Atypical dermal melanocytosis: a diagnostic clue in constitutional mismatch repair deficiency syndrome

DEAR EDITOR, A 23-month-old female presented with abnormal cutaneous pigmentation since birth. She had a past history of mediastinal non-Hodgkin lymphoma diagnosed at 9 months of age and treated with surgery and chemotherapy. Family history revealed her grandfathers were brothers, and both died of colon cancer in their fifth decade. Her parents were both fit and well in their early 30s. The patient had Fitzpatrick skin type IV, with 10 caf e au lait macules of up to 10 cm in diameter, and six hypomelanotic macules of 0 5–1 cm. In addition, she had extensive atypical dermal melanocytosis, with multiple blue-grey macules predominantly on her back, of 1–10 cm, with an irregular outline (Fig. 1). The remainder of her physical examination was normal. A clinical diagnosis of constitutional mismatch repair deficiency syndrome (CMMRD) was made. Interphase fluorescence in situ hybridization revealed a normal germline female karyotype with no chromosomal rearrangements. Next-generation sequencing (NGS) of leukocyte DNA of the mismatch repair genes MLH1, MSH2 and MSH6 revealed a novel homozygous mutation in MSH6 (c.3934_3937dupGTTA, p.(Ile1313SerfsTer7)) predicted to be pathogenic, confirming the clinical diagnosis. Both parents were confirmed to be heterozygous for the same mutation. As somatic mutations in GNA11 and GNAQ can be a cause of extensive or atypical dermal melanocytosis, DNA was extracted directly from a skin biopsy of an area of dermal melanocytosis. Targeted NGS of mutation hotspots (codons 183 and 209) revealed wild-type sequence, excluding these as a cause of this aspect of the phenotype. Mismatch repair is a critical mechanism during DNA replication for maintenance of genome integrity. Mutations in mismatch repair (MMR) genes MLH1, MSH2, MSH6 or PMS2 result in increased cancer susceptibility. Lynch syndrome, or hereditary nonpolyposis colorectal cancer, results from monoallelic (heterozygous) germline mutations in MMR genes. This autosomal dominant cancer predisposition syndrome is characterized by colorectal, endometrial, ovarian, gastric, small intestinal or urinary tract cancers from early adulthood. Tumorigenesis results from loss of the remaining MMR gene wild-type alleles and accumulation of further mutations in cancer genes. CMMRD is a rare autosomal recessive disease resulting from biallelic germline mutations, either homozygous or compound heterozygous, in one of the four mismatch repair genes. It can also be known as biallelic mismatch repair disorder (BMMRD), highlighting that a history of consanguinity is an important early diagnostic clue, as there may not be a striking family history of cancers in the extended family. It was first reported in 1999, and over 100 cases have been reported to date. In contrast to Lynch syndrome, which presents with cancers from the fourth decade, patients with biallelic MMR gene mutations develop a diverse spectrum of childhood malignancies, and often multiple malignancies, in early life. Central nervous system (CNS), haematological and colorectal