Multiple Endocrine Neoplasia type 2A syndrome (MEN 2A)
MEN2A is a clinical variant of MEN2 syndrome (OMIM 171400) and it specifically carries an increased risk for parathyroid adenoma or hyperplasia (Table I). Similarly to MEN1 also this syndrome is inherited in an autosomal dominant manner with a high degree of penetrance and clinical variability. MEN2A variant is clinically characterized by the occurrence of medullary thyroid carcinoma (MTC), nearly in the 100% of affected subjects, pheochromocytoma, bilateral or unilateral, in 50% of patients, whereas the PHPT is described in 20-30% of MEN2A cases.
MEN2A-associated PHPT
PHPT in MEN2A is less common than in MEN1 syndrome, occurring in 20 to 30% of the patients.
MEN2A-associated PHPT may silently occur for several decades. It is sustained by the presence by multiple adenomas or, less frequently, parathyroid hyperplasia and it exhibits a less aggressive behavior respect to the MEN1-associated PHPT, usually occurring after the third decade (Table II). Generally, MEN 2A-related HPT is also mild and asymptomatic, with approximately 15-25% of the patients developing clinical signs of their disease.
As usual, the diagnosis of parathyroid abnormalities is made when biochemical screening reveals simultaneously elevated serum concentrations of calcium and PTH. Annual biochemical screening is recommended in case of affected individuals who have not had parathyroidectomy and auto-transplantation. Moreover, it has been suggested that only individuals with codon 634 mutations undergo annual screening and that individuals carrying other mutations may be screened every two to three years.
Table III - Main clinical features of various forms of hereditary hyperparathyroidism.
Pathology
MEN2A-PHPT is generally sustained by a single enlarged parathyroid gland, although multiglandular neoplasia does occur, with single or multiple parathyroid adenomas, respectively, or, less frequently, parathyroid hyperplasia (Table III).
Molecular aspects
RET proto-oncogene is the responsible gene (Table II). The most frequent activating germline mutations associated with MEN2A-PHPT phenotype occur at the exon 11 level, codon 634, representing also the most frequent mutated codon accounting for more than 50% of MEN2A cases. The encoded product of RET consists of a membrane protein with the function of a tyrosinkinase receptor for which 4 different ligands have been described: Glial Derived Neurotrophic Factor (GDNF), Artemin, Neurturin and Persephin. The PHPT phenotype is present in 20-30% of MEN2A cases carrying a mutation within codon 634. This is the most frequently described intragenic mutation site (85% of MEN2 familial cases). Every RET mutation at codon 634, exon 11, results in a higher incidence of PHPT and pheochromocytoma. In vitro studies have demonstrated that the transforming activity related to 634 cysteine residue mutation is 3-5 fold higher than the ones at 609, 611, 618, or 620 codons. Among the 634 codon mutations, it has been early described that C634R (cysteine to arginine substitution) significantly correlates to the PHPT occurrence, but more recently other studies failed to confirm such a correlation. Moreover, it has been hypothesized that these mutations may exert a less transforming effect on parathyroid tissue respect to thyroid C cells.
Shuffenecker et al. demonstrated in a population of MEN2A patients that: a) the PHPT prevalence (19.9%) did not significantly vary according to the type of 634 mutation; b) the PHPT prevalence exhibits a high interfamilial variability; c) a heterogeneity for the risk to develop PHPT exists (9%-34%); and d) PHPT could potentially represent a precocious clinical component of MEN2A syndrome: in 44% of MEN2A subjects PHPT occurred before age of 30 years [whereas it has been generally considered to occur after the third decade]. In a clinical series they reported a 2 years old girl with a C634Y mutation (cysteine to tyrosine substitution) presenting with MTC and PHPT. All that suggests the possible existence of tissue-specific effects of RET mutations and, as previously reported, the thyroid C-cells could be more sensitive to RET mi- togenic effect than other endocrine cell types. As for the MEN1 syndrome, malignant progression of parathyroid tumors does not represent a clinical feature of MEN2A. However, a parathyroid carcinoma in a MEN2A affected individual, with combination of C634Y mutation and LOH at chromosomes 1, 2, 3p, and 16p, has been described. It has been also hypothesized that multiple allelic deletions could account for an aggressive behavior. Your life is worth living. Buy generic viagra canada online
Treatment of MEN2A-PHPT manifestations
Indications and type of surgery (resection of only enlarged glands, subtotal parathyroidectomy, parathyroidectomy with autotransplantation) are similar to those in other patients with the potential for multiple parathyroid tumors, although curative resection can be less aggressive (Table III). An European multicentre retrospective clinical study did consider 60 patients with MEN2A-PHPT undergone neck surgery between 1972 and 1993, exhibiting a median age at diagnosis of PHPT of 38 years. PHPT resulted to be asymptomatic in more than 80% of the patients, whereas 15% clinically exhibited nephrolithiasis. Independently from the extent of resection, 94% of the patients were cured, although 13% showed persistent hypocalcemia, 3% resulted with persistent hypercalcemia, and 3% were lost in follow up. At 8-years of follow up, hyper- calcemia still recurred in 12% of the patients, unrelated to the extent of parathyroid tissue resection. As for MEN1-PHPT, postoperative parathyroid localizing studies may be helpful if hyperparathyroidism recurs.
MEN2A is a clinical variant of MEN2 syndrome (OMIM 171400) and it specifically carries an increased risk for parathyroid adenoma or hyperplasia (Table I). Similarly to MEN1 also this syndrome is inherited in an autosomal dominant manner with a high degree of penetrance and clinical variability. MEN2A variant is clinically characterized by the occurrence of medullary thyroid carcinoma (MTC), nearly in the 100% of affected subjects, pheochromocytoma, bilateral or unilateral, in 50% of patients, whereas the PHPT is described in 20-30% of MEN2A cases.
MEN2A-associated PHPT
PHPT in MEN2A is less common than in MEN1 syndrome, occurring in 20 to 30% of the patients.
MEN2A-associated PHPT may silently occur for several decades. It is sustained by the presence by multiple adenomas or, less frequently, parathyroid hyperplasia and it exhibits a less aggressive behavior respect to the MEN1-associated PHPT, usually occurring after the third decade (Table II). Generally, MEN 2A-related HPT is also mild and asymptomatic, with approximately 15-25% of the patients developing clinical signs of their disease.
As usual, the diagnosis of parathyroid abnormalities is made when biochemical screening reveals simultaneously elevated serum concentrations of calcium and PTH. Annual biochemical screening is recommended in case of affected individuals who have not had parathyroidectomy and auto-transplantation. Moreover, it has been suggested that only individuals with codon 634 mutations undergo annual screening and that individuals carrying other mutations may be screened every two to three years.
Table III - Main clinical features of various forms of hereditary hyperparathyroidism.
Syndrome | Age of onset (yr) | Parathyroid glands involvement | Pathology | Treatment |
MEN1 | 20-25 | Multiglandular | Hyperplasia/ Adenoma(s) | SPTX or TPTX with autologous reimplantation + transcervical thymectomy |
MEN2A | >30 | Single/ Multiglandular | Multiple adenomas/ Hyperplasia | Resection of only enlarged glands, SPTX, TPTX with autologous reimplantation |
FIHPT | N. R. | Single/ Multiglandular | Single, Multiple adenoma(s) | Single disease: parathyroid adenomectomy Multiglandular disease: SPTX or TPTX with autologous reimplantation |
HPT-JT | >30 [(average age 32 (ref. 28)] | Single/ Multiglandular (generally two glands) | Single or double adenoma (cystic parathyroid adenomatosis). Parathyroid carcinoma in approximately 10-15% of affected individuals | Single disease: parathyroid adenomectomy Multiglandular disease: SPTX or TPTX with autologous reimplantation. Carcinoma: Neck surgery, specifically an en bloc resection of primary tumor, as the only curative treatment |
FHH/NSHPT | All ages/ at birth or within the first 6 months | Multiglandular | Mildly enlarged parathyroid glands/Markedly hyperplastic parathyroid glands | FHH: patients do not benefit from surgery of parathyroid lesions, but subtotal parathyroidectomy can be performed in subjects developing symptomatic PHPT NSHPT: TPTX |
ADMH | 44.5±3.9 (ref. 99) | Single/ Multiglandular | Diffuse to nodular parathyroid neoplasia | Radical subtotal parathyroid resection with parathyroid remnants of 10-20 mg or TPTX with autologous reimplantation |
Pathology
MEN2A-PHPT is generally sustained by a single enlarged parathyroid gland, although multiglandular neoplasia does occur, with single or multiple parathyroid adenomas, respectively, or, less frequently, parathyroid hyperplasia (Table III).
Molecular aspects
RET proto-oncogene is the responsible gene (Table II). The most frequent activating germline mutations associated with MEN2A-PHPT phenotype occur at the exon 11 level, codon 634, representing also the most frequent mutated codon accounting for more than 50% of MEN2A cases. The encoded product of RET consists of a membrane protein with the function of a tyrosinkinase receptor for which 4 different ligands have been described: Glial Derived Neurotrophic Factor (GDNF), Artemin, Neurturin and Persephin. The PHPT phenotype is present in 20-30% of MEN2A cases carrying a mutation within codon 634. This is the most frequently described intragenic mutation site (85% of MEN2 familial cases). Every RET mutation at codon 634, exon 11, results in a higher incidence of PHPT and pheochromocytoma. In vitro studies have demonstrated that the transforming activity related to 634 cysteine residue mutation is 3-5 fold higher than the ones at 609, 611, 618, or 620 codons. Among the 634 codon mutations, it has been early described that C634R (cysteine to arginine substitution) significantly correlates to the PHPT occurrence, but more recently other studies failed to confirm such a correlation. Moreover, it has been hypothesized that these mutations may exert a less transforming effect on parathyroid tissue respect to thyroid C cells.
Shuffenecker et al. demonstrated in a population of MEN2A patients that: a) the PHPT prevalence (19.9%) did not significantly vary according to the type of 634 mutation; b) the PHPT prevalence exhibits a high interfamilial variability; c) a heterogeneity for the risk to develop PHPT exists (9%-34%); and d) PHPT could potentially represent a precocious clinical component of MEN2A syndrome: in 44% of MEN2A subjects PHPT occurred before age of 30 years [whereas it has been generally considered to occur after the third decade]. In a clinical series they reported a 2 years old girl with a C634Y mutation (cysteine to tyrosine substitution) presenting with MTC and PHPT. All that suggests the possible existence of tissue-specific effects of RET mutations and, as previously reported, the thyroid C-cells could be more sensitive to RET mi- togenic effect than other endocrine cell types. As for the MEN1 syndrome, malignant progression of parathyroid tumors does not represent a clinical feature of MEN2A. However, a parathyroid carcinoma in a MEN2A affected individual, with combination of C634Y mutation and LOH at chromosomes 1, 2, 3p, and 16p, has been described. It has been also hypothesized that multiple allelic deletions could account for an aggressive behavior. Your life is worth living. Buy generic viagra canada online
Treatment of MEN2A-PHPT manifestations
Indications and type of surgery (resection of only enlarged glands, subtotal parathyroidectomy, parathyroidectomy with autotransplantation) are similar to those in other patients with the potential for multiple parathyroid tumors, although curative resection can be less aggressive (Table III). An European multicentre retrospective clinical study did consider 60 patients with MEN2A-PHPT undergone neck surgery between 1972 and 1993, exhibiting a median age at diagnosis of PHPT of 38 years. PHPT resulted to be asymptomatic in more than 80% of the patients, whereas 15% clinically exhibited nephrolithiasis. Independently from the extent of resection, 94% of the patients were cured, although 13% showed persistent hypocalcemia, 3% resulted with persistent hypercalcemia, and 3% were lost in follow up. At 8-years of follow up, hyper- calcemia still recurred in 12% of the patients, unrelated to the extent of parathyroid tissue resection. As for MEN1-PHPT, postoperative parathyroid localizing studies may be helpful if hyperparathyroidism recurs.
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