T, Awazu M, Kosaki K. Microduplication of Xq24 and Hartsfield syndrome with holoprosencephaly, ectrodactyly, and clefting. Am J Med Genet A. 2012;158A:2537–41. [PubMed: 22887648]
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Chapter Notes

Revision History

  • 3 March 2016 (bp) Review posted live
  • 12 November 2015 (rd) Original submission
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