Humans have two pairs of parathyroid glands lying in the anterior cervical region. The fetal parathyroid glands begin developing at 5 weeks from the third and fourth pharyngeal pouches. The third pharyngeal pouch that contains tissue that will become the thymus and parathyroid migrates downward and gives rise to the two inferior parathyroid glands normally located at the lower poles of the thyroid. The fourth pharyngeal pouch does not migrate and gives rise to the two upper parathyroid glands that normally are attached to the upper poles of the thyroid.
Eighty- five percent of normal adults have four parathyroid glands, but the number can vary markedly in some individuals. The location of the glands is also variable with the upper glands sometimes located behind the pharynx or the oesophagus. The lower glands may be found close to or within the thymus in the superior mediastinum. Because of the variability in location surgical exploration of the neck can be problematic especially in hyperparathyroidism of chronic kidney disease. Use of preoperative localization techniques, such as technetium- 99- sestamibi scanning, ultrasound, MRI, or CT scanning may be helpful in localizing enlarged parathyroid glands, however referral to an experienced parathyroid surgeon is essential to maximize localization of affected glands and minimize complications. Conversely, hypoparathyroidism most commonly occurs as a result of surgical excision of, or damage to, the parathyroid glands during non- parathyroid surgery, for example, total thyroidectomy for thyroid cancer and radical neck dissection for laryngeal or oesophageal carcinoma, as well as repeated surgery for hyperparathyroidism.
Most patients with primary hyperparathyroidism, about 80%, have a single benign adenoma. Multiple (so- called) adenomas are rarely found and probably represent asynchronous parathyroid hyperplasia. Hyperplasia accounts for 15– 20% of cases, and malignant parathyroid carcinoma is extremely rare, less than 1% of cases. In secondary hyperparathyroidism, all four glands are enlarged.
The chief cell is the predominant parathyroid cell type in hu mans, with some oxyphil cells, which have an acidophilic cytoplasm and mitochondria also present. Parathyroid cells have limited numbers of secretory granules containing parathyroid hormone (PTH), indicating that relatively little hormone is stored in the gland. Parathyroid cells normally divide at an extremely slow rate— mitoses are rarely observed.
Knowledge of the embryological formation of the parathyroids has been gained by study, on the one hand, of mouse models in which deletion of specific genes has led to lack of parathyroid gland development, and, on the other, of human inherited (autosomal dominant, autosomal recessive, or X- linked) familial hypoparathyroidism in which the formation of the parathyroid glands is defective.
The mouse has a single pair of parathyroid glands, and at day e10 both the precursor thymus and parathyroid cells in the third pharyngeal pouch endoderm, express the four transcription factors, Hoxa3, Pax1, Eya1, and Pax9. The conjoined thymus and parathyroid rudiment develop at day e11 and the primordium also expresses transcription factors Six1 and Pbx1. At day e12, separate pathways distinct for the different parts of the rudiment that will develop into the thymus and parathyroid become apparent. Signalling molecules including sonic hedgehog, bone morphogenetic protein- 4, noggin, and fibroblast growth factor- 8 act in a complex fashion to affect the outgrowth of the parathyroid precursor. By day e13.5, the parathyroid cell mass and thymus cell mass are separate. The thymic cells express Foxn1 that is not present in the parathyroid cells and that in turn specifically express glial cells missing- 2 (Gcm2). Gcm2 ex pression continues into adulthood and it transactivates the calcium- sensing receptor (Casr) gene and thereby influences the expression of the parathyroid calciostat.
In humans, hypoparathyroidism is part of several syndromes, for example, the DiGeorge type 1 syndrome that occurs because of a 22q11.2 microdeletion. Congenital defects arise as a result of the failure to develop the derivatives of the third and fourth pharyngeal pouches leading to agenesis or hypoplasia of the parathyroid glands and thymus. Haploinsufficiency of the TBX1 transcription factor gene appears to play an important role in the disorder. In DiGeorge syndrome type 2 patients harbour 10p13- 14 deletions encoding the actin- binding protein nebulette (NEBL) although its mechanistic link to hypoparathyroidism is not clear. Some DiGeorge patients have features of the CHARGE syndrome which is caused by heterozygous mutations in the chromodomain helicase DNA- binding 7 gene (CHD7) on 8q12.2 that is expressed within pharyngeal ectoderm. Hypoparathyroidism is a part of the Barakat or HDR (Hypoparathyroidism nerve Deafness, and Renal dysplasia) syndrome that maps to 10p15. HDR is due to haploinsufficiency and loss- of- function mutations in the GATA3 gene that encodes a zinc finger transcription factor. GATA3 is essential for normal embryonic development of the parathyroids, auditory system, and kidney in humans. Hypoparathyroidism together with growth and mental Retardation, and characteristic Dysmorphism (HRD) occur in autosomal recessive Kenny- Caffey type 1 and Sanjad- Sakati syndromes. The HRD syndrome is due to mutations in the tubulin chaperone E (TBCE) gene that maps to 1q42.3. Autosomal dominant forms of Kenny- Caffey type 2 and Gracile bone dysplasia with hypoparathyroidism are due to mutations in the family with sequence similarity 111 member A (FAM111A) gene on 11q12.1 in volved in DNA replication and chromatin maturation.
Rare cases of primary hypoparathyroidism inherited in either an autosomal recessive or dominant manner due to mutations in the GCM2 gene on chromosome 6p24 have been identified. In the latter case, the mutated GCM2 acts in a dominant- negative fashion. Heterozygous and homozygous mutations in the PTH gene cause rare cases of hypoparathyroidism and more commonly heterozygous activating mutations in the CASR gene are implicated in hypoparathyroidism (see next). In an X- linked recessive form of hypoparathyroidism there is an interstitial deletion- insertion involving chromosomes 2p25.3 and Xq27.1 near the SOX3 gene that encodes a high mobility group box transcription factor. It is proposed that the hypoparathyroidism is caused by disruption of regulatory elements of the SOX3 gene.
