Hereditary primary hyperparathyroidism or (Hereditary hyperparathyroidisms) - Genes CASR, MEN1, HRPT2


Hereditary hyperparathyroidism include a group of processes, also called primary hyperparathyroidism (PHPT: Primary Hereditary hyperparathyroidism), characterized by the presence of persistent high serum calcium (hypercalcemia), of varying degrees, and elevated serum parathyroid hormone . Both serum calcium levels such as parathyroid hormone, can sometimes be found within normal limits . Hyperparathyroidism, is usually caused by tumors that develop in the parathyroid glands, usually in one of the four parathyroid glands, but in some people, tumors, usually benign adenomas are found in more than one gland. Hypercalcemia can cause kidney stones, osteoporosis, nausea, vomiting, hypertension, weakness and fatigue.

Syndromes or hereditary primary hyperparathyroidism presenting with hypercalcemia include:

  • Hypercalcemia familial hypocalciuric (FHH: Hypercalcemia Familial hypocalciuria) hypocalciuric hypercalcemia or family benign (FBHH: Benign Familial hypocalciuria hypercalcemia). This process is caused by heterozygous mutations inactivating CASR gene. It is characterized by hypercalcemia and hypocalciuria, although those affected often no symptoms of involvement. Sometimes, the affected have enlarged parathyroid glands and slightly elevated parathyroid hormone levels.
  • Severe neonatal hyperparathyroidism (NSHPT: Severe neonatal hyperparathyroidism), caused by homozygous mutations inactivating CASR gene. This process by presenting homozygous mutations, is considered by some of autosomal recessive inheritance. In this process, both copies of the gene are altered, so it is a potentially fatal process that occurs in children less than 6 months old. Affected have high parathyroid hormone levels in blood. Excess hormone stimulates calcium release blood causing hypercalcemia. Calcium released from bone, causing bone abnormalities. The high hypercalcemia can cause neurological problems that interfere with nerve signals.
  • Hiperparairoidismo moderate autosomal dominant (ADMH: Hyperparathyroidism Autosomal Dominant Moderate). This process occurs with hypercalcemia and hypercalciuria, and is due to mutations CASR gene.
  • Familial isolated hyperparathyroidism (FIHP: Familial Isolated Hyperparathyroidism). This may be caused by mutations in the gene MEN1 (20-33% of cases), CASR (14 to 18% of cases), or HRPT2 (lower frequency). Rarely, people with familial isolated hyperparathyroidism develop a cancerous tumor, and parathyroid carcinoma.
  • Multiple endocrine neoplasia type 1 (MEN1: Multiple Endocrine Neoplasia type 1), 2A / 2B (MEN2A / 2B: Multiple Endocrine Neoplasia type 2A / 2B) and 4 (MEN4), being caused by mutations of MEN1, RET and CDKN1B genes, respectively. - see Multiple Endocrine Neoplasia, types 1, 2 and 4 -.
  • Hyperparathyroidism syndrome-tumor mandibular (HPT-JT: Hyperparathyroidism-Jaw tumor syndrome) due to mutations in the gene HRPT2. Individuals with hyperparathyroidism-jaw tumor syndrome often develop tumors, benign or cancerous. Approximately 15% of people develop parathyroid carcinoma between 25% and 50% fibroma in the mandible, 75% of women affected tumors of the uterus. In addition, kidneys are affected in about 20% of people with hyperparathyroidism-jaw tumor syndrome.

CASR gene, located on the long arm of chromosome 3 (3q13), encodes a protein called the calcium sensing receptor (CaSR), which helps to regulate the amount of calcium in the body, partly by controlling production parathyroid hormone. When calcium binds to the protein in cells CaSR of the parathyroid gland, the activated receptor sends signals that block the synthesis and release of parathyroid hormone. Without parathyroid hormone, calcium is not released into the blood. Mutations in the CASR gene, changing amino acids in CaSR, resulting in the coding of a less sensitive CaSR protein which requires an abnormally high concentration of calcium to trigger signaling. As a result, parathyroid hormone occurs even when the calcium concentration in the blood rises, allowing calcium levels to increase. In addition, parathyroid cells can grow uncontrollably, which sometimes causes enlargement of the parathyroid glands in patients with familial isolated hyperparathyroidism. Overproduction of parathyroid hormone from these abnormal glands may further stimulate the release of calcium in the blood. High concentrations of calcium lead to signs and symptoms of the disease.

MEN1 gene, located on the long arm of chromosome 11 (11q13), encodes a protein called menin that acts as a tumor suppressor, which normally prevents cells grow and divide too fast or uncontrolled. Additionally, it is believed that menin protein plays a role in the copy and DNA repair and regulation of cell apoptosis. Menin protein is present in the core of many different cell types and appears to be active at all stages of development. This protein interacts with many other proteins, including several transcription factors, helping to control activity of various genes. Some of these genes likely play a role in cell growth and division. Work is to identify proteins that interact with menin and determine their specific role as a tumor suppressor. Mutations in gene MEN1, result in an altered protein menin is not able to control growth and cell division. The resulting increase in cell proliferation leads to the formation of an adenoma that affects one or more parathyroid glands. Overproduction of parathyroid hormone of these abnormal glands stimulates the release of excess calcium in the blood, leading to the signs and symptoms of familial isolated hyperparathyroidism. It is unclear why this change only affects the parathyroid glands.

The HRPT2 gene (CDC73), located on the long arm of chromosome 1 (1q25), encoding the protein parafibromina, also believed to act as a tumor suppressor. It is likely that this protein participates in the regulation of the activity of other genes and cell proliferation. Mutations in the gene cause a decrease in protein activity parafibromina. Loss of tumor suppressor function of parafibromina can lead to the development of parathyroid adenoma or, rarely, parathyroid carcinoma.

Hereditary hyperparathyroidism normally inherited in an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to result in the alteration.

Tests performed in IVAMI: in IVAMI perform detection of mutations associated with hereditary hyperparathyroidism, by complete PCR amplification of the exons of the MEN1, CDC73 and CASR, respectively, and subsequent sequencing genes.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).