Clinical implications of genotype-p

Clinical implications of genotype-phenotype
correlations
Patients with a codon 918 mutation and MEN2B are at
high risk of aggressive MTC occurring at a young age (31).
In contrast, patients with codon 791 mutations are at a
relatively low risk of aggressive disease and develop slowgrowing
tumors as a late manifestation (27). According to
recent data, membrane proximity of the mutation seems to
be an important determinant of tumor development in
carriers of RET mutations in exon 10 (32,33). These
genotype-phenotype correlations between mutation, age of
onset, tumor aggressiveness, and onset of pheochromocytoma
and parathyroid disease may be used to predict the
phenotype and make recommendations regarding the ages
at which to perform prophylactic thyroidectomy and begin
biochemical screening for pheochromocytoma and hyperparathyroidism
(Table 2). This is particularly true in
presymptomatic RET mutation carriers because a prophylactic
thyroidectomy should be performed before the
development of MTC, or at least when the MTC is confined
within the thyroid and before the spread of disease beyond
the gland. The multicentric and bilateral nature of hereditary
MTC implicates a total thyroidectomy.
Recommendations for the timing of prophylactic thyroidectomy
and the extent of surgical resection are based on
a model that utilizes these genotype-phenotype correlations
to stratify mutations into risk levels (A–D) (Table 2) (4).
Patients with American Thyroid Association (ATA) A
mutations (exon 5, codon 321; exon 8, codons 531, 515 and
533; exon 10, codons 600, 603 and 606; exon 11, codons 649
and 666; exon 13, codons 768, 777, 790 and 791; exon 14,
codons 804, 819, 833 and 844; and exon 15, codons 866, 891
and 912), which mainly include phenotypic FMTC, are at
the lowest risk for the development and aggressiveness of
MTC; patients with ATA B mutations (exon 10, codons 609,
611, 618 and 620; and exon 11, codons 630, 631 and 633) are
at intermediate risk; patients with ATA C mutations, the
classical MEN2A mutation (exon 11, codon 634) are at a
higher risk than patients with ATA B mutations; and
patients with ATA D mutations have the typical MEN2B
mutation (exon 15, codon 883; and exon 16, codon 918) and
are at the highest risk of developing MTC with a high rate of
growth