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Atypical Multiple Endocrine Neoplasia cases SCOBEC Training day

Atypical Multiple Endocrine Neoplasia cases SCOBEC Training day. Melissa Sloman Royal Devon and Exeter Foundation Trust. Medullary thyroid carcinoma. Hyperparathyroidism. Phaeochromocytoma. Pancreatic – Gastrinoma, Insulinoma. Pituitary – Prolactinoma, Acromegaly. Hyperparathyroidism.

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Atypical Multiple Endocrine Neoplasia cases SCOBEC Training day

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  1. Atypical Multiple Endocrine Neoplasia casesSCOBEC Training day Melissa Sloman Royal Devon and Exeter Foundation Trust

  2. Medullary thyroid carcinoma Hyperparathyroidism Phaeochromocytoma Pancreatic – Gastrinoma, Insulinoma Pituitary – Prolactinoma, Acromegaly Hyperparathyroidism Multiple Endocrine Neoplasia Type 2 Type 1 → Mutations in RET gene → Mutations in MEN1 gene

  3. Sporadic: 2/3 tumours (parathyroid, pancreatic, pituitary) Criteria for testing MEN1 screening Familial: 2/3 tumours plus one 1st degree relative with 1/3 tumours • Atypical MEN1: • Two or more MEN1-related tumours • Multiple parathyroid tumours before the age of 30 • Recurrent hyperparathyroidism • Gastrinoma or multiple islet cell tumours • Familial isolated hyperparathyroidism Brandi et al. J Clin Endocrinol Metab. 2001 86(12):5658-71

  4. Phaeochromocytoma/ Paragangliomas diagnosis NF1 clinical criteria Bilateral adrenal tumours Family history or syndromic presentation Extra-adrenal or multiple tumours Malignant tumour Apparently sporadic presentation Age <35 years VHL + RET RET + VHL SDHB VHL + SDHB + SDHD SDHD + SDHB + VHL RET/ VHL/ SDHB/ SDHD SDHB + SDHD SDHB + SDHD VHL + SDHD Criteria for testing All cases of medullary thyroid carcinoma RET screening Phaeochromocytoma Working Group, Clin End (2006)

  5. Case 1 MEN2 • 71 year old female • Medullary thyroid carcinoma • Non-functioning pancreatic tumour • No family history • Children have normal calcitonin levels (MTC marker) MEN1 RET mutation analysis (whole gene) → no mutation identified Patient does not fit MEN1 criteria →MEN1 mutation analysis ‘to exclude a diagnosis of MEN1’

  6. Case 1 Patient heterozygous for a novel missense mutation in exon 2 of the MEN1 gene Alamut T76S (c.226A>T) Polyphen = benign Sift = Tolerated Not reported in the literature Not identified in UK and international labs

  7. Case 1 Interim Report: ‘XXXXXX is heterozygous for a novel missense mutation (T76S) in exon 2 of the MEN1 gene. This A>T mutation at nucleotide 226 (c.226A>T) results in the substitution of serine for threonine at codon 76 (p.Thr76Ser). The pathogenicity of this variant is uncertain and a further report will be issued when further information is available.’ Emailed clinician: Offer testing for Loss of Heterozygosity (LOH) if tumour tissue available

  8. Case 2 • 78 year old male • Extra adrenal abdominal paraganglioma (cortisol secreting, diagnosed aged 70) • Recurrent duodenal gastric ulcers • Cyst in one kidney • Nodules in thyroid/parathyroid • Father had an ulcer • No other family history RET RET (?MTC/hyperparathyroidism) RET mutation analysis → no mutation identified

  9. Phaeochromocytoma/ Paragangliomas diagnosis NF1 clinical criteria Bilateral adrenal tumours Family history or syndromic presentation Extra-adrenal or multiple tumours Malignant tumour Apparently sporadic presentation Age <35 years VHL + RET RET + VHL SDHB VHL + SDHB + SDHD SDHD + SDHB + VHL RET/ VHL/ SDHB/ SDHD SDHB + SDHD SDHB + SDHD VHL + SDHD Case 2 Extra adrenal abdominal paraganglioma (diagnosed aged 70) → Analysis of SDHB, SDHD, and VHL did not identify a mutation

  10. Case 2 • 78 year old male • Extra adrenal abdominal paraganglioma (cortisol secreting, diagnosed aged 70) • Recurrent duodenal gastric ulcers • Cyst in one kidney • Nodules in thyroid/parathyroid • Father had an ulcer • No other family history MEN1 (?Gastrinoma) MEN1 (?hyperparathyroidism) MEN1 (?Gastrinoma) Patient does not strictly fit MEN1 criteria →MEN1 mutation analysis ‘to ensure not missing wider MEN condition’

  11. Case 2 Patient heterozygous for a novel synonymous variant in exon 8 of the MEN1 gene I360I (c.1380C>T) Not seen in 500 patients tested Not recorded on dbSNP Not reported in the literature Not identified in 4 other UK labs

  12. Intron Exon ccctacagagaccccactgctctcacag|CTACAACTAC Case 2 I360I located 30bp from splice acceptor site of intron 7 Polypyrimidine tract is weak as it is interrupted with purines → weak polypyrimidine tracts often require Exonic Splicing enhancers (ESE) to promote splicing  ?I360I affect an ESE

  13. Case 2 ESEfinder (v3.0) in Alamut Highlight differences Abolishes ESE which binds SC35

  14. Case 2 ?I360I abolish an ESE causing a splicing defect • Further work: • mRNA analysis – only theoretical prediction which would need to be confirmed/refuted • LOH studies on paraganglioma or thyroid/parathyroid nodule if tissue available Reported: Sequencing of the coding region and splice sites of this patient’s MEN1 gene has identified a novel heterozygous synonymous variant (c.1080C>T; p.Ile360Ile) which is of unknown clinical significance. The C nucleotide at position 1080 of the MEN1 gene is conserved across all species. In silico analysis using splicing prediction software (ESE finder 3.0) suggests that c.1080C>T may affect splicing regulation. We recommend that testing for loss of heterozygosity (LOH) at the MEN1 locus is undertaken on paraganglioma or thyroid/parathyroid nodule tissue if available. If LOH is indicated, or if tumour tissue is unavailable, then analysis of mRNA could be performed.

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