Pediatric Case Challenge: An 8-Year-Old Boy With Autism, Lupus, Fever, and Chest Pain

Agnes Reschke, MD; Liora Schultz, MD; Catherine Aftandilian, MD; Norman Lacayo, MD


May 03, 2023

CMMRD is a biallelic germline mutation in the mismatch repair (MMR) genes that results in dysfunction of the DNA mismatch repair system. This leads to an inability to correct replication errors in dividing cells, causing a rapid accumulation of mutations and a predisposition to cancer in childhood.[1] This is related to the more common Lynch syndrome, which is a heterogeneous mutation in MMR genes that is characterized by gastrointestinal and genitourinary cancers in adults.[1]

The median age of onset to the first tumor in children with CMMRD is 7.5 years.[1] Median survival after the diagnosis of the primary tumor is less than 30 months. CMMRD has a wide spectrum of related tumors; however, brain tumors, gastrointestinal tumors, and hematologic tumors predominate.[1,2] The most common brain tumors include glioblastomas or other high-grade gliomas, supratentorial primitive neuroendocrine tumors, and medulloblastomas. The mean age of onset is between 9 and 10.3 years.[1,2] Glioblastomas are the most common cause of death in patients with CMMRD.[2]

Colorectal adenomas occur in a third of patients with CMMRD and typically lead to gastrointestinal cancers (mainly colorectal carcinomas and small bowel cancer) at an average age of 16.4 years.[2] Hematologic cancers associated with this syndrome primarily include non-Hodgkin lymphoma and acute lymphoblastic leukemia/lymphoma, which occur at an average age of 6.6 years.[1] Although patients with CMMRD and hematologic cancers respond well to chemotherapy, evidence suggests high rates of relapse after completion of treatment.[3]

CMMRD is often misdiagnosed as NF1 due to the presence of hyperpigmented and hypopigmented macules in most patients, particularly before the development of CMRMD-associated cancer. CMMRD should always be considered on the differential diagnosis of NF1, particularly if no NF1 findings are present and if a history of consanguinity is noted.[4] Patients can also be found to have pilomatricomas, a benign skin lesion that typically occurs within the first two decades of life. Additional non-neoplastic manifestations include developmental venous anomalies, agenesis of the corpus callosum, and mild immunodeficiency.[1] The European "Care for CMMR-D" consortium developed a scoring system based on a set of criteria that is highly sensitive for CMMRD.[5] It includes cancers/precancers, as well as additional features. If a patient fulfills the criteria, genetic counseling is recommended.

SLE is rarely diagnosed in a patient as young as the one in this case. This calls into question whether the SLE was related to the patient's underlying CMMRD. SLE is most commonly diagnosed between 11 and 12 years of age, and approximately 80% of patients are girls.[4] Although evidence in the literature is scant, five patients have been reported with a concurrent diagnosis of CMMRD and pediatric SLE, all of whom were girls. These cases indicate that the incidence of SLE in patients with CMMRD is about 2.5%, which is significantly higher than the 0.003%-0.0088% incidence of SLE in the general population.[4] The pathogenesis of SLE in patients with CMMRD is poorly understood. It could be related to the dysfunctional immune response that is associated with CMMRD, which may lead to autoimmunity.[4] Based on these case reports, the presence of a diagnosis of SLE, particularly at a young age, should increase the index of suspicion of CCMMRD in a child with other features.[4]


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