title: Hippocampal malformation associated with sudden death in early childhood: a neuropathologic study: Part 2 of the investigations of The San Diego SUDC Research Project.
abstract: OBJECTIVE
  Sudden unexplained death in childhood (SUDC), while rare, accounts for an important fraction of unexpected deaths in children >1 year of age. Previously we reported an association between febrile seizures, hippocampal maldevelopment, and sudden, unexpected deaths in young children (1-6 years), termed "hippocampal maldevelopment associated with sudden death (HMASD)." Here, we characterize in greater detail the hippocampal pathology in a large cohort of cases (n = 42) of this entity, and attempt to define possible new entities responsible for sudden, unexplained death in young children without HMASD/febrile seizure phenotypes.
  
  
  METHODS
  We performed comparative analysis on cases, which we classified in a cohort of 89 sudden and unexpected deaths as HMASD, explained deaths, SUDC with febrile seizure phenotype (SUDC-FS) but without hippocampal pathology, and SUDC (without hippocampal pathology or febrile seizure phenotype).
  
  
  RESULTS
  The frequency of each subgroup was: HMASD 48% (40/83); SUDC 27% (22/83); SUDC-FS 18% (15/83); explained 7% (6/83). HMASD was characterized clinically by sudden, sleep-related death, term birth, and discovery in the prone position. Key morphologic features of HMASD were focal granule cell bilamination of the dentate gyrus with or without asymmetry and/or malrotation of the hippocampus, associated with significantly increased frequencies of 11 other developmental abnormalities. We identified no other distinct phenotype in the unexplained categories, except for an association of febrile seizures without hippocampal maldevelopment.
  
  
  CONCLUSIONS
  HMASD is a distinct clinicopathologic entity characterized by a likely developmental failure of neuronal migration in the dentate gyrus. Future research is needed to determine the causal role of HMASD in sudden death in early childhood.
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA, USA. marco.hefti@mountsinai.org.|Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA. marco.hefti@mountsinai.org.|Division of Neuropathology, Department of Pathology, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA. marco.hefti@mountsinai.org.
authors.forename: Marco M
authors.initials: MM
authors.lastname: Hefti
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Cryan
authors.affiliation: Department of Pathology, Rady Children's Hospital-San Diego, San Diego, CA, USA.
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Haas
authors.affiliation: Department of Pathology, Rady Children's Hospital-San Diego, San Diego, CA, USA.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Chadwick
authors.affiliation: SUDC Foundation, Hackensack, NJ, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Crandall
authors.affiliation: New England Research Institutes, Watertown, MA, USA.
authors.forename: Felicia L
authors.initials: FL
authors.lastname: Trachtenberg
authors.affiliation: Department of Pathology, Emeritus, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Dawna D
authors.initials: DD
authors.lastname: Armstrong
authors.affiliation: Department of Pathology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Grafe
authors.affiliation: Department of Pediatrics, UCSD School of Medicine, La Jolla, CA, USA.
authors.forename: Henry F
authors.initials: HF
authors.lastname: Krous
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Hannah C
authors.initials: HC
authors.lastname: Kinney
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003645:Death, Sudden / Q000209:etiology*; D018891:Dentate Gyrus / Q000473:pathology; D005260:Female; D049429:Forensic Pathology; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology*; D006801:Humans; D007223:Infant; D008297:Male; D009474:Neurons / Q000473:pathology; D016684:Prone Position; D012189:Retrospective Studies; D012890:Sleep; D013702:Temporal Lobe / Q000473:pathology; D047929:Term Birth
keywords: Dentate gyrus; Febrile seizures; Neurogenesis; Sudden unexplained death in childhood (SUDC); Sudden unexplained death in epilepsy (SUDEP)