Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0221002 (primary hyperparathyroidism)
 4,921 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple endocrine neoplasia type 2 is an autosomal-dominant hereditary cancer syndrome caused by missense gain-of-function mutations of the rearranged during transfection proto-oncogene, which encodes the receptor tyrosine kinase, on chromosome 10. It has a strong penetrance of medullary thyroid carcinomas and can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Multiple endocrine neoplasia type 2 is divided into three varieties depending on its clinical features: multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, and familial medullary thyroid carcinoma. The specific rearranged during transfection mutation may suggest a predilection toward a particular phenotype and clinical course of medullary thyroid carcinoma, with strong genotype-phenotype correlations. Offering rearranged during transfection testing is the best practice for the clinical management of patients at risk of developing multiple endocrine neoplasia type 2, and multiple endocrine neoplasia type 2 has become a classic model for the integration of molecular medicine into patient care. Recommendations on the timing of prophylactic thyroidectomy and extent of surgery are based on the classification of rearranged during transfection mutations into risk levels according to genotype-phenotype correlations. Earlier identification of patients with hereditary medullary thyroid carcinoma can change the presentation from clinical tumor to preclinical disease, resulting in a high cure rate of affected patients and a much better prognoses.
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PMID:Genotype-phenotype correlation in multiple endocrine neoplasia type 2. 2258 9

The REarranged during Transfection (RET) proto-oncogene is a receptor tyrosine kinase involved in growth and differentiation during embryogenesis and maintenance of the urogenital and nervous systems in mammals. Distinct mutations across hotspot RET exons can cause Multiple Endocrine Neoplasia Type 2A (MEN2A) characterised by development of medullary thyroid cancer (MTC), phaeochromocytoma (PCC) and primary hyperparathyroidism (PHPT), with a strong correlation between genotype and phenotype. Here, we report a 42-year-old man presented in the clinic with a unilateral PCC, with subsequent investigations revealing a nodular and cystic thyroid gland. He proceeded to thyroidectomy, which showed bilateral C-cell hyperplasia (CCH) without evidence of MTC. His brother had neonatal Hirschsprung disease (HSCR). Genetic testing revealed the presence of a heterozygous variant of unknown significance (VUS) in the cysteine-rich region of exon 10 in the RET gene (c.1846G>C, p.E616Q), in both affected siblings and their unaffected mother. Exon 10 RET mutations are known to be associated with HSCR and MEN2. Variants in the cysteine-rich region of the RET gene, outside of the key cysteine residues, may contribute to the development of MEN2 in a less aggressive manner, with a lower penetrance of MTC. Currently, a VUS in RET cannot be used to inform clinical management and direct future care. Analysis of RETE616Q reveals a gain of function mutant phenotype for this variant, which has not previously been reported, indicating that this VUS should be considered at risk for future clinical management.
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PMID:The RET E616Q Variant is a Gain of Function Mutation Present in a Family with Features of Multiple Endocrine Neoplasia 2A. 2770 98

Primary hyperparathyroidism (PHPT) is a common endocrinopathy characterized by hypercalcemia and elevated levels of parathyroid hormone. The primary cause of PHPT is a benign overgrowth of parathyroid tissue causing excessive secretion of parathyroid hormone. However, the molecular etiology of PHPT is incompletely defined. Here, we demonstrate that semaphorin3d (Sema3d), a secreted glycoprotein, is expressed in the developing parathyroid gland in mice. We also observed that genetic deletion of Sema3d leads to parathyroid hyperplasia, causing PHPT. In vivo and in vitro experiments using histology, immunohistochemistry, biochemical, RT-qPCR, and immunoblotting assays revealed that Sema3d inhibits parathyroid cell proliferation by decreasing the epidermal growth factor receptor (EGFR)/Erb-B2 receptor tyrosine kinase (ERBB) signaling pathway. We further demonstrate that EGFR signaling is elevated in Sema3d -/- parathyroid glands and that pharmacological inhibition of EGFR signaling can partially rescue the parathyroid hyperplasia phenotype. We propose that because Sema3d is a secreted protein, it may be possible to use recombinant Sema3d or derived peptides to inhibit parathyroid cell proliferation causing hyperplasia and hyperparathyroidism. Collectively, these findings identify Sema3d as a negative regulator of parathyroid growth.
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PMID:Deficiency in the secreted protein Semaphorin3d causes abnormal parathyroid development in mice. 3097 23