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Original article
From gestalt to gene: early predictive dysmorphic features of PMM2-CDG
  1. Antonio Martinez-Monseny1,
  2. Daniel Cuadras2,
  3. Mercè Bolasell1,
  4. Jordi Muchart3,4,
  5. César Arjona1,
  6. Mar Borregan1,
  7. Adi Algrabli5,
  8. Raquel Montero3,4,
  9. Rafael Artuch3,4,
  10. Ramón Velázquez-Fragua6,
  11. Alfons Macaya7,
  12. Celia Pérez-Cerdá8,
  13. Belén Pérez-Dueñas7,
  14. Belén Pérez8,
  15. Mercedes Serrano1,3,4
  16. the CDG Spanish Consortium
    1. 1Genetics and Molecular Medicine Department and Pediatric Institute of Rare Diseases (IPER), Hospital Sant Joan de Déu, Barcelona, Spain
    2. 2Statistics Department, Fundació Sant Joan de Déu, Barcelona, Spain
    3. 3Neuropediatric, Radiology and Clinical Biochemistry Departments, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
    4. 4U-703 Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain
    5. 5Face2gene, FDNA Inc, Boston, Massachusetts, USA
    6. 6Pediatric Neurology Department, Hospital Universitario La Paz, Madrid, Spain
    7. 7Secció de Neurologia Pediàtrica, Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona, Hospital Universitari Vall d’Hebron, Barcelona, Spain
    8. 8Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Universidad Autónoma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBERER) Madrid, Instituto de Salud Carlos III, Madrid, Spain
    1. Correspondence to Dr Antonio Martinez-Monseny, Genetics and Molecular Medicine Deparment and Pediatric Institute of Rare Diseases (IPER), Hospital Sant Joan de Déu, Barcelona, 08950, Spain; afmartinez{at}sjdhospitalbarcelona.org and Dr. Mercedes Serrano, Genetics and Molecular Medicine Department and Pediatric Institute of Rare Diseases (IPER) Hospital Sant Joan de Déu, Barcelona, 08950, Spain; mserrano{at}sjdhospitalbarcelona.org

    Abstract

    Introduction Phosphomannomutase-2 deficiency (PMM2-CDG) is associated with a recognisable facial pattern. There are no early severity predictors for this disorder and no phenotype–genotype correlation. We performed a detailed dysmorphology evaluation to describe facial gestalt and its changes over time, to train digital recognition facial analysis tools and to identify early severity predictors.

    Methods Paediatric PMM2-CDG patients were evaluated and compared with controls. A computer-assisted recognition tool was trained. Through the evaluation of dysmorphic features (DFs), a simple categorisation was created and correlated with clinical and neurological scores, and neuroimaging.

    Results Dysmorphology analysis of 31 patients (4–19 years of age) identified eight major DFs (strabismus, upslanted eyes, long fingers, lipodystrophy, wide mouth, inverted nipples, long philtrum and joint laxity) with predictive value using receiver operating characteristic (ROC) curveanalysis (p<0.001). Dysmorphology categorisation using lipodystrophy and inverted nipples was employed to divide patients into three groups that are correlated with global clinical and neurological scores, and neuroimaging (p=0.005, 0.003 and 0.002, respectively). After Face2Gene training, PMM2-CDG patients were correctly identified at different ages.

    Conclusions PMM2-CDG patients’ DFs are consistent and inform about clinical severity when no clear phenotype–genotype correlation is known. We propose a classification of DFs into major and minor with diagnostic risk implications. At present, Face2Gene is useful to suggest PMM2-CDG. Regarding the prognostic value of DFs, we elaborated a simple severity dysmorphology categorisation with predictive value, and we identified five major DFs associated with clinical severity. Both dysmorphology and digital analysis may help physicians to diagnose PMM2-CDG sooner.

    • automated facial analysis software
    • cerebellar disorders
    • congenital disorders of glycosylation
    • dysmorphology
    • phosphomannomutase

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    Footnotes

    • Contributors AM-M and MS planned and designed the study, wrote the manuscript and submitted the article. DC did the statistics aspect and supervised the text. MB and CA collaborated at the figures design, acquisition of data and patients' agreements. JM did the radiological evaluations and help with the data analysis and supervision of the manuscript. AA did the Face2Gene assessment, statistical analysis and whole text supervision. RM and RA collaborated at metabolic diagnosis and help with the data analysis and supervision of the manuscript. RV-F, AM and B-D collaborated at the neurological assessment, data acquisition and review of the final file. CP-C and BP collaborated at the biochemical and genetic diagnosis, and help with the data analysis and supervision of the manuscript.

    • Funding This work was supported by national grants PI14/00021, PI11/01096, PI11/01250, PI16/00573 and PI17/00101 from the National Plan on I+D+I, cofinanced by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación Sanitaria) and FEDER (Fondo Europeo de Desarrollo Regional) and was supported by the Spanish CDG Association (AESCDG) and Fundación Isabel Gemio-Fundación La Caixa (LCF/PR/PR16/11110018). Two research groups (U-746 and U-703) from CIBERER, Instituto de Salud Carlos III, Spain worked together in the present study.

    • Competing interests None declared.

    • Patient consent Obtained.

    • Ethics approval This study was approved by the Research and Ethics Committee of the ‘Sant Joan de Déu Hospital (SJDH)’ (Internal code PIC-108–14). Samples and data were obtained in accordance with the Helsinki Declaration of 1964, as revised in October 2013 (Fortaleza, Brazil).

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators CDG Spanish Consortium: Sergio Aguilera-Albesa (Pediatric Neurology Unit, Department of Pediatrics, Complejo Hospitalario de Navarra, Navarrabiomed, Spain), Luis G Gutierrez-Solana (Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús de Madrid, Madrid, Spain), Laura López (Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús de Madrid, Madrid, Spain), Ana Felipe (Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona, Secció de Neurologia Pediàtrica, Hospital Universitari Vall d’Hebron, Barcelona, Spain), Mª Concepción Miranda (Pediatric Neurology Unit, H.G.U Gregorio Marañón, Madrid, Spain), Francisco Carratala (Pediatric Neurology Department, University Hospital Sant Joan d’Alacant, Spain), M Eugenia Yoldi (Pediatric Neurology Unit, Department of Pediatrics, Complejo Hospitalario de Navarra, Navarrabiomed, Spain), Eduardo López-Laso (Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Pediatric Neurology Unit, Reina Sofia University Hospital, CIBERER, Córdoba, Spain), Mª Concepción Sierra-Córcoles (Unidad de Neuropediatría, Hospital de Jaén, Jaén, Spain), Irma Sebastián-García (Unidad de Neurología Infantil, Servicio de Pediatria del Hospital Universitario Materno Infantil de Canarias, Spain), Eduardo Aísa (Unitat de Desenvolupament Infantil, Hospital Nostra Senyora de Meritxell, Escaldes-Engordany, Andorra), Ramon Cancho-Candela (Pediatric Neurology Unit. Pediatrics Department. Hospital Universitario Río Hortega. Valladolid, Spain), M Llanos Carrasco-Marina (Departament of Pediatrics, University Hospital Severo Ochoa de Leganés. Madrid. Spain), María L Couce (Unit of Diagnosis and Treatment of Congenital Metabolic Diseases. Department of Pediatrics, Hospital Clínico Universitario de Santiago. CIBERER. Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain), Susana Roldán (Pediatric Department. Hospital Universitario Materno-Infantil Virgen de las Nieves. Granada, Spain), Montserrat Morales (Department of Internal Medicine, Hospital Universitario 12 de Octubre, Madrid, Spain), Noemi Conde-Lorenzo (Pediatric Department, Complexo Hospitalario Universitario de Ourense, Ourense, Spain), Oscar Garcia (Pediatric Department, Hospital Virgen de la Salud, Toledo, Spain).

    • Correction notice This article has been corrected since it was published Online First. Mercedes Serrano has been added as co-corresponding author.

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