Thyroid Pathology Findings in Cowden Syndrome: A Clue for the Diagnosis of the PTEN Hamartoma Tumor Syndrome.

OBJECTIVES: PTEN hamartoma tumor syndrome (PHTS) is a hereditary disorder caused by germline inactivating mutations of the PTEN gene. PHTS includes Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome. We describe how the peculiar pathologic and immunohistochemical thyroid features lead pathologists to suggest PHTS. METHODS: A 28-year-old white Spanish woman had a multinodular goiter. Total thyroidectomy was performed after fine-needle aspiration biopsy. Microscopic, immunohistochemical, and molecular analyses of the thyroid lesions were realized. RESULTS: The thyroid was multinodular, showing one papillary microcarcinoma, five follicular adenomas, three adenolipomas, 46 tiny adenomatous nodules (microadenomas), scattered foci of adipose tissue, and lymphocytic thyroiditis. Tumors were positive for thyroglobulin, thyroperoxidase, pendrin, cyclin D1, and p27 but negative for calcitonin and PTEN. A germline heterozygous deletion of one adenine at nucleotide 827 in exon 8 of the PTEN gene was confirmed. No BRAF, NRAS, or KRAS somatic mutations were detected in the papillary microcarcinoma, follicular adenoma, adenolipomas, or microadenomas. Negativity for PTEN was also found in the colonic tubulovillous adenoma and the storiform collagenoma. CONCLUSIONS: Pathologists play a crucial role in recognizing pathologic thyroid findings associated with PHTS for selecting patients for genetic testing.

Birt-Hogg-Dubé syndrome in a patient with localized fibrofolliculomas and a novel mutation in the FLCN gene.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) is characterized by skin fibrofolliculomas (FF), multiple lung cysts, spontaneous pneumothorax, and renal cancer. Cutaneous lesions are usually distributed over the face, neck, and upper trunk. The presence of FF confined to a circumscribed region of the skin has rarely been reported. CASE REPORT: A 64-year-old woman presented with a 20-year history of asymptomatic skin lesions located on the neck. Multiple skin-colored papules with a clinical plaque-like appearance were confined to the right side of the neck. Histopathological findings were typical for FF, and BHDS was suspected. The novel heterozygous mutation p.Val126SerfsX4 was identified in exon 5 of the FLCN gene. Colonoscopy, abdominal ultrasound, and abdominal thoracic scan revealed no associated pathologies, except for benign renal and hepatic cysts. DISCUSSION: To date, only two cases of localized FF in BHDS have been reported. Mutation analysis was not performed, but the authors considered the lesions to represent a localized variant of BHDS and speculated that this unusual form of the disease may be associated with a lack of visceral involvement as no signs of systemic disease were detected. CONCLUSIONS: We identified the novel germline mutation p.Vall26SerfsX4 as responsible for this aspect of the patient's phenotype, which suggests that alterations in the FLCN gene are also responsible for localized forms of BHDS. Moreover, the localized distribution of skin lesions may be related to a less severe form of the disease.

Lamellar ichthyosis with a novel homozygous C-terminal mutation in the transglutaminase-1 gene.

BACKGROUND: The majority of cases of Lamellar ichthyosis (LI) are caused by mutations in the transglutaminase-1 (TGM1) gene. The mutations in the beta-barrel domains of the TGM1 gene are found very infrequently and several authors have suggested that these domains are not essential for the function of the enzyme. Other authors have postulated that mutations in these loci are pathogenic but they imply a less severe clinical picture of LI. CASE REPORT: We report a patient with a severe phenotype of LI who had a homozygous mutation affecting the beta-barrel 2 domain of the TGM1. CONCLUSIONS: This finding indicates that the integrity of beta-barrel domains is important for the correct function of the enzyme and that we are still far away from a consistent genotype-phenotype correlation.