Revealing an Unclassified 611 Variant of the RET Proto-Oncogene As a Disease-Causing Mutation: Clinical Phenotype and Management of a MEN2A-Family

Presentation Number: LBS-063
Date of Presentation: March 7th, 2015

Loes Moernaut1, Tatjana Sajevets2, Martine Cools3, Katleen Dewaele2, Saskia Van Der Straaten2, Sandra Janssens4, Guy G. T'Sjoen5 and Bruno Lapauw*5
1Ghent University Hospital, 2UZ Gent, 3Univ Hosp Ghent, Ghent, Belgium, 4UZGent, 5Ghent University Hospital, Gent, Belgium

Abstract

Background.

Activating mutations of the RET proto-oncogene can give rise to Multiple Endocrine Neoplasia type 2 (MEN2) as well as Hirschsprung’s disease. The penetrance and severity of the associated disease, especially with respect to medullary thyroid cancer (MTC), strongly depends on the underlying RET mutation. Based on this genotype-phenotype correlation, screening protocols for documented carriers have been proposed1 and the ATA has issued a risk classification level to guide decision making with respect to prophylactic thyroidectomy.2

Today, more than 150 different RET sequence changes relevant to MEN2 syndromes have been reported, however for many of them a clear description of the MEN2 phenotype and age of onset of MTC is lacking.3 We now describe the clinical phenotype of a large MEN2A-family with a pathogenic mutation in exon 10, codon 611 (Cys611Arg (c.1831 T>C)), which has previously only been reported in one patient with Hirschsprung’s disease, one 52-yr old female patient with MTC and one 57-yr old female patient with bilateral pheochromocytoma.

Clinical report

In this family, the mutation was first detected in a newborn who died of sepsis following Hirschsprung’s disease. Further genetic testing of the family revealed a positive carrier status in the maternal grandfather (66yr, G1), the newborn’s mother and 4 out of 5 of her siblings (aged 29-42 yrs, G2), as well as in 1 brother, 2 cousins and 2 nieces (1.8-15y, G3). 

After clinical and biochemical screening, the grandfather had no evidence of disease. In the 2nd generation (G2), screening revealed a pheochromocytoma in 2 subjects (age of youngest subject 38 yrs), and MTC in 3 subjects (all pT1N0M0; age of youngest subject: 28 yrs; all had strongly elevated calcitonin levels). All patients were free of active disease after surgery. In G3, all children had normal calcitonin levels and a normal thyroid ultrasound. Together with the mild clinical phenotype and the family’s preference, prophylactic thyroidectomy was delayed in these children and calcitonin-based surveillance was initiated. No subjects presented with elevated calcium levels.

Conclusion

This previously unclassified variant, affecting a cysteine residu in codon 611 within exon 10 of the RET proto-oncogene, can now be considered to cause MEN2A syndrome. This family presents with a rather mild clinical phenotype, with a first, non-metastasized MTC detected at 29 years and a first pheochromocytoma at 38 years of age. Although ATA guidelines suggest performing prophylactic thyroidectomy in carriers of a 611 RET-mutations at young age, a more individual approach with delayed thyroidectomy and calcitonin-based surveillance of children and adults can be considered in certain genotypes.

 

Nothing to Disclose: LM, TS, MC, KD, SV, SJ, GGT, BL