Presentation: Child with suspected monogenic inflammatory bowel disease

An 18-month-old male infant presents to clinic with a three-month history of loose stools with intermittent blood. He was born at term after an uncomplicated pregnancy. There had been multiple relatively mild infections in the first year of life including inner-ear infections requiring three courses of antibiotics. There was no significant family history. On examination, he was not dysmorphic. There was no organomegaly, although the abdomen was slightly tender. Some soreness was noted in the perianal region.

• Patients with monogenic inflammatory bowel disease (IBD) can present with a diverse spectrum of symptoms. In many cases, suspicion is raised by infantile onset of inflammatory bowel disease and presence of extraintestinal problems, such as:
  • infection susceptibility;
  • inflammation in other organ systems; or
  • congenital problems of the gastrointestinal tract or malignancy.
• Cases may also present in atypical ways, with predominance of extra-intestinal symptoms, and are not always reflective of the example clinical scenario above.
• To be eligible for testing, patients must have a confirmed diagnosis of IBD in line with the modified Porto criteria, itself detailed in the article by Levine and others.
• Frequently, additional investigations will be performed alongside genomic testing, including an immune work-up, screening for infection, and screening for additional autoimmune or autoinflammatory conditions.
• Genomic testing should be considered in cases of IBD for:
  • all children with IBD onset under 2 years of age; and
  • children with IBD onset under 6 years of age, with severe course (requiring biologics or surgery) or with relevant comorbidities and extra-intestinal manifestations.
• Testing may occasionally be appropriate outside these criteria following discussion in a specialist multidisciplinary team meeting (for example, paediatric or young adult IBD with documented severity criteria, for instance a relevant family history, comorbidities and extra-intestinal manifestations such as infection susceptibility).
• Additional features suggestive of monogenic IBD are:
  • infection susceptibility in the presence of abnormal laboratory tests – immunodeficiency;
  • inflammatory features – inborn error of immunity (IPEX syndrome or haemophagocytic lymphohistiocytosis);
  • congenital multiple intestinal atresias or congenital diarrhoea;
  • early-onset malignancy (<25 years of age); and
  • family history of suspected monogenic IBD.

Semi-rapid testing

If a patient is acutely unwell and a genetic diagnosis could affect management, then it is possible to request semi-urgent testing. All cases must be agreed in advance. Please contact Great Ormond Street Hospital’s genetics lab, as the lead testing laboratory in addition to the steps below.

• Consult the National Genomic Test Directory. From here, you can access the rare and inherited disease eligibility criteria, which contains information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family.
• For patients who meet test directory eligibility criteria, select the following:
  • R15 Primary immunodeficiency or monogenic Inflammatory Bowel Disease: This includes monogenic IBD genes.
• For tests that are undertaken using WGS, including R15, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and their parents. Include details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
  • complete an NHS GMS record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• As a DNA-based test, an EDTA sample (typically a purple-topped tube) is required.
• Note that if a monogenic cause of IBD is identified, the family should be referred to clinical genetics for discussion of implications for the wider family and reproductive risk.
• Information about patient eligibility and test indications were correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• Genomics England: NHS Genomic Medicine Service Signed Off Panels Resource
• NHS England: National Genomic Test Directory

References:

• Bolton C, Smillie CS, Pandey S and others. ‘An Integrated Taxonomy for Monogenic Inflammatory Bowel Disease’. Gastroenterology 2022: volume 162, issue 3, pages 859–876. DOI: 10.1053/j.gastro.2021.11.014
• Levine A, Koletzko S, Turner D and others. ‘ESPGHAN Revised Porto Criteria for the Diagnosis of Inflammatory Bowel Disease in Children and Adolescents‘. Journal of Pediatric Gastroenterology and Nutrition 2014: volume 58, issue 6, pages 795–806. DOI: 10.1097/MPG.0000000000000239
• Uhlig H, Charbit-Henrion F, Kotlarz D and others. ‘Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition‘. Journal of Pediatric Gastroenterology and Nutrition 2021: volume 72, issue 3, pages 456–473. DOI: 10.1097/MPG.0000000000003017

For patients

• CGD Society
• CICRA (Crohn’s In Childhood Research Association): Very early onset IBD
• Crohn’s & Colitis UK: New guidelines on genomic testing for people with a rare type of Crohn’s or Colitis
• Immunodeficiency UK
• University Hospital Southampton: Monogenic Inflammatory Bowel Disease (IBD) Information for Patients (video, 4 minutes)