The great mimicker: Phenotypic overlap between constitutional mismatch repair deficiency and Tuberous Sclerosis complex

Abstract

Constitutional mismatch repair deficiency is a rare cancer predisposition syndrome caused by biallelic mutations in one of the four mismatch repair genes. Patients are predisposed to various tumors including hematological malignancies, brain tumors and colorectal carcinomas. Phenotypic overlap with Neurofibromatosis-1 is well known, with most patients presenting with café-au-lait macules. Other common features include axillary and/or inguinal freckling and intracranial MRI foci of high T2W/FLAIR signal intensity similar to the typical FASI seen in Neurofibromatosis-1. In this cohort of eight patients with constitutional mismatch repair deficiency we describe overlapping phenotypical features with Tuberous Sclerosis complex. In addition to "ash-leaf like" hypomelanotic macules (five patients), we detected intracranial tuber-like lesions (three patients), renal cysts (three patients) and renal angiomyolipomas (two patients).All our patients also had Neurofibromatosis-1 like features, mainly café-au-lait macules.This study suggests that features of Tuberous sclerosis especially when overlapping with those of Neurofibromatosis 1 or malignancies atypical for these syndromes should raise the possibility of constitutional mismatch repair deficiency. Correct diagnosis is essential for appropriate genetic counseling and pre-emptive cancer surveillance.

Eruptive nevi in a patient with constitutional mismatch repair deficiency (CMMRD)

“…Cutaneous manifestations of CMMRD overlap with findings of neurofibromatosis, including neurofibromas, café‐au‐lait macules (CALMs), and axillary and inguinal freckling 2 . Of note, the CALMs in CMMRD, such as in our patient, may have ragged and less defined borders in comparison with those in neurofibromatosis 3 .…”

“…Of note, the CALMs in CMMRD, such as in our patient, may have ragged and less defined borders in comparison with those in neurofibromatosis 3 . CMMRD patients can also present with hypopigmented patches reminiscent of the “ash leaf” spots of tuberous sclerosis 2 . Other skin findings include pilomatricomas and vascular malformations 2 .…”

Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group

“…Other clinical features reported in CMMRD patients include agenesis of the corpus callosum, grey matter heterotopia 47 , venous anomalies 48 , multiple pilomatrixoma 49 , paediatric systemic lupus erythematosus 50 , intracranial tuber-like lesions and renal angiomyolipoma. 51 Decreased IgA and/or IgG2/4 levels 1 have also been reported, however, this was not substantiated in a recent study that could not consistently identify clinical or routine immunological laboratory parameters suggestive of primary immunodeficiency in 15 unrelated CMMRD patients. 52 These abnormalities have no clinical impacts in terms of immunodeficiency for the vast majority of patients.…”

“…58 Early-onset malignancies can also overlap with Li-Fraumeni syndrome, caused by germline TP53 mutations, which increases the risk for hematological, sarcoma, brain and GI cancers presenting at early ages. 59 There has also been overlap with conditions that have CALM, skin manifestation such as NF1 and Legius syndromes, 45,60 and tuberous sclerosis 51 . Parallel to MMR analysis, other syndromes should be searched through multi-gene panel testing encompassing hereditary colorectal and polyposis conditions, childhood malignancy conditions (i.e.…”

Atypical Renal Cyst (Clear Cell Type)

“…In the largest publication on atypical renal cysts, Matoso et al [1] divide them into three groups: clear cell, eosinophilic strati ed; eosinophilic papillary. Atypical renal cysts usually occur in patients with complex syndromes (autosomal dominant polycystic kidney disease (APDK), von-Hipple-Lindau disease (VHLD), tuberous sclerosis complex (TSC)) or patients in chronic hemodialysis [1,[10][11][12] . Rarely, atypical renal cysts occur in patients who do not suffer from end-stage renal disease.…”