Presentation of a kindred with familial medullary thyroid carcinoma and Cys611Phe mutation of the RET proto-oncogene demonstrating low grade malignancy

Abstract

Objective: Both multiple endocrine neoplasia type 2A (MEN 2A) and familial medullary thyroid carcinoma (FMTC) are caused by germline mutations of the RET proto-oncogene. A broad spectrum of malignancy within and between families has been described with no clear genotype±phenotype correlation due to a scarcity of available data of large kindreds. Design: Here we present the only known family with a germline mutation of codon 611 TGC to TTC (exon 10) in the RET proto-oncogene leading to a replacement of cysteine by phenylalanine (Cys611Phe or C611F). Results: Twenty family members of this large kindred are gene carriers (GCs) and seven (5±13 years old) are potential carriers but have yet to be analysed. The clinical course of medullary thyroid carcinoma (MTC) in this family is characterized by a very slow evolution and progression of the tumour with no MTC-related death to date. Of 11 patients (30±69 years old) having undergone thyroidectomy six were classified as pT 1 , four as pT 2 and one as C-cell hyperplasia according to the TNM system of the International Union Against Cancer. Due to cervical and mediastinal lymph node metastasis one patient (44 years old) had to be operated on a second time. The seven non-operated GCs of the fourth and fifth generation (17±26 years old) are yearly monitored with pentagastrin stimulation tests; one non-operated GC (43 years old) has refused any further investigations. Screening for primary hyperparathyroidism and phaeochromocytoma was negative in all cases. Conclusion: We suggest from these experiences that the general advice for thyroidectomy in early childhood should be modified in certain families, depending on genotype.

Prevalence by Age and Predictors of Medullary Thyroid Cancer in Patients with Lower Risk GermlineRETProto-Oncogene Mutations

“…Interestingly, all 6 of the MTC patients with a codon 791 mutation in this study are part of the same kindred from Brazil (55). The index case did have sequencing of RET exons 8, 10, 11, and [13][14][15][16], though the relatives were tested only for the presence of the 791 mutation, making it possible but unlikely that another deleterious RET mutation [52][53][54][55][56][57][58][59][60] [CI], 95% confidence interval; NA, not reached.…”

Review of Multiple Endocrine Neoplasia Type 2A in Children: Therapeutic Results of Early Thyroidectomy and Prognostic Value of Codon Analysis

“…In contrast, the c620 mutations bear low risk for postoperative morbidity and delayed TT in analogy to recommendations for c611 mutations might be appropriate. 53,66 However, more clinical data on all relevant codons and the possible influence of different point mutations in the same codon are needed to define definitive codon-specific guidelines in the future. Until then, ETT in combination with preoperative calcitonin screening is a save approach and can assure maximal cure rate in all kindred of MEN-2A families.…”

Diagnosis and management of medullary thyroid carcinoma

“…Other less common variants of MEN2 are FMTC [63,64], MEN2A with cutaneous lichen amyloidosis [65,66], and MEN2A or FMTC with Hirschsprung's disease [4,67,68]. MEN2A carriers usually develop bilateral MTC before 10 years of age.…”

“…For example, families who have MEN2A and parathyroid neoplasia or the cutaneous lichen amyloidosis syndrome have a mutation in codon 634 [4,91]. In a family that has a rare germ-line mutation at exon 10 in codon 611 (Cys611Phe) [64], the clinical course of MTC is characterized by late onset and slow progression with no tumor-related deaths. This suggests that thyroidectomy in early childhood may not be appropriate in certain MEN2 kindreds.…”

“…By 2001, pheochromocytoma had been found in kindreds with all RET mutations except those in codons 609, val804met and 891; this suggested that these were the only mutations that cause FMTC [3]. RET mutations in FMTC are believed to occur at exon 13 in codons 609 and at exon 14 in codons 804 [64,92], 844 1 [92], or with S836S polymorphism. A study of a large FMTC kindred with the uncommon mutation at codon 15 of an A891S RET mutation found two family members in whom phenotype and genotype were not concordant; this represented the first evidence of FMTC phenocopies [93].…”