Café-au-lait spots-what lies underneath

An 11-year-old girl was diagnosed with high-grade osteosarcoma. She had a history of T acute lymphoblastic leukemia at 6 years of age. On examination, she had multiple café-au-lait spots on the trunk. Due to the presence of café-au-lait spots, 2^nd malignancy, and 3^rd degree consanguinity, we investigated for cancer predisposition syndromes which revealed a homozygous mutation in PMS2 exon 2 (c.128_130del) suggestive of constitutional mismatch repair deficiency (CMMRD) syndrome.

Family screening revealed multiple café-au-lait spots and the same homozygous mutation in the 5-year-old asymptomatic brother [Figure 1] and heterozygous mutation in the parents.

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Figure 1:

Asymptomatic sibling of index case (a) Multiple café-aulait spots on the back. (b) Multiple café-au-lait spots on the trunk.

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Differential diagnosis of café-au-lait spots and predisposition to malignancy includes CMMRD, Fanconi anemia, Neurofibromatosis, Bloom syndrome, Noonan syndrome, Tuberous sclerosis, and Ataxia telangiectasia.

CMMRD is a rare autosomal recessive disorder, with an incidence of 1 per million patients, caused by biallelic mutations in MMR genes including MLH1, MSH2, MSH6, or PMS2, resulting in increased susceptibility to mainly hematological, colorectal, and brain tumors. Heterozygous mutations in these genes lead to autosomal dominant Lynch syndrome predisposing to colorectal and endometrial malignancies, usually not before 40 years of age.

Suspicion and early diagnosis of CMMRD help provide appropriate counseling and design surveillance strategies for further malignancies.