Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes.
OBJECTIVE
Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population.


METHODS
We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres.


CONCLUSIONS
The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.
Romei
Cristina
C
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy.
Mariotti
Stefano
S
Fugazzola
Laura
L
Taccaliti
Augusto
A
Pacini
Furio
F
Opocher
Giuseppe
G
Mian
Caterina
C
Castellano
Maurizio
M
degli Uberti
Ettore
E
Ceccherini
Isabella
I
Cremonini
Nadia
N
Seregni
Ettore
E
Orlandi
Fabio
F
Ferolla
Piero
P
Puxeddu
Efisio
E
Giorgino
Francesco
F
Colao
Annamaria
A
Loli
Paola
P
Bondi
Fabio
F
Cosci
Barbara
B
Bottici
Valeria
V
Cappai
Antonello
A
Pinna
Giovanni
G
Persani
Luca
L
Verga
Uberta
U
Uberta
Verga
V
Boscaro
Marco
M
Castagna
Maria Grazia
MG
Cappelli
Carlo
C
Zatelli
Maria Chiara
MC
Faggiano
Antongiulio
A
Francia
Giuseppe
G
Brandi
Maria Luisa
ML
Falchetti
Alberto
A
Pinchera
Aldo
A
Elisei
Rossella
R
D016009:Chi-Square Distribution; D005260:Female; D056726:Genetic Association Studies; D005820:Genetic Testing; D005838:Genotype; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007558:Italy; D008297:Male; D018813:Multiple Endocrine Neoplasia Type 2a / Q000235:genetics*; D018814:Multiple Endocrine Neoplasia Type 2b / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*
D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human