Recognition of Macrocephaly for Early Detection of Cowden Syndrome With Differentiated Thyroid Cancer and Melanoma

Cowden syndrome (CS) is an autosomal dominant genodermatosis associated with mutations in the phosphatase and tensin homolog gene ( PTEN ). Due to its rarity and variable expressivity, CS may escape detection for many years. We report a case of CS in which the patient presented with the follicular variant of papillary thyroid cancer (FVPTC) and no indication of a genetic abnormality until she was found to have a melanoma and macrocephaly. The patient presented at age 31 with a 3.3 cm thyroid nodule and fine needle aspirate (FNA) that showed a Bethesda IV lesion. She underwent left lobectomy, revealing FVPTC. A completion thyroidectomy showed multiple small foci of FVPTC, the largest of which was 8 mm. Initially, there were no apparent pathologic mucocutaneous lesions, intellectual deficits, or family history of CS. At age 39, the patient developed a Stage IA malignant melanoma. She was simultaneously noted to have macrocephaly with a head circumference of 62 cm (>99 percentile). Analysis of 69 genes revealed a pathogenic variant in the PTEN gene. Macrocephaly is seen in 93%–100% of patients with PTEN pathogenic variants. There is an increased risk of melanoma in differentiated thyroid cancer (DTC) of two to fourfold with a 6% absolute risk in CS. We recommend that head circumference be measured in all patients with DTC. Patients with DTC should have a thorough skin examination.