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Chapter 567 Hyperparathyroidism

Excessive production of parathyroid hormone (PTH) can result from a primary defect of the parathyroid glands such as an adenoma or hyperplasia (primary hyperparathyroidism).

More often, the increased production of PTH is compensatory, usually aimed at correcting hypocalcemic states of diverse origins (secondary hyperparathyroidism). In vitamin D–deficient rickets and the malabsorption syndromes, intestinal absorption of calcium is deficient but hypocalcemia and tetany may be averted by increased activity of the parathyroid glands. In pseudohypoparathyroidism, PTH levels are elevated because a mutation in the Gsα protein interferes with response to PTH. Early in chronic renal disease, hyperphosphatemia results in a reciprocal fall in the calcium concentration with a consequent increase in PTH, but in advanced stages of renal failure, production of 1,25(OH)2D3 is also decreased, leading to worsening hypocalcemia and further stimulation of PTH. In some instances, if stimulation of the parathyroid glands has been sufficiently intense and protracted, the glands continue to secrete increased levels of PTH for months or years after kidney transplantation, with resulting hypercalcemia.


Childhood hyperparathyroidism is rare. Onset during childhood is usually the result of a single benign adenoma. It usually becomes manifested after 10 yr of age. There have been a number of kindreds in which multiple members have hyperparathyroidism transmitted in an autosomal dominant fashion. Most of the affected family members are adults, but children have been involved in about 30% of the pedigrees. Some affected patients in these families are asymptomatic, and disease is detected only by careful study. In other kindreds, hyperparathyroidism occurs as part of the constellation known as the multiple endocrine neoplasia (MEN) syndromes or of the hyperparathyroidism–jaw tumor syndrome.

Neonatal severe hyperparathyroidism is a rare disorder. Symptoms develop shortly after birth and consist of anorexia, irritability, lethargy, constipation, and failure to thrive. Radiographs reveal subperiosteal bone resorption, osteoporosis, and pathologic fractures. Symptoms may be mild, resolving without treatment, or can have a rapidly fatal course if diagnosis and treatment are delayed. Histologically, the parathyroid glands show diffuse hyperplasia. Affected siblings have been observed in some kindreds, and parental consanguinity has been reported in several kindreds. Most cases have occurred in kindreds with the clinical and biochemical features of familial hypocalciuric hypercalcemia. Infants with neonatal severe hyperparathyroidism may be homozygous or heterozygous for the mutation in the Ca2+-sensing receptor gene, whereas most persons with 1 copy of this mutation exhibit autosomal dominant familial hypocalciuric hypercalcemia.

MEN type I is an autosomal dominant disorder characterized by hyperplasia or neoplasia of the endocrine pancreas (which secretes gastrin, insulin, pancreatic polypeptide, and occasionally glucagon), the anterior pituitary (which usually secretes prolactin), and the parathyroid glands. In most kindreds, hyperparathyroidism is usually the presenting manifestation, with a prevalence approaching 100% by 50 yr of age and occurring only rarely in children <18 yr of age. With appropriate DNA probes, it is possible to detect carriers of the gene with 99% accuracy at birth, avoiding unnecessary biochemical screening programs.

The gene for MEN type I is on chromosome 11q13; it appears to function as a tumor suppressor gene and follows the two-hit hypothesis of tumor development. The first mutation (germinal) is inherited and is recessive to the dominant allele; this does not result in tumor formation. A second mutation (somatic) is required to eliminate the normal allele, which then leads to tumor formation.

Hyperparathyroidism–jaw tumor syndrome is an autosomal dominant disorder characterized by parathyroid adenomas and fibro-osseous jaw tumors. Affected patients can also have polycystic kidney disease, renal hamartomas, and Wilms tumor. Although the condition affects adults primarily, it has been diagnosed as early as age 10 yr.

MEN type II may also be associated with hyperparathyroidism (Chapter 563.2).

Transient neonatal hyperparathyroidism has occurred in a few infants born to mothers with hypoparathyroidism (idiopathic or surgical) or with pseudohypoparathyroidism. In each case, the maternal disorder had been undiagnosed or inadequately treated during pregnancy. The cause of the condition is chronic intrauterine exposure to hypocalcemia with resultant hyperplasia of the fetal parathyroid glands. In the newborn, manifestations involve the bones primarily, and healing occurs between 4 and 7 mo of age.