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