SciELO - Scientific Electronic Library Online

 
vol.30 issue5Social cost of mental disorders: Disability and work days lost. Results from the Mexican survey of psychiatric epidemiologySelf-esteem, depressive symptomatology, and suicidal ideation in adolescents: results of three studies author indexsubject indexsearch form
Home Pagealphabetic serial listing  

Services on Demand

Journal

Article

Indicators

Related links

  • Have no similar articlesSimilars in SciELO

Share


Salud mental

Print version ISSN 0185-3325

Salud Ment vol.30 n.5 México Sep./Oct. 2007

 

Artículos originales

Anomalías físicas menores y esquizofrenia

Francisco Caballero*  1 

Ana Fresán** 

Juan Jorge Palacios*** 

Soledad Rodríguez-Verdugo**** 

* Hospital de Salud Mental "Villahermosa".

** Subdirección de Investigaciones Clínicas, Instituto Nacional de Psiquiatría Ramón de la Fuente.

*** Servicio de Genética Médica, Instituto Nacional de Psiquiatría Ramón de la Fuente.

**** Jefa de la Clínica de Esquizofrenia, Instituto Nacional de Psiquiatría Ramón de la Fuente.

Resumen:

La hipótesis del papel que desempeña el neurodesarrollo en la génesis de la esquizofrenia es un constructo teórico que intenta explicar, al menos en parte, la etiopatogenia de esta entidad. Desde sus primeras descripciones se ha sugerido la idea de que la esquizofrenia es una enfermedad relacionada con la estructura del Sistema Nervioso y desde entonces hasta la fecha se ha intentado demostrar la existencia de marcadores biológicos.

Las anomalías físicas menores (AFM) son ligeras desviaciones de algunas de las características físicas externas de los individuos, que no representan una consecuencia médica seria ni un conflicto estético. Si se entiende a la esquizofrenia como una enfermedad que tiene su origen en una alteración del neurodesarrollo en los primeros meses de vida intrauterina, las AFM pueden ser consideradas como un marcador biológico válido en su evaluación, y al igual que los dermatoglifos, ser vistos como indicios "fósiles" que reflejarían el ambiente in utero. Podrían servir como una medida indirecta de la existencia de una alteración de las estructuras que se relacionan en su origen embriológico con el Sistema Nervioso Central, o bien con aquellas que pertenecen a campos de desarrollo embrionario adyacentes a las estructuras cerebrales.

Se ha especulado acerca de la existencia de un subtipo de esquizofrenia llamado «congénita» y que estaría asociado con una serie de características clínicas en las que el factor de las alteraciones del neurodesarrollo tendría una importancia prevalente dentro de la etiopatogenia de la enfermedad.

El instrumento más utilizado para la medición de estas anomalías es la escala de Waldrop, a la que se le han hecho múltiples modificaciones. Aunque se considera confiable y con buena consistencia interna, hay muchas limitaciones en la interpretación de los resultados. En los estudios clínicos realizados se ha encontrado una mayor prevalencia de AFM en pacientes con esquizofrenia comparados con grupos de control. Estas alteraciones se observan igualmente en pacientes con otros trastornos como retraso mental, autismo, déficit de atención y conducta violenta en la adolescencia, por lo que no se considera que haya una especificidad para la esquizofrenia. Sin embargo, entre los pocos datos sólidos obtenidos que se correlacionan con un mayor número de AFM están: correlación positiva con el sexo masculino, alteraciones cerebrales en neuroimagen, carga genética para esquizofrenia, mayor frecuencia de complicaciones obstétricas y deterioro cognitivo más notable. Otros estudios informan sobre una correlación positiva con un bajo ajuste premórbido, un inicio más temprano, predominio de síntomas negativos y mayor tendencia para desarrollar discinesia tardía, pero estos datos han tenido resultados que parecen ser contradictorios. Aunque las variantes fenotípicas de los diversos grupos étnicos limitan la interpretación de la presencia de una u otra anomalía física menor, la mayoría han encontrado un predominio de éstas en el área cráneo facial, principalmente en orejas y boca.

Se puede concluir que las AFM pueden ser un marcador biológico de rasgo que nos ayude a caracterizar al menos a un subgrupo de pacientes con esquizofrenia o que tienen predisposición a presentar ciertas características clínicas relacionadas, pero se precisa desarrollar un instrumento de medición que incluya medidas antropométricas objetivas para poder compararlas con las variantes fenotípicas de cada grupo étnico, además de realizar estudios de genética para tratar de determinar cuáles de esas variantes son determinadas genéticamente y cuales se han visto influidas por un factor ambiental o por la interacción de estos dos factores. La existencia de un tipo de esquizofrenia clínicamente reconocible y para el que se cuenta con una hipótesis etiopatogénica es un asunto aún en discusión que amerita mayores esfuerzos en su investigación y que nos puede ayudar eventualmente a replantear el concepto mismo de esquizofrenia.

Palabras clave: Esquizofrenia; anomalías físicas menores; neurodesarrollo

Summary:

The neurodevelopment hypothesis in schizophrenia is a theoretic construction that tries to explain, at least partially, the etiopatho-geny of this disease. Since Kraepelin's early descriptions it has been suggested that schizophrenia is a disease linked to the Central Nervous System structure, and vast efforts have been made to prove the existence of the biological markers of schizophrenia that include clinically distinguishable features (like dermatoglyphs and neuropsychological tests), electrophysiological, endocrine, immunologic and genetic tests, and neuroimaging studies.

The Minor Physical Anomalies (MPAs) are slight anatomical deviations of an individual's external physical features, which imply neither a serious medical consequence nor an aesthetic problem. MPAs could be considered a valid biological marker in the evaluation of schizophrenia if we interpret this disease as a disorder originating in the early months of intrauterine life during the first stages of neurodevelopment. Like dermatoglyphs, the MPAs may be seen as "fossil" signs that reflect the intrauterine environment.

They could be useful as an indirect measurement of an alteration of structures related to the Central Nervous System in its embryologic origin, or in nervous structures and non-neuronal epidermic and other superficial tissues derived from ectoderm, especially in skin, eyes and ears, or else with those that belong to embrionary developmental fields adjacent to brain structures, that may induce cranial-facial alterations.

This developmental fields theory explains the existence of a relationship between tissues or structures that do not have a common embryologic origin. After embryogenesis, they determine topographic zones of development, and the presence of a defect could affect a single structure (monotopic defect), but those that appear earlier would promote several areas in the body (polytopic field defects). Due to these complex interactions, it is not easy to correlate the intensity of the damage with the moment in which this occurred. A minor malformation could even have been generated in blastogenesis and could therefore be related to associated defects. It is not always a 'benign' abnormality. This observation is important if we consider that several genetic syndromes exist that present specific malformations. These are strongly associated with a high risk to develop schizophrenia (around 25 fold), such as the 22qll.2 deletion (velocardiofacial syndrome, DiGeorge syndrome and other variations).

There has been speculation around a so-called "congenital" schizophrenia subtype on the basis of an association with several clinical features such as gender, age of onset, positive or negative symptoms, brain abnormalities that show up in MRI scans, additional cognitive impairment and a worse evolution and prognosis in which the neurodevelopmental disturbances factor would have a widespread significance in the etiopathogeny of the disease.

The Waldrop's Scale for Minor Physical Anomalies has been the most used tool to measure these abnormalities and has been subject to numerous modifications. Even though it is considered a reliable instrument, with a good internal consistence, numerous limitations in results interpretation have been noted, most of them derived of limited inter-evaluator reliability, lack of consensus about the relative importance of each item and the extensive interracial variability in the presentation of MPAs. In the 1980's, the neurodevelopmental theory emerged as an explanation of the origin of schizophrenia and a number of investigations have been carried out, to measure MPAs and other biologic markers of neurodevelopment (like dermatoglyphs). Most studies have shown a greater prevalence of MPAs in schizophrenic patients compared to control groups, as it has been observed in other disorders like mental retardation, autism, attention-deficit disorder and violent behavior in adolescence. Nevertheless, there are only a few consistent data sets that correlate with an increased number of MPAs, and amongst them we can point out a positive correlation with male gender, neuroimaging brain alterations, genetic charge for schizophrenia, more frequent obstetric complications and a more perceptible cognitive impairment. Additionally, other investigations draw attention to a positive correlation with a lower premorbid adjustment, an earlier beginning of the disease, a predominance of negative symptoms and a larger tendency to develop late dyskinesia, although these data show contradictory results. Even though the diverse ethnic groups' phenotypic variants tend to limit the interpretation of each minor physical anomaly, most investigations have found a prevalence of these abnormalities in the cranial-facial area, most of them in ears and mouth, although the peripheral zones are not unaffected.

When we consider those studies, we notice that the diversity of data is predominant. We can explain this if we bear in mind that some of the MPAs can be normal phenotypic features in some ethnic groups, or frequent enough to be a normal variant without discriminative meaning. We must also take into account that different scales have been used for the measurements. For this specific problem it has been suggested to use anthropometric scales, similar to those used by cranial-facial surgeons.

The variability of the presentation of MPAs and the phenotypic variations compel us to conduct local investigations focused on determining which variants are outstanding or not in any ethnic group in relation to neurodevelopment deviations.

We can conclude than MPAs might be a biological marker that can help us to characterize at least a subgroup of clinically recognizable schizophrenic patients, or those that have predisposition to present some clinical features, but it is necessary to develop an objective evaluation tool that ideally would incorporate anthropometric measurements in order to compare these MPAs with the phenotypic variants in each ethnic group. It is necessary to design and carry out genetic studies (first among first and second-degree relatives and afterwards in bigger populations and also comparative studies with the general population) with the aim to distinguish between genetically-determined variants and those resulting from environmental factors, as well as establishing the interaction of both types of variants.

The existence of a clinically recognizable subtype of schizophrenia on which we can rely on as an etiopathogeny hypothesis is an appreciable area that is still under discussion and which deserves further investigation efforts. This could have implications on our approach to nosologic, diagnostic and even prognostic features of this heterogeneous disorder. Such investigation could help us to reformulate the schizophrenia notion itself.

Key words: Schizophrenia; minor physical anomalies; neurodevelopment

Texto completo disponible sólo en PDF.

Agradecimientos

Los autores agradecen a Marcel Bernard Croon, M.Sc. por la revisión del texto en inglés y sus valiosos comentarios.

Referencias

1. AASE JM: Diagnostic Dysmorphology. Plenum Medical Book Company. Nueva York y Londres, 1992. [ Links ]

2. AKABALIEV VH, SIVKOV ST: Sexual dimorphism in minor physical anomalies in schizophrenic patients and normal controls. Compr Psychiatry, 44(4):341-8, 2003. [ Links ]

3. ALEXANDER RC, MUKHERJEE S, RICHTER J, KAUFMANN CA: Minor physical anomalies in schizophrenia. J Nerv Ment Dis, 182(11):639-44, 1994. [ Links ]

4. ARSENEAULT L, TREMBLAY RE, BOULERICE B, SÉGUIN JR, SAUCIER JF : Minor Physical Anomalies and Family Adversity as Risk Factors for Violent Delinquency in Adolescence. Am J Psychiatry, 157:917-923, 2000. [ Links ]

5. ASOCIACION PSIQUIATRICA AMERICANA: Manual Diagnóstico y Estadístico de los Trastornos Mentales. DSM-IV-TR. Masson, Barcelona, 2002. [ Links ]

6. BUCKLEY PF: The clinical stigmata of aberrant neurodevelopment in schizophrenia. J Nerv Ment Dis , 186(2):79-86, 1998. [ Links ]

7. CAMPBELL M, GELLER B, SMALL AM, PETTI TA, FERRIS SH: Minor physical anomalies in young psychotic children. Am J Psychiatry , 135(5):573-5 1978. [ Links ]

8. CANNON TD, VAN ERP TG, BEARDEN CE, LOEWY R y cols.: Early and late neurodevelopmental influences in the prodrome to schizophrenia: contributions of genes, environment, and their interactions. Schizophr Bull, 29(4):653-69, 2003. [ Links ]

9. CANTOR-GRAAE E, ISMAIL B, MCNEIL TF: Are neurological abnormalities in schizophrenic patients and their siblings the result of perinatal trauma? Acta Psychiatr Scand, 101(2):142-7, 2000. [ Links ]

10. CANTOR-GRAAE E , MCNEIL TF , TORREY EF, QUINN P y cols.: Link between pregnancy complications and minor physical anomalies in monozygotic twins discordant for schizophrenia. Am J Psychiatry , 151(8):1188-93, 1994. [ Links ]

11. CHOK JT, KWAPIL TR, SCHEUERMANN A: Dermatoglyphic anomalies in psychometrically identified schizotypic young adults. Schiz Research, 72(2-3):205-214, 2005. [ Links ]

12. DE LA CRUZ AR, FAÑANAS L: Los dermatoglifos como marcadors de neurodesarrollo alterado en esquizofrenia. En: Obiols JE (ed.). Neurodesarrollo y Esquizofrenia. Aproximaciones Actuales. Ars Medica, 25-39, Barcelona, 2001. [ Links ]

13. ELIZARRARAS-RIVAS J, FRAGOSO-HERRERA R, CERDAN-SANCHEZ LF, RAMOS-ZEPEDA R y cols.: Minor physical anomalies and anthropometric measures in schizophrenia: a pilot study from Mexico. Schizophr Res. 62(3):285-7, 2003. [ Links ]

14. GOURION D, GOLDBERGER C, BOURDEL MC, BAYLE FJ y cols.: Neurological soft-signs and minor physical anomalies in schizophrenia: differential transmission within families. Schizophr Res , 63(1-2):181-7, 2003. [ Links ]

15. GOURION D , GOLDBERGER C , BOURDEL MC , JEAN BAYLE F y cols.: Minor physical anomalies in patients with schizophrenia and their parents: prevalence and pattern of craniofacial abnormalities. Psychiatry Res, 125(1):21-8, 2004. [ Links ]

16. GOURION D , GOLDBERGER C , OLIE JP, LOO H, KREBS MO: Neurological and morphological anomalies and the genetic liability to schizophrenia: a composite phenotype. Schizophr Res , 67(1):23-31, 2004. [ Links ]

17. GOURION D , GOUREVITCH R, LEPROVOST JB, OLIE H LOO JP, KREBS MO . L'hypothèse neurodéveloppementale dans la schizophrénie. Encéphale, 30(2):109-18, 2004. [ Links ]

18. GREEN MF, BRACHA HS, SATZ P, CHRISTENSON CD: Preliminary evidence for an association between minor physical anomalies and second trimester neurodevelopment in schizophrenia. Psychiatry Res , 53(2):119-27, 1994. [ Links ]

19. GREEN MF , SATZ P , CHRISTENSON C: Minor physical anomalies in schizophrenia patients, bipolar patients, and their siblings. Schizophr Bull , 20(3):433-40, 1994. [ Links ]

20. GREEN MF , SATZ P , GAIER DJ, GANZELL S, KHARABI F: Minor physical anomalies in schizophrenia. Schizophr Bull , 15(1):91-9, 1989. [ Links ]

21. GREEN MF , SATZ P , SOPER HV, KHARABI F : Relationship between physical anomalies and age at onset of schizophrenia. Am J Psychiatry , 144(5):666-7, 1987. [ Links ]

22. GRIFFITHS TD, SIGMUNDSSON T, TAKEI N, FRANGOU S y cols.: Minor physical anomalies in familial and sporadic schizophrenia: The Maudsley family study. J Neurol Neurosurg Psychiatry, 64(1):56-60, 1998. [ Links ]

23. GUY JD, MAJORSKI LV, WALLACE CJ, GUY MP: The incidence of minor physical anomalies in adult male schizophrenics. Schizophr Bull , 9(4):571-82, 1983. [ Links ]

24. HATA K, IIDA J, IWASAKA H, NEGORO H, KISHIMOTO T: Association between minor physical anomalies and lateral ventricular enlargement in childhood and adolescent onset schizophrenia. Acta Psychiatr Scand , 108(2):147-51, 2003. [ Links ]

25. HIPPIUS H, MÜLLER-SPAHN F: Los marcadores biológicos de la esquizofrenia y otras psicosis. Salud Mental, 10(3):35-41, 1987. [ Links ]

26. ISMAIL B , CANTOR-GRAAE E , MCNEIL TF : Minor physical anomalies in schizophrenia: cognitive, neurological and other clinical correlates. J Psych Res, (34):45-56, 2000. [ Links ]

27. ISMAIL B , CANTOR-GRAAE E , MCNEIL TF : Minor physical anomalies in schizophrenic patients and their siblings. Am J Psychiatry , 155(12):1695-702, 1998. [ Links ]

28. ISMAIL B , CANTOR-GRAAE E , MCNEIL TF : Problems with the Waldrop scale. Reply. Am J Psychiatry , 157(3):486, 2000. [ Links ]

29. ISMAIL B T, CANTOR-GRAAE E , CARDENAL S, MCNEIL TF : Neurological abnormalities in schizophrenia: clinical, etiological and demographic correlates. Schizophrenia Res, 30:229-238, 1998. [ Links ]

30. JOHNSTONE EC, CROW TC, FRITH CD y cols.: Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet, 2:924-926, 1976. [ Links ]

31. JONES KL: Minor anomalies as clues to more serious problems and toward the recognition of malformation syndromes. En: Jones, KL (ed.). Smith's Recognizable Patterns of Human Malformations. 5a ed. WB Saunders Company, 727-747, Philadelphia, 1997. [ Links ]

32. LANE A, KINSELLA A, MURPHY P, BYRNE M y cols.: The anthropometric assessment of dysmorphic features in schizophrenia as an index of its developmental origins. Psychol Med, 27(5):1155-64, 1997. [ Links ]

33. LOBATO MI, BELMONTE-DE-ABREU P, KNIJNIK D, TERUCHKIN B y cols.: Neurodevelopmental risk factors in schizophrenia. Braz J Med Biol Res, 34(2):155-63, 2001. [ Links ]

34. LOHR JB, FLYNN K: Minor physical anomalies in schizophrenia and mood disorders. Schizophr Bull , 19(3):551-6, 1993. [ Links ]

35. MARCUS J, HANS SL, BYHOUWER B, NOREM J: Relationships among neurological functioning, intelligence quotients, and physical anomalies. Schizophr Bull , 11(1):101-8, 1985. [ Links ]

36. MARTINEZ-FRIAS ML, FRIAS JL, OPITZ JM: Errors of morphogenesis and developmental field theory. Am J Med Genetics, (76):291-296, 1998. [ Links ]

37. MCCLURE RK, LIEBERMAN JA: Neurodevelopmental and neurodegenerative hipotheses of schizophrenia: a review and critique. Curr Opin Psychiatry, 16(supl 2):S15-S28, 2003. [ Links ]

38. MCGRATH J, EL-SAADI O, GRIM V, CARDY S, CHAPPLE B y cols.: Minor physical anomalies and quantitative measures of the head and face in patients with psychosis. Arch Gen Psychiatry, 59(5):458-64, 2002. [ Links ]

39. MCNEIL TF , CANTOR-GRAAE E , WEINBERGER DR: Relationship of obstetric complications and differences in size of brain structures in monozygotic twin pairs discordant for schizophrenia. Am J Psychiatry , 157(2):203-12, 2000. [ Links ]

40. MCNEIL TF , CANTOR-GRAAE E : Does preexisting abnormality cause labor-delivery complications in fetuses who will develop schizophrenia? Schizpphr Bull, 25(3):425-35, 1999. [ Links ]

41. MURPHY KC, OWEN MJ: Minor physical anomalies and their relationship to the aetiology of schizophrenia. Br J Psychiatry, 168(2):139-42, 1996. [ Links ]

42. MURRAY RM: Neurodevelopmental schizophrenia: the rediscovery of dementia praecox. Br J Psychiatry (Supl, 25):6-12, 1994. [ Links ]

43. NAVARRO-MATEU F: Anomalías físicas menores y esquizofrenia. En: Obiols JE (ed.). Neurodesarrollo y Esquizofrenia. Aproximaciones Actuales. Ars Medica, 41-51, Barcelona, 2001. [ Links ]

44. NAVARRO-MATEU F, MARTINEZ S, VAN OS J, BARCIA D: La hipótesis del neurodesarrollo en las psicosis funcionales. Actas Esp Psiquiatr, 27(4):264-72, 1999. [ Links ]

45. O'CALLAGHAN E, BUCKLEY P, MADIGAN C, REDMOND O y cols.: The relationship of minor physical anomalies and other putative indices of developmental disturbance in schizophrenia to abnormalities of cerebral structure on magnetic resonance imaging. Biol Psychiatry, 38(8):516-24, 1995. [ Links ]

46. O'CALLAGHAN E , LARKIN C, KINSELLA A , WADDINGTON JL: Familial, obstetric, and other clinical correlates of minor physical anomalies in schizophrenia. Am J Psychiatry , 148(4):479-83, 1991. [ Links ]

47. OPITZ JM : Development and malformation. American J Medical Genetics Semin Med Genet), 115:203-204, 2002. [ Links ]

48. PAEZ F, APIQUIAN R, FRESAN A, PUIG A y cols.: Dermatoglyphic study of positive and negative symptoms in schizophrenia. Salud Mental , 24(1):28-33,2001. [ Links ]

49. RAPAPORT MH, DELRAHIM KK: An abbreviated review of immune abnormalities in schizophrenia. CNS Spectr, (5):392-7, 2001. [ Links ]

50. RAPOPORT JL, ADDINGTON AM, FRANGOU S , PSYCH MR: The neurodevelopmental model of schizophrenia: update 2005. Mol Psychiatry, 10(5):434-49, 2005. [ Links ]

51. ROBERTS GW: Schizophrenia: a neuropathological perspective. Br J Psychiatry , 158:8-17, 1991. [ Links ]

52. SCHIFFMAN J, EKSTROM M, LABRIE J, SCHULSINGER F y cols.: Minor physical anomalies and schizophrenia spectrum disorders: a prospective investigation. Am J Psychiatry , 159(2):238-43, 2002. [ Links ]

53. SIVKOV ST , AKABALIEV VH : Discriminating value of total minor physical anomaly score on the Waldrop physical anomaly scale between schizophrenia patients and normal control subjects. Schizophr Bull , 30(2):361-6, 2004. [ Links ]

54. SIVKOV ST , AKABALIEV VH : Minor physical anomalies in schizophrenic patients and normal controls. Psychiatry, (3):222-33, 2003. [ Links ]

55. STEVENSON RE: Human Malformations and Related Anomalies. Vols. I - II. Oxford University Press. Nueva York/Oxford. 1993. [ Links ]

56. TARRANT CJ, JONES PB: Precursors to schizophrenia: do biological markers have specificity? Can J Psychiatry , 44(4):335-49, 1999. [ Links ]

57. THOMPSON JL, WATSON JR, STEINHAUER SR, GOLDSTEIN G y cols.: Indicators of Genetic Liability to Schizophrenia: A Sibling Study of Neuropsychological Performance. Schizophrenia Bulletin, 31(1):85-96, 2005. [ Links ]

58. TRIXLER M, TÉNYI T, CSABI G, SZABO G, MEHES K: Informative morphogenetic variants in patients with schizophrenia and alcohol-dependent patients: beyond the Waldrop Scale. Am J Psychiatry 154(5):691-3, 1997. [ Links ]

59. TRIXLER M, TÉNYI T: Problems with the Waldrop scale. Am J Psychiatry (3):486, 2000. [ Links ]

60. WADDINGTON JL , LANE A , LARKIN C , O'CALLAGHAN: The neurodevelopmental basis of schizophrenia; Clinical clues from cerebro-craniofacial dysmorphogenesis, and the roots of a lifetime trajectory of disease. Biol Psychiatry 46:31-39, 1999. [ Links ]

61. WADDINGTON JL , O'CALLAGHAN E , BUCKLEY P , MADIGAN C y cols.: Tardive dyskinesia in schizophrenia. Relationship to minor physical anomalies, frontal lobe dysfunction and cerebral structure on magnetic resonance imaging. Br J Psychiatry 167(1):41-4, 1995. [ Links ]

62. WALDROP M, PEDERSEN F, BELL R: Minor physical anomalies and behavior in preschool children. Chil Development, 39:391-400, 1968. [ Links ]

63. WEINSTEIN DD, DIFORIO D, SCHIFFMAN J , WALKER E, BONSALL R: Minor physical anomalies, dermatoglyphic asymmetries, and cortisol levels in adolescents with schizotypal personality disorder. Am J Psychiatry 156(4):617-23, 1999. [ Links ]

Recibido: 17 de Agosto de 2006; Aprobado: 18 de Abril de 2007

1 Correspondencia: Francisco Caballero Prado. Hospital de Salud Mental "Villahermosa", Ramón Mendoza s/n. Col. José María Pino Suárez. Villahermosa, Tabasco, México. E.mail: caballerofco@gmail.com Tel: +52 (993) 3570789.

Creative Commons License Este es un artículo publicado en acceso abierto bajo una licencia Creative Commons