Polyclonality of Parathyroid Tumors in Neonatal Severe Hyperparathyroidism

Abstract

Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder characterized by major hypercalcemia, elevated parathyroid hormone levels, and marked enlargement of multiple parathyroid glands, usually associated with germline mutations in the calcium receptor gene CASR. However, little is known about the outgrowth of parathyroid tumors in NSHPT, including whether they represent monoclonal or polyclonal expansions. We sought to examine the clonality of parathyroid tissues resected from a patient with NSHPT and biallelic CASR mutations. DNA from two distinct parathyroid tumors resected from a girl with NSHPT, plus polyclonal/monoclonal control samples, were subjected to analyses of clonality by two independent methods, X-chromosome inactivation analysis at the androgen receptor locus (HUMARA) and BAC array comparative genomic hybridization (CGH). Both parathyroid tumor samples revealed polyclonal patterns by X-inactivation analysis, with polyclonal and monoclonal controls yielding the expected patterns. Similarly, by BAC array CGH, neither parathyroid sample contained monoclonal copy number changes and both appeared identical to the patient-matched polyclonal controls. Our observations provide direct experimental evidence that the markedly enlarged parathyroid tumors in the setting of NSHPT constitute polyclonal, generalized hyperplastic growths rather than monoclonal neoplasms.

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

“…As patients' compliance appears rather low, the patients' own therapeutic goal seems to be the absence of hypocalcemic symptoms (82). Studies of NSHPT kindred frequently report mental impairment in adults (13,75,82,84). This may reflect detrimental effects of mutated CASR itself on intrauterine and postnatal development and on body functions.…”

“…This may reflect detrimental effects of mutated CASR itself on intrauterine and postnatal development and on body functions. Severe absolute or relative hypocalcemia after parathyroidectomy may also contribute to the impairment of physical and mental development and function (13,75,82,84). Whether serum calcium levels within or even above the normal range would be more advantageous is an open question.…”

Familial Hyperparathyroidism – Disorders of Growth and Secretion in Hormone-Secretory Tissue

“…And the accompanying hyperparathyroid bone disease at birth indicates that this parathyroid tissue process had begun in utero. The parathyroid enlargement is probably hyperplastic (i. e., polyclonal), but this suggestion is based on inconclusive histology in all cases plus careful analysis of clonality in only two glands of one case [44].…”

Clinical and Molecular Genetics of Primary Hyperparathyroidism

“…The phenotype of neonatal severe hyperparathyroidism (NSHPT) typically results from the homozygous or compound heterozygous inheritance of two loss-of-function mutant CASR alleles [83]. Molecular genetic analysis of the hyperfunctioning parathyroid glands removed from a patient with NSHPT demonstrated generalized polyclonal hyperplasia rather than the monoclonality that would be expected in true parathyroid tumors, underscoring the non-neoplastic nature of the abnormal parathyroids associated with CASR loss-of-function mutation [84].…”