Anne-Louise Richardson

Male breast cancer in Cowden syndrome patients with germline PTEN mutations.

Cowden syndrome (CS) (OMIM 158350) is a multiple hamartoma syndrome associated with germline mutations in thePTEN tumour suppressor gene. While CS is characterised most commonly by non-cancerous lesions (mucocutaneous trichilemmomas, acral and palmoplantar keratoses, and papillomatous papules), it is also associated with an increased susceptibility to breast cancer (in females) and thyroid cancer, as well as non-cancerous conditions of the breast and thyroid. Here we report two cases of male breast cancer occurring in patients with classical CS phenotypes and germline PTEN mutations. The first subject was diagnosed with CS indicated primarily by mucocutaneous papillomatosis, facial trichilemmomas, and macrocephaly with frontal bossing at the age of 31 years. He developed breast cancer at 41 years and subsequently died of the disease. A PTENmutation, c.802delG, was identified in this subject, yet none of his family members showed evidence of a CS phenotype, suggesting that thisPTEN mutation may be a de novo occurrence. The second subject had a CS phenotype including multiple trichilemmomas and thyroid adenoma, developed male breast cancer at 43 years, and died of the disease at 57 years. He was a carrier of aPTEN mutation c.347-351delACAAT that cosegregated with the CS phenotype in affected family members. These two cases of male breast cancer associated with germlinePTEN mutations and the CS phenotype suggest that CS may be associated with an increased risk of early onset male as well as female breast cancer.

Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP)

Familial forms of primary hyperparathyroidism (PHPT) constitute a broad group of disorders in which PHPT is either a main or an associated feature. With the advances in disease gene identification, some of the genetic abnormalities underlying familial PHPT have been clarified.1,2 In hyperparathyroidism–jaw tumour syndrome (HPT-JT; OMIM #145001) the affected family members frequently develop PHPT, ossifying jaw fibromas, and cystic and neoplastic renal lesions.3–6 A typical feature of HPT-JT is adenomas and carcinomas of the parathyroid glands, which often have cystic features.1 This is in contrast to the other forms of familial PHPT in which the parathyroid tumours are generally benign.nnThe disease locus was first mapped to chromosomal region 1q25–q32 by linkage in affected families3,5–7 and recently the causal HRPT2 gene was isolated through a positional cloning approach.3 The HRPT2 gene consists of 17 exons encoding an evolutionarily well conserved, 531 amino acid protein named parafibromin. The inactivating mutations demonstrated in the germline of HPT-JT kindreds and as somatic events in some sporadic parathyroid adenomas3 are in agreement with the observations of somatic loss of the wild type alleles,6 suggesting that parafibromin has a tumour suppressor function.3,6nnThe importance of the multiple endocrine neoplasia type 1 gene ( MEN1 ) in familial PHPT has been well established. MEN1 is a tumour suppressor gene located in 11q13,8–10 and its encoded protein menin has been shown to interact with several proteins involved in transcriptional regulation.11,12 The MEN1 syndrome (OMIM #131100) is clinically characterised by the frequent development of tumours in the parathyroids, the endocrine pancreas and duodenum, and the anterior pituitary gland. MEN1, which is the most common form of hereditary PHPT, is caused by germline mutations of MEN1 , both in the form of inherited …

Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations

Objective and designu2002 Genetic screening in multiple endocrine neoplasia type 2 (MEN 2) has led to specific management guidelines based on genotype–phenotype analysis. However, there is controversy regarding the appropriate age for prophylactic thyroidectomy in families with mutations in codon 804 in exon 14 of the RET proto‐oncogene, where medullary thyroid cancer (MTC) may not develop until adulthood. We prospectively studied two MEN 2A families, one with the V804L and the other with the V804M RET mutation, to report our experience of genetic and biochemical screening and prophylactic thyroidectomy. Family 1 is one of the largest MEN 2A families in the literature, where 22 prophylactic thyroidectomies have been performed.

Denaturing high performance liquid chromatography detection of SDHB, SDHD, and VHL germline mutations in pheochromocytoma.

BACKGROUNDnPheochromocytomas are neuroendocrine tumors of chromaffin cell origin which arise from the adrenal medulla and less commonly the extra-adrenal sympathetic paraganglia. Pheochromocytomas are component tumors of the familial syndromes multiple endocrine neoplasia Type 2, von Hippel Lindau disease, Neurofibromatosis Type 1, and the pheochromocytoma/paraganglioma syndromes caused by mutations in the RET, VHL, NF1, SDHB, and SDHD genes, respectively. The aim of this study was to evaluate denaturing high performance liquid chromatography (dHPLC) as a screening tool for the detection of germline mutations within VHL, SDHB, and SDHD in pheochromocytoma patients.nnnMETHODSnPolymerase chain reaction of all exons of VHL, SDHB, and SDHD genes was performed on leukocyte DNA extracted from stored blood samples of 74 unrelated patients treated for pheochromocytoma. After dHPLC analysis, all samples demonstrating variance were selected for sequencing.nnnRESULTSnOf the 74 patients, 12 mutations and 16 polymorphisms were identified by dHPLC and confirmed on sequencing. More specifically, a total of 5 mutations and 15 polymorphisms were detected in SDHB and 7 mutations and 1 polymorphism were identified in VHL. No SDHD mutations or polymorphisms were identified. By sequencing only dHPLC variants, the total amount of DNA sequencing required was reduced by approximately 88%.nnnCONCLUSIONSndHPLC is an effective screening tool for the detection of germline mutations in SDHB, SDHD, and VHL and has application for diagnostic germline mutation analysis in pheochromocytoma patients.