Table 3 Selection strategy for CMMRD counselling and testing in a child suspected to have NF1/Legius syndrome (without cancer) and a negative outcome of NF1/SPRED1 germline mutation analysis.

From: ERN GENTURIS guidelines on constitutional mismatch repair deficiency diagnosis, genetic counselling, surveillance, quality of life, and clinical management

Prerequisites:

► Suspicion of NF1 due to the presence of at least one diagnostic NF1 featurea, including at least two hyperpigmented skin patches reminiscent of CALMs.

► No (likely) pathogenic germline variant in NF1 and SPRED1 detected using comprehensive and highly sensitive mutation analysis protocolsb.

► Absence of diagnostic NF1 sign(s) in both parents.

Additional features, at least one (either in the family or in the patient) is required:

In the family:

► Consanguineous parents.

► Genetic diagnosis of Lynch syndrome in one or both parental families.

► Sibling with diagnostic NF1 sign(s).

► A (deceased) siblingc with any type of childhood malignancy.

► One of the following carcinomas of the Lynch syndrome spectrum: Colorectal, endometrial, small bowel, urothelial, gastric, ovarian, and biliary tract cancer, before the age of 60 years in a first-degree or second-degree relative.

In the patient:

► Atypical CALMs (irregular borders and/or pigmentation).

► Multiple hypopigmented skin patches.

► One or more pilomatrixoma(s) in the patient.

► Agenesis of the corpus callosum.

► Non-therapy-induced cavernoma.

► Multiple developmental venous anomalies (DVA, also known as cerebral venous angiomas) in separate regions of the brain.

  1. CMMRD Constitutional mismatch repair deficiency, NF1 Neurofibromatosis type 1, CALMs Café-au-lait macules.
  2. aLegius et al. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genet Med 2021; 23(8):1506–1513.
  3. bAnalysis protocol should include methods that identify and/or characterise unusual splice variants.
  4. cThis can be expanded to second-degree and third-degree relatives in populations with a high prevalence of founder mutations.
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