Phenotypic and Genotypic Characterisation of Inflammatory Bowel Disease Presenting Before the Age of 2 years.
OBJECTIVE
Inflammatory bowel disease [IBD] presenting in early childhood is extremely rare. More recently, progress has been made to identify children with monogenic forms of IBD predominantly presenting very early in life. In this study, we describe the heterogeneous phenotypes and genotypes of patients with IBD presenting before the age of 2 years and establish phenotypic features associated with underlying monogenicity.


METHODS
Phenotype data of 62 children with disease onset before the age of 2 years presenting over the past 20 years were reviewed. Children without previously established genetic diagnosis were prospectively recruited for next-generation sequencing.


RESULTS
In all, 62 patients [55% male] were identified. The median disease onset was 3 months of age (interquartile range [IQR]: 1 to 11). Conventional IBD classification only applied to 15 patients with Crohn's disease [CD]-like [24%] and three with ulcerative colitis [UC]-like [5%] phenotype; 44 patients [71%] were diagnosed with otherwise unclassifiable IBD. Patients frequently required parenteral nutrition [40%], extensive immunosuppression [31%], haematopoietic stem-cell transplantation [29%], and abdominal surgery [19%]. In 31% of patients, underlying monogenic diseases were established [EPCAM, IL10, IL10RA, IL10RB, FOXP3, LRBA, SKIV2L, TTC37, TTC7A]. Phenotypic features significantly more prevalent in monogenic IBD were: consanguinity, disease onset before the 6th month of life, stunting, extensive intestinal disease and histological evidence of epithelial abnormalities.


CONCLUSIONS
IBD in children with disease onset before the age of 2 years is frequently unclassifiable into Crohn's disease and ulcerative colitis, particularly treatment resistant, and can be indistinguishable from monogenic diseases with IBD-like phenotype.
Genetics and Genomic Medicine, Institute of Child Health, University College London, London, UK j.kammermeier@ucl.ac.uk.|Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Jochen
J
Kammermeier
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Robert
R
Dziubak
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Matilde
M
Pescarin
Genetics and Genomic Medicine, Institute of Child Health, University College London, London, UK.|NE Thames Regional Genetics Laboratory, Great Ormond Street Hospital, London, UK.
Suzanne
S
Drury
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Heather
H
Godwin
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Kate
K
Reeve
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Sibongile
S
Chadokufa
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Bonita
B
Huggett
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Sara
S
Sider
Genetics and Genomic Medicine, Institute of Child Health, University College London, London, UK.
Chela
C
James
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Nikki
N
Acton
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Elena
E
Cernat
Department of Paediatric Gastroenterology, Addenbrookes Hospital, Cambridge, UK.
Marco
M
Gasparetto
Department of Paediatric Gastroenterology, Addenbrookes Hospital, Cambridge, UK.
Gabi
G
Noble-Jamieson
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Fevronia
F
Kiparissi
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Mamoun
M
Elawad
Genetics and Genomic Medicine, Institute of Child Health, University College London, London, UK.
Phil L
PL
Beales
Department of Histopathology, Great Ormond Street Hospital, London, UK.
Neil J
NJ
Sebire
Department of Immunology, Great Ormond Street Hospital, London, UK.
Kimberly
K
Gilmour
Transitional Gastroenterology Unit, Nuffield Department of Medicine and Department of Paediatrics, University of Oxford, UK.
Holm H
HH
Uhlig
Genetics and Genomic Medicine, Institute of Child Health, University College London, London, UK.
Chiara
C
Bacchelli
Department of Gastroenterology, Great Ormond Street Hospital, London, UK.
Neil
N
Shah
D017668:Age of Onset; D003093:Colitis, Ulcerative / Q000235:genetics / Q000473:pathology; D003424:Crohn Disease / Q000235:genetics / Q000473:pathology; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D015212:Inflammatory Bowel Diseases / Q000235:genetics / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D008297:Male; D010641:Phenotype
Inflammatory bowel disease; genetics; immunodeficiency; infantile-onset; next-generation sequencing; paediatrics; phenotype