Introduction
Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition
syndrome that results from biallelic germline mutations in one of the four MMR genes,
MLH1, MSH2, MSH6, or PMS2. These genes can identify and correct incorrect base insertion,
deletion, and disincorporation that may occur during deoxyribonucleic acid (DNA) damage,
replication, and recombination.[1] These genes are also associated with immunoglobulin (Ig) class switch recombination.[2]
[3] This condition is characterized by a wide range of early-onset malignancies, such
as brain tumors, colorectal cancers, hematologic cancers, and others.[4]
Here we presented the case of a girl child patient with T-cell acute lymphoblastic
lymphoma and selective immunoglobulin A (IgA) deficiency who was later diagnosed with
CMMRD.
Case History
An 11-year-old girl who was born out of a consanguineous marriage presented with a
history of dyspnea and orthopnea. Chest radiography and computed tomography (CT) scan
revealed the presence of an anterior mediastinal mass that was diagnosed as T-cell
acute lymphoblastic lymphoma, for which she was started with chemotherapy. She experienced
repeated seizures shortly after that, along with vision loss, which was treated with
antiepileptic drugs. The frontal and parietal lobes on magnetic resonance imaging
(MRI) displayed multiple cortical and subcortical T2/fluid attenuated inversion recovery
(FLAIR) hyperintensities showing subtle enhancement; these did not exhibit any diffusion
restriction ([Fig. 1]). Blood culture and cerebrospinal fluid (CSF) analysis did not reveal any signs
of infection. However, a thorough clinical history revealed that hypertension was
present at the time of the seizure events. A diagnosis of hypertension-induced posterior
reversible encephalopathy syndrome (PRES) was given and she was managed with antiepileptics
and antihypertensives.
Fig. 1 (A–D) Baseline magnetic resonance imaging (MRI) of the brain of the girl shows multiple
cortical and subcortical T2/fluid attenuated inversion recovery (FLAIR) hyperintensities
in bilateral frontoparietal lobes showing subtle enhancement.
A follow-up scan was done after 3 months, which showed partial resolution of the brain
lesions in the bilateral frontoparietal lobes, and later at 2 years, they showed complete
resolution. However, the lesion in the left frontal lobe subcortical and deep white
matter location persisted, which was subtly enhancing, T2/FLAIR hyperintense, and
showed no diffusion restriction ([Fig. 2]). Magnetic resonance spectroscopy (MRS) study showed elevated choline levels with
depressed N-acetyl aspartate (NAA) levels in the lesion, having a choline-to-NAA ratio
of 1.81. This raised the suspicion of diffuse glioma in addition to the already known
diagnosis of PRES. She also began experiencing recurrent lower respiratory tract infection
(LRTI) attacks and was repeatedly hospitalized as a result. The existence of a polymicrobial
infection involving Cladophialophora and Haemophilus influenza spp. was discovered by bronchoalveolar lavage. The girl had a specific IgA deficiency,
as determined by an Ig panel.
Fig. 2 Follow-up magnetic resonance imaging (MRI) of the brain after 2 years showing persistence
of left frontal lobe signal and disappearance of the bilateral high frontoparietal
lobe lesions.
In addition to having a comparable history of dyspnea, her younger sibling also had
an anterior mediastinal tumor that was later determined to be a T-cell acute lymphoblastic
lymphoma. He had a pontine cavernous hemangioma, which was known. A routine follow-up
MRI revealed a single subcortical T2/FLAIR hyperintensity in the left high frontal
lobe in the subcortical white matter, which showed no enhancement and no restricted
diffusion ([Fig. 3]).
Fig. 3 Magnetic resonance imaging (MRI) of the brain of the younger sibling showing nonenhancing
T2/fluid attenuated inversion recovery (FLAIR) hyperintensity in the subcortical region
of the left frontal lobe.
A syndrome that could explain these findings was suspected and the case was discussed
in a multidisciplinary clinic. Later, it was discovered that the girl had a homozygous
MSH6 gene mutation, which was indicative of constitutional mismatch repair impairment
(CMMRD). Later her brother was also tested and he was also found to have a homozygous
MSH6 gene mutation.
Discussion
One of the four MMR genes—MLH1, MSH2, MSH6, or PMS2—can develop a biallelic germline
mutation that causes CMMRD, a syndrome that predisposes people to cancer. It has a
substantial correlation with hematologic cancers, high-grade gliomas (HGGs) in the
brain, and colon cancers of the Lynch syndrome (LS) spectrum.[4]
[5] It is not unusual for someone with CMMRD to have multiple primary cancers. It also
resembles neurofibromatosis type 1 (NF1) phenotypically.[6]
According to Wimmer et al,[4] of all the hematologic malignancies associated with CMMRD, the most commonly seen
is non-Hodgkin's lymphoma (NHL) accounting for about 14% of all CMMRD-associated malignancies.
Among these, 65% of CMMRD-associated NHL were of T-cell lineage and at least 42% were
T-cell lymphoblastic lymphomas.[4]
[7] Both the siblings mentioned in the case were initially diagnosed with T-cell acute
lymphoblastic lymphoma.
Less cases of CMMRD have been documented in which selective IgA deficiency was reported.
It leads to more serious and persistent infections. Yet, neither is this finding too
uncommon in the general population nor is it a finding specifically for CMMRD. Impaired
Ig class switch recombination has been found to result from a constitutional deficit
of the PMS2 and MSH6 genes.[8]
[9] IgG2, IgG4, and IgA levels may drop or disappear as a result, and IgM levels may
rise. The same argument can be made for parents who were married consanguineously,
as consanguinity is common among many ethnic and religious groups and cannot be considered
unique to CMMRD.[4]
Both neoplastic and non-neoplastic characteristics may be present in imaging that
are frequently observed in CMMRD. The most frequent malignant findings are diffuse
astrocytoma and glioblastoma.[10]
[11] Developmental venous anomalies (DVAs) and cavernous hemangiomas are examples of
non-neoplastic abnormalities.[12]
[13] A known incidence of pontine cavernous hemangioma in the sibling mentioned in the
case added to the suspicion of CMMRD. In addition, individuals with CMMRD can exhibit
nonspecific subcortical T2/FLAIR hyperintensities, primarily in the frontal and parietal
lobes. They typically do not exhibit diffusion restriction or enhancement. Most of
the time, these lesions are stable, although they can develop into gliomas later on
due to malignant change.[10]
[14] Thus, imaging should be used to periodically monitor such lesions. The index case
had subcortical T2/FLAIR hyperintensities involving the left frontal lobe and bilateral
high frontoparietal lobe, which were subtly enhancing and showed no diffusion restriction
([Fig. 1]). They were initially thought to be PRES-related changes. The bilateral high frontoparietal
lobe lesions gradually resolved over the next 2 years, but the frontal lobe lesion
persisted ([Fig. 2]). It was also seen involving the deep white matter. Further, an MRS study of this
lesion showed elevated choline levels with depressed NAA levels and choline-to-NAA
ratio of 1.81. MRS is a noninvasive imaging method that detects metabolite signals,
like choline-containing compounds (Cho), NAA, and creatine (Cr). This can help identify
malignant lesions like gliomas and can also help in grading gliomas into low-grade
gliomas (LGGs) and HGG. Studies have shown that Cho:NAA values between 1.2 and 1.8
(mean: 1.6) are suggestive of LGGs and those between 2.0 and 7.5 (mean: 5.1) are suggestive
of HGGs.[15] Hence, the lesion seen in the index case was more in favor of diffuse infiltrative
glioma. The younger sibling also showed solitary T2/FLAIR hyperintensity in the subcortical
region of the high frontal lobe, which was nonenhancing and showed no diffusion restriction
([Fig. 3]). It could represent a nonspecific subcortical T2/FLAIR hyperintensity usually seen
in cases of CMMRD or could be a diffuse glioma.
For several reasons, a CMMRD diagnosis that is both accurate and early is crucial.
Providing screening or surveillance for the often-linked malignancies can increase
long-term survival rates because these people are more likely to develop numerous
malignancies over time.[16] The increased likelihood that family members would develop cancer is still another
cause for concern. Siblings may have a 25% chance of recurrence, and heterozygous
mutation carriers—especially both parents—had a higher risk of LS-related malignancy.[4] Hence, it is important to keep an eye on your first-degree relatives. Through genetic
counseling, the families of those who are afflicted should be made aware of the illness
and its effects.
A 3-point scoring system for clinical indicators that should trigger suspicion for
CMMRD has been proposed by the European consortium “Care for CMMRD.” According to
Wimmer et al,[4] the girl, in this case, had a score of 5, which raised a strong suspicion for CMMRD.
Conclusion
CMMRD is a rare cancer predisposition syndrome, which necessitates the importance
of surveillance and screening of both the affected individuals and their close relatives.
The available information regarding this syndrome is substantial, but further focused
systematic studies are necessary for collecting data on screening and treatment of
this condition. This will help in formulating better recommendations for the management
of CMMRD.
