<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03757247</url>
  </required_header>
  <id_info>
    <org_study_id>CMMRD_2018</org_study_id>
    <nct_id>NCT03757247</nct_id>
  </id_info>
  <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</brief_title>
  <acronym>CMMRD in NF1</acronym>
  <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</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Medical University Innsbruck</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Medical University Innsbruck</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Frequency of constitutional mismatch-repair deficiency among suspected neurofibromatosis type&#xD;
      1 patients without a NF1 mutation Constitutional mismatch repair deficiency (CMMRD) is a rare&#xD;
      inherited condition. Individuals with CMMRD have an extraordinarily high risk to develop a&#xD;
      malignant tumor in childhood or adolescence. Nearly all known CMMRD patients developed a&#xD;
      malignancy within the first three decades of life and most often in (early) childhood. Since&#xD;
      early cancer detection improves the chances to survive, these patients should be included&#xD;
      from early childhood on in intensive cancer surveillance protocols. Typically patients are&#xD;
      diagnosed with CMMRD only when they develop their first malignant tumor.&#xD;
&#xD;
      Many children with CMMRD show already before the onset of the first malignant tumor clinical&#xD;
      signs that may serve as a signpost of this severe condition. Often CMMRD patient show skin&#xD;
      patches of milk coffee-like color, termed café au lait maculae (CALM), which are very typical&#xD;
      for a different inherited condition named neurofibromatosis type 1 (NF1). NF1, which is much&#xD;
      more frequent than CMMRD, also leads to tumor development. But NF1 tumors are usually benign&#xD;
      and NF1 children need different, less rigorous, tumor surveillance programs than CMMRD&#xD;
      patients. A child with &gt;5 CALM is suspected of having NF1. However, if this diagnosis cannot&#xD;
      be confirmed by identification of the causative genetic alteration (NF1-mutation), CMMRD is&#xD;
      one possible, but presumably rare, alternative (= differential) diagnosis. Therefore, human&#xD;
      geneticists and pediatricians discuss internationally, whether these children should be&#xD;
      tested for CMMRD. Diagnosing CMMRD in this situation would allow offering appropriate cancer&#xD;
      surveillance protocols to these patients before they develop their first malignant tumor.&#xD;
      However, CMMRD testing in this situation may also cause difficulties. Genetic testing may for&#xD;
      instance render an ambiguous result, which can neither confirm nor rule out CMMRD. Such a&#xD;
      result would create great uncertainty of the appropriate management of the patient. It would&#xD;
      be not clear whether intensive cancer surveillance, that may be very stressful for the&#xD;
      patient and the family, should be applied or not. Such potential disadvantages of (with&#xD;
      respect to tumor development) predictive CMMRD testing argue more against testing when the&#xD;
      chances to identify CMMRD in a patient and consequently achieving a benefit for the patient&#xD;
      are low. But currently the frequency of CMMRD patients among suspected NF1 patients without a&#xD;
      causative NF1 mutation is unknown.&#xD;
&#xD;
      It is the aim of this project to get a reliable estimation on the frequency of the&#xD;
      differential diagnosis CMMRD in children with NF1 signs in whom the diagnosis NF1 cannot be&#xD;
      confirmed. This information is needed to evaluate and weight the benefits and potential&#xD;
      disadvantage of CMMRD testing in these children. To know this frequency is also important for&#xD;
      appropriate genetic counseling of at risk children and their parents.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 1, 2019</start_date>
  <completion_date type="Anticipated">January 1, 2021</completion_date>
  <primary_completion_date type="Anticipated">January 1, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Other</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Diagnosis CMMRD</measure>
    <time_frame>day1</time_frame>
    <description>yes/no</description>
  </primary_outcome>
  <enrollment type="Anticipated">670</enrollment>
  <condition>Neurofibromatosis Type 1</condition>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      We will analyze at least 670 archived gDNA and cDNA samples of suspected NF1 patients. To&#xD;
      avoid generating data for individual patients, we will analyze only fully anonymized samples.&#xD;
      However, to get some overall information on the phenotype of the CMMRD patients which will be&#xD;
      identified in this study, we will form clinical subgroups within the total cohort.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        670 archived gDNA and cDNA samples of suspectef NF1 patients.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Since CALM or CALM-like pigmentation alterations are the most prevalent NF1 sign in&#xD;
             CMMRD patients, at least two should be present in the patient. Therefore, we will&#xD;
             include any suspected de novo (=non-familial = NF1 signs absent in parents) NF1&#xD;
             patient who falls into one of three clinical groups:&#xD;
&#xD;
               1. &gt;5 CALM with or without skinfold freckling and no other NIH NF1 criterion,&#xD;
&#xD;
               2. &gt;5 CALM with or without skinfold freckling and one or more other NIH NF1&#xD;
                  criteria,&#xD;
&#xD;
               3. 2-5 CALM and one or more NIH NF1 criteria other than CALM.&#xD;
&#xD;
          2. The patient's age must be below 17 years, since the vast majority of CMMRD cases will&#xD;
             have developed a tumor by this age. However, overall we aim that the large majority of&#xD;
             patients is below the age of 10 years which is the mean age of tumor onset in CMMRD&#xD;
             patients.&#xD;
&#xD;
          3. A causative NF1 or SPRED1 mutation must be largely excluded by mutation analysis&#xD;
             protocols that reach highest mutation detection rates in bona fide NF1 patients (i.e.&#xD;
             familial cases who fulfill NIH criteria)* and sufficient amounts of gDNA and cDNA must&#xD;
             be available for subsequent massive-parallel sequencing-based mutation analysis which&#xD;
             potentially needs to be complemented with RNA-based techniques (cDNA) particularly for&#xD;
             the notoriously difficult PMS2 gene.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>16 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Katharina Wimmer, Prof. Dr.</last_name>
    <phone>+43512900370</phone>
    <phone_ext>513</phone_ext>
    <email>katharina.wimmer@i-med.ac.at</email>
  </overall_contact>
  <verification_date>November 2018</verification_date>
  <study_first_submitted>November 26, 2018</study_first_submitted>
  <study_first_submitted_qc>November 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">November 28, 2018</study_first_posted>
  <last_update_submitted>November 27, 2018</last_update_submitted>
  <last_update_submitted_qc>November 27, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">November 28, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neurofibromatoses</mesh_term>
    <mesh_term>Neurofibromatosis 1</mesh_term>
    <mesh_term>Neurofibroma</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03757247
org study id: CMMRD_2018
nct id: NCT03757247
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
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.
observational model: Other
time perspective: Prospective
measure: Diagnosis CMMRD
time frame: day1
description: yes/no
We will analyze at least 670 archived gDNA and cDNA samples of suspected NF1 patients. To
      avoid generating data for individual patients, we will analyze only fully anonymized samples.
      However, to get some overall information on the phenotype of the CMMRD patients which will be
      identified in this study, we will form clinical subgroups within the total cohort.
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 16 Years
healthy volunteers: No
last name: Katharina Wimmer, Prof. Dr.
phone: +43512900370
phone ext: 513
email: katharina.wimmer@i-med.ac.at
responsible party type: Sponsor
mesh term: Neurofibromatoses
mesh term: Neurofibromatosis 1
mesh term: Neurofibroma