Prevalence of Constitutional Mismatch-repair Deficiency Among Suspected Neurofibromatosis Type 1/Legius Syndrome Children Without a Malignancy and Without a NF1 or SPRED1 Mutation

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Brief Title

Prevalence of Constitutional Mismatch-repair Deficiency Among Suspected Neurofibromatosis Type 1/Legius Syndrome Children Without a Malignancy and Without a NF1 or SPRED1 Mutation

Official Title

Prevalence of Constitutional Mismatch-repair Deficiency Among Suspected Neurofibromatosis Type 1/Legius Syndrome Children Without a Malignancy and Without a NF1 or SPRED1 Mutation

Brief Summary

      Frequency of constitutional mismatch-repair deficiency among suspected neurofibromatosis type
      1 patients without a NF1 mutation Constitutional mismatch repair deficiency (CMMRD) is a rare
      inherited condition. Individuals with CMMRD have an extraordinarily high risk to develop a
      malignant tumor in childhood or adolescence. Nearly all known CMMRD patients developed a
      malignancy within the first three decades of life and most often in (early) childhood. Since
      early cancer detection improves the chances to survive, these patients should be included
      from early childhood on in intensive cancer surveillance protocols. Typically patients are
      diagnosed with CMMRD only when they develop their first malignant tumor.

      Many children with CMMRD show already before the onset of the first malignant tumor clinical
      signs that may serve as a signpost of this severe condition. Often CMMRD patient show skin
      patches of milk coffee-like color, termed café au lait maculae (CALM), which are very typical
      for a different inherited condition named neurofibromatosis type 1 (NF1). NF1, which is much
      more frequent than CMMRD, also leads to tumor development. But NF1 tumors are usually benign
      and NF1 children need different, less rigorous, tumor surveillance programs than CMMRD
      patients. A child with >5 CALM is suspected of having NF1. However, if this diagnosis cannot
      be confirmed by identification of the causative genetic alteration (NF1-mutation), CMMRD is
      one possible, but presumably rare, alternative (= differential) diagnosis. Therefore, human
      geneticists and pediatricians discuss internationally, whether these children should be
      tested for CMMRD. Diagnosing CMMRD in this situation would allow offering appropriate cancer
      surveillance protocols to these patients before they develop their first malignant tumor.
      However, CMMRD testing in this situation may also cause difficulties. Genetic testing may for
      instance render an ambiguous result, which can neither confirm nor rule out CMMRD. Such a
      result would create great uncertainty of the appropriate management of the patient. It would
      be not clear whether intensive cancer surveillance, that may be very stressful for the
      patient and the family, should be applied or not. Such potential disadvantages of (with
      respect to tumor development) predictive CMMRD testing argue more against testing when the
      chances to identify CMMRD in a patient and consequently achieving a benefit for the patient
      are low. But currently the frequency of CMMRD patients among suspected NF1 patients without a
      causative NF1 mutation is unknown.

      It is the aim of this project to get a reliable estimation on the frequency of the
      differential diagnosis CMMRD in children with NF1 signs in whom the diagnosis NF1 cannot be
      confirmed. This information is needed to evaluate and weight the benefits and potential
      disadvantage of CMMRD testing in these children. To know this frequency is also important for
      appropriate genetic counseling of at risk children and their parents.
    



Study Type

Observational


Primary Outcome

Diagnosis CMMRD


Condition

Neurofibromatosis Type 1



Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information



Estimated Enrollment

670

Start Date

January 1, 2019

Completion Date

January 1, 2021

Primary Completion Date

January 1, 2021

Eligibility Criteria

        Inclusion Criteria:

          1. Since CALM or CALM-like pigmentation alterations are the most prevalent NF1 sign in
             CMMRD patients, at least two should be present in the patient. Therefore, we will
             include any suspected de novo (=non-familial = NF1 signs absent in parents) NF1
             patient who falls into one of three clinical groups:

               1. >5 CALM with or without skinfold freckling and no other NIH NF1 criterion,

               2. >5 CALM with or without skinfold freckling and one or more other NIH NF1
                  criteria,

               3. 2-5 CALM and one or more NIH NF1 criteria other than CALM.

          2. The patient's age must be below 17 years, since the vast majority of CMMRD cases will
             have developed a tumor by this age. However, overall we aim that the large majority of
             patients is below the age of 10 years which is the mean age of tumor onset in CMMRD
             patients.

          3. A causative NF1 or SPRED1 mutation must be largely excluded by mutation analysis
             protocols that reach highest mutation detection rates in bona fide NF1 patients (i.e.
             familial cases who fulfill NIH criteria)* and sufficient amounts of gDNA and cDNA must
             be available for subsequent massive-parallel sequencing-based mutation analysis which
             potentially needs to be complemented with RNA-based techniques (cDNA) particularly for
             the notoriously difficult PMS2 gene.

        Exclusion Criteria:

        -
      

Gender

All

Ages

N/A - 16 Years

Accepts Healthy Volunteers

No

Contacts

, +43512900370, [email protected]



Administrative Informations


NCT ID

NCT03757247

Organization ID

CMMRD_2018


Responsible Party

Sponsor

Study Sponsor

Medical University Innsbruck


Study Sponsor

, , 


Verification Date

November 2018