Multiple café‐au‐lait macules, axillary freckling, and hypopigmented macules in a child

An 8-year-old male presented with hyperpigmented macules and patches over the body present since birth. He was otherwise healthy with normal development. Evaluation revealed six café-au-lait macules (CALMs) larger than 5 mm in diameter (Figure 1), bilateral axillary freckling (Figure 2), and multiple hypopigmented macules over his back (Figure 3). He lacked cutaneous neurofibromas or pilomatricomas. Pediatric ophthalmologic exam was normal with no evidence of optic gliomas or Lisch nodules. The patient's sister also had multiple CALMs and a history of T-cell lymphoblastic lymphoma. His two other siblings were asymptomatic, and the parents were first cousins. Prior genetic testing did not identify any pathogenic variants in neurofibromin 1 (NF1) or Sprouty Related EVH1 Domain Containing 1 (SPRED1). While the patient met the clinical diagnostic criteria for neurofibromatosis type 1 (NF1),1 the combination of a sibling with features of NF1 and cancer; negative NF1 genetic testing; and a history of consanguinity was highly suggestive of constitutional mismatch repair deficiency (CMMRD). The family was referred to Medical Genetics for further assessment. Given the suspicion for CMMRD, mismatch repair immunohistochemistry was performed on his sister's tumor, which demonstrated loss of PMS1 homolog 2, mismatch repair system component (PMS2) expression in the tumor, and a germline multi-gene panel for CMMRD identified a homozygous pathogenic variant in PMS2 (c.1624delA), confirming the diagnosis of CMMRD in his sister. Our patient was tested and confirmed to share the same homozygous pathogenic PMS2 variant. CMMRD is a rare autosomal recessive syndrome linked to an increased cancer risk and results from biallelic pathogenic variants in one of four mismatch repair (MMR) genes: MutL protein Homolog 1 (MLH1), MutS Homolog 2 (MSH2), MutS Homolog 6 (MSH6), and PMS2.2-4 Affected individuals develop tumors early in life, including T-cell non-Hodgkin lymphoma, high-grade gliomas, colorectal cancers, and adenomas.2, 4 Approximately 80% of patients experience their first malignancy before age 18.2 Nearly all patients eventually develop a malignancy, and some experience multiple primary cancers.2, 4 Patients may exhibit a phenotype akin to NF1 which can delay diagnosis and management.2 The majority of patients with CMMRD will have café-au-lait macules, with many meeting clinical diagnostic criteria for NF1. Rarely, patients with CMMRD can also develop additional features of NF1 such as subcutaneous nodules, iris nodules, skeletal abnormalities, or optic pathway tumors, but interestingly these NF1-like findings are only seen in CMMRD patients with CALMs.2 Multiple CALMs may be the initial presenting feature, appearing within the first year of life, followed by skinfold freckling during school years.2 After puberty or in early adulthood, additional NF1-like manifestations may arise.2 Some patients do not develop café-au-lait macules but may have other cutaneous findings such as nevus depigmentosus or pilomatricomas.2, 5 When a child presents with café-au-lait macules and other signs indicative of NF1, especially when there is a sibling but no parent with of NF1 features, malignancy in a sibling, and parental consanguinity, CMMRD should be strongly considered in the differential diagnosis.2, 5 The prevalence of CMMRD is presently unknown, but it is estimated to be around one in one million unrelated parents.2 Approximately, 40%–45% of affected families are consanguineous.2 An estimated 1 in 258 (0.4%) children suspected of having NF1 with negative NF1/SPRED1 testing have CMMRD.2 Diagnosing CMMRD can be complex, but generally involves genetic investigations and ancillary testing, such as immunohistochemistry for the four MMR proteins.6, 7 Early diagnosis of CMMRD in children can help initiate cancer surveillance, though determining individual cancer risks remains challenging.2 A diagnosis of CMMRD in a child implies both parents carry a single pathogenic MMR gene, typically establishing a diagnosis of Lynch syndrome in the parents with implications for their medical management.2 An inherited pathogenic variant in a single allele of one of the four MMR genes can cause Lynch syndrome, an autosomal dominant disorder. Individuals with deleterious germline mutations in both alleles of the MMR genes develop the autosomal recessive disorder, CMMRD.8 Parents can receive counseling on family planning, as there is a 25% chance of other children having CMMRD, and a 50% chance that other children will have Lynch syndrome.2 The risk of diagnosing Lynch syndrome in minors must be balanced with potential benefits of early diagnosis of CMMRD.2 Once the diagnosis is established, patients should be monitored with clinical examination and brain MRI scans every 6 months, along with annual whole-body MRI scans starting at age six.2, 6 Tumor surveillance of the entire gastrointestinal tract involves annual screening with ileocolonoscopy, video capsule endoscopy, and/or colonoscopy, commencing between ages four to six, unless polyps are detected earlier.2, 6 Monitoring for leukemia/lymphoma involves biannual complete blood counts from the time of diagnosis, supplemented by abdominal ultrasound every 6 months starting at 1 year of age for lymphadenopathy and/or organ involvement.6 Gynecological exam, transvaginal ultrasound, urine cytology, and dipstick are recommended annually starting from the age of 20 years.2, 6 This case highlights the importance of a careful family history and awareness of the differential diagnosis of NF1, specifically the importance of asking about consanguinity and malignancy history. Such an approach could facilitate the early identification of CMMRD before the onset of cancer.2, 4 The dermatologist may play a crucial role in facilitating early diagnosis, significantly improving the prognosis.4 Authors made significant contribution to study conception and design, data collection, analysis and interpretation of results, and draft manuscript preparation. All authors read and approved the final version. This article has no funding source. The authors declare no conflicts of interest.

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